The Journal of Community and Supportive Oncology

Myrna R. Rosenfeld, MD, PhD, Karen Albright, CRNP, and Amy A. Pruitt, MD

University of Pennsylvania School of Medicine, Philadelphia, PA

Manuscript received December 1, 2010; accepted April 15, 2011.

Correspondence to: Myrna R. Rosenfeld, MD, PhD, Department of Neurology, 3 W. Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; telephone: 215-746-2820; fax: 215-746-2818; e-mail: [email protected].

Despite treatment, glioblastoma (GB) inevitably recurs, and there is often no clear standard of care to follow. This article reviews the treatment options for recurrent GB and anaplastic gliomas. The three FDA-approved treatments for recurrent GB are biodegradable carmustine-impregnated wafers; bevacizumab; and the NovoTTF-100A System, which delivers low-intensity, alternating electrical fields to the tumor bed. Treatment decisions must take into consideration prior therapies, the extent and location of recurrence, and the patient’s general medical condition, as well as the rapidity of tumor growth, extent of edema, mass effect, need for steroids, and symptoms. New treatment strategies are emerging based on the identification of prognostic and predictive markers and defining distinct molecular subtypes of GB.

Glioblastoma (grade IV glioma, GB) is the most common of the primary malignant gliomas. Advances in the past decade have clarified that adjuvant treatment can improve quality of life and survival. The current standard of care for newly diagnosed patients with GB after optimal resection is focal radiation with concurrent (chemoradiation) and post-radiation temozolomide (Temodar). This regimen was shown to improve overall survival in a randomized phase III study.1 Furthermore, a subgroup of patients whose tumors were shown to have low levels of O6-methylguanine DNA methyltransferase (MGMT), the enzyme that repairs DNA damage due to temozolomide, showed overall survival of 46% at 2 years and 14% at 5 years.2,3

Biodegradable wafers impregnated with carmustine (Gliadel) implanted at the time of resection are another approved therapy for patients with newly diagnosed high-grade gliomas (GB and anaplastic gliomas, grade III glioma).4 Although short-term survivals for GB patients are similar with Gliadel compared to focal radiation with concurrent and post-radiation temozolomide, the latter results in superior long-term survival (1.9% at 56 months for Gliadel and 9.8% at 60 months for temozolomide).3,5 The nitrosoureas lomustine (CeeNU) and carmustine (BiCNU) were approved in the 1970s for use as single agents or in combination therapy in patients with glioma who had received surgery and/or radiation. These agents no longer have a clear role in the initial treatment of malignant glioma, although practitioners use them, often in combination therapy, for patients with recurrent GB and anaplastic oligodendrogliomas, a ¬chemosensitive subtype of glioma.6

Despite the use of the above approved therapies, GB invariably recurs. In the absence of effective treatment options, treatment approaches for recurrent GB have been varied. This article will review the most common accepted treatment options for recurrent GB and discuss emerging strategies. In the absence of a clear standard of care for newly diagnosed anaplastic gliomas, treatment at recurrence is largely dictated by prior therapies received, as noted below.

Tumor progression or treatment effect?

Glioblastoma recurrence is suspected when a previously stable patient develops recurrent or new neurologic signs and symptoms or when surveillance imaging (preferably MRI with gadolinium) shows increased tumor size or new enhancement likely associated with increased edema. However, clinical and imaging changes may result from perioperative complications such as infection or ischemia, a change in steroid use, or radiation necrosis (also called pseudoprogression). In fact, studies have shown that up to half of patients with presumed early tumor progression during or after chemoradiation actually have radiation necrosis (Figure 1).7 These data have led some clinicians to suggest that a minimum of 3 cycles of adjuvant temozolomide be given before a conclusion of tumor progression is made.

Several imaging modalities, such as magnetic resonance perfusion with or without spectroscopy and positron emission tomography, are used to help distinguish tumor recurrence from pseudoprogression but are not always reliable.8 In these cases, repeat imaging can be useful, although surgery may be necessary to relieve mass effect and obtain a tissue diagnosis.

Approved therapies for recurrent glioblastoma

There are currently three US Food and Drug Administration (FDA)–approved therapies for recurrent GB: Gliadel wafers; bevacizumab (Avastin), a humanized monoclonal antibody that sequesters vascular endothelial growth factor-A (VEGF); and the NovoTTF-100A System (NovoCure; Portsmouth, NH), which delivers low-intensity, alternating electrical fields (called tumor treatment fields) to the tumor bed that may inhibit cell growth by disrupting microtubule formation.9

The prospective randomized study that led to the approval of Gliadel demonstrated a modest increase in overall survival, from 23 weeks in those patients who received placebo wafers to 31 weeks for those receiving Gliadel.4 This study included recurrent anaplastic gliomas and GB, and the benefit in the GB subgroup was smaller than in the group as a whole. Furthermore, this and other studies predated the use of chemoradiation and adjuvant temozolomide, and it is unclear what benefit, if any, Gliadel offers in recurrent GB patients treated with prior temozolomide.

The approval of bevacizumab for recurrent GB in the United States was based on two clinical trials that evaluated bevacizumab as a single agent or combined with irinotecan in patients with tumor recurrence after initial treatment with chemoradiation and adjuvant temozolomide. The comparative study enrolled 167 patients, 85 in the bevacizumab-alone arm and 82 in the bevacizumab plus irinotecan arm.10 The objective response rate was 25.9% in patients who received bevacizumab monotherapy. There were no complete responses per outside review. The median duration of response was 4.2 months, and the 6-month progression-free survival (PFS-6) was 36.0 %. The single-arm study enrolled 56 patients with recurrent high-grade glioma.11 Objective response as determined by independent review was 19.6%. The median duration of response was 3.9 months.

The FDA approved bevacizumab for use as a single agent based on the improvement in objective response rate in these studies (albeit without improvement in disease-related symptoms or increased survival) and on the fact that patients receiving bevacizumab as a single agent had less toxicity than those receiving the combination with irinotecan and similar outcomes. Subsequent studies with bevacizumab as a single agent in recurrent GB have shown similar PFS-6 rates of between 29% and 42%; smaller studies in recurrent anaplastic gliomas reported response rates ranging between 34% and 68% and PFS-6 rates ranging between 32% and 68%.12,13

The NovoTTF-100A System received approval in the spring of 2011 based on the results of a single multinational study of 237 patients with recurrent GB.14 Patients were randomized to receive either the NovoTTF-100A System or chemotherapy of their physician’s choice. The NovoTTF device includes a battery pack (weighing about 6 pounds) and electrodes, which are placed on the scalp and designed to be worn for about 20 hours a day. The results showed that patients who used the NovoTTF-100A System had higher objective response rates (12% for NovoTTF compared with 6% in the chemotherapy group) and a favorable overall survival rate of 6.6 months compared with 6.0 months for the chemotherapy group. The device was well tolerated, with a significantly higher incidence of toxicities (hematologic and other) in the patients receiving chemotherapy.

Temozolomide is approved in Europe for recurrent high-grade gliomas, including both GB and anaplastic astrocytoma, but in the United States, it is only approved for recurrent anaplastic astrocytoma. These approvals were based on studies in mostly chemotherapy-naive patients, and although it is less clear that rechallenge with temozolomide is useful, as noted below, ongoing studies may clarify this issue.

Approach to the patient with recurrent GB

In the absence of enrollment in a clinical trial, which is encouraged for all glioma patients, the approach to the patient with recurrent GB should take into consideration prior therapies, extent of recurrence and location, and general medical condition. An initial consideration is whether the patient is a candidate for further resection and/or radiation. Re-resection can relieve mass effect and reduce the need for steroids, can provide histologic confirmation of the diagnosis, and likely can increase survival, although this has not been shown in randomized studies.15 For a patient with contraindications for further systemic chemotherapy and who is undergoing resection, Gliadel is a reasonable consideration, and it does not preclude use of bevacizumab or NovoTTF.

Re-irradiation with single-fraction or fractionated stereotactic radiation is feasible in patients with localized recurrent disease. Small, single-arm prospective studies and retrospective reviews suggest a benefit, and the focused delivery modalities reduce the dose to surrounding brain tissue, minimizing the risk of radiation toxicity.16 In some studies, low-dose temozolomide or bevacizumab was combined with re-irradiation with results suggesting both tolerability and efficacy.17 We have found re-irradiation to be a good alternative for those patients who develop profound and prolonged myelosuppression (usually thrombocytopenia) during initial treatment with temozolomide and who have tumor progression before recovery of the counts.

Bevacizumab is currently the most common single agent used for glioma recurrence and is usually dosed at 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or the decision to discontinue care. Due to its potent anti-VEGF activity, which results in normalization of highly permeable tumor vessels, bevacizumab often produces rapid and marked reduction in edema and contrast enhancement on neuroimaging.18 This can produce rapid clinical and imaging responses, although whether this reflects true antiglioma activity remains under debate.

Resolution of mass effect and contrast enhancement can also coexist with progression of nonenhancing fluid-attenuated recovery (FLAIR) abnormality that reflects a phenotypically invasive tumor recurrence pattern, with GB co-option of normal cerebral vessels and diffuse, multilobar perivascular spread of tumor cells. The imaging changes can make evaluation of tumor response and progression difficult if one relies on the standard criteria of two-dimensional measurement of enhancing disease; new criteria that take into consideration nonenhancing signal abnormality changes have been proposed.19

Bevacizumab is well tolerated in the brain tumor population, with the same spectrum of side effects seen in other cancer populations (hemorrhage, thrombosis, hypertension, bowel perforation, impaired wound healing, and proteinuria).12,13 The incidence of life-threatening events, such as significant intracranial hemorrhage (3%) or thromboembolism (2%–12%), is within the expected range for the population and is not clearly increased by ¬bevacizumab.12

Several small series have reported that corticosteroid reductions were feasible in 33%–59% of patients with recurrent GB after bevacizumab treatment, and others have reported average corticosteroid dose reductions of 72% and 59%.11,13 This is an important benefit of bevacizumab, as chronic or high-dose corticosteroid use in patients with glioma is associated with significant morbidity. The ability of bevacizumab to control edema confounds the definition of tumor progression. Figure 2 shows a patient who had early neurologic improvement after initiation of bevacizumab and then remained clinically stable without corticosteroids over 14 months of therapy, despite slow continuous growth of the tumor mass.

Bevacizumab is also tolerated by older patients; there is an intriguing study suggesting that not only do older patients tolerate bevacizumab, they may also have increased benefit over younger patients (age separation: younger than 55 years or 55 years and older).20

Another option for some patients, prior to bevacizumab, is rechallenge with temozolomide at alternative dosing schedules, which result in prolonged exposure to higher cumulative doses than that achieved by standard 5-day dosing.21 Resistance to temozolomide occurs through direct repair of DNA by MGMT; a proposed mechanism to overcome resistance would be to deplete tumor-cell MGMT. Several studies have shown that prolonged exposure of peripheral blood mononuclear cells results in depletion of MGMT, and it has been suggested that this could also occur in glioma cells.22 Other studies suggest that prolonged exposure to temozolomide may be directly toxic to endothelial cells.23 These data provide a rationale for temozolomide rechallenge using alternative dose and dosing schedules that deliver higher culmulative doses over prolonged periods.

Commonly tried temozolomide schedules have been 21 days on/7 days off at doses of 75–100 mg/m2, 7 days on/7 days off at a dose of 150 mg/m2, and continuous daily dosing at 50 mg/m2 (Table 1). These schedules were well tolerated in these pretreated patients, with cumulative leukopenia after several cycles. Results have shown PFS-6 of 23%–48% with a suggestion (not supported by all studies) that best responses are seen in patients who were rechallenged after a treatment-free interval (from standard adjuvant temozolomide).24–27 Responses were also similar in patients with high and low levels of tumor MGMT, suggesting that these regimens may overcome -MGMT-mediated resistance.28

In addition to bevacizumab and temozolomide, lomustine, carmustine, irinotecan, cisplatin, and carboplatin have shown modest efficacy in studies as single agents or in combination regimens.29–31 The populations in these studies usually included both recurrent GB and anaplastic tumors, including oligodendrogliomas, and were carried out prior to standard use of chemoradiation and adjuvant temozolomide. Thus, it is difficult to extrapolate how these results would translate into today’s patient population. Interestingly, in a recent randomized phase III trial of recurrent GB (after prior temozolomide), lomustine was found to be superior to the investigational pan--VEFG receptor inhibitor cediranib.32

As noted, the NovoTTF-100A System was only recently approved, and experience is limited. Despite the need for patients to wear the device for 20 hours a day, and for intermittent adjustments to electrode placement at a clinic site, patient compliance in the study was good, and toxicities were minimal. It is clearly an option for patients with recurrent GB, but additional experience is needed to clarify the optimal time of use. The device is currently under study for the treatment of newly diagnosed GB; results of this study may help clarify the role of NovoTTF in treating this ¬malignancy.

In deciding which of the above strategies to use at first or even subsequent recurrences, we take into consideration the rapidity of tumor growth, extent of edema, mass effect, need for corticosteroids, and symptoms. Furthermore, to date there are no agents that improve outcomes when combined with bevacizumab or used after relapse on bevacizumab. This is often the last treatment regimen many patients receive before palliative end-of-life care. Thus, for a patient with a small, asymptomatic recurrence found on surveillance imaging and in the absence of an available clinical trial, we initiate therapy with any of the above-mentioned standard chemotherapeutic agents. At tumor progression and if chemotherapy is still tolerated, another agent may be tried. In contrast, the patient with a rapidly growing, large, or symptomatic recurrence requiring increasing doses of steroids will usually have an immediate clinical benefit from bevacizumab, which will improve quality of life.

Recurrent anaplastic gliomas

There is less consensus on how to treat anaplastic gliomas (anaplastic as¬tro¬cytoma, anaplastic oligodendroglioma, and mixed anaplastic oligoastrocytoma) at initial diagnosis and therefore even more variability in how these patients are treated at recurrence. The study that showed the benefit of chemoradiation and adjuvant temozolomide for newly diagnosed GB excluded patients with anaplastic tumors.1 A meta-analysis of clinical trials included adults with high-grade glioma who after initial surgery were treated with radiation plus chemotherapy (most often a nitrosourea) or radiation. The results only suggested that chemotherapy provided an additional survival benefit over radiotherapy alone for both GB and anaplastic patients.

Many cite the above data as the rationale for including temozolomide in the initial treatment of anaplastic tumors.33 Others, however, cite the results of NOA-04, a large study of patients with anaplastic glioma randomized to receive initial therapy with radiation or one of two chemotherapy regimens: procarbazine (Matulane), lomustine, and vincristine (PCV) or temozolomide.34 At tumor progression, patients who had received radiation were treated with either PCV or temozolomide, and those initially treated with either chemotherapy regimen were irradiated. This study demonstrated no difference in time to treatment failure or PFS among the three groups or any significant difference between the two chemotherapy regimens. Patients with anaplastic astrocytomas fared worse than those with anaplastic oligodendrogliomas or mixed tumors, suggesting that the latter groups may do well with initial chemotherapy only and then radiation at recurrence.

For patients with anaplastic tumors who have not previously been treated with temozolomide, studies do suggest that its use at recurrence is beneficial. In one phase II study, temozolomide-naive patients, or those who had previously received a nitrosourea, showed a 35% overall response rate and PFS-6 of 46% when treated with temozolomide at first recurrence.35 A recent study (RESCUE) evaluating a continuous low-dose temozolomide regimen of 50 mg/m2 in recurrent GB and anaplastic tumors demonstrated a PFS-6 of 35.7% for the anaplastic subgroup that contained patients who had previously had a variety of initial therapies, including chemoradiation.25

With the knowledge that the presence of chromosome 1p/19q codeletions in anaplastic tumors is prognostic for better outcomes,36 two ongoing studies will hopefully provide definitive answers for the treatment of recurrent anaplastic gliomas. The Chemoradiation and Adjuvant Temozolomide in Non-deleted Anaplastic Tumors (CATNON) study will randomly assign patients after surgery to receive either chemoradiation or radiation alone. Following this therapy, there is a second randomization to adjuvant temozolomide or observation only. The trial endpoint is overall survival. The phase III intergroup study of radiotherapy versus temozolomide alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with 1p/19q codeleted anaplastic glioma (CODEL) will determine whether these patients with inherently better outcomes may do just as well with less aggressive therapy.

Several studies of bevacizumab have included recurrent anaplastic gliomas. Two studies of the combination of bevacizumab and irinotecan produced response rates of 55%–66% and PFS-6 of 56%–61%, suggesting activity.12,37 Extrapolating from the GB data, it is likely that single-agent bevacizumab would be efficacious and less toxic than this combination.

Emerging strategies

The identification of prognostic and predictive markers is paving the way for individualized treatment planning. In addition to the prognostic value of 1p/19q codeletions in anaplastic gliomas, the presence of MGMT promoter methylation in GB is likely predictive of response to temozolomide, although this is still under debate. There has been recent excitement about the demonstration that the presence of mutated isocitrate dehydrogenase 1 (IDH1) in gliomas is a robust independent factor associated with better outcome.38 For example, in a series of patients with anaplastic glioma, patients with the IDH1 mutation had a median survival four times longer than that of those without the mutation (81.1 months vs 19.4 months).39 This raises the question of the role of mutated IDH1 in glioma biology and makes it a potentially valuable therapeutic target.

Ongoing gene-expression profiling studies are showing that histologically indistinguishable GB can be clustered into distinct molecular subtypes, with widely different outcomes and responses to treatment.40 This likely contributed to the failure of past clinical trials, as the populations under study were, in fact, too diverse; potentially efficacious agents for one or more subtypes may have been overlooked. These studies are also identifying novel cellular targets such as MET, fibroblast growth factor receptor (FGFR), heat shock protein-90 (HSP-90), and hypoxia-inducible factor 1? (HIF1?).41 Other research is focusing on targets involved in glioma migration and invasion such as tenascin, the Src family of nonreceptor tyrosine kinases, the Rho family of small GTPases, and integrins. The role of glioma stem cells in glioma development and resistance to therapy is another emerging area of study and has led to the identification of specific glioma stem cell targets such as Notch and Sonic hedgehog.42

Conclusion

High-grade gliomas are challenging to treat, and there is often no clear standard of care. The Glioma Outcomes Project tracked clinical practice patterns and outcomes among North American patients with malignant glioma between 1997 and 2000.43 The results showed that patients treated at academic centers were significantly more likely to receive chemotherapy or radiation therapy, to participate in clinical trials, and to have longer survival times than those treated at community centers. Whether these results would be the same today, with the routine use of temozolomide and bevacizumab, is unclear, but they do support referral of these patients to centers with multispecialty clinics. This is, however, not always feasible, and patients may choose to stay close to home.

For patients with recurrent high-grade gliomas, there are several available therapeutic options, including operation, irradiation, and additional systemic therapies, which are available at most centers. Although the optimal sequence in which therapies should be given has not been clarified, these treatments can delay the onset of neurologic deficits and result in improved quality of life and likely prolonged survival. Additionally, the appropriate management of comorbidities such as seizures and brain edema is essential, and several pertinent reviews are available.44,45

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ABOUT THE AUTHORS

Affiliations: Dr. Rosenfeld is Adjunct Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA; Ms. Albright is a Certified Registerd Nurse Practitioner at the University of Pennsylvania School of Medicine; and Dr. Pruitt is Associate Professor of Neurology at the University of Pennsylvania School of Medicine.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 Pseudoprogression after chemoradiation. MRI of a biopsy-proven grade III astrocytoma before treatment (left panel). Three weeks after completion of chemoradiation, there is an increase in the size of the cystic component and enhancement (middle panel), which could be interpreted as tumor progression. After 4 cycles of post-radiation temozolomide, the right panel shows a decrease in size and enhancement, supporting the earlier imaging changes as reflective of pseudoprogression. All images are T1 post gadolinium with a 1.5 Tesla magnet.

FIGURE 2 Imaging changes with bevacizumab. This 57-year-old woman presented with a second recurrence of glioblastoma 2 years after chemoradiation and 6 cycles of adjuvant temozolomide and 6 months after 8 cycles of low-dose temozolomide. The images show post-contrast T1-weighted sequences (A, C, E) and fluid-attenuated recovery (FLAIR) sequences (B, D, F). Baseline images (A, B) show a left frontal mass with enhancement, edema, and some mass effect. Eight months later, after 4 cycles of bevacizumab (dosed every 2 weeks with 3 doses per cycle), there is decreased periventricular enhancement and edema (C) and improved FLAIR signal (D) but enlargement of the enhancing left frontal mass, which would meet standard definitions of tumor progression. The patient was neurologically stable and remained on treatment. Nine months later, after 5 additional cycles, she remained neurologically stable (and was not receiving corticosteroids). At this time, the mass has continued to increase in size (note: there is also invasion of the frontal sinus; E), with increasing FLAIR abnormality, likely reflecting a progressive infiltrating nonenhancing tumor (F).

Myrna R. Rosenfeld, MD, PhD, Karen Albright, CRNP, and Amy A. Pruitt, MD

University of Pennsylvania School of Medicine, Philadelphia, PA

Manuscript received December 1, 2010; accepted April 15, 2011.

Correspondence to: Myrna R. Rosenfeld, MD, PhD, Department of Neurology, 3 W. Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; telephone: 215-746-2820; fax: 215-746-2818; e-mail: [email protected].

Despite treatment, glioblastoma (GB) inevitably recurs, and there is often no clear standard of care to follow. This article reviews the treatment options for recurrent GB and anaplastic gliomas. The three FDA-approved treatments for recurrent GB are biodegradable carmustine-impregnated wafers; bevacizumab; and the NovoTTF-100A System, which delivers low-intensity, alternating electrical fields to the tumor bed. Treatment decisions must take into consideration prior therapies, the extent and location of recurrence, and the patient’s general medical condition, as well as the rapidity of tumor growth, extent of edema, mass effect, need for steroids, and symptoms. New treatment strategies are emerging based on the identification of prognostic and predictive markers and defining distinct molecular subtypes of GB.

Glioblastoma (grade IV glioma, GB) is the most common of the primary malignant gliomas. Advances in the past decade have clarified that adjuvant treatment can improve quality of life and survival. The current standard of care for newly diagnosed patients with GB after optimal resection is focal radiation with concurrent (chemoradiation) and post-radiation temozolomide (Temodar). This regimen was shown to improve overall survival in a randomized phase III study.1 Furthermore, a subgroup of patients whose tumors were shown to have low levels of O6-methylguanine DNA methyltransferase (MGMT), the enzyme that repairs DNA damage due to temozolomide, showed overall survival of 46% at 2 years and 14% at 5 years.2,3

Biodegradable wafers impregnated with carmustine (Gliadel) implanted at the time of resection are another approved therapy for patients with newly diagnosed high-grade gliomas (GB and anaplastic gliomas, grade III glioma).4 Although short-term survivals for GB patients are similar with Gliadel compared to focal radiation with concurrent and post-radiation temozolomide, the latter results in superior long-term survival (1.9% at 56 months for Gliadel and 9.8% at 60 months for temozolomide).3,5 The nitrosoureas lomustine (CeeNU) and carmustine (BiCNU) were approved in the 1970s for use as single agents or in combination therapy in patients with glioma who had received surgery and/or radiation. These agents no longer have a clear role in the initial treatment of malignant glioma, although practitioners use them, often in combination therapy, for patients with recurrent GB and anaplastic oligodendrogliomas, a ¬chemosensitive subtype of glioma.6

Despite the use of the above approved therapies, GB invariably recurs. In the absence of effective treatment options, treatment approaches for recurrent GB have been varied. This article will review the most common accepted treatment options for recurrent GB and discuss emerging strategies. In the absence of a clear standard of care for newly diagnosed anaplastic gliomas, treatment at recurrence is largely dictated by prior therapies received, as noted below.

Tumor progression or treatment effect?

Glioblastoma recurrence is suspected when a previously stable patient develops recurrent or new neurologic signs and symptoms or when surveillance imaging (preferably MRI with gadolinium) shows increased tumor size or new enhancement likely associated with increased edema. However, clinical and imaging changes may result from perioperative complications such as infection or ischemia, a change in steroid use, or radiation necrosis (also called pseudoprogression). In fact, studies have shown that up to half of patients with presumed early tumor progression during or after chemoradiation actually have radiation necrosis (Figure 1).7 These data have led some clinicians to suggest that a minimum of 3 cycles of adjuvant temozolomide be given before a conclusion of tumor progression is made.

Several imaging modalities, such as magnetic resonance perfusion with or without spectroscopy and positron emission tomography, are used to help distinguish tumor recurrence from pseudoprogression but are not always reliable.8 In these cases, repeat imaging can be useful, although surgery may be necessary to relieve mass effect and obtain a tissue diagnosis.

Approved therapies for recurrent glioblastoma

There are currently three US Food and Drug Administration (FDA)–approved therapies for recurrent GB: Gliadel wafers; bevacizumab (Avastin), a humanized monoclonal antibody that sequesters vascular endothelial growth factor-A (VEGF); and the NovoTTF-100A System (NovoCure; Portsmouth, NH), which delivers low-intensity, alternating electrical fields (called tumor treatment fields) to the tumor bed that may inhibit cell growth by disrupting microtubule formation.9

The prospective randomized study that led to the approval of Gliadel demonstrated a modest increase in overall survival, from 23 weeks in those patients who received placebo wafers to 31 weeks for those receiving Gliadel.4 This study included recurrent anaplastic gliomas and GB, and the benefit in the GB subgroup was smaller than in the group as a whole. Furthermore, this and other studies predated the use of chemoradiation and adjuvant temozolomide, and it is unclear what benefit, if any, Gliadel offers in recurrent GB patients treated with prior temozolomide.

The approval of bevacizumab for recurrent GB in the United States was based on two clinical trials that evaluated bevacizumab as a single agent or combined with irinotecan in patients with tumor recurrence after initial treatment with chemoradiation and adjuvant temozolomide. The comparative study enrolled 167 patients, 85 in the bevacizumab-alone arm and 82 in the bevacizumab plus irinotecan arm.10 The objective response rate was 25.9% in patients who received bevacizumab monotherapy. There were no complete responses per outside review. The median duration of response was 4.2 months, and the 6-month progression-free survival (PFS-6) was 36.0 %. The single-arm study enrolled 56 patients with recurrent high-grade glioma.11 Objective response as determined by independent review was 19.6%. The median duration of response was 3.9 months.

The FDA approved bevacizumab for use as a single agent based on the improvement in objective response rate in these studies (albeit without improvement in disease-related symptoms or increased survival) and on the fact that patients receiving bevacizumab as a single agent had less toxicity than those receiving the combination with irinotecan and similar outcomes. Subsequent studies with bevacizumab as a single agent in recurrent GB have shown similar PFS-6 rates of between 29% and 42%; smaller studies in recurrent anaplastic gliomas reported response rates ranging between 34% and 68% and PFS-6 rates ranging between 32% and 68%.12,13

The NovoTTF-100A System received approval in the spring of 2011 based on the results of a single multinational study of 237 patients with recurrent GB.14 Patients were randomized to receive either the NovoTTF-100A System or chemotherapy of their physician’s choice. The NovoTTF device includes a battery pack (weighing about 6 pounds) and electrodes, which are placed on the scalp and designed to be worn for about 20 hours a day. The results showed that patients who used the NovoTTF-100A System had higher objective response rates (12% for NovoTTF compared with 6% in the chemotherapy group) and a favorable overall survival rate of 6.6 months compared with 6.0 months for the chemotherapy group. The device was well tolerated, with a significantly higher incidence of toxicities (hematologic and other) in the patients receiving chemotherapy.

Temozolomide is approved in Europe for recurrent high-grade gliomas, including both GB and anaplastic astrocytoma, but in the United States, it is only approved for recurrent anaplastic astrocytoma. These approvals were based on studies in mostly chemotherapy-naive patients, and although it is less clear that rechallenge with temozolomide is useful, as noted below, ongoing studies may clarify this issue.

Approach to the patient with recurrent GB

In the absence of enrollment in a clinical trial, which is encouraged for all glioma patients, the approach to the patient with recurrent GB should take into consideration prior therapies, extent of recurrence and location, and general medical condition. An initial consideration is whether the patient is a candidate for further resection and/or radiation. Re-resection can relieve mass effect and reduce the need for steroids, can provide histologic confirmation of the diagnosis, and likely can increase survival, although this has not been shown in randomized studies.15 For a patient with contraindications for further systemic chemotherapy and who is undergoing resection, Gliadel is a reasonable consideration, and it does not preclude use of bevacizumab or NovoTTF.

Re-irradiation with single-fraction or fractionated stereotactic radiation is feasible in patients with localized recurrent disease. Small, single-arm prospective studies and retrospective reviews suggest a benefit, and the focused delivery modalities reduce the dose to surrounding brain tissue, minimizing the risk of radiation toxicity.16 In some studies, low-dose temozolomide or bevacizumab was combined with re-irradiation with results suggesting both tolerability and efficacy.17 We have found re-irradiation to be a good alternative for those patients who develop profound and prolonged myelosuppression (usually thrombocytopenia) during initial treatment with temozolomide and who have tumor progression before recovery of the counts.

Bevacizumab is currently the most common single agent used for glioma recurrence and is usually dosed at 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or the decision to discontinue care. Due to its potent anti-VEGF activity, which results in normalization of highly permeable tumor vessels, bevacizumab often produces rapid and marked reduction in edema and contrast enhancement on neuroimaging.18 This can produce rapid clinical and imaging responses, although whether this reflects true antiglioma activity remains under debate.

Resolution of mass effect and contrast enhancement can also coexist with progression of nonenhancing fluid-attenuated recovery (FLAIR) abnormality that reflects a phenotypically invasive tumor recurrence pattern, with GB co-option of normal cerebral vessels and diffuse, multilobar perivascular spread of tumor cells. The imaging changes can make evaluation of tumor response and progression difficult if one relies on the standard criteria of two-dimensional measurement of enhancing disease; new criteria that take into consideration nonenhancing signal abnormality changes have been proposed.19

Bevacizumab is well tolerated in the brain tumor population, with the same spectrum of side effects seen in other cancer populations (hemorrhage, thrombosis, hypertension, bowel perforation, impaired wound healing, and proteinuria).12,13 The incidence of life-threatening events, such as significant intracranial hemorrhage (3%) or thromboembolism (2%–12%), is within the expected range for the population and is not clearly increased by ¬bevacizumab.12

Several small series have reported that corticosteroid reductions were feasible in 33%–59% of patients with recurrent GB after bevacizumab treatment, and others have reported average corticosteroid dose reductions of 72% and 59%.11,13 This is an important benefit of bevacizumab, as chronic or high-dose corticosteroid use in patients with glioma is associated with significant morbidity. The ability of bevacizumab to control edema confounds the definition of tumor progression. Figure 2 shows a patient who had early neurologic improvement after initiation of bevacizumab and then remained clinically stable without corticosteroids over 14 months of therapy, despite slow continuous growth of the tumor mass.

Bevacizumab is also tolerated by older patients; there is an intriguing study suggesting that not only do older patients tolerate bevacizumab, they may also have increased benefit over younger patients (age separation: younger than 55 years or 55 years and older).20

Another option for some patients, prior to bevacizumab, is rechallenge with temozolomide at alternative dosing schedules, which result in prolonged exposure to higher cumulative doses than that achieved by standard 5-day dosing.21 Resistance to temozolomide occurs through direct repair of DNA by MGMT; a proposed mechanism to overcome resistance would be to deplete tumor-cell MGMT. Several studies have shown that prolonged exposure of peripheral blood mononuclear cells results in depletion of MGMT, and it has been suggested that this could also occur in glioma cells.22 Other studies suggest that prolonged exposure to temozolomide may be directly toxic to endothelial cells.23 These data provide a rationale for temozolomide rechallenge using alternative dose and dosing schedules that deliver higher culmulative doses over prolonged periods.

Commonly tried temozolomide schedules have been 21 days on/7 days off at doses of 75–100 mg/m2, 7 days on/7 days off at a dose of 150 mg/m2, and continuous daily dosing at 50 mg/m2 (Table 1). These schedules were well tolerated in these pretreated patients, with cumulative leukopenia after several cycles. Results have shown PFS-6 of 23%–48% with a suggestion (not supported by all studies) that best responses are seen in patients who were rechallenged after a treatment-free interval (from standard adjuvant temozolomide).24–27 Responses were also similar in patients with high and low levels of tumor MGMT, suggesting that these regimens may overcome -MGMT-mediated resistance.28

In addition to bevacizumab and temozolomide, lomustine, carmustine, irinotecan, cisplatin, and carboplatin have shown modest efficacy in studies as single agents or in combination regimens.29–31 The populations in these studies usually included both recurrent GB and anaplastic tumors, including oligodendrogliomas, and were carried out prior to standard use of chemoradiation and adjuvant temozolomide. Thus, it is difficult to extrapolate how these results would translate into today’s patient population. Interestingly, in a recent randomized phase III trial of recurrent GB (after prior temozolomide), lomustine was found to be superior to the investigational pan--VEFG receptor inhibitor cediranib.32

As noted, the NovoTTF-100A System was only recently approved, and experience is limited. Despite the need for patients to wear the device for 20 hours a day, and for intermittent adjustments to electrode placement at a clinic site, patient compliance in the study was good, and toxicities were minimal. It is clearly an option for patients with recurrent GB, but additional experience is needed to clarify the optimal time of use. The device is currently under study for the treatment of newly diagnosed GB; results of this study may help clarify the role of NovoTTF in treating this ¬malignancy.

In deciding which of the above strategies to use at first or even subsequent recurrences, we take into consideration the rapidity of tumor growth, extent of edema, mass effect, need for corticosteroids, and symptoms. Furthermore, to date there are no agents that improve outcomes when combined with bevacizumab or used after relapse on bevacizumab. This is often the last treatment regimen many patients receive before palliative end-of-life care. Thus, for a patient with a small, asymptomatic recurrence found on surveillance imaging and in the absence of an available clinical trial, we initiate therapy with any of the above-mentioned standard chemotherapeutic agents. At tumor progression and if chemotherapy is still tolerated, another agent may be tried. In contrast, the patient with a rapidly growing, large, or symptomatic recurrence requiring increasing doses of steroids will usually have an immediate clinical benefit from bevacizumab, which will improve quality of life.

Recurrent anaplastic gliomas

There is less consensus on how to treat anaplastic gliomas (anaplastic as¬tro¬cytoma, anaplastic oligodendroglioma, and mixed anaplastic oligoastrocytoma) at initial diagnosis and therefore even more variability in how these patients are treated at recurrence. The study that showed the benefit of chemoradiation and adjuvant temozolomide for newly diagnosed GB excluded patients with anaplastic tumors.1 A meta-analysis of clinical trials included adults with high-grade glioma who after initial surgery were treated with radiation plus chemotherapy (most often a nitrosourea) or radiation. The results only suggested that chemotherapy provided an additional survival benefit over radiotherapy alone for both GB and anaplastic patients.

Many cite the above data as the rationale for including temozolomide in the initial treatment of anaplastic tumors.33 Others, however, cite the results of NOA-04, a large study of patients with anaplastic glioma randomized to receive initial therapy with radiation or one of two chemotherapy regimens: procarbazine (Matulane), lomustine, and vincristine (PCV) or temozolomide.34 At tumor progression, patients who had received radiation were treated with either PCV or temozolomide, and those initially treated with either chemotherapy regimen were irradiated. This study demonstrated no difference in time to treatment failure or PFS among the three groups or any significant difference between the two chemotherapy regimens. Patients with anaplastic astrocytomas fared worse than those with anaplastic oligodendrogliomas or mixed tumors, suggesting that the latter groups may do well with initial chemotherapy only and then radiation at recurrence.

For patients with anaplastic tumors who have not previously been treated with temozolomide, studies do suggest that its use at recurrence is beneficial. In one phase II study, temozolomide-naive patients, or those who had previously received a nitrosourea, showed a 35% overall response rate and PFS-6 of 46% when treated with temozolomide at first recurrence.35 A recent study (RESCUE) evaluating a continuous low-dose temozolomide regimen of 50 mg/m2 in recurrent GB and anaplastic tumors demonstrated a PFS-6 of 35.7% for the anaplastic subgroup that contained patients who had previously had a variety of initial therapies, including chemoradiation.25

With the knowledge that the presence of chromosome 1p/19q codeletions in anaplastic tumors is prognostic for better outcomes,36 two ongoing studies will hopefully provide definitive answers for the treatment of recurrent anaplastic gliomas. The Chemoradiation and Adjuvant Temozolomide in Non-deleted Anaplastic Tumors (CATNON) study will randomly assign patients after surgery to receive either chemoradiation or radiation alone. Following this therapy, there is a second randomization to adjuvant temozolomide or observation only. The trial endpoint is overall survival. The phase III intergroup study of radiotherapy versus temozolomide alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with 1p/19q codeleted anaplastic glioma (CODEL) will determine whether these patients with inherently better outcomes may do just as well with less aggressive therapy.

Several studies of bevacizumab have included recurrent anaplastic gliomas. Two studies of the combination of bevacizumab and irinotecan produced response rates of 55%–66% and PFS-6 of 56%–61%, suggesting activity.12,37 Extrapolating from the GB data, it is likely that single-agent bevacizumab would be efficacious and less toxic than this combination.

Emerging strategies

The identification of prognostic and predictive markers is paving the way for individualized treatment planning. In addition to the prognostic value of 1p/19q codeletions in anaplastic gliomas, the presence of MGMT promoter methylation in GB is likely predictive of response to temozolomide, although this is still under debate. There has been recent excitement about the demonstration that the presence of mutated isocitrate dehydrogenase 1 (IDH1) in gliomas is a robust independent factor associated with better outcome.38 For example, in a series of patients with anaplastic glioma, patients with the IDH1 mutation had a median survival four times longer than that of those without the mutation (81.1 months vs 19.4 months).39 This raises the question of the role of mutated IDH1 in glioma biology and makes it a potentially valuable therapeutic target.

Ongoing gene-expression profiling studies are showing that histologically indistinguishable GB can be clustered into distinct molecular subtypes, with widely different outcomes and responses to treatment.40 This likely contributed to the failure of past clinical trials, as the populations under study were, in fact, too diverse; potentially efficacious agents for one or more subtypes may have been overlooked. These studies are also identifying novel cellular targets such as MET, fibroblast growth factor receptor (FGFR), heat shock protein-90 (HSP-90), and hypoxia-inducible factor 1? (HIF1?).41 Other research is focusing on targets involved in glioma migration and invasion such as tenascin, the Src family of nonreceptor tyrosine kinases, the Rho family of small GTPases, and integrins. The role of glioma stem cells in glioma development and resistance to therapy is another emerging area of study and has led to the identification of specific glioma stem cell targets such as Notch and Sonic hedgehog.42

Conclusion

High-grade gliomas are challenging to treat, and there is often no clear standard of care. The Glioma Outcomes Project tracked clinical practice patterns and outcomes among North American patients with malignant glioma between 1997 and 2000.43 The results showed that patients treated at academic centers were significantly more likely to receive chemotherapy or radiation therapy, to participate in clinical trials, and to have longer survival times than those treated at community centers. Whether these results would be the same today, with the routine use of temozolomide and bevacizumab, is unclear, but they do support referral of these patients to centers with multispecialty clinics. This is, however, not always feasible, and patients may choose to stay close to home.

For patients with recurrent high-grade gliomas, there are several available therapeutic options, including operation, irradiation, and additional systemic therapies, which are available at most centers. Although the optimal sequence in which therapies should be given has not been clarified, these treatments can delay the onset of neurologic deficits and result in improved quality of life and likely prolonged survival. Additionally, the appropriate management of comorbidities such as seizures and brain edema is essential, and several pertinent reviews are available.44,45

References

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ABOUT THE AUTHORS

Affiliations: Dr. Rosenfeld is Adjunct Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA; Ms. Albright is a Certified Registerd Nurse Practitioner at the University of Pennsylvania School of Medicine; and Dr. Pruitt is Associate Professor of Neurology at the University of Pennsylvania School of Medicine.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 Pseudoprogression after chemoradiation. MRI of a biopsy-proven grade III astrocytoma before treatment (left panel). Three weeks after completion of chemoradiation, there is an increase in the size of the cystic component and enhancement (middle panel), which could be interpreted as tumor progression. After 4 cycles of post-radiation temozolomide, the right panel shows a decrease in size and enhancement, supporting the earlier imaging changes as reflective of pseudoprogression. All images are T1 post gadolinium with a 1.5 Tesla magnet.

FIGURE 2 Imaging changes with bevacizumab. This 57-year-old woman presented with a second recurrence of glioblastoma 2 years after chemoradiation and 6 cycles of adjuvant temozolomide and 6 months after 8 cycles of low-dose temozolomide. The images show post-contrast T1-weighted sequences (A, C, E) and fluid-attenuated recovery (FLAIR) sequences (B, D, F). Baseline images (A, B) show a left frontal mass with enhancement, edema, and some mass effect. Eight months later, after 4 cycles of bevacizumab (dosed every 2 weeks with 3 doses per cycle), there is decreased periventricular enhancement and edema (C) and improved FLAIR signal (D) but enlargement of the enhancing left frontal mass, which would meet standard definitions of tumor progression. The patient was neurologically stable and remained on treatment. Nine months later, after 5 additional cycles, she remained neurologically stable (and was not receiving corticosteroids). At this time, the mass has continued to increase in size (note: there is also invasion of the frontal sinus; E), with increasing FLAIR abnormality, likely reflecting a progressive infiltrating nonenhancing tumor (F).

Myrna R. Rosenfeld, MD, PhD, Karen Albright, CRNP, and Amy A. Pruitt, MD

University of Pennsylvania School of Medicine, Philadelphia, PA

Manuscript received December 1, 2010; accepted April 15, 2011.

Correspondence to: Myrna R. Rosenfeld, MD, PhD, Department of Neurology, 3 W. Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; telephone: 215-746-2820; fax: 215-746-2818; e-mail: [email protected].

Despite treatment, glioblastoma (GB) inevitably recurs, and there is often no clear standard of care to follow. This article reviews the treatment options for recurrent GB and anaplastic gliomas. The three FDA-approved treatments for recurrent GB are biodegradable carmustine-impregnated wafers; bevacizumab; and the NovoTTF-100A System, which delivers low-intensity, alternating electrical fields to the tumor bed. Treatment decisions must take into consideration prior therapies, the extent and location of recurrence, and the patient’s general medical condition, as well as the rapidity of tumor growth, extent of edema, mass effect, need for steroids, and symptoms. New treatment strategies are emerging based on the identification of prognostic and predictive markers and defining distinct molecular subtypes of GB.

Glioblastoma (grade IV glioma, GB) is the most common of the primary malignant gliomas. Advances in the past decade have clarified that adjuvant treatment can improve quality of life and survival. The current standard of care for newly diagnosed patients with GB after optimal resection is focal radiation with concurrent (chemoradiation) and post-radiation temozolomide (Temodar). This regimen was shown to improve overall survival in a randomized phase III study.1 Furthermore, a subgroup of patients whose tumors were shown to have low levels of O6-methylguanine DNA methyltransferase (MGMT), the enzyme that repairs DNA damage due to temozolomide, showed overall survival of 46% at 2 years and 14% at 5 years.2,3

Biodegradable wafers impregnated with carmustine (Gliadel) implanted at the time of resection are another approved therapy for patients with newly diagnosed high-grade gliomas (GB and anaplastic gliomas, grade III glioma).4 Although short-term survivals for GB patients are similar with Gliadel compared to focal radiation with concurrent and post-radiation temozolomide, the latter results in superior long-term survival (1.9% at 56 months for Gliadel and 9.8% at 60 months for temozolomide).3,5 The nitrosoureas lomustine (CeeNU) and carmustine (BiCNU) were approved in the 1970s for use as single agents or in combination therapy in patients with glioma who had received surgery and/or radiation. These agents no longer have a clear role in the initial treatment of malignant glioma, although practitioners use them, often in combination therapy, for patients with recurrent GB and anaplastic oligodendrogliomas, a ¬chemosensitive subtype of glioma.6

Despite the use of the above approved therapies, GB invariably recurs. In the absence of effective treatment options, treatment approaches for recurrent GB have been varied. This article will review the most common accepted treatment options for recurrent GB and discuss emerging strategies. In the absence of a clear standard of care for newly diagnosed anaplastic gliomas, treatment at recurrence is largely dictated by prior therapies received, as noted below.

Tumor progression or treatment effect?

Glioblastoma recurrence is suspected when a previously stable patient develops recurrent or new neurologic signs and symptoms or when surveillance imaging (preferably MRI with gadolinium) shows increased tumor size or new enhancement likely associated with increased edema. However, clinical and imaging changes may result from perioperative complications such as infection or ischemia, a change in steroid use, or radiation necrosis (also called pseudoprogression). In fact, studies have shown that up to half of patients with presumed early tumor progression during or after chemoradiation actually have radiation necrosis (Figure 1).7 These data have led some clinicians to suggest that a minimum of 3 cycles of adjuvant temozolomide be given before a conclusion of tumor progression is made.

Several imaging modalities, such as magnetic resonance perfusion with or without spectroscopy and positron emission tomography, are used to help distinguish tumor recurrence from pseudoprogression but are not always reliable.8 In these cases, repeat imaging can be useful, although surgery may be necessary to relieve mass effect and obtain a tissue diagnosis.

Approved therapies for recurrent glioblastoma

There are currently three US Food and Drug Administration (FDA)–approved therapies for recurrent GB: Gliadel wafers; bevacizumab (Avastin), a humanized monoclonal antibody that sequesters vascular endothelial growth factor-A (VEGF); and the NovoTTF-100A System (NovoCure; Portsmouth, NH), which delivers low-intensity, alternating electrical fields (called tumor treatment fields) to the tumor bed that may inhibit cell growth by disrupting microtubule formation.9

The prospective randomized study that led to the approval of Gliadel demonstrated a modest increase in overall survival, from 23 weeks in those patients who received placebo wafers to 31 weeks for those receiving Gliadel.4 This study included recurrent anaplastic gliomas and GB, and the benefit in the GB subgroup was smaller than in the group as a whole. Furthermore, this and other studies predated the use of chemoradiation and adjuvant temozolomide, and it is unclear what benefit, if any, Gliadel offers in recurrent GB patients treated with prior temozolomide.

The approval of bevacizumab for recurrent GB in the United States was based on two clinical trials that evaluated bevacizumab as a single agent or combined with irinotecan in patients with tumor recurrence after initial treatment with chemoradiation and adjuvant temozolomide. The comparative study enrolled 167 patients, 85 in the bevacizumab-alone arm and 82 in the bevacizumab plus irinotecan arm.10 The objective response rate was 25.9% in patients who received bevacizumab monotherapy. There were no complete responses per outside review. The median duration of response was 4.2 months, and the 6-month progression-free survival (PFS-6) was 36.0 %. The single-arm study enrolled 56 patients with recurrent high-grade glioma.11 Objective response as determined by independent review was 19.6%. The median duration of response was 3.9 months.

The FDA approved bevacizumab for use as a single agent based on the improvement in objective response rate in these studies (albeit without improvement in disease-related symptoms or increased survival) and on the fact that patients receiving bevacizumab as a single agent had less toxicity than those receiving the combination with irinotecan and similar outcomes. Subsequent studies with bevacizumab as a single agent in recurrent GB have shown similar PFS-6 rates of between 29% and 42%; smaller studies in recurrent anaplastic gliomas reported response rates ranging between 34% and 68% and PFS-6 rates ranging between 32% and 68%.12,13

The NovoTTF-100A System received approval in the spring of 2011 based on the results of a single multinational study of 237 patients with recurrent GB.14 Patients were randomized to receive either the NovoTTF-100A System or chemotherapy of their physician’s choice. The NovoTTF device includes a battery pack (weighing about 6 pounds) and electrodes, which are placed on the scalp and designed to be worn for about 20 hours a day. The results showed that patients who used the NovoTTF-100A System had higher objective response rates (12% for NovoTTF compared with 6% in the chemotherapy group) and a favorable overall survival rate of 6.6 months compared with 6.0 months for the chemotherapy group. The device was well tolerated, with a significantly higher incidence of toxicities (hematologic and other) in the patients receiving chemotherapy.

Temozolomide is approved in Europe for recurrent high-grade gliomas, including both GB and anaplastic astrocytoma, but in the United States, it is only approved for recurrent anaplastic astrocytoma. These approvals were based on studies in mostly chemotherapy-naive patients, and although it is less clear that rechallenge with temozolomide is useful, as noted below, ongoing studies may clarify this issue.

Approach to the patient with recurrent GB

In the absence of enrollment in a clinical trial, which is encouraged for all glioma patients, the approach to the patient with recurrent GB should take into consideration prior therapies, extent of recurrence and location, and general medical condition. An initial consideration is whether the patient is a candidate for further resection and/or radiation. Re-resection can relieve mass effect and reduce the need for steroids, can provide histologic confirmation of the diagnosis, and likely can increase survival, although this has not been shown in randomized studies.15 For a patient with contraindications for further systemic chemotherapy and who is undergoing resection, Gliadel is a reasonable consideration, and it does not preclude use of bevacizumab or NovoTTF.

Re-irradiation with single-fraction or fractionated stereotactic radiation is feasible in patients with localized recurrent disease. Small, single-arm prospective studies and retrospective reviews suggest a benefit, and the focused delivery modalities reduce the dose to surrounding brain tissue, minimizing the risk of radiation toxicity.16 In some studies, low-dose temozolomide or bevacizumab was combined with re-irradiation with results suggesting both tolerability and efficacy.17 We have found re-irradiation to be a good alternative for those patients who develop profound and prolonged myelosuppression (usually thrombocytopenia) during initial treatment with temozolomide and who have tumor progression before recovery of the counts.

Bevacizumab is currently the most common single agent used for glioma recurrence and is usually dosed at 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or the decision to discontinue care. Due to its potent anti-VEGF activity, which results in normalization of highly permeable tumor vessels, bevacizumab often produces rapid and marked reduction in edema and contrast enhancement on neuroimaging.18 This can produce rapid clinical and imaging responses, although whether this reflects true antiglioma activity remains under debate.

Resolution of mass effect and contrast enhancement can also coexist with progression of nonenhancing fluid-attenuated recovery (FLAIR) abnormality that reflects a phenotypically invasive tumor recurrence pattern, with GB co-option of normal cerebral vessels and diffuse, multilobar perivascular spread of tumor cells. The imaging changes can make evaluation of tumor response and progression difficult if one relies on the standard criteria of two-dimensional measurement of enhancing disease; new criteria that take into consideration nonenhancing signal abnormality changes have been proposed.19

Bevacizumab is well tolerated in the brain tumor population, with the same spectrum of side effects seen in other cancer populations (hemorrhage, thrombosis, hypertension, bowel perforation, impaired wound healing, and proteinuria).12,13 The incidence of life-threatening events, such as significant intracranial hemorrhage (3%) or thromboembolism (2%–12%), is within the expected range for the population and is not clearly increased by ¬bevacizumab.12

Several small series have reported that corticosteroid reductions were feasible in 33%–59% of patients with recurrent GB after bevacizumab treatment, and others have reported average corticosteroid dose reductions of 72% and 59%.11,13 This is an important benefit of bevacizumab, as chronic or high-dose corticosteroid use in patients with glioma is associated with significant morbidity. The ability of bevacizumab to control edema confounds the definition of tumor progression. Figure 2 shows a patient who had early neurologic improvement after initiation of bevacizumab and then remained clinically stable without corticosteroids over 14 months of therapy, despite slow continuous growth of the tumor mass.

Bevacizumab is also tolerated by older patients; there is an intriguing study suggesting that not only do older patients tolerate bevacizumab, they may also have increased benefit over younger patients (age separation: younger than 55 years or 55 years and older).20

Another option for some patients, prior to bevacizumab, is rechallenge with temozolomide at alternative dosing schedules, which result in prolonged exposure to higher cumulative doses than that achieved by standard 5-day dosing.21 Resistance to temozolomide occurs through direct repair of DNA by MGMT; a proposed mechanism to overcome resistance would be to deplete tumor-cell MGMT. Several studies have shown that prolonged exposure of peripheral blood mononuclear cells results in depletion of MGMT, and it has been suggested that this could also occur in glioma cells.22 Other studies suggest that prolonged exposure to temozolomide may be directly toxic to endothelial cells.23 These data provide a rationale for temozolomide rechallenge using alternative dose and dosing schedules that deliver higher culmulative doses over prolonged periods.

Commonly tried temozolomide schedules have been 21 days on/7 days off at doses of 75–100 mg/m2, 7 days on/7 days off at a dose of 150 mg/m2, and continuous daily dosing at 50 mg/m2 (Table 1). These schedules were well tolerated in these pretreated patients, with cumulative leukopenia after several cycles. Results have shown PFS-6 of 23%–48% with a suggestion (not supported by all studies) that best responses are seen in patients who were rechallenged after a treatment-free interval (from standard adjuvant temozolomide).24–27 Responses were also similar in patients with high and low levels of tumor MGMT, suggesting that these regimens may overcome -MGMT-mediated resistance.28

In addition to bevacizumab and temozolomide, lomustine, carmustine, irinotecan, cisplatin, and carboplatin have shown modest efficacy in studies as single agents or in combination regimens.29–31 The populations in these studies usually included both recurrent GB and anaplastic tumors, including oligodendrogliomas, and were carried out prior to standard use of chemoradiation and adjuvant temozolomide. Thus, it is difficult to extrapolate how these results would translate into today’s patient population. Interestingly, in a recent randomized phase III trial of recurrent GB (after prior temozolomide), lomustine was found to be superior to the investigational pan--VEFG receptor inhibitor cediranib.32

As noted, the NovoTTF-100A System was only recently approved, and experience is limited. Despite the need for patients to wear the device for 20 hours a day, and for intermittent adjustments to electrode placement at a clinic site, patient compliance in the study was good, and toxicities were minimal. It is clearly an option for patients with recurrent GB, but additional experience is needed to clarify the optimal time of use. The device is currently under study for the treatment of newly diagnosed GB; results of this study may help clarify the role of NovoTTF in treating this ¬malignancy.

In deciding which of the above strategies to use at first or even subsequent recurrences, we take into consideration the rapidity of tumor growth, extent of edema, mass effect, need for corticosteroids, and symptoms. Furthermore, to date there are no agents that improve outcomes when combined with bevacizumab or used after relapse on bevacizumab. This is often the last treatment regimen many patients receive before palliative end-of-life care. Thus, for a patient with a small, asymptomatic recurrence found on surveillance imaging and in the absence of an available clinical trial, we initiate therapy with any of the above-mentioned standard chemotherapeutic agents. At tumor progression and if chemotherapy is still tolerated, another agent may be tried. In contrast, the patient with a rapidly growing, large, or symptomatic recurrence requiring increasing doses of steroids will usually have an immediate clinical benefit from bevacizumab, which will improve quality of life.

Recurrent anaplastic gliomas

There is less consensus on how to treat anaplastic gliomas (anaplastic as¬tro¬cytoma, anaplastic oligodendroglioma, and mixed anaplastic oligoastrocytoma) at initial diagnosis and therefore even more variability in how these patients are treated at recurrence. The study that showed the benefit of chemoradiation and adjuvant temozolomide for newly diagnosed GB excluded patients with anaplastic tumors.1 A meta-analysis of clinical trials included adults with high-grade glioma who after initial surgery were treated with radiation plus chemotherapy (most often a nitrosourea) or radiation. The results only suggested that chemotherapy provided an additional survival benefit over radiotherapy alone for both GB and anaplastic patients.

Many cite the above data as the rationale for including temozolomide in the initial treatment of anaplastic tumors.33 Others, however, cite the results of NOA-04, a large study of patients with anaplastic glioma randomized to receive initial therapy with radiation or one of two chemotherapy regimens: procarbazine (Matulane), lomustine, and vincristine (PCV) or temozolomide.34 At tumor progression, patients who had received radiation were treated with either PCV or temozolomide, and those initially treated with either chemotherapy regimen were irradiated. This study demonstrated no difference in time to treatment failure or PFS among the three groups or any significant difference between the two chemotherapy regimens. Patients with anaplastic astrocytomas fared worse than those with anaplastic oligodendrogliomas or mixed tumors, suggesting that the latter groups may do well with initial chemotherapy only and then radiation at recurrence.

For patients with anaplastic tumors who have not previously been treated with temozolomide, studies do suggest that its use at recurrence is beneficial. In one phase II study, temozolomide-naive patients, or those who had previously received a nitrosourea, showed a 35% overall response rate and PFS-6 of 46% when treated with temozolomide at first recurrence.35 A recent study (RESCUE) evaluating a continuous low-dose temozolomide regimen of 50 mg/m2 in recurrent GB and anaplastic tumors demonstrated a PFS-6 of 35.7% for the anaplastic subgroup that contained patients who had previously had a variety of initial therapies, including chemoradiation.25

With the knowledge that the presence of chromosome 1p/19q codeletions in anaplastic tumors is prognostic for better outcomes,36 two ongoing studies will hopefully provide definitive answers for the treatment of recurrent anaplastic gliomas. The Chemoradiation and Adjuvant Temozolomide in Non-deleted Anaplastic Tumors (CATNON) study will randomly assign patients after surgery to receive either chemoradiation or radiation alone. Following this therapy, there is a second randomization to adjuvant temozolomide or observation only. The trial endpoint is overall survival. The phase III intergroup study of radiotherapy versus temozolomide alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with 1p/19q codeleted anaplastic glioma (CODEL) will determine whether these patients with inherently better outcomes may do just as well with less aggressive therapy.

Several studies of bevacizumab have included recurrent anaplastic gliomas. Two studies of the combination of bevacizumab and irinotecan produced response rates of 55%–66% and PFS-6 of 56%–61%, suggesting activity.12,37 Extrapolating from the GB data, it is likely that single-agent bevacizumab would be efficacious and less toxic than this combination.

Emerging strategies

The identification of prognostic and predictive markers is paving the way for individualized treatment planning. In addition to the prognostic value of 1p/19q codeletions in anaplastic gliomas, the presence of MGMT promoter methylation in GB is likely predictive of response to temozolomide, although this is still under debate. There has been recent excitement about the demonstration that the presence of mutated isocitrate dehydrogenase 1 (IDH1) in gliomas is a robust independent factor associated with better outcome.38 For example, in a series of patients with anaplastic glioma, patients with the IDH1 mutation had a median survival four times longer than that of those without the mutation (81.1 months vs 19.4 months).39 This raises the question of the role of mutated IDH1 in glioma biology and makes it a potentially valuable therapeutic target.

Ongoing gene-expression profiling studies are showing that histologically indistinguishable GB can be clustered into distinct molecular subtypes, with widely different outcomes and responses to treatment.40 This likely contributed to the failure of past clinical trials, as the populations under study were, in fact, too diverse; potentially efficacious agents for one or more subtypes may have been overlooked. These studies are also identifying novel cellular targets such as MET, fibroblast growth factor receptor (FGFR), heat shock protein-90 (HSP-90), and hypoxia-inducible factor 1? (HIF1?).41 Other research is focusing on targets involved in glioma migration and invasion such as tenascin, the Src family of nonreceptor tyrosine kinases, the Rho family of small GTPases, and integrins. The role of glioma stem cells in glioma development and resistance to therapy is another emerging area of study and has led to the identification of specific glioma stem cell targets such as Notch and Sonic hedgehog.42

Conclusion

High-grade gliomas are challenging to treat, and there is often no clear standard of care. The Glioma Outcomes Project tracked clinical practice patterns and outcomes among North American patients with malignant glioma between 1997 and 2000.43 The results showed that patients treated at academic centers were significantly more likely to receive chemotherapy or radiation therapy, to participate in clinical trials, and to have longer survival times than those treated at community centers. Whether these results would be the same today, with the routine use of temozolomide and bevacizumab, is unclear, but they do support referral of these patients to centers with multispecialty clinics. This is, however, not always feasible, and patients may choose to stay close to home.

For patients with recurrent high-grade gliomas, there are several available therapeutic options, including operation, irradiation, and additional systemic therapies, which are available at most centers. Although the optimal sequence in which therapies should be given has not been clarified, these treatments can delay the onset of neurologic deficits and result in improved quality of life and likely prolonged survival. Additionally, the appropriate management of comorbidities such as seizures and brain edema is essential, and several pertinent reviews are available.44,45

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ABOUT THE AUTHORS

Affiliations: Dr. Rosenfeld is Adjunct Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA; Ms. Albright is a Certified Registerd Nurse Practitioner at the University of Pennsylvania School of Medicine; and Dr. Pruitt is Associate Professor of Neurology at the University of Pennsylvania School of Medicine.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 Pseudoprogression after chemoradiation. MRI of a biopsy-proven grade III astrocytoma before treatment (left panel). Three weeks after completion of chemoradiation, there is an increase in the size of the cystic component and enhancement (middle panel), which could be interpreted as tumor progression. After 4 cycles of post-radiation temozolomide, the right panel shows a decrease in size and enhancement, supporting the earlier imaging changes as reflective of pseudoprogression. All images are T1 post gadolinium with a 1.5 Tesla magnet.

FIGURE 2 Imaging changes with bevacizumab. This 57-year-old woman presented with a second recurrence of glioblastoma 2 years after chemoradiation and 6 cycles of adjuvant temozolomide and 6 months after 8 cycles of low-dose temozolomide. The images show post-contrast T1-weighted sequences (A, C, E) and fluid-attenuated recovery (FLAIR) sequences (B, D, F). Baseline images (A, B) show a left frontal mass with enhancement, edema, and some mass effect. Eight months later, after 4 cycles of bevacizumab (dosed every 2 weeks with 3 doses per cycle), there is decreased periventricular enhancement and edema (C) and improved FLAIR signal (D) but enlargement of the enhancing left frontal mass, which would meet standard definitions of tumor progression. The patient was neurologically stable and remained on treatment. Nine months later, after 5 additional cycles, she remained neurologically stable (and was not receiving corticosteroids). At this time, the mass has continued to increase in size (note: there is also invasion of the frontal sinus; E), with increasing FLAIR abnormality, likely reflecting a progressive infiltrating nonenhancing tumor (F).

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX

What does an oncologist need to know about OIGs, RACs, and ZPICs? Plenty. They are some of the auditors who can make life difficult if a practice is not in compliance with Medicare and Medicaid billing and utilization procedures, Roberta L. Buell said at this journal’s annual Community Oncology Conference in Las Vegas.

The government is financing health¬care reform in part through audits to recover stolen and misused money, she explained. Thus far, it has recovered impressive sums, suggesting that the auditors are here to stay no matter how reform plays out. Anyone who runs a practice could be audited, cautioned Ms. Buell, a principal and coding and reimbursement specialist at onPoint Oncology in Sausalito, California. She discussed some of the key types of auditors and their roles.

Acronyms with a mission

Office of Inspector General auditors (OIGs) are responsible for ensuring appropriate use of Medicare funds. Their activities range from conducting basic audits to arranging arrests if a practice is deemed to have done something criminal.

OIGs will be scrutinizing a host of issues in 2011 and 2012, according to Ms. Buell. One is “place-of-service” errors, whereby a claim indicates a patient was treated in an office, where reimbursement is higher, but treatment actually took place in a hospital or ambulatory surgical center. This can be tricky for oncologists who sell their practices to a hospital but maintain a separate office. When physicians see patients in the office, “they’re…billing Part B. But if they walk across the hall to the infusion center and they see [patients] over there,…their place of service will be the hospital,” she said.

The OIGs will also be taking a close look at evaluation and management (E/M) codes to assess whether the codes accurately reflect the type, setting, and complexity of services provided as well as patient status—new or established. Also within the E/M category, auditors will be on the look out for identical (boilerplate) documentation across patients, sometimes a result of use of electronic medical records.

Error-prone providers, such as those with high numbers of duplicate claims, will catch the auditors’ attention as well. To avoid this, Ms. Buell recommended following up with a phone call when a claim goes unpaid, rather than resubmitting the claim. Medicare incentive payments for use of electronic medical records will also feature in the auditors’ work plan. “People are going to be randomly audited to make sure that they had 90 days of consecutive meaningful use—and it has to be for all patients, not just for Medicare patients,” Ms. Buell said.

Compliance with the Health Insurance Portability and Accountability Act will also be assessed. Some large fines have already been levied because of data-security breaches, so practices need to be especially vigilant about not leaving records around or losing laptops.

The OIGs will also scrutinize a variety of issues related to the Part D prescription drug program, such as inclusion of Part A and B claims with Part D claims. Ms. Buell cited billing practices for erythropoiesis-stimulating agents and pegfilgrastim (Neulasta) as an example: a practice might bill through Part D for Neulasta because it is “under water” on it, but “that is going to come back to haunt [you], because that’s not supposed to happen.”

A related aspect of Part D billing is the duplication of drug claims for hospice patients. “If somebody is in the hospice and is getting a drug through the hospice, but comes to your practice and gets it again, that’s going to be looked at,” she explained.

Zone Program Integrity Contractors (ZPICs) “are the [auditors] you really have to worry about. These are the folks who are looking for fraud.” Their data-analysis program is intended to identify provider billing practices and services that pose the greatest financial risk to the Medicare program, for example, high-volume and high-cost services that are being widely overused. But they also investigate credible whistle-blower (qui tam) complaints.

ZPICs can send a practice two types of letters. One is a request for records within 30 days, which usually means the practice was flagged by the screening program and the auditors want to take a closer look at the documentation. In this case, an attorney is not necessary. “But you have to have people look very hard at those records…[so] that everything that is done is justified in the record,” she said. The other type of letter usually arrives by fax and states that auditors will be on site within a few days. “That means that they have a complaint, either by a patient or more likely by a disgruntled physician or employee,” Ms. Buell noted. Here, the stakes are criminal penalties, and there should be an attorney on site during the visit.

Recovery Audit Contractors (RACs) “are bounty hunters,” she said. They are focused on recovering misspent Medicare funds and are paid a contingency fee of 9%–12% of the amount recovered. However, they are not active in practices because they have enjoyed such success in hospitals. At present, they do automated screening of practices’ Part B payments. “If you fall out of the screen, they ask for the money back and that’s the end,” Ms. Buell said. She cautioned, however, that RACs might start doing complex reviews later this year. And if they do, drugs are likely to be an early focus “because there is so much money involved and they have seen that [in the hospitals].”

Medicaid Integrity Contractors (MICs) review Medicaid claims for inappropriate payments and fraud, using a data-driven approach to identify aberrant billing practices. Unlike RACs, who receive a contingency fee, MICs are paid for their services and receive a quality-related bonus. Their look-back period for medical records varies by state. At present, they target mainly hospitals and, to a lesser extent, skilled nursing facilities, nursing homes, and hospices. Physicians are low on the list of priorities, “but…if you have a heavy Medicaid load, you do have to worry about [it],” Ms. Buell said.

Medicare Administrative Contractors (MACs) process claims for both Part A and Part B services and therefore can review discrepancies between the two sets of claims, revise payments, and increase denials. Some ongoing MAC activities include audits regarding usage of the 99204 and 99205 procedure codes for new patients.

Minimizing the risks

Given this environment, what can oncology practices do to minimize their risk? “Have a compliance [program] and make it a priority,” Ms. Buell recommended, adding that it is also a requirement of healthcare reform. Be sure to fix anything the program identifies, because auditors will take a much stiffer stance if they discover issues that were known but not resolved.

Practices can refer to a set of components that the OIG has set forth as the foundation of an effective compliance and ethics program (www.oig.hhs.gov/authorities/docs/physician.pdf). For example, there should be standard policies and procedures in the practice for things such as documentation, education and training, and updates on Medicare regulations. The enforcement of these policies is also a key element of an effective compliance program, as is a prevention component that anticipates mistakes and prevents them from occurring whenever possible.

The healthcare reform legislation requires that practices report and return Medicare and Medicaid overpayments. “If you find that you have been overpaid, for any reason, even if it’s their mistake, give the money back,” Ms. Buell said, because there is a good chance that auditors will eventually discover it.

Any practice that is concerned about being at risk for whistle-blower incidents should obtain legal help. “If you think there is…someone out there who can hurt you, you need to have your compliance program administered by an attorney.”

Finally, “educate, educate, educate,” she advised, to keep physicians and other practice members current on compliance issues.

What does an oncologist need to know about OIGs, RACs, and ZPICs? Plenty. They are some of the auditors who can make life difficult if a practice is not in compliance with Medicare and Medicaid billing and utilization procedures, Roberta L. Buell said at this journal’s annual Community Oncology Conference in Las Vegas.

The government is financing health¬care reform in part through audits to recover stolen and misused money, she explained. Thus far, it has recovered impressive sums, suggesting that the auditors are here to stay no matter how reform plays out. Anyone who runs a practice could be audited, cautioned Ms. Buell, a principal and coding and reimbursement specialist at onPoint Oncology in Sausalito, California. She discussed some of the key types of auditors and their roles.

Acronyms with a mission

Office of Inspector General auditors (OIGs) are responsible for ensuring appropriate use of Medicare funds. Their activities range from conducting basic audits to arranging arrests if a practice is deemed to have done something criminal.

OIGs will be scrutinizing a host of issues in 2011 and 2012, according to Ms. Buell. One is “place-of-service” errors, whereby a claim indicates a patient was treated in an office, where reimbursement is higher, but treatment actually took place in a hospital or ambulatory surgical center. This can be tricky for oncologists who sell their practices to a hospital but maintain a separate office. When physicians see patients in the office, “they’re…billing Part B. But if they walk across the hall to the infusion center and they see [patients] over there,…their place of service will be the hospital,” she said.

The OIGs will also be taking a close look at evaluation and management (E/M) codes to assess whether the codes accurately reflect the type, setting, and complexity of services provided as well as patient status—new or established. Also within the E/M category, auditors will be on the look out for identical (boilerplate) documentation across patients, sometimes a result of use of electronic medical records.

Error-prone providers, such as those with high numbers of duplicate claims, will catch the auditors’ attention as well. To avoid this, Ms. Buell recommended following up with a phone call when a claim goes unpaid, rather than resubmitting the claim. Medicare incentive payments for use of electronic medical records will also feature in the auditors’ work plan. “People are going to be randomly audited to make sure that they had 90 days of consecutive meaningful use—and it has to be for all patients, not just for Medicare patients,” Ms. Buell said.

Compliance with the Health Insurance Portability and Accountability Act will also be assessed. Some large fines have already been levied because of data-security breaches, so practices need to be especially vigilant about not leaving records around or losing laptops.

The OIGs will also scrutinize a variety of issues related to the Part D prescription drug program, such as inclusion of Part A and B claims with Part D claims. Ms. Buell cited billing practices for erythropoiesis-stimulating agents and pegfilgrastim (Neulasta) as an example: a practice might bill through Part D for Neulasta because it is “under water” on it, but “that is going to come back to haunt [you], because that’s not supposed to happen.”

A related aspect of Part D billing is the duplication of drug claims for hospice patients. “If somebody is in the hospice and is getting a drug through the hospice, but comes to your practice and gets it again, that’s going to be looked at,” she explained.

Zone Program Integrity Contractors (ZPICs) “are the [auditors] you really have to worry about. These are the folks who are looking for fraud.” Their data-analysis program is intended to identify provider billing practices and services that pose the greatest financial risk to the Medicare program, for example, high-volume and high-cost services that are being widely overused. But they also investigate credible whistle-blower (qui tam) complaints.

ZPICs can send a practice two types of letters. One is a request for records within 30 days, which usually means the practice was flagged by the screening program and the auditors want to take a closer look at the documentation. In this case, an attorney is not necessary. “But you have to have people look very hard at those records…[so] that everything that is done is justified in the record,” she said. The other type of letter usually arrives by fax and states that auditors will be on site within a few days. “That means that they have a complaint, either by a patient or more likely by a disgruntled physician or employee,” Ms. Buell noted. Here, the stakes are criminal penalties, and there should be an attorney on site during the visit.

Recovery Audit Contractors (RACs) “are bounty hunters,” she said. They are focused on recovering misspent Medicare funds and are paid a contingency fee of 9%–12% of the amount recovered. However, they are not active in practices because they have enjoyed such success in hospitals. At present, they do automated screening of practices’ Part B payments. “If you fall out of the screen, they ask for the money back and that’s the end,” Ms. Buell said. She cautioned, however, that RACs might start doing complex reviews later this year. And if they do, drugs are likely to be an early focus “because there is so much money involved and they have seen that [in the hospitals].”

Medicaid Integrity Contractors (MICs) review Medicaid claims for inappropriate payments and fraud, using a data-driven approach to identify aberrant billing practices. Unlike RACs, who receive a contingency fee, MICs are paid for their services and receive a quality-related bonus. Their look-back period for medical records varies by state. At present, they target mainly hospitals and, to a lesser extent, skilled nursing facilities, nursing homes, and hospices. Physicians are low on the list of priorities, “but…if you have a heavy Medicaid load, you do have to worry about [it],” Ms. Buell said.

Medicare Administrative Contractors (MACs) process claims for both Part A and Part B services and therefore can review discrepancies between the two sets of claims, revise payments, and increase denials. Some ongoing MAC activities include audits regarding usage of the 99204 and 99205 procedure codes for new patients.

Minimizing the risks

Given this environment, what can oncology practices do to minimize their risk? “Have a compliance [program] and make it a priority,” Ms. Buell recommended, adding that it is also a requirement of healthcare reform. Be sure to fix anything the program identifies, because auditors will take a much stiffer stance if they discover issues that were known but not resolved.

Practices can refer to a set of components that the OIG has set forth as the foundation of an effective compliance and ethics program (www.oig.hhs.gov/authorities/docs/physician.pdf). For example, there should be standard policies and procedures in the practice for things such as documentation, education and training, and updates on Medicare regulations. The enforcement of these policies is also a key element of an effective compliance program, as is a prevention component that anticipates mistakes and prevents them from occurring whenever possible.

The healthcare reform legislation requires that practices report and return Medicare and Medicaid overpayments. “If you find that you have been overpaid, for any reason, even if it’s their mistake, give the money back,” Ms. Buell said, because there is a good chance that auditors will eventually discover it.

Any practice that is concerned about being at risk for whistle-blower incidents should obtain legal help. “If you think there is…someone out there who can hurt you, you need to have your compliance program administered by an attorney.”

Finally, “educate, educate, educate,” she advised, to keep physicians and other practice members current on compliance issues.

What does an oncologist need to know about OIGs, RACs, and ZPICs? Plenty. They are some of the auditors who can make life difficult if a practice is not in compliance with Medicare and Medicaid billing and utilization procedures, Roberta L. Buell said at this journal’s annual Community Oncology Conference in Las Vegas.

The government is financing health¬care reform in part through audits to recover stolen and misused money, she explained. Thus far, it has recovered impressive sums, suggesting that the auditors are here to stay no matter how reform plays out. Anyone who runs a practice could be audited, cautioned Ms. Buell, a principal and coding and reimbursement specialist at onPoint Oncology in Sausalito, California. She discussed some of the key types of auditors and their roles.

Acronyms with a mission

Office of Inspector General auditors (OIGs) are responsible for ensuring appropriate use of Medicare funds. Their activities range from conducting basic audits to arranging arrests if a practice is deemed to have done something criminal.

OIGs will be scrutinizing a host of issues in 2011 and 2012, according to Ms. Buell. One is “place-of-service” errors, whereby a claim indicates a patient was treated in an office, where reimbursement is higher, but treatment actually took place in a hospital or ambulatory surgical center. This can be tricky for oncologists who sell their practices to a hospital but maintain a separate office. When physicians see patients in the office, “they’re…billing Part B. But if they walk across the hall to the infusion center and they see [patients] over there,…their place of service will be the hospital,” she said.

The OIGs will also be taking a close look at evaluation and management (E/M) codes to assess whether the codes accurately reflect the type, setting, and complexity of services provided as well as patient status—new or established. Also within the E/M category, auditors will be on the look out for identical (boilerplate) documentation across patients, sometimes a result of use of electronic medical records.

Error-prone providers, such as those with high numbers of duplicate claims, will catch the auditors’ attention as well. To avoid this, Ms. Buell recommended following up with a phone call when a claim goes unpaid, rather than resubmitting the claim. Medicare incentive payments for use of electronic medical records will also feature in the auditors’ work plan. “People are going to be randomly audited to make sure that they had 90 days of consecutive meaningful use—and it has to be for all patients, not just for Medicare patients,” Ms. Buell said.

Compliance with the Health Insurance Portability and Accountability Act will also be assessed. Some large fines have already been levied because of data-security breaches, so practices need to be especially vigilant about not leaving records around or losing laptops.

The OIGs will also scrutinize a variety of issues related to the Part D prescription drug program, such as inclusion of Part A and B claims with Part D claims. Ms. Buell cited billing practices for erythropoiesis-stimulating agents and pegfilgrastim (Neulasta) as an example: a practice might bill through Part D for Neulasta because it is “under water” on it, but “that is going to come back to haunt [you], because that’s not supposed to happen.”

A related aspect of Part D billing is the duplication of drug claims for hospice patients. “If somebody is in the hospice and is getting a drug through the hospice, but comes to your practice and gets it again, that’s going to be looked at,” she explained.

Zone Program Integrity Contractors (ZPICs) “are the [auditors] you really have to worry about. These are the folks who are looking for fraud.” Their data-analysis program is intended to identify provider billing practices and services that pose the greatest financial risk to the Medicare program, for example, high-volume and high-cost services that are being widely overused. But they also investigate credible whistle-blower (qui tam) complaints.

ZPICs can send a practice two types of letters. One is a request for records within 30 days, which usually means the practice was flagged by the screening program and the auditors want to take a closer look at the documentation. In this case, an attorney is not necessary. “But you have to have people look very hard at those records…[so] that everything that is done is justified in the record,” she said. The other type of letter usually arrives by fax and states that auditors will be on site within a few days. “That means that they have a complaint, either by a patient or more likely by a disgruntled physician or employee,” Ms. Buell noted. Here, the stakes are criminal penalties, and there should be an attorney on site during the visit.

Recovery Audit Contractors (RACs) “are bounty hunters,” she said. They are focused on recovering misspent Medicare funds and are paid a contingency fee of 9%–12% of the amount recovered. However, they are not active in practices because they have enjoyed such success in hospitals. At present, they do automated screening of practices’ Part B payments. “If you fall out of the screen, they ask for the money back and that’s the end,” Ms. Buell said. She cautioned, however, that RACs might start doing complex reviews later this year. And if they do, drugs are likely to be an early focus “because there is so much money involved and they have seen that [in the hospitals].”

Medicaid Integrity Contractors (MICs) review Medicaid claims for inappropriate payments and fraud, using a data-driven approach to identify aberrant billing practices. Unlike RACs, who receive a contingency fee, MICs are paid for their services and receive a quality-related bonus. Their look-back period for medical records varies by state. At present, they target mainly hospitals and, to a lesser extent, skilled nursing facilities, nursing homes, and hospices. Physicians are low on the list of priorities, “but…if you have a heavy Medicaid load, you do have to worry about [it],” Ms. Buell said.

Medicare Administrative Contractors (MACs) process claims for both Part A and Part B services and therefore can review discrepancies between the two sets of claims, revise payments, and increase denials. Some ongoing MAC activities include audits regarding usage of the 99204 and 99205 procedure codes for new patients.

Minimizing the risks

Given this environment, what can oncology practices do to minimize their risk? “Have a compliance [program] and make it a priority,” Ms. Buell recommended, adding that it is also a requirement of healthcare reform. Be sure to fix anything the program identifies, because auditors will take a much stiffer stance if they discover issues that were known but not resolved.

Practices can refer to a set of components that the OIG has set forth as the foundation of an effective compliance and ethics program (www.oig.hhs.gov/authorities/docs/physician.pdf). For example, there should be standard policies and procedures in the practice for things such as documentation, education and training, and updates on Medicare regulations. The enforcement of these policies is also a key element of an effective compliance program, as is a prevention component that anticipates mistakes and prevents them from occurring whenever possible.

The healthcare reform legislation requires that practices report and return Medicare and Medicaid overpayments. “If you find that you have been overpaid, for any reason, even if it’s their mistake, give the money back,” Ms. Buell said, because there is a good chance that auditors will eventually discover it.

Any practice that is concerned about being at risk for whistle-blower incidents should obtain legal help. “If you think there is…someone out there who can hurt you, you need to have your compliance program administered by an attorney.”

Finally, “educate, educate, educate,” she advised, to keep physicians and other practice members current on compliance issues.

Treatment for head and neck cancer is most often a rigorous regimen of combination therapies, producing a multitude of distressing symptoms and side effects. While it is nearly impossible to circumvent the physical and psychosocial insults caused by such treatment, some interventions directed toward educating and supporting patients during active treatment have met with success.^{[1], [2], [3] and [4]} Conversely, other efforts have demonstrated little impact^{[5] and [6]} or have been poorly received,⁷ pointing to the need for effective, acceptable means to provide support during such difficult treatment.

Treatment for head and neck cancer is most often a rigorous regimen of combination therapies, producing a multitude of distressing symptoms and side effects. While it is nearly impossible to circumvent the physical and psychosocial insults caused by such treatment, some interventions directed toward educating and supporting patients during active treatment have met with success.^{[1], [2], [3] and [4]} Conversely, other efforts have demonstrated little impact^{[5] and [6]} or have been poorly received,⁷ pointing to the need for effective, acceptable means to provide support during such difficult treatment.