Head & Neck/Thyroid Cancers

Preservation of saliva production in patients undergoing radiotherapy for head and neck cancer may be improved by use of radiation technologies that spare regions of the salivary gland abundant in stem cells, according to researchers.

By tracking the stem cell marker c-Kit, investigators determined that stem cells were not uniformly distributed throughout the parotid gland, but were most abundant in the major ducts in the central region. In rats, irradiation of the center area of the parotid gland, compared with the exterior, resulted in a greater loss, and progressive loss, of saliva production after 1 year. Tissue morphology indicated clear differences in long-term regenerative capacities of the different regions of the gland (Sci Trans Med. 2015 Sep 16. doi:10.1126/scitranslmed.aac4441).

The findings suggest that irradiation localized to the central region where the major ducts are found may result in gland dysfunction. The radiation dose to this area predicted dysfunction.

©Jana Blaskova/thinkstockphotos.com

Stem cell distribution and parotid gland regeneration studies were done in mice and rats. A retrospective study of 74 patients with head and neck cancer correlated radiotherapy dose by region with salivary gland function.

To further evaluate the effects of radiation to the central gland region, the researchers compared two treatment plans in 22 patients. The first plan used a minimum mean dose to the entire gland, and the second minimized the dose to the critical region. The results indicated the second treatment plan resulted in dose redistribution that spared the stem cell region and was predicted to result in better posttreatment gland function.

Radiotherapy of tumors in the head and neck area often leads to irreversible hyposalivation, which severely compromises quality of life for patients. Whether radiation field optimization will eventually result in less xerostomia, or dry mouth, among patients remains to be determined, and a clinical trial is currently underway.

These findings confirm the importance of stem cells in long-term salivary gland function, according to Peter van Luijk, Ph.D., of the department of radiation oncology, University Medical Center, Groningen, the Netherlands, and his colleagues.

“It also suggests that autologous transductal stem cell transplantation may be a viable treatment strategy in patients where sparing this specific subvolume of the salivary glands is not feasible,” they wrote.

Dr. van Luijk reported having no disclosures.

Preservation of saliva production in patients undergoing radiotherapy for head and neck cancer may be improved by use of radiation technologies that spare regions of the salivary gland abundant in stem cells, according to researchers.

By tracking the stem cell marker c-Kit, investigators determined that stem cells were not uniformly distributed throughout the parotid gland, but were most abundant in the major ducts in the central region. In rats, irradiation of the center area of the parotid gland, compared with the exterior, resulted in a greater loss, and progressive loss, of saliva production after 1 year. Tissue morphology indicated clear differences in long-term regenerative capacities of the different regions of the gland (Sci Trans Med. 2015 Sep 16. doi:10.1126/scitranslmed.aac4441).

The findings suggest that irradiation localized to the central region where the major ducts are found may result in gland dysfunction. The radiation dose to this area predicted dysfunction.

©Jana Blaskova/thinkstockphotos.com

Stem cell distribution and parotid gland regeneration studies were done in mice and rats. A retrospective study of 74 patients with head and neck cancer correlated radiotherapy dose by region with salivary gland function.

To further evaluate the effects of radiation to the central gland region, the researchers compared two treatment plans in 22 patients. The first plan used a minimum mean dose to the entire gland, and the second minimized the dose to the critical region. The results indicated the second treatment plan resulted in dose redistribution that spared the stem cell region and was predicted to result in better posttreatment gland function.

Radiotherapy of tumors in the head and neck area often leads to irreversible hyposalivation, which severely compromises quality of life for patients. Whether radiation field optimization will eventually result in less xerostomia, or dry mouth, among patients remains to be determined, and a clinical trial is currently underway.

These findings confirm the importance of stem cells in long-term salivary gland function, according to Peter van Luijk, Ph.D., of the department of radiation oncology, University Medical Center, Groningen, the Netherlands, and his colleagues.

“It also suggests that autologous transductal stem cell transplantation may be a viable treatment strategy in patients where sparing this specific subvolume of the salivary glands is not feasible,” they wrote.

Dr. van Luijk reported having no disclosures.

Preservation of saliva production in patients undergoing radiotherapy for head and neck cancer may be improved by use of radiation technologies that spare regions of the salivary gland abundant in stem cells, according to researchers.

By tracking the stem cell marker c-Kit, investigators determined that stem cells were not uniformly distributed throughout the parotid gland, but were most abundant in the major ducts in the central region. In rats, irradiation of the center area of the parotid gland, compared with the exterior, resulted in a greater loss, and progressive loss, of saliva production after 1 year. Tissue morphology indicated clear differences in long-term regenerative capacities of the different regions of the gland (Sci Trans Med. 2015 Sep 16. doi:10.1126/scitranslmed.aac4441).

The findings suggest that irradiation localized to the central region where the major ducts are found may result in gland dysfunction. The radiation dose to this area predicted dysfunction.

©Jana Blaskova/thinkstockphotos.com

Stem cell distribution and parotid gland regeneration studies were done in mice and rats. A retrospective study of 74 patients with head and neck cancer correlated radiotherapy dose by region with salivary gland function.

To further evaluate the effects of radiation to the central gland region, the researchers compared two treatment plans in 22 patients. The first plan used a minimum mean dose to the entire gland, and the second minimized the dose to the critical region. The results indicated the second treatment plan resulted in dose redistribution that spared the stem cell region and was predicted to result in better posttreatment gland function.

Radiotherapy of tumors in the head and neck area often leads to irreversible hyposalivation, which severely compromises quality of life for patients. Whether radiation field optimization will eventually result in less xerostomia, or dry mouth, among patients remains to be determined, and a clinical trial is currently underway.

These findings confirm the importance of stem cells in long-term salivary gland function, according to Peter van Luijk, Ph.D., of the department of radiation oncology, University Medical Center, Groningen, the Netherlands, and his colleagues.

“It also suggests that autologous transductal stem cell transplantation may be a viable treatment strategy in patients where sparing this specific subvolume of the salivary glands is not feasible,” they wrote.

Dr. van Luijk reported having no disclosures.

The Journal of Clinical Oncology has published a special series issue on head and neck cancers, with a major focus on squamous cell carcinomas arising from the upper aerodigestive tract mucosa.

“In addition, we also address nasopharyngeal cancer, nonmelanoma cutaneous head and neck cancer, and squamous carcinoma of the neck of unknown primary origin,” writes Dr. Danny Rischin of the Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia, and associates in an overview for the issue.

©xrender/Thinkstock.com

The 16 articles in the issue provide the reader with an overview of current evidence and management, recent developments, and insights into future directions, they write.

It was only recently that human papillomavirus was identified as a cause of oropharyngeal cancer and that HPV-associated oropharyngeal cancer was found to have its own unique biologic signature. Three articles are included in the series that review the rapidly evolving understanding of HPV-related head and neck cancers.

Find the overview and series of 16 articles in the Sept. 7 issue of the Journal of Clinical Oncology.

[email protected]

The Journal of Clinical Oncology has published a special series issue on head and neck cancers, with a major focus on squamous cell carcinomas arising from the upper aerodigestive tract mucosa.

“In addition, we also address nasopharyngeal cancer, nonmelanoma cutaneous head and neck cancer, and squamous carcinoma of the neck of unknown primary origin,” writes Dr. Danny Rischin of the Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia, and associates in an overview for the issue.

©xrender/Thinkstock.com

The 16 articles in the issue provide the reader with an overview of current evidence and management, recent developments, and insights into future directions, they write.

It was only recently that human papillomavirus was identified as a cause of oropharyngeal cancer and that HPV-associated oropharyngeal cancer was found to have its own unique biologic signature. Three articles are included in the series that review the rapidly evolving understanding of HPV-related head and neck cancers.

Find the overview and series of 16 articles in the Sept. 7 issue of the Journal of Clinical Oncology.

[email protected]

The Journal of Clinical Oncology has published a special series issue on head and neck cancers, with a major focus on squamous cell carcinomas arising from the upper aerodigestive tract mucosa.

“In addition, we also address nasopharyngeal cancer, nonmelanoma cutaneous head and neck cancer, and squamous carcinoma of the neck of unknown primary origin,” writes Dr. Danny Rischin of the Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia, and associates in an overview for the issue.

©xrender/Thinkstock.com

The 16 articles in the issue provide the reader with an overview of current evidence and management, recent developments, and insights into future directions, they write.

It was only recently that human papillomavirus was identified as a cause of oropharyngeal cancer and that HPV-associated oropharyngeal cancer was found to have its own unique biologic signature. Three articles are included in the series that review the rapidly evolving understanding of HPV-related head and neck cancers.

Find the overview and series of 16 articles in the Sept. 7 issue of the Journal of Clinical Oncology.

[email protected]

Thyroid cancer is the ninth most common malignancy in the U.S. At the time of diagnosis, thyroid cancer is mostly confined to the thyroid gland and regional lymph nodes. However, around 4% of patients with thyroid cancer present with metastatic disease. When compared with localized and regional thyroid cancer, 5-year survival rates for metastatic thyroid cancer are significantly worse (99.9%, 97.6%, and 54.7%, respectively).¹ Treatment options for metastatic thyroid cancer are limited and largely depend on the pathology and the type of thyroid cancer.

Thyroid cancer can be divided into differentiated, medullary, and anaplastic subtypes based on pathology. The treatment for metastatic differentiated thyroid cancer (DTC) consists of radioactive iodine therapy, thyroid-stimulating hormone (TSH) suppression (thyroxine hormone) therapy, and external beam radiotherapy. Systemic therapy is considered in patients with metastatic DTC who progress despite the above treatment modalities. In the case of metastatic medullary thyroid cancer (MTC), patients who are not candidates for surgery or radiation are considered for systemic therapy, because MTC does not respond to radioactive iodine or TSH suppressive therapy. On the other hand, metastatic anaplastic thyroid cancer is a very aggressive subtype with no effective therapy available to date. Palliation of symptoms is the main goal for these patients, which can be achieved by loco-regional resection and palliative irradiation.^2,3

This review focuses on the newer treatment options for metastatic DTC and MTC that are based on inhibition of cellular kinases.

Differentiated Thyroid Cancer

Differentiated thyroid cancer is the most common histologic type of thyroid cancer, accounting for 95% of all thyroid cancers and consists of papillary, follicular, and poorly differentiated thyroid cancer.^2,3 Surgery is the treatment of choice for DTC. Based on tumor size and its local extension in the neck, treatment options include unilateral lobectomy and isthmectomy, total thyroidectomy, central neck dissection, and more extensive resection.^2,3 After surgery, radioactive iodine is recommended in patients with known metastatic disease; locally invasive tumor, regardless of size; or primary tumor > 4 cm, in the absence of other high-risk features.2 This should be followed by TSH suppressive hormone therapy.²

About 7% to 23% of patients with DTC develop distant metastases.⁴ Two-thirds of these patients become refractory to radioactive iodine.⁵ Prognosis remains poor in these patients, with a 10-year survival rate from the time detection of metastasis of only 10%.^5-7 Treatment options are limited. However, recently the understanding of cell biology in terms of key signaling pathways called kinases has been elucidated. The kinases that can stabilize progressive metastatic disease seem to be attractive therapeutic targets in treating patients whose disease no longer responds to radioiodine and TSH suppressive hormone therapy.

Papillary thyroid cancers frequently carry gene mutations and rearrangements that lead to activation of the mitogen-activated protein kinase (MAPK), which promotes cell division. The sequential components leading to activation of MAPK include rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS.8,9 Similarly, overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS genes, is found in follicular adenomas, follicular cancers, and occasionally papillary cancers.^10-14 Increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) might have a role in thyroid carcinoma as well.¹⁵

These kinases (the serine kinase BRAF and tyrosine kinases RET and RAS, and the contributory roles of tyrosine kinases in growth factor receptors such as the VEGFR) stimulate tumor proliferation, angiogenesis, invasion, metastasis, and inhibit tumor cell apoptosis. Kinase inhibitors target these signaling kinases, affecting tumor cell biology and its microenvironment.^16,17

A wide variety of multitargeted kinase inhibitors (MKIs) have entered clinical trials for patients with advanced or progressive metastatic thyroid cancers. Two such agents, sorafenib and lenvatinib, are approved by the FDA for use in selected patients with refractory metastatic DTC, whereas many other drugs remain investigational for this disease. In phase 2 and 3 trials, most of the treatment responses for MKIs were partial. Complete responses were rare, and no study has reported a complete analysis of overall survival (OS) outcomes. Results from some new randomized trials indicate an improvement in progression-free survival (PFS) compared with placebo, and additional trials are underway.

Sorafenib

Sorafenib was approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.¹⁸ Sorafenib is an oral, small molecule MKI. It works on VEGFRs 1, 2, and 3; platelet-derived growth factor receptor (PDGFR); common RET/PTC subtypes; KIT; and less potently, BRAF.19 The recommended dose is 400 mg orally twice a day.

In April 2014, Brose and colleagues published the phase 3 DECISION study on sorafenib.²⁰ It was a multicenter, randomized, double-blinded, placebo-controlled trial of 417 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the previous 14 months.²⁰ The results of the trial were promising. The median PFS was 5 months longer in the sorafenib group (10.8 mo) than in the placebo group (5.8 mo; hazard ratio [HR], 0.59; 95% conidence interval [CI], 0.45-0.76; P < .0001). The primary endpoint of the trial was PFS, and crossover from placebo to sorafenib was permitted upon progression. Overall survival did not differ significantly between the treatment groups (placebo vs sorafenib) at the time of the primary analysis data cutoff. However, OS results may have been confounded by postprogression crossover from placebo to open-label sorafenib by the majority of placebo patients.

In subgroup analysis, patients with BRAF and RAS mutations and wild-type BRAF and RAS subgroups had a significant increase in median PFS in the sorafenib treatment group compared with the placebo group (Table 1).²⁰

Adverse events (AEs) occurred in 98.6% of patients receiving sorafenib during the double-blind period and in 87.6% of patients receiving placebo. Most AEs were grade 1 or 2. The most common AEs were hand-foot-skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Toxicities led to dose modification in 78% of patients and permanent discontinuation of therapy in 19%.²⁰ Like other BRAF inhibitors, sorafenib has been associated with an increased incidence of cutaneous squamous cell carcinomas (5%), keratoacanthomas, and other premalignant actinic lesions.²¹

Lenvatinib

In February 2015, lenvatinib was approved for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.²² Lenvatinib is a MKI of VEGFRs 1, 2, and 3; fibroblast growth factor receptors 1 through 4; PDGFR-α; RET, and KIT.^23,24 The recommended dose is 24 mg orally once daily.

Schlumberger and colleagues published results from the SELECT trial, a randomized, double-blinded, multicenter phase 3 study involving 392 patients with progressive thyroid cancer that was refractory to iodine-131.²⁵ A total of 261 patients received lenvatinib, and 131 patients received a placebo. Upon disease progression, patients in the placebo group were allowed to receive open-label lenvatinib. The study’s primary endpoint was PFS. Secondary endpoints were the response rate (RR), OS, and safety. The median PFS was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (HR, 0.21; 99% CI, 0.14-0.31; P < .001). The RR was 64.8% in the lenvatinib group (4 complete and 165 partial responses) and 1.5% in the placebo group (P < .001). There was no significant difference in OS between the 2 groups (HR for death, 0.73; 95% CI, 0.50-1.07; P = .10). This difference became larger when a potential crossover bias was considered (rank-preserving structural failure time model; HR, 0.62; 95% CI, 0.40-1.00; P = .05).²⁵

In a subgroup analysis, median PFS was about 14 months in the absence of prior anti-VEGFR therapy and 11 months of prior therapy. The treatmentrelated AEs were 97.3% in the lenvatinib group, and 75.9% were grade 3 or higher. Common treatmentrelated AEs of any grade in the lenvatinib group included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The study drug had to be discontinued because of AEs in 14% of patients who received lenvatinib and 2% of patients who received placebo. In the lenvatinib group, 2.3% patients had treatment-related fatal events (6 patients).²⁵

Summary

Patients with DTC who progress after radioactive iodine therapy, TSH suppressive therapy, and external beam radiotherapy should be considered for systemic therapy. Systemic therapy consists of MKIs, which can stabilize progressive metastatic disease. These newer drugs have significant toxicities. Therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. Patients treated with systemic agents should have a good baseline performance status, such as being ambulatory at least 50% (Eastern Cooperative Oncology Group performance score of 2) of the day to tolerate these treatments.

Patients who have disease progression or are unable to tolerate sorafenib and lenvatinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include vandetinib, pazopanib, and sunitinib, which finished phase 2 trials and showed some partial responses.^26-30 If the patients are unable to tolerate MKIs, they can try doxorubicin-based conventional chemotherapy regimens.³¹

Medullary Thyroid Cancer

Medullary thyroid cancer is a neuroendocrine tumor arising from the thyroid parafollicular cells, accounting for about 4% of thyroid carcinomas, most of which are sporadic. However, some are familial as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes, which are transmitted in an autosomal dominant fashion.^32,33 Similar to DTC, the primary treatment option is surgery. Medullary thyroid cancer can be cured only by complete resection of the thyroid tumor and any local and regional metastases. Compared with DTC, metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither concentrates iodine nor is TSH dependent.^34,35

The 10-year OS rate in MTC is ≤ 40% in patients with locally advanced or metastatic disease.^32,36,37 In hereditary MTC, germline mutations in the c-ret proto-oncogene occur in virtually all patients. In sporadic MTC, 85% of patients have the M918T mutation, and somatic c-ret mutations are seen in about 50% of patients.^38-42

Similar to DTC, due to the presence of mutations involving RET receptor tyrosine kinase, molecular targeted therapeutics with activity against RET demonstrate a potential therapeutic target in MTC.^43-45 Other signaling pathways likely to contribute to the growth and invasiveness of MTC include VEGFR-dependent tumor angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumor cell proliferation.⁴⁶

In 2011 and 2012, the FDA approved tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib for metastatic MTC. Similar to treatment for DTC, systemic therapy is mainly based on targeted therapies. Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy.

Vandetanib

Vandetanib is approved for unresectable, locally advanced or metastatic sporadic or hereditary MTC.47 The daily recommended dose is 300 mg/d. It is an oral MKI that targets VEGFR, RET/PTC, and the EGFR.48

The ZETA trial was an international randomized phase 3 trial involving patients with unresectable locally advanced or metastatic sporadic or hereditary MTC.⁴⁸ In a ZETA trial study by Wells Jr and colleagues, patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. After objective disease progression, patients could elect to receive openlabel vandetanib. The primary endpoint was PFS, determined by independent central Response Evaluation Criteria in Solid Tumors assessments.

A total of 331 patients were randomly assigned to receive vandetanib (231 patients) or placebo (100 patients). At data cutoff, with median follow-up of 24 months, PFS was significantly prolonged in patients randomly assigned to vandetanib vs placebo (30.5 mo vs 19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR was significantly higher in the vandetanib group (45% vs 13%). The presence of a somatic RET M918T mutation predicted an improved PFS.

Common AEs (any grade) noted with vandetanib vs placebo include diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%). Torsades de pointes and sudden death were reported in patients receiving vandetanib. Data on OS were immature at data cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival analysis will take place when 50% of the patients have died.⁴⁸

Vandetanib is currently approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about serious heart-related risks. Electrocardiograms and serum potassium, calcium, magnesium, and TSH should be taken at 2 to 4 weeks and 8 to 12 weeks after starting treatment and every 3 months after that. Patients with diarrhea may require more frequent monitoring.

Cabozantinib

In 2012, the FDA approved cabozantinib for the treatment of progressive, metastatic MTC.⁴⁹ It is an oral, small molecule TKI that targets VEGFRs 1 and 2, MET, and RET. The inhibitory activity against MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC.⁵⁰ The daily recommended dose is 140 mg/d. A phase 3 randomized EXAM trial in patients with progressive, metastatic, or unresectable locally advanced MTC.⁵¹ Three hundred thirty patients were randomly assigned to receive either cabozantinib 140 mg or placebo once daily. Progressionfree survival was improved with cabozantinib compared with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI, 0.19-0.40). Partial responses were observed in 27% vs 0% in placebo. A planned interim analysis of OS was conducted, including 96 (44%) of the 217 patient deaths required for the final analysis, with no statistically significant difference observed between the treatment arms (HR, 0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to continue until at least 217 deaths have been observed.

There was markedly improved PFS in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS mutations (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10).⁵¹

The most common AEs, occurring in ≥ 25% of patients, were diarrhea, stomatitis, hand and foot syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant AEs also included fistula formation and osteonecrosis of the jaw.

Summary

Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy. Though not curative, TKIs can only stabilize disease progression. Initiation of TKIs should be considered in rapidly progressive disease, because these drugs are associated with considerable AEs affecting the quality of life (QOL).

Patients who progressed or were unable to tolerate vandetanib or cabozantinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include pazopanib, sunitinib, and sorafenib, which finished phase 2 trials and showed some partial responses.^29,52-57 If patients are unable to tolerate MKIs, they can try conventional chemotherapy consisting of dacarbazine with other agents or doxorubin.^58-60

Conclusions

Molecular targeted therapy is an emerging treatment option for patients with metastatic thyroid cancer (Table 2). The authors suggest that such patients participate in clinical trials in the hope of developing more effective and tolerable drugs and recommend oral TKIs for patients with rapidly progressive disease who cannot participate in a clinical trial. For patients who cannot tolerate or fail one TKI, the authors recommend trying other TKIs before initiating cytotoxic chemotherapy.

Before initiation of treatment for metastatic disease, an important factor to consider is the pace of disease progression. Patients who are asymptomatic and have the very indolent disease may postpone kinase inhibitor therapy until they become rapidly progressive or symptomatic, because the AEs of treatment will adversely affect the patient’s QOL. In patients with symptomatic and rapidly progressive disease, initiation of treatment with kinase inhibitor therapy can lead to stabilization of disease, although at the cost of some AEs. More structured clinical trials are needed, along with an evaluation of newer molecular targets for the management of this progressive metastatic disease with a dismal prognosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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Thyroid cancer is the ninth most common malignancy in the U.S. At the time of diagnosis, thyroid cancer is mostly confined to the thyroid gland and regional lymph nodes. However, around 4% of patients with thyroid cancer present with metastatic disease. When compared with localized and regional thyroid cancer, 5-year survival rates for metastatic thyroid cancer are significantly worse (99.9%, 97.6%, and 54.7%, respectively).¹ Treatment options for metastatic thyroid cancer are limited and largely depend on the pathology and the type of thyroid cancer.

Thyroid cancer can be divided into differentiated, medullary, and anaplastic subtypes based on pathology. The treatment for metastatic differentiated thyroid cancer (DTC) consists of radioactive iodine therapy, thyroid-stimulating hormone (TSH) suppression (thyroxine hormone) therapy, and external beam radiotherapy. Systemic therapy is considered in patients with metastatic DTC who progress despite the above treatment modalities. In the case of metastatic medullary thyroid cancer (MTC), patients who are not candidates for surgery or radiation are considered for systemic therapy, because MTC does not respond to radioactive iodine or TSH suppressive therapy. On the other hand, metastatic anaplastic thyroid cancer is a very aggressive subtype with no effective therapy available to date. Palliation of symptoms is the main goal for these patients, which can be achieved by loco-regional resection and palliative irradiation.^2,3

This review focuses on the newer treatment options for metastatic DTC and MTC that are based on inhibition of cellular kinases.

Differentiated Thyroid Cancer

Differentiated thyroid cancer is the most common histologic type of thyroid cancer, accounting for 95% of all thyroid cancers and consists of papillary, follicular, and poorly differentiated thyroid cancer.^2,3 Surgery is the treatment of choice for DTC. Based on tumor size and its local extension in the neck, treatment options include unilateral lobectomy and isthmectomy, total thyroidectomy, central neck dissection, and more extensive resection.^2,3 After surgery, radioactive iodine is recommended in patients with known metastatic disease; locally invasive tumor, regardless of size; or primary tumor > 4 cm, in the absence of other high-risk features.2 This should be followed by TSH suppressive hormone therapy.²

About 7% to 23% of patients with DTC develop distant metastases.⁴ Two-thirds of these patients become refractory to radioactive iodine.⁵ Prognosis remains poor in these patients, with a 10-year survival rate from the time detection of metastasis of only 10%.^5-7 Treatment options are limited. However, recently the understanding of cell biology in terms of key signaling pathways called kinases has been elucidated. The kinases that can stabilize progressive metastatic disease seem to be attractive therapeutic targets in treating patients whose disease no longer responds to radioiodine and TSH suppressive hormone therapy.

Papillary thyroid cancers frequently carry gene mutations and rearrangements that lead to activation of the mitogen-activated protein kinase (MAPK), which promotes cell division. The sequential components leading to activation of MAPK include rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS.8,9 Similarly, overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS genes, is found in follicular adenomas, follicular cancers, and occasionally papillary cancers.^10-14 Increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) might have a role in thyroid carcinoma as well.¹⁵

These kinases (the serine kinase BRAF and tyrosine kinases RET and RAS, and the contributory roles of tyrosine kinases in growth factor receptors such as the VEGFR) stimulate tumor proliferation, angiogenesis, invasion, metastasis, and inhibit tumor cell apoptosis. Kinase inhibitors target these signaling kinases, affecting tumor cell biology and its microenvironment.^16,17

A wide variety of multitargeted kinase inhibitors (MKIs) have entered clinical trials for patients with advanced or progressive metastatic thyroid cancers. Two such agents, sorafenib and lenvatinib, are approved by the FDA for use in selected patients with refractory metastatic DTC, whereas many other drugs remain investigational for this disease. In phase 2 and 3 trials, most of the treatment responses for MKIs were partial. Complete responses were rare, and no study has reported a complete analysis of overall survival (OS) outcomes. Results from some new randomized trials indicate an improvement in progression-free survival (PFS) compared with placebo, and additional trials are underway.

Sorafenib

Sorafenib was approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.¹⁸ Sorafenib is an oral, small molecule MKI. It works on VEGFRs 1, 2, and 3; platelet-derived growth factor receptor (PDGFR); common RET/PTC subtypes; KIT; and less potently, BRAF.19 The recommended dose is 400 mg orally twice a day.

In April 2014, Brose and colleagues published the phase 3 DECISION study on sorafenib.²⁰ It was a multicenter, randomized, double-blinded, placebo-controlled trial of 417 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the previous 14 months.²⁰ The results of the trial were promising. The median PFS was 5 months longer in the sorafenib group (10.8 mo) than in the placebo group (5.8 mo; hazard ratio [HR], 0.59; 95% conidence interval [CI], 0.45-0.76; P < .0001). The primary endpoint of the trial was PFS, and crossover from placebo to sorafenib was permitted upon progression. Overall survival did not differ significantly between the treatment groups (placebo vs sorafenib) at the time of the primary analysis data cutoff. However, OS results may have been confounded by postprogression crossover from placebo to open-label sorafenib by the majority of placebo patients.

In subgroup analysis, patients with BRAF and RAS mutations and wild-type BRAF and RAS subgroups had a significant increase in median PFS in the sorafenib treatment group compared with the placebo group (Table 1).²⁰

Adverse events (AEs) occurred in 98.6% of patients receiving sorafenib during the double-blind period and in 87.6% of patients receiving placebo. Most AEs were grade 1 or 2. The most common AEs were hand-foot-skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Toxicities led to dose modification in 78% of patients and permanent discontinuation of therapy in 19%.²⁰ Like other BRAF inhibitors, sorafenib has been associated with an increased incidence of cutaneous squamous cell carcinomas (5%), keratoacanthomas, and other premalignant actinic lesions.²¹

Lenvatinib

In February 2015, lenvatinib was approved for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.²² Lenvatinib is a MKI of VEGFRs 1, 2, and 3; fibroblast growth factor receptors 1 through 4; PDGFR-α; RET, and KIT.^23,24 The recommended dose is 24 mg orally once daily.

Schlumberger and colleagues published results from the SELECT trial, a randomized, double-blinded, multicenter phase 3 study involving 392 patients with progressive thyroid cancer that was refractory to iodine-131.²⁵ A total of 261 patients received lenvatinib, and 131 patients received a placebo. Upon disease progression, patients in the placebo group were allowed to receive open-label lenvatinib. The study’s primary endpoint was PFS. Secondary endpoints were the response rate (RR), OS, and safety. The median PFS was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (HR, 0.21; 99% CI, 0.14-0.31; P < .001). The RR was 64.8% in the lenvatinib group (4 complete and 165 partial responses) and 1.5% in the placebo group (P < .001). There was no significant difference in OS between the 2 groups (HR for death, 0.73; 95% CI, 0.50-1.07; P = .10). This difference became larger when a potential crossover bias was considered (rank-preserving structural failure time model; HR, 0.62; 95% CI, 0.40-1.00; P = .05).²⁵

In a subgroup analysis, median PFS was about 14 months in the absence of prior anti-VEGFR therapy and 11 months of prior therapy. The treatmentrelated AEs were 97.3% in the lenvatinib group, and 75.9% were grade 3 or higher. Common treatmentrelated AEs of any grade in the lenvatinib group included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The study drug had to be discontinued because of AEs in 14% of patients who received lenvatinib and 2% of patients who received placebo. In the lenvatinib group, 2.3% patients had treatment-related fatal events (6 patients).²⁵

Summary

Patients with DTC who progress after radioactive iodine therapy, TSH suppressive therapy, and external beam radiotherapy should be considered for systemic therapy. Systemic therapy consists of MKIs, which can stabilize progressive metastatic disease. These newer drugs have significant toxicities. Therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. Patients treated with systemic agents should have a good baseline performance status, such as being ambulatory at least 50% (Eastern Cooperative Oncology Group performance score of 2) of the day to tolerate these treatments.

Patients who have disease progression or are unable to tolerate sorafenib and lenvatinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include vandetinib, pazopanib, and sunitinib, which finished phase 2 trials and showed some partial responses.^26-30 If the patients are unable to tolerate MKIs, they can try doxorubicin-based conventional chemotherapy regimens.³¹

Medullary Thyroid Cancer

Medullary thyroid cancer is a neuroendocrine tumor arising from the thyroid parafollicular cells, accounting for about 4% of thyroid carcinomas, most of which are sporadic. However, some are familial as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes, which are transmitted in an autosomal dominant fashion.^32,33 Similar to DTC, the primary treatment option is surgery. Medullary thyroid cancer can be cured only by complete resection of the thyroid tumor and any local and regional metastases. Compared with DTC, metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither concentrates iodine nor is TSH dependent.^34,35

The 10-year OS rate in MTC is ≤ 40% in patients with locally advanced or metastatic disease.^32,36,37 In hereditary MTC, germline mutations in the c-ret proto-oncogene occur in virtually all patients. In sporadic MTC, 85% of patients have the M918T mutation, and somatic c-ret mutations are seen in about 50% of patients.^38-42

Similar to DTC, due to the presence of mutations involving RET receptor tyrosine kinase, molecular targeted therapeutics with activity against RET demonstrate a potential therapeutic target in MTC.^43-45 Other signaling pathways likely to contribute to the growth and invasiveness of MTC include VEGFR-dependent tumor angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumor cell proliferation.⁴⁶

In 2011 and 2012, the FDA approved tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib for metastatic MTC. Similar to treatment for DTC, systemic therapy is mainly based on targeted therapies. Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy.

Vandetanib

Vandetanib is approved for unresectable, locally advanced or metastatic sporadic or hereditary MTC.47 The daily recommended dose is 300 mg/d. It is an oral MKI that targets VEGFR, RET/PTC, and the EGFR.48

The ZETA trial was an international randomized phase 3 trial involving patients with unresectable locally advanced or metastatic sporadic or hereditary MTC.⁴⁸ In a ZETA trial study by Wells Jr and colleagues, patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. After objective disease progression, patients could elect to receive openlabel vandetanib. The primary endpoint was PFS, determined by independent central Response Evaluation Criteria in Solid Tumors assessments.

A total of 331 patients were randomly assigned to receive vandetanib (231 patients) or placebo (100 patients). At data cutoff, with median follow-up of 24 months, PFS was significantly prolonged in patients randomly assigned to vandetanib vs placebo (30.5 mo vs 19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR was significantly higher in the vandetanib group (45% vs 13%). The presence of a somatic RET M918T mutation predicted an improved PFS.

Common AEs (any grade) noted with vandetanib vs placebo include diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%). Torsades de pointes and sudden death were reported in patients receiving vandetanib. Data on OS were immature at data cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival analysis will take place when 50% of the patients have died.⁴⁸

Vandetanib is currently approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about serious heart-related risks. Electrocardiograms and serum potassium, calcium, magnesium, and TSH should be taken at 2 to 4 weeks and 8 to 12 weeks after starting treatment and every 3 months after that. Patients with diarrhea may require more frequent monitoring.

Cabozantinib

In 2012, the FDA approved cabozantinib for the treatment of progressive, metastatic MTC.⁴⁹ It is an oral, small molecule TKI that targets VEGFRs 1 and 2, MET, and RET. The inhibitory activity against MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC.⁵⁰ The daily recommended dose is 140 mg/d. A phase 3 randomized EXAM trial in patients with progressive, metastatic, or unresectable locally advanced MTC.⁵¹ Three hundred thirty patients were randomly assigned to receive either cabozantinib 140 mg or placebo once daily. Progressionfree survival was improved with cabozantinib compared with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI, 0.19-0.40). Partial responses were observed in 27% vs 0% in placebo. A planned interim analysis of OS was conducted, including 96 (44%) of the 217 patient deaths required for the final analysis, with no statistically significant difference observed between the treatment arms (HR, 0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to continue until at least 217 deaths have been observed.

There was markedly improved PFS in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS mutations (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10).⁵¹

The most common AEs, occurring in ≥ 25% of patients, were diarrhea, stomatitis, hand and foot syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant AEs also included fistula formation and osteonecrosis of the jaw.

Summary

Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy. Though not curative, TKIs can only stabilize disease progression. Initiation of TKIs should be considered in rapidly progressive disease, because these drugs are associated with considerable AEs affecting the quality of life (QOL).

Patients who progressed or were unable to tolerate vandetanib or cabozantinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include pazopanib, sunitinib, and sorafenib, which finished phase 2 trials and showed some partial responses.^29,52-57 If patients are unable to tolerate MKIs, they can try conventional chemotherapy consisting of dacarbazine with other agents or doxorubin.^58-60

Conclusions

Molecular targeted therapy is an emerging treatment option for patients with metastatic thyroid cancer (Table 2). The authors suggest that such patients participate in clinical trials in the hope of developing more effective and tolerable drugs and recommend oral TKIs for patients with rapidly progressive disease who cannot participate in a clinical trial. For patients who cannot tolerate or fail one TKI, the authors recommend trying other TKIs before initiating cytotoxic chemotherapy.

Before initiation of treatment for metastatic disease, an important factor to consider is the pace of disease progression. Patients who are asymptomatic and have the very indolent disease may postpone kinase inhibitor therapy until they become rapidly progressive or symptomatic, because the AEs of treatment will adversely affect the patient’s QOL. In patients with symptomatic and rapidly progressive disease, initiation of treatment with kinase inhibitor therapy can lead to stabilization of disease, although at the cost of some AEs. More structured clinical trials are needed, along with an evaluation of newer molecular targets for the management of this progressive metastatic disease with a dismal prognosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Thyroid cancer is the ninth most common malignancy in the U.S. At the time of diagnosis, thyroid cancer is mostly confined to the thyroid gland and regional lymph nodes. However, around 4% of patients with thyroid cancer present with metastatic disease. When compared with localized and regional thyroid cancer, 5-year survival rates for metastatic thyroid cancer are significantly worse (99.9%, 97.6%, and 54.7%, respectively).¹ Treatment options for metastatic thyroid cancer are limited and largely depend on the pathology and the type of thyroid cancer.

Thyroid cancer can be divided into differentiated, medullary, and anaplastic subtypes based on pathology. The treatment for metastatic differentiated thyroid cancer (DTC) consists of radioactive iodine therapy, thyroid-stimulating hormone (TSH) suppression (thyroxine hormone) therapy, and external beam radiotherapy. Systemic therapy is considered in patients with metastatic DTC who progress despite the above treatment modalities. In the case of metastatic medullary thyroid cancer (MTC), patients who are not candidates for surgery or radiation are considered for systemic therapy, because MTC does not respond to radioactive iodine or TSH suppressive therapy. On the other hand, metastatic anaplastic thyroid cancer is a very aggressive subtype with no effective therapy available to date. Palliation of symptoms is the main goal for these patients, which can be achieved by loco-regional resection and palliative irradiation.^2,3

This review focuses on the newer treatment options for metastatic DTC and MTC that are based on inhibition of cellular kinases.

Differentiated Thyroid Cancer

Differentiated thyroid cancer is the most common histologic type of thyroid cancer, accounting for 95% of all thyroid cancers and consists of papillary, follicular, and poorly differentiated thyroid cancer.^2,3 Surgery is the treatment of choice for DTC. Based on tumor size and its local extension in the neck, treatment options include unilateral lobectomy and isthmectomy, total thyroidectomy, central neck dissection, and more extensive resection.^2,3 After surgery, radioactive iodine is recommended in patients with known metastatic disease; locally invasive tumor, regardless of size; or primary tumor > 4 cm, in the absence of other high-risk features.2 This should be followed by TSH suppressive hormone therapy.²

About 7% to 23% of patients with DTC develop distant metastases.⁴ Two-thirds of these patients become refractory to radioactive iodine.⁵ Prognosis remains poor in these patients, with a 10-year survival rate from the time detection of metastasis of only 10%.^5-7 Treatment options are limited. However, recently the understanding of cell biology in terms of key signaling pathways called kinases has been elucidated. The kinases that can stabilize progressive metastatic disease seem to be attractive therapeutic targets in treating patients whose disease no longer responds to radioiodine and TSH suppressive hormone therapy.

Papillary thyroid cancers frequently carry gene mutations and rearrangements that lead to activation of the mitogen-activated protein kinase (MAPK), which promotes cell division. The sequential components leading to activation of MAPK include rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS.8,9 Similarly, overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS genes, is found in follicular adenomas, follicular cancers, and occasionally papillary cancers.^10-14 Increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) might have a role in thyroid carcinoma as well.¹⁵

These kinases (the serine kinase BRAF and tyrosine kinases RET and RAS, and the contributory roles of tyrosine kinases in growth factor receptors such as the VEGFR) stimulate tumor proliferation, angiogenesis, invasion, metastasis, and inhibit tumor cell apoptosis. Kinase inhibitors target these signaling kinases, affecting tumor cell biology and its microenvironment.^16,17

A wide variety of multitargeted kinase inhibitors (MKIs) have entered clinical trials for patients with advanced or progressive metastatic thyroid cancers. Two such agents, sorafenib and lenvatinib, are approved by the FDA for use in selected patients with refractory metastatic DTC, whereas many other drugs remain investigational for this disease. In phase 2 and 3 trials, most of the treatment responses for MKIs were partial. Complete responses were rare, and no study has reported a complete analysis of overall survival (OS) outcomes. Results from some new randomized trials indicate an improvement in progression-free survival (PFS) compared with placebo, and additional trials are underway.

Sorafenib

Sorafenib was approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.¹⁸ Sorafenib is an oral, small molecule MKI. It works on VEGFRs 1, 2, and 3; platelet-derived growth factor receptor (PDGFR); common RET/PTC subtypes; KIT; and less potently, BRAF.19 The recommended dose is 400 mg orally twice a day.

In April 2014, Brose and colleagues published the phase 3 DECISION study on sorafenib.²⁰ It was a multicenter, randomized, double-blinded, placebo-controlled trial of 417 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the previous 14 months.²⁰ The results of the trial were promising. The median PFS was 5 months longer in the sorafenib group (10.8 mo) than in the placebo group (5.8 mo; hazard ratio [HR], 0.59; 95% conidence interval [CI], 0.45-0.76; P < .0001). The primary endpoint of the trial was PFS, and crossover from placebo to sorafenib was permitted upon progression. Overall survival did not differ significantly between the treatment groups (placebo vs sorafenib) at the time of the primary analysis data cutoff. However, OS results may have been confounded by postprogression crossover from placebo to open-label sorafenib by the majority of placebo patients.

In subgroup analysis, patients with BRAF and RAS mutations and wild-type BRAF and RAS subgroups had a significant increase in median PFS in the sorafenib treatment group compared with the placebo group (Table 1).²⁰

Adverse events (AEs) occurred in 98.6% of patients receiving sorafenib during the double-blind period and in 87.6% of patients receiving placebo. Most AEs were grade 1 or 2. The most common AEs were hand-foot-skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Toxicities led to dose modification in 78% of patients and permanent discontinuation of therapy in 19%.²⁰ Like other BRAF inhibitors, sorafenib has been associated with an increased incidence of cutaneous squamous cell carcinomas (5%), keratoacanthomas, and other premalignant actinic lesions.²¹

Lenvatinib

In February 2015, lenvatinib was approved for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment.²² Lenvatinib is a MKI of VEGFRs 1, 2, and 3; fibroblast growth factor receptors 1 through 4; PDGFR-α; RET, and KIT.^23,24 The recommended dose is 24 mg orally once daily.

Schlumberger and colleagues published results from the SELECT trial, a randomized, double-blinded, multicenter phase 3 study involving 392 patients with progressive thyroid cancer that was refractory to iodine-131.²⁵ A total of 261 patients received lenvatinib, and 131 patients received a placebo. Upon disease progression, patients in the placebo group were allowed to receive open-label lenvatinib. The study’s primary endpoint was PFS. Secondary endpoints were the response rate (RR), OS, and safety. The median PFS was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (HR, 0.21; 99% CI, 0.14-0.31; P < .001). The RR was 64.8% in the lenvatinib group (4 complete and 165 partial responses) and 1.5% in the placebo group (P < .001). There was no significant difference in OS between the 2 groups (HR for death, 0.73; 95% CI, 0.50-1.07; P = .10). This difference became larger when a potential crossover bias was considered (rank-preserving structural failure time model; HR, 0.62; 95% CI, 0.40-1.00; P = .05).²⁵

In a subgroup analysis, median PFS was about 14 months in the absence of prior anti-VEGFR therapy and 11 months of prior therapy. The treatmentrelated AEs were 97.3% in the lenvatinib group, and 75.9% were grade 3 or higher. Common treatmentrelated AEs of any grade in the lenvatinib group included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The study drug had to be discontinued because of AEs in 14% of patients who received lenvatinib and 2% of patients who received placebo. In the lenvatinib group, 2.3% patients had treatment-related fatal events (6 patients).²⁵

Summary

Patients with DTC who progress after radioactive iodine therapy, TSH suppressive therapy, and external beam radiotherapy should be considered for systemic therapy. Systemic therapy consists of MKIs, which can stabilize progressive metastatic disease. These newer drugs have significant toxicities. Therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. Patients treated with systemic agents should have a good baseline performance status, such as being ambulatory at least 50% (Eastern Cooperative Oncology Group performance score of 2) of the day to tolerate these treatments.

Patients who have disease progression or are unable to tolerate sorafenib and lenvatinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include vandetinib, pazopanib, and sunitinib, which finished phase 2 trials and showed some partial responses.^26-30 If the patients are unable to tolerate MKIs, they can try doxorubicin-based conventional chemotherapy regimens.³¹

Medullary Thyroid Cancer

Medullary thyroid cancer is a neuroendocrine tumor arising from the thyroid parafollicular cells, accounting for about 4% of thyroid carcinomas, most of which are sporadic. However, some are familial as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes, which are transmitted in an autosomal dominant fashion.^32,33 Similar to DTC, the primary treatment option is surgery. Medullary thyroid cancer can be cured only by complete resection of the thyroid tumor and any local and regional metastases. Compared with DTC, metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither concentrates iodine nor is TSH dependent.^34,35

The 10-year OS rate in MTC is ≤ 40% in patients with locally advanced or metastatic disease.^32,36,37 In hereditary MTC, germline mutations in the c-ret proto-oncogene occur in virtually all patients. In sporadic MTC, 85% of patients have the M918T mutation, and somatic c-ret mutations are seen in about 50% of patients.^38-42

Similar to DTC, due to the presence of mutations involving RET receptor tyrosine kinase, molecular targeted therapeutics with activity against RET demonstrate a potential therapeutic target in MTC.^43-45 Other signaling pathways likely to contribute to the growth and invasiveness of MTC include VEGFR-dependent tumor angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumor cell proliferation.⁴⁶

In 2011 and 2012, the FDA approved tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib for metastatic MTC. Similar to treatment for DTC, systemic therapy is mainly based on targeted therapies. Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy.

Vandetanib

Vandetanib is approved for unresectable, locally advanced or metastatic sporadic or hereditary MTC.47 The daily recommended dose is 300 mg/d. It is an oral MKI that targets VEGFR, RET/PTC, and the EGFR.48

The ZETA trial was an international randomized phase 3 trial involving patients with unresectable locally advanced or metastatic sporadic or hereditary MTC.⁴⁸ In a ZETA trial study by Wells Jr and colleagues, patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. After objective disease progression, patients could elect to receive openlabel vandetanib. The primary endpoint was PFS, determined by independent central Response Evaluation Criteria in Solid Tumors assessments.

A total of 331 patients were randomly assigned to receive vandetanib (231 patients) or placebo (100 patients). At data cutoff, with median follow-up of 24 months, PFS was significantly prolonged in patients randomly assigned to vandetanib vs placebo (30.5 mo vs 19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR was significantly higher in the vandetanib group (45% vs 13%). The presence of a somatic RET M918T mutation predicted an improved PFS.

Common AEs (any grade) noted with vandetanib vs placebo include diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%). Torsades de pointes and sudden death were reported in patients receiving vandetanib. Data on OS were immature at data cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival analysis will take place when 50% of the patients have died.⁴⁸

Vandetanib is currently approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about serious heart-related risks. Electrocardiograms and serum potassium, calcium, magnesium, and TSH should be taken at 2 to 4 weeks and 8 to 12 weeks after starting treatment and every 3 months after that. Patients with diarrhea may require more frequent monitoring.

Cabozantinib

In 2012, the FDA approved cabozantinib for the treatment of progressive, metastatic MTC.⁴⁹ It is an oral, small molecule TKI that targets VEGFRs 1 and 2, MET, and RET. The inhibitory activity against MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC.⁵⁰ The daily recommended dose is 140 mg/d. A phase 3 randomized EXAM trial in patients with progressive, metastatic, or unresectable locally advanced MTC.⁵¹ Three hundred thirty patients were randomly assigned to receive either cabozantinib 140 mg or placebo once daily. Progressionfree survival was improved with cabozantinib compared with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI, 0.19-0.40). Partial responses were observed in 27% vs 0% in placebo. A planned interim analysis of OS was conducted, including 96 (44%) of the 217 patient deaths required for the final analysis, with no statistically significant difference observed between the treatment arms (HR, 0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to continue until at least 217 deaths have been observed.

There was markedly improved PFS in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS mutations (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10).⁵¹

The most common AEs, occurring in ≥ 25% of patients, were diarrhea, stomatitis, hand and foot syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant AEs also included fistula formation and osteonecrosis of the jaw.

Summary

Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy. Though not curative, TKIs can only stabilize disease progression. Initiation of TKIs should be considered in rapidly progressive disease, because these drugs are associated with considerable AEs affecting the quality of life (QOL).

Patients who progressed or were unable to tolerate vandetanib or cabozantinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include pazopanib, sunitinib, and sorafenib, which finished phase 2 trials and showed some partial responses.^29,52-57 If patients are unable to tolerate MKIs, they can try conventional chemotherapy consisting of dacarbazine with other agents or doxorubin.^58-60

Conclusions

Molecular targeted therapy is an emerging treatment option for patients with metastatic thyroid cancer (Table 2). The authors suggest that such patients participate in clinical trials in the hope of developing more effective and tolerable drugs and recommend oral TKIs for patients with rapidly progressive disease who cannot participate in a clinical trial. For patients who cannot tolerate or fail one TKI, the authors recommend trying other TKIs before initiating cytotoxic chemotherapy.

Before initiation of treatment for metastatic disease, an important factor to consider is the pace of disease progression. Patients who are asymptomatic and have the very indolent disease may postpone kinase inhibitor therapy until they become rapidly progressive or symptomatic, because the AEs of treatment will adversely affect the patient’s QOL. In patients with symptomatic and rapidly progressive disease, initiation of treatment with kinase inhibitor therapy can lead to stabilization of disease, although at the cost of some AEs. More structured clinical trials are needed, along with an evaluation of newer molecular targets for the management of this progressive metastatic disease with a dismal prognosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

The thyroid ablation rate with recombinant human thyroid stimulating hormone injections, or rhTSH, was shown in the randomized phase III Etude Stimulation Ablation trial to be similar to that with thyroid hormone withdrawal when used with either 1.1 or 3.7 GBq iodine-131 in patients with thyroid cancer, but a new analysis of data from the trial shows that the use of rhTSH would not be cost effective.

While rhTSH was associated with stable health-related quality of life and was more effective than thyroid hormone withdrawal (THW) with respect to quality-adjusted life-years (mean increase of 0.013 vs. THW), it is far more expensive, and a cost-effectiveness analysis showed that at a willingness-to-pay threshold of $53,300 per QALY, the probability that rhTSH would be cost effective was 47% when direct costs were considered. This increased to 70% when the cost of rhTSH was lowered by 30%, Isabelle Borget, Pharm.D., Ph.D., of Gustave Roussy, Villejuif, France, and her colleagues reported online in the Journal of Clinical Oncology.

Using 1.1 rather than 3.7 GBq of iodine-131 decreased efficacy slightly (mean decrease of 0.007 QALY), but also reduced costs by $1,018, and the probability of cost-effectiveness at the lower iodine-131 level was 65%, the investigators said (J Clin Oncol. 2015 Aug 3. doi: 10.1200/JCO.2015.61.6722).

Although rhTSH was not associated with the transient deterioration in health-related quality of life seen with thyroid hormone withdrawal in the first few months of treatment, it was cost effective only when the price was reduced by 30%; lower iodine-131 activity also reduced overall costs, they concluded.

Dr. Borget reported receiving honoraria from Roche and Janssen-Cilag, and travel, accommodations, and expenses from Janssen-Cilag. Several coauthors reported relationships with Genzyme, Sanofi, Novartis, and/or GE Healthcare, including receiving research support, honoraria, travel/accommodations/expenses, and/or serving as a consultant or advisor.

[email protected]

The thyroid ablation rate with recombinant human thyroid stimulating hormone injections, or rhTSH, was shown in the randomized phase III Etude Stimulation Ablation trial to be similar to that with thyroid hormone withdrawal when used with either 1.1 or 3.7 GBq iodine-131 in patients with thyroid cancer, but a new analysis of data from the trial shows that the use of rhTSH would not be cost effective.

While rhTSH was associated with stable health-related quality of life and was more effective than thyroid hormone withdrawal (THW) with respect to quality-adjusted life-years (mean increase of 0.013 vs. THW), it is far more expensive, and a cost-effectiveness analysis showed that at a willingness-to-pay threshold of $53,300 per QALY, the probability that rhTSH would be cost effective was 47% when direct costs were considered. This increased to 70% when the cost of rhTSH was lowered by 30%, Isabelle Borget, Pharm.D., Ph.D., of Gustave Roussy, Villejuif, France, and her colleagues reported online in the Journal of Clinical Oncology.

Using 1.1 rather than 3.7 GBq of iodine-131 decreased efficacy slightly (mean decrease of 0.007 QALY), but also reduced costs by $1,018, and the probability of cost-effectiveness at the lower iodine-131 level was 65%, the investigators said (J Clin Oncol. 2015 Aug 3. doi: 10.1200/JCO.2015.61.6722).

Although rhTSH was not associated with the transient deterioration in health-related quality of life seen with thyroid hormone withdrawal in the first few months of treatment, it was cost effective only when the price was reduced by 30%; lower iodine-131 activity also reduced overall costs, they concluded.

Dr. Borget reported receiving honoraria from Roche and Janssen-Cilag, and travel, accommodations, and expenses from Janssen-Cilag. Several coauthors reported relationships with Genzyme, Sanofi, Novartis, and/or GE Healthcare, including receiving research support, honoraria, travel/accommodations/expenses, and/or serving as a consultant or advisor.

[email protected]

The thyroid ablation rate with recombinant human thyroid stimulating hormone injections, or rhTSH, was shown in the randomized phase III Etude Stimulation Ablation trial to be similar to that with thyroid hormone withdrawal when used with either 1.1 or 3.7 GBq iodine-131 in patients with thyroid cancer, but a new analysis of data from the trial shows that the use of rhTSH would not be cost effective.

While rhTSH was associated with stable health-related quality of life and was more effective than thyroid hormone withdrawal (THW) with respect to quality-adjusted life-years (mean increase of 0.013 vs. THW), it is far more expensive, and a cost-effectiveness analysis showed that at a willingness-to-pay threshold of $53,300 per QALY, the probability that rhTSH would be cost effective was 47% when direct costs were considered. This increased to 70% when the cost of rhTSH was lowered by 30%, Isabelle Borget, Pharm.D., Ph.D., of Gustave Roussy, Villejuif, France, and her colleagues reported online in the Journal of Clinical Oncology.

Using 1.1 rather than 3.7 GBq of iodine-131 decreased efficacy slightly (mean decrease of 0.007 QALY), but also reduced costs by $1,018, and the probability of cost-effectiveness at the lower iodine-131 level was 65%, the investigators said (J Clin Oncol. 2015 Aug 3. doi: 10.1200/JCO.2015.61.6722).

Although rhTSH was not associated with the transient deterioration in health-related quality of life seen with thyroid hormone withdrawal in the first few months of treatment, it was cost effective only when the price was reduced by 30%; lower iodine-131 activity also reduced overall costs, they concluded.

Dr. Borget reported receiving honoraria from Roche and Janssen-Cilag, and travel, accommodations, and expenses from Janssen-Cilag. Several coauthors reported relationships with Genzyme, Sanofi, Novartis, and/or GE Healthcare, including receiving research support, honoraria, travel/accommodations/expenses, and/or serving as a consultant or advisor.

[email protected]

Patients with human papillomavirus–related oropharyngeal carcinoma (HPV-OPC) who had human papillomavirus type 16 (HPV16) detected in oral rinses both at diagnosis and at any time after treatment were more likely to have OPC recurrence, according to a report published online in JAMA Oncology.

Detection of HPV16 DNA was frequent among patients at diagnosis (67 of 124 patients), but rare posttreatment (6 of 124 patients). Persistent HPV16 detection (at and after diagnosis) was associated with greater risk of disease recurrence (hazard ratio, 29.7) and death (HR, 23.5).

National Cancer Institute

Approximately 10%-25% of patients with HPV-OPC experience progression after treatment, and surgical salvage is the most favorable treatment in these cases. However, surgery is not feasible for the significant proportion of HPV-OPC cases that have already spread to distant sites at the time of diagnosis.

“There is a need for clinically relevant biomarkers of disease recurrence to facilitate timely initiation of aggressive diagnostic investigation and subsequent salvage treatment to potentially improve outcomes for the growing population of HPV-OPC survivors,” wrote Dr. Eleni M. Rettig of the department of otolaryngology–head and neck surgery, Johns Hopkins University, Baltimore, and her colleagues (JAMA Oncol. 2015 July 30 [doi:10.1001/jamaoncol.2015.2524]).

“Detection of recurrent local or locoregional disease prior to distant spread is particularly desirable given the favorable response of HPV-OPC to surgical salvage,” the study authors observed.

The multisite, prospective cohort study evaluated 124 patients with HPV-related oropharyngeal carcinoma who had at least one posttreatment oral rinse sample. Most patients with HPV16 DNA detected at diagnosis had none detected after treatment (62 of 67 patients). Contrary to persistent HPV16 DNA detection, HPV16 detected at diagnosis was not significantly associated with disease-free or overall survival.

Based on the six patients who had posttreatment detection of HPV16 DNA in oral rinses, the sensitivity and specificity of predicting recurrence at 9-12 months were 43% and 100%, respectively. Considering only local disease recurrence, the sensitivity and specificity were 100% and 100%, respectively.

The median time from the first posttreatment detection of HPV16 DNA to recurrence was 7.0 months. That “clinically meaningful lead time” is important in evaluating HPV16 DNA detection in oral rinses as “a valuable tool for long-term posttreatment surveillance of HPV-OPC for local recurrence,” the investigators concluded.

Dr. Rettig reported having no disclosures. Several coauthors reported ties to industry sources.

Patients with human papillomavirus–related oropharyngeal carcinoma (HPV-OPC) who had human papillomavirus type 16 (HPV16) detected in oral rinses both at diagnosis and at any time after treatment were more likely to have OPC recurrence, according to a report published online in JAMA Oncology.

Detection of HPV16 DNA was frequent among patients at diagnosis (67 of 124 patients), but rare posttreatment (6 of 124 patients). Persistent HPV16 detection (at and after diagnosis) was associated with greater risk of disease recurrence (hazard ratio, 29.7) and death (HR, 23.5).

National Cancer Institute

Approximately 10%-25% of patients with HPV-OPC experience progression after treatment, and surgical salvage is the most favorable treatment in these cases. However, surgery is not feasible for the significant proportion of HPV-OPC cases that have already spread to distant sites at the time of diagnosis.

“There is a need for clinically relevant biomarkers of disease recurrence to facilitate timely initiation of aggressive diagnostic investigation and subsequent salvage treatment to potentially improve outcomes for the growing population of HPV-OPC survivors,” wrote Dr. Eleni M. Rettig of the department of otolaryngology–head and neck surgery, Johns Hopkins University, Baltimore, and her colleagues (JAMA Oncol. 2015 July 30 [doi:10.1001/jamaoncol.2015.2524]).

“Detection of recurrent local or locoregional disease prior to distant spread is particularly desirable given the favorable response of HPV-OPC to surgical salvage,” the study authors observed.

The multisite, prospective cohort study evaluated 124 patients with HPV-related oropharyngeal carcinoma who had at least one posttreatment oral rinse sample. Most patients with HPV16 DNA detected at diagnosis had none detected after treatment (62 of 67 patients). Contrary to persistent HPV16 DNA detection, HPV16 detected at diagnosis was not significantly associated with disease-free or overall survival.

Based on the six patients who had posttreatment detection of HPV16 DNA in oral rinses, the sensitivity and specificity of predicting recurrence at 9-12 months were 43% and 100%, respectively. Considering only local disease recurrence, the sensitivity and specificity were 100% and 100%, respectively.

The median time from the first posttreatment detection of HPV16 DNA to recurrence was 7.0 months. That “clinically meaningful lead time” is important in evaluating HPV16 DNA detection in oral rinses as “a valuable tool for long-term posttreatment surveillance of HPV-OPC for local recurrence,” the investigators concluded.

Dr. Rettig reported having no disclosures. Several coauthors reported ties to industry sources.

Patients with human papillomavirus–related oropharyngeal carcinoma (HPV-OPC) who had human papillomavirus type 16 (HPV16) detected in oral rinses both at diagnosis and at any time after treatment were more likely to have OPC recurrence, according to a report published online in JAMA Oncology.

Detection of HPV16 DNA was frequent among patients at diagnosis (67 of 124 patients), but rare posttreatment (6 of 124 patients). Persistent HPV16 detection (at and after diagnosis) was associated with greater risk of disease recurrence (hazard ratio, 29.7) and death (HR, 23.5).

National Cancer Institute

Approximately 10%-25% of patients with HPV-OPC experience progression after treatment, and surgical salvage is the most favorable treatment in these cases. However, surgery is not feasible for the significant proportion of HPV-OPC cases that have already spread to distant sites at the time of diagnosis.

“There is a need for clinically relevant biomarkers of disease recurrence to facilitate timely initiation of aggressive diagnostic investigation and subsequent salvage treatment to potentially improve outcomes for the growing population of HPV-OPC survivors,” wrote Dr. Eleni M. Rettig of the department of otolaryngology–head and neck surgery, Johns Hopkins University, Baltimore, and her colleagues (JAMA Oncol. 2015 July 30 [doi:10.1001/jamaoncol.2015.2524]).

“Detection of recurrent local or locoregional disease prior to distant spread is particularly desirable given the favorable response of HPV-OPC to surgical salvage,” the study authors observed.

The multisite, prospective cohort study evaluated 124 patients with HPV-related oropharyngeal carcinoma who had at least one posttreatment oral rinse sample. Most patients with HPV16 DNA detected at diagnosis had none detected after treatment (62 of 67 patients). Contrary to persistent HPV16 DNA detection, HPV16 detected at diagnosis was not significantly associated with disease-free or overall survival.

Based on the six patients who had posttreatment detection of HPV16 DNA in oral rinses, the sensitivity and specificity of predicting recurrence at 9-12 months were 43% and 100%, respectively. Considering only local disease recurrence, the sensitivity and specificity were 100% and 100%, respectively.

The median time from the first posttreatment detection of HPV16 DNA to recurrence was 7.0 months. That “clinically meaningful lead time” is important in evaluating HPV16 DNA detection in oral rinses as “a valuable tool for long-term posttreatment surveillance of HPV-OPC for local recurrence,” the investigators concluded.

Dr. Rettig reported having no disclosures. Several coauthors reported ties to industry sources.

For patients with esophageal cancer, salvage surgery after definitive chemoradiotherapy had similar mortality and morbidity rates, and similar survival outcomes, to the combination of neoadjuvant chemoradiation and planned surgery, according to a study published online in the Journal of Clinical Oncology.

Definitive chemoradiotherapy (dCRT) is an alternative to highly invasive surgical resection, which carries a significant rate of morbidity and mortality; however, recent data indicate that 50% of patients with complete response to dCRT experience tumor recurrence.

“Our study demonstrated a similar survival and recurrence pattern for the SALV [salvage surgery after definitive chemoradiotherapy] and NCRS [neoadjuvant chemoradiation and planned surgery] groups, potentially validating an approach of dCRT with reserved SALV for persistent or recurrent disease. Importantly, there were no differences in oncologic safety of surgery, including extent of nodal dissection, between the SALV and NCRS groups,” wrote Dr. Sheraz Markar, a clinical research fellow from Imperial College, London, and colleagues (Journ. Clin. Onc. 2015 July 20 [doi:10.1200/JCO.2014.59.9092]).

The retrospective study compared 308 patients with esophageal cancer who underwent SALV with 540 patients who received NCRS at European centers from 2000 to 2010. After a median follow up of 54 months, the SALV and NCRS groups had similar rates of 3-year overall survival (43.3% vs. 40.1% ) and disease-free survival (39.2% vs. 32.8%). The two groups also had similar rates tumor recurrence: overall (46.8% vs. 47.9%), locoregional (18.8% vs. 15.9%), distant (24.3% vs. 28.1%) and mixed (13.0% vs. 13.5%).

The SALV and NCRS groups had similar rates of in-hospital mortality (8.4% vs. 9.3%) and morbidity (63.6% vs. 58.9%), but SALV patients had significantly more complications from anastomotic leak (17.2% vs. 10.7%) and surgical site infection (18.5% vs. 12.2%).

Subset analysis of the SALV group showed that patients who received a total radiation dose ≥ 55 Gy (compared with SALV patients who received a lower dose) had significantly increased in-hospital mortality (27.8% vs. 4.3%; P < .001), overall morbidity (75.9% vs. 61%; P = .039), anastomotic leak (27.8% vs. 15%; P = .023), surgical site infection (29.6% vs. 16.1%; P = .02), and pulmonary complications (55.6% vs. 40.2%; P = .038).

“Currently, there is no evidence in terms of locoregional control or survival benefit to support a high total radiation dose (> 50 Gy) in patients receiving dCRT,” according to the researchers, who noted that the findings suggest, “an upper threshold of 50 Gy should be used in these patients to optimize the benefits of dCRT without compromising the safety of SALV, if required.”

Patients who underwent SALV at high-volume centers had significantly lower rates of in-hospital mortality (6.3% vs. 16.2%; P = .009) and overall morbidity (58.8% vs. 80.9%; P = .001) compared with procedures done at low-volume centers.

Compared with recurrent disease, patients with persistent disease after dCRT had poorer long-term prognoses, suggesting a more aggressive tumor biology. Early identification of CRT-resistant tumors to allow early surgical treatment is an important area for future investigation, the investigators said.

For patients with esophageal cancer, salvage surgery after definitive chemoradiotherapy had similar mortality and morbidity rates, and similar survival outcomes, to the combination of neoadjuvant chemoradiation and planned surgery, according to a study published online in the Journal of Clinical Oncology.

Definitive chemoradiotherapy (dCRT) is an alternative to highly invasive surgical resection, which carries a significant rate of morbidity and mortality; however, recent data indicate that 50% of patients with complete response to dCRT experience tumor recurrence.

“Our study demonstrated a similar survival and recurrence pattern for the SALV [salvage surgery after definitive chemoradiotherapy] and NCRS [neoadjuvant chemoradiation and planned surgery] groups, potentially validating an approach of dCRT with reserved SALV for persistent or recurrent disease. Importantly, there were no differences in oncologic safety of surgery, including extent of nodal dissection, between the SALV and NCRS groups,” wrote Dr. Sheraz Markar, a clinical research fellow from Imperial College, London, and colleagues (Journ. Clin. Onc. 2015 July 20 [doi:10.1200/JCO.2014.59.9092]).

The retrospective study compared 308 patients with esophageal cancer who underwent SALV with 540 patients who received NCRS at European centers from 2000 to 2010. After a median follow up of 54 months, the SALV and NCRS groups had similar rates of 3-year overall survival (43.3% vs. 40.1% ) and disease-free survival (39.2% vs. 32.8%). The two groups also had similar rates tumor recurrence: overall (46.8% vs. 47.9%), locoregional (18.8% vs. 15.9%), distant (24.3% vs. 28.1%) and mixed (13.0% vs. 13.5%).

The SALV and NCRS groups had similar rates of in-hospital mortality (8.4% vs. 9.3%) and morbidity (63.6% vs. 58.9%), but SALV patients had significantly more complications from anastomotic leak (17.2% vs. 10.7%) and surgical site infection (18.5% vs. 12.2%).

Subset analysis of the SALV group showed that patients who received a total radiation dose ≥ 55 Gy (compared with SALV patients who received a lower dose) had significantly increased in-hospital mortality (27.8% vs. 4.3%; P < .001), overall morbidity (75.9% vs. 61%; P = .039), anastomotic leak (27.8% vs. 15%; P = .023), surgical site infection (29.6% vs. 16.1%; P = .02), and pulmonary complications (55.6% vs. 40.2%; P = .038).

“Currently, there is no evidence in terms of locoregional control or survival benefit to support a high total radiation dose (> 50 Gy) in patients receiving dCRT,” according to the researchers, who noted that the findings suggest, “an upper threshold of 50 Gy should be used in these patients to optimize the benefits of dCRT without compromising the safety of SALV, if required.”

Patients who underwent SALV at high-volume centers had significantly lower rates of in-hospital mortality (6.3% vs. 16.2%; P = .009) and overall morbidity (58.8% vs. 80.9%; P = .001) compared with procedures done at low-volume centers.

Compared with recurrent disease, patients with persistent disease after dCRT had poorer long-term prognoses, suggesting a more aggressive tumor biology. Early identification of CRT-resistant tumors to allow early surgical treatment is an important area for future investigation, the investigators said.

For patients with esophageal cancer, salvage surgery after definitive chemoradiotherapy had similar mortality and morbidity rates, and similar survival outcomes, to the combination of neoadjuvant chemoradiation and planned surgery, according to a study published online in the Journal of Clinical Oncology.

Definitive chemoradiotherapy (dCRT) is an alternative to highly invasive surgical resection, which carries a significant rate of morbidity and mortality; however, recent data indicate that 50% of patients with complete response to dCRT experience tumor recurrence.

“Our study demonstrated a similar survival and recurrence pattern for the SALV [salvage surgery after definitive chemoradiotherapy] and NCRS [neoadjuvant chemoradiation and planned surgery] groups, potentially validating an approach of dCRT with reserved SALV for persistent or recurrent disease. Importantly, there were no differences in oncologic safety of surgery, including extent of nodal dissection, between the SALV and NCRS groups,” wrote Dr. Sheraz Markar, a clinical research fellow from Imperial College, London, and colleagues (Journ. Clin. Onc. 2015 July 20 [doi:10.1200/JCO.2014.59.9092]).

The retrospective study compared 308 patients with esophageal cancer who underwent SALV with 540 patients who received NCRS at European centers from 2000 to 2010. After a median follow up of 54 months, the SALV and NCRS groups had similar rates of 3-year overall survival (43.3% vs. 40.1% ) and disease-free survival (39.2% vs. 32.8%). The two groups also had similar rates tumor recurrence: overall (46.8% vs. 47.9%), locoregional (18.8% vs. 15.9%), distant (24.3% vs. 28.1%) and mixed (13.0% vs. 13.5%).

The SALV and NCRS groups had similar rates of in-hospital mortality (8.4% vs. 9.3%) and morbidity (63.6% vs. 58.9%), but SALV patients had significantly more complications from anastomotic leak (17.2% vs. 10.7%) and surgical site infection (18.5% vs. 12.2%).

Subset analysis of the SALV group showed that patients who received a total radiation dose ≥ 55 Gy (compared with SALV patients who received a lower dose) had significantly increased in-hospital mortality (27.8% vs. 4.3%; P < .001), overall morbidity (75.9% vs. 61%; P = .039), anastomotic leak (27.8% vs. 15%; P = .023), surgical site infection (29.6% vs. 16.1%; P = .02), and pulmonary complications (55.6% vs. 40.2%; P = .038).

“Currently, there is no evidence in terms of locoregional control or survival benefit to support a high total radiation dose (> 50 Gy) in patients receiving dCRT,” according to the researchers, who noted that the findings suggest, “an upper threshold of 50 Gy should be used in these patients to optimize the benefits of dCRT without compromising the safety of SALV, if required.”

Patients who underwent SALV at high-volume centers had significantly lower rates of in-hospital mortality (6.3% vs. 16.2%; P = .009) and overall morbidity (58.8% vs. 80.9%; P = .001) compared with procedures done at low-volume centers.

Compared with recurrent disease, patients with persistent disease after dCRT had poorer long-term prognoses, suggesting a more aggressive tumor biology. Early identification of CRT-resistant tumors to allow early surgical treatment is an important area for future investigation, the investigators said.