The Journal of Community and Supportive Oncology

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

We often make note in these pages of the remarkable advances occurring in the realm of new oncologic therapeutics based on the burgeoning understanding of cancer biology. Although no one would argue about the importance of treating the cancer, we should always remember that the goal of treatment is to take care of the patient as a whole, working also to heal the emotional, psychological, and social upheaval that can follow a cancer diagnosis.

Indeed, that focus on the patient’s overall needs is now termed patient-centered care, and it is a fundamental attribute in approaching any therapeutic maneuver. No group of patients requires a more comprehensive approach to patient-centered care than do cancer patients. Faced with an existential crisis, huge costs of care, physical and psychological symptoms, and frequent and progressive loss of independence and function, it is no surprise that these patients— and their families—routinely suffer great psychosocial distress while battling the disease.

The Institute of Medicine’s 2007 report Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs was an attempt to categorize the challenges faced by cancer patients and the scope of available services for addressing those challenges at the local, regional, and national levels. I was privileged to serve on the committee that reviewed the evidence and formulated solutions to the problem. A number of recommendations arose from that report.


* For a PDF of the full article, click in the link to the left of this introduction.

We often make note in these pages of the remarkable advances occurring in the realm of new oncologic therapeutics based on the burgeoning understanding of cancer biology. Although no one would argue about the importance of treating the cancer, we should always remember that the goal of treatment is to take care of the patient as a whole, working also to heal the emotional, psychological, and social upheaval that can follow a cancer diagnosis.

Indeed, that focus on the patient’s overall needs is now termed patient-centered care, and it is a fundamental attribute in approaching any therapeutic maneuver. No group of patients requires a more comprehensive approach to patient-centered care than do cancer patients. Faced with an existential crisis, huge costs of care, physical and psychological symptoms, and frequent and progressive loss of independence and function, it is no surprise that these patients— and their families—routinely suffer great psychosocial distress while battling the disease.

The Institute of Medicine’s 2007 report Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs was an attempt to categorize the challenges faced by cancer patients and the scope of available services for addressing those challenges at the local, regional, and national levels. I was privileged to serve on the committee that reviewed the evidence and formulated solutions to the problem. A number of recommendations arose from that report.


* For a PDF of the full article, click in the link to the left of this introduction.

We often make note in these pages of the remarkable advances occurring in the realm of new oncologic therapeutics based on the burgeoning understanding of cancer biology. Although no one would argue about the importance of treating the cancer, we should always remember that the goal of treatment is to take care of the patient as a whole, working also to heal the emotional, psychological, and social upheaval that can follow a cancer diagnosis.

Indeed, that focus on the patient’s overall needs is now termed patient-centered care, and it is a fundamental attribute in approaching any therapeutic maneuver. No group of patients requires a more comprehensive approach to patient-centered care than do cancer patients. Faced with an existential crisis, huge costs of care, physical and psychological symptoms, and frequent and progressive loss of independence and function, it is no surprise that these patients— and their families—routinely suffer great psychosocial distress while battling the disease.

The Institute of Medicine’s 2007 report Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs was an attempt to categorize the challenges faced by cancer patients and the scope of available services for addressing those challenges at the local, regional, and national levels. I was privileged to serve on the committee that reviewed the evidence and formulated solutions to the problem. A number of recommendations arose from that report.


* For a PDF of the full article, click in the link to the left of this introduction.

In his audio overview of the October issue of Community Oncology, Dr. David Henry offers a salient summary on the role of low-dose computed tomographic screening to detect lung cancer, an unusual presentation of metastatic melanoma, and summary reports from the European Multidisciplinary Cancer Congress and the American Society for Radiation Oncology.

In his audio overview of the October issue of Community Oncology, Dr. David Henry offers a salient summary on the role of low-dose computed tomographic screening to detect lung cancer, an unusual presentation of metastatic melanoma, and summary reports from the European Multidisciplinary Cancer Congress and the American Society for Radiation Oncology.

In his audio overview of the October issue of Community Oncology, Dr. David Henry offers a salient summary on the role of low-dose computed tomographic screening to detect lung cancer, an unusual presentation of metastatic melanoma, and summary reports from the European Multidisciplinary Cancer Congress and the American Society for Radiation Oncology.

Physicians should start end-of-life conversations early. They can start prognosis discussions by asking broad open-ended questions. Dr. Susan Block shares her practice wisdom at the Chicago Supportive Oncology Conference.

Physicians should start end-of-life conversations early. They can start prognosis discussions by asking broad open-ended questions. Dr. Susan Block shares her practice wisdom at the Chicago Supportive Oncology Conference.

Physicians should start end-of-life conversations early. They can start prognosis discussions by asking broad open-ended questions. Dr. Susan Block shares her practice wisdom at the Chicago Supportive Oncology Conference.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

One of the most exciting developments in oncology in recent years has been the advent of targeted therapies, which have paved the way for personalized medicine. These therapies have been developed specifically to take advantage of a mutation or deficiency in a tumor or a surface characteristic that make it susceptible to the targeted therapy. This is even more exciting given that for the past 50 years, we have been delivering therapies that affect all of the cells in the body (often with substantial toxic effect) in the hopes that we will hurt the cancer cells the most and perhaps even kill them off. This, of course, is chemotherapy, and while it will not be going away any time soon, the prospect of personalized and targeted cancer therapy promises better outcomes with fewer toxicities since the cancer cells are the sole focus of the treatment.

As exciting as these new therapies might seem, we must be mindful that our ultimate goal should be to prevent cancer through early detection. Mammograms, pap smears, and colonoscopies are all proven strategies for detecting cancers and precancers at an earlier stage when they can be more easily cured, and the positive effects and outcomes of these prevention efforts have been well documented.

Early detection vs cost-effectiveness in screening for lung cancer
On page 441 of this issue of Community Oncology, we highlight another early detection screening strategy—for lung cancer—that is bound to change practice. In a study of more than 50,000 persons aged 55 years and older and at high risk for lung cancer (a history of smoking of 30 pack-years), participants were randomized to receive low-dose CT screening or chest radiography annually for 3 years. The investigators found that lung cancer was detected at an earlier stage in the CT-scan group for a 20% reduction in mortality compared with the radiography group. ...

* For a PDF of the full article, click in the link to the left of this introduction.

One of the most exciting developments in oncology in recent years has been the advent of targeted therapies, which have paved the way for personalized medicine. These therapies have been developed specifically to take advantage of a mutation or deficiency in a tumor or a surface characteristic that make it susceptible to the targeted therapy. This is even more exciting given that for the past 50 years, we have been delivering therapies that affect all of the cells in the body (often with substantial toxic effect) in the hopes that we will hurt the cancer cells the most and perhaps even kill them off. This, of course, is chemotherapy, and while it will not be going away any time soon, the prospect of personalized and targeted cancer therapy promises better outcomes with fewer toxicities since the cancer cells are the sole focus of the treatment.

As exciting as these new therapies might seem, we must be mindful that our ultimate goal should be to prevent cancer through early detection. Mammograms, pap smears, and colonoscopies are all proven strategies for detecting cancers and precancers at an earlier stage when they can be more easily cured, and the positive effects and outcomes of these prevention efforts have been well documented.

Early detection vs cost-effectiveness in screening for lung cancer
On page 441 of this issue of Community Oncology, we highlight another early detection screening strategy—for lung cancer—that is bound to change practice. In a study of more than 50,000 persons aged 55 years and older and at high risk for lung cancer (a history of smoking of 30 pack-years), participants were randomized to receive low-dose CT screening or chest radiography annually for 3 years. The investigators found that lung cancer was detected at an earlier stage in the CT-scan group for a 20% reduction in mortality compared with the radiography group. ...

* For a PDF of the full article, click in the link to the left of this introduction.

One of the most exciting developments in oncology in recent years has been the advent of targeted therapies, which have paved the way for personalized medicine. These therapies have been developed specifically to take advantage of a mutation or deficiency in a tumor or a surface characteristic that make it susceptible to the targeted therapy. This is even more exciting given that for the past 50 years, we have been delivering therapies that affect all of the cells in the body (often with substantial toxic effect) in the hopes that we will hurt the cancer cells the most and perhaps even kill them off. This, of course, is chemotherapy, and while it will not be going away any time soon, the prospect of personalized and targeted cancer therapy promises better outcomes with fewer toxicities since the cancer cells are the sole focus of the treatment.

As exciting as these new therapies might seem, we must be mindful that our ultimate goal should be to prevent cancer through early detection. Mammograms, pap smears, and colonoscopies are all proven strategies for detecting cancers and precancers at an earlier stage when they can be more easily cured, and the positive effects and outcomes of these prevention efforts have been well documented.

Early detection vs cost-effectiveness in screening for lung cancer
On page 441 of this issue of Community Oncology, we highlight another early detection screening strategy—for lung cancer—that is bound to change practice. In a study of more than 50,000 persons aged 55 years and older and at high risk for lung cancer (a history of smoking of 30 pack-years), participants were randomized to receive low-dose CT screening or chest radiography annually for 3 years. The investigators found that lung cancer was detected at an earlier stage in the CT-scan group for a 20% reduction in mortality compared with the radiography group. ...

* For a PDF of the full article, click in the link to the left of this introduction.

The National Lung Screening Trial Research Team of the National Cancer Research Institute has recently reported a large-scale trial showing that screening with low-dose computed tomography (CT) is associated with a significant reduction in lung cancer mortality compared with chest radiography in persons at high risk for lung cancer.^1,2

From August 2002 through April 2004, 53,454 persons at high risk for lung cancer were enrolled at 33 US medical centers and randomized to three annual screenings with either low-dose CT (n = 26,722) or singleview posteroanterior chest radiography (n = 26,732). Data on lung cancer cases and deaths were collected through the end of December 2009. Eligible participants were aged between 55 and 74 years, had a history of smoking of at least 30 pack-years and, if former smokers, had quit within the past 15 years. Persons with a previous diagnosis of lung cancer, a chest CT within the preceding 18 months, hemoptysis, or unexplained weight loss of more than 15 lb in the preceding year were excluded from the study. Participants in the two groups were well matched for age at randomization, gender distribution (59% men in each group), and proportion of current smokers (48% in each group). The participants in the trial were younger, had a higher level of education, and were more likely to be former smokers than were respondents to a 2002– 2004 US Census survey of tobacco use who matched the age and smoking history criteria of the trial. ...

* For a full PDF of this article, click on the link to the left of this introduction.

The National Lung Screening Trial Research Team of the National Cancer Research Institute has recently reported a large-scale trial showing that screening with low-dose computed tomography (CT) is associated with a significant reduction in lung cancer mortality compared with chest radiography in persons at high risk for lung cancer.^1,2

From August 2002 through April 2004, 53,454 persons at high risk for lung cancer were enrolled at 33 US medical centers and randomized to three annual screenings with either low-dose CT (n = 26,722) or singleview posteroanterior chest radiography (n = 26,732). Data on lung cancer cases and deaths were collected through the end of December 2009. Eligible participants were aged between 55 and 74 years, had a history of smoking of at least 30 pack-years and, if former smokers, had quit within the past 15 years. Persons with a previous diagnosis of lung cancer, a chest CT within the preceding 18 months, hemoptysis, or unexplained weight loss of more than 15 lb in the preceding year were excluded from the study. Participants in the two groups were well matched for age at randomization, gender distribution (59% men in each group), and proportion of current smokers (48% in each group). The participants in the trial were younger, had a higher level of education, and were more likely to be former smokers than were respondents to a 2002– 2004 US Census survey of tobacco use who matched the age and smoking history criteria of the trial. ...

* For a full PDF of this article, click on the link to the left of this introduction.

The National Lung Screening Trial Research Team of the National Cancer Research Institute has recently reported a large-scale trial showing that screening with low-dose computed tomography (CT) is associated with a significant reduction in lung cancer mortality compared with chest radiography in persons at high risk for lung cancer.^1,2

From August 2002 through April 2004, 53,454 persons at high risk for lung cancer were enrolled at 33 US medical centers and randomized to three annual screenings with either low-dose CT (n = 26,722) or singleview posteroanterior chest radiography (n = 26,732). Data on lung cancer cases and deaths were collected through the end of December 2009. Eligible participants were aged between 55 and 74 years, had a history of smoking of at least 30 pack-years and, if former smokers, had quit within the past 15 years. Persons with a previous diagnosis of lung cancer, a chest CT within the preceding 18 months, hemoptysis, or unexplained weight loss of more than 15 lb in the preceding year were excluded from the study. Participants in the two groups were well matched for age at randomization, gender distribution (59% men in each group), and proportion of current smokers (48% in each group). The participants in the trial were younger, had a higher level of education, and were more likely to be former smokers than were respondents to a 2002– 2004 US Census survey of tobacco use who matched the age and smoking history criteria of the trial. ...

* For a full PDF of this article, click on the link to the left of this introduction.

Join Community Oncology Editor David Henry as he reviews 10 tips for implementing quality improvement, what oncologists need to know about direct-to-consumer genetic testing, an analysis of value-based reimbursement, and a practical biostatistics approach to counting what really counts in the irinotecan in recurrent glioblastoma trial results.

Join Community Oncology Editor David Henry as he reviews 10 tips for implementing quality improvement, what oncologists need to know about direct-to-consumer genetic testing, an analysis of value-based reimbursement, and a practical biostatistics approach to counting what really counts in the irinotecan in recurrent glioblastoma trial results.

Join Community Oncology Editor David Henry as he reviews 10 tips for implementing quality improvement, what oncologists need to know about direct-to-consumer genetic testing, an analysis of value-based reimbursement, and a practical biostatistics approach to counting what really counts in the irinotecan in recurrent glioblastoma trial results.

The Journal of Supportive Oncology
Volume 9, Issue 4, July-August 2011, Pages 127-128
doi:10.1016/j.suponc.2011.04.006 | Permissions & Reprints

Available online 2 July 2011.

Peer Viewpoint

Does One Size Fit All? Is There a Standard Radiation Dose for Malignant Spinal Cord Compression?

Ramachandran Venkitaraman MD, MRCP, FRCR

^, 

Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).

In this edition of the Journal of Supportive Oncology, Loblaw and Mitera have published a succinct review of trials of radiotherapy (RT) dose schedules for treating malignant spinal cord compression (MSCC). Treatment options for MSCC include surgery and RT, with the latter being the most commonly utilized option as the majority of patients are unfit to undergo surgery. This concise review of RT dose for spinal cord compression sheds light in an area where there are very few randomized controlled trials. Clinicians have historically favored multiple fraction regimens for treating patients with MSCC. The most common regimes are either 20 Gy in five fractions or 30 Gy in 10 fractions, with a single fraction of 8 Gy mainly reserved for patients with a poor performance status. Prospective studies suggest a different set of prognostic factors for deciding the dose of RT in these patients.

The histology of the primary tumor is one of the important predictive factors for outcome. Patients with myeloma, breast, prostate, and thyroid malignancies have a favorable outcome. The survival rate for patients with tumors such as lung, melanoma, and sarcoma is generally dismal.^[1] Mainly, primary tumors that are very sensitive to RT are lymphomas, myeloma, and seminomatous germ-cell tumors, as well as breast and prostate cancers. Gastrointestinal tract cancer, lung cancer, renal tumors, sarcomas, and gynecological tumors are considered to have poor radiosensitivity.

Randomized trials, especially in patients with unfavorable tumor histology, do not show any superiority for fractionated treatments compared to a single fraction of 8 Gy. ^{[2] , [3] and [4]} Single-fraction RT is advantageous in terms of time, cost, resources, and patient comfort. It should be considered as the standard dose for patients with extensive metastatic disease and a life expectancy of less than six months and for less radiosensitive primary tumors such as lung, melanoma, and sarcoma.

In patients with favorable histology, retrospective and nonrandomized evidence suggests a trend toward superiority of the higher fractionation schedules in terms of benefit in local control, with fewer in-field recurrences. ^{[1] , [5] , [6] , [7] and [8]} In the prospective SCORE-1 study, there was a statistically significant improved progression-free survival (72% at 12 months after long-course and 55% after short-course RT, P = 0.034) and local control (12-month local control rate, 77% after long-course and 61% after short-course RT, P = 0.032).5 With the ever-improving systemic treatment options for malignancies and the survival of these patients with metastatic disease showing an incremental increase with each decade, preventing recurrence of spinal cord compression becomes even more important. Long-course RT with doses of 30 Gy in 10 fractions offers no benefit compared to shorter regimens in terms of survival. However, long-course RT appears to improve local control, and there are fewer in-field recurrences, which would be an advantage in patients with favorable histology.^[5] The longer schedule of RT, 30 Gy in 10 fractions, should also be considered in the postoperative setting, subject to recovery from the surgery. There is no practical advantage in offering treatments greater or longer than 30 Gy in 10 fractions in any patient subgroup.^[9]

Similarly, in retrospective studies, for patients with limited metastases who are expected to live longer, survival is associated with tumor type, ambulatory status, slower development of motor deficits, and long-course RT.^[10] The six factors demonstrated on multivariate analysis to be significant for survival outcome by Rades et al1 are primary tumor histology, visceral metastases, other extensive bone metastases, ambulatory status before RT, interval between tumor diagnosis and MSCC, and length of time in developing motor deficits. RT dose does not appear to affect the outcome in patients with low scores on these prognostic systems, while a longer-course RT may be effective in patients scoring highly.1

As recommended in the review article by Loblaw and Mitera, risk stratification of patients with MSCC is essential for deciding the dose of RT. A single fraction of 8 Gy is ideal for patients with poor prognostic factors. Randomized controlled trials of single vs. multifractionated treatments, similar to the SCORAD trial, determine the optimal dose-fractionation schedule of RT for MSCC with favorable prognostic factors.

References [PubMed ID in brackets]

1 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstens, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol,  24 21 (2006), pp. 3388–3393.

2 E. Maranzano, P. Latini, S. Beneventi, L. Marafioti, F. Piro, E. Perrucci and M. Lupattelli, Comparison of two different radiotherapy schedules for spinal cord compression in prostate cancer. Tumori,  84 4 (1998), pp. 472–477.

3 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol,  23 15 (2005), pp. 3358–3365.

4 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial. Radiother Oncol,  93 2 (2009), pp. 174–179.

5 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys,  73 1 (2009), pp. 228–234.

6 D. Rades, P.J. Hoskin, L.J. Stalpers, R. Schulte, P. Poortmans, T. Veninga, J. Dahm-Daphi, N. Obralic, I. Wildfang, R. Bahrehmand, R. Engenhart-Cabilic and S.E. Schild, Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys,  64 5 (2006), pp. 1452–1457.

7 D. Rades, L.J. Stalpers, T. Veninga, V. Rudat, R. Schulte and P.J. Hoskin, Evaluation of functional outcome and local control after radiotherapy for metastatic spinal cord compression in patients with prostate cancer. J Urol,  175 2 (2006), pp. 552–556.

8 D. Rades, T. Veninga, L.J. Stalpers, R. Schulte, P.J. Hoskin, P. Poortmans, S.E. Schild and V. Rudat, Prognostic factors predicting functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord compression in breast cancer patients. Int J Radiat Oncol Biol Phys,  64 1 (2006), pp. 182–188.

9 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study. Cancer,  101 11 (2004), pp. 2687–2692.

10 D. Rades, T. Veninga, L.J. Stalpers, H. Basic, V. Rudat, J.H. Karstens, J. Dunst and S.E. Schild, Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol,  25 1 (2007), pp. 50–56.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Correspondence to: Ramachandran Venkitaraman, MD, MRCP, FRCR, Suffolk Oncology Centre, Ipswich Hospital NHS, Heath Road, Ipswich, IP4 5PD, UK; telephone: (0044) 1473704177; fax: (0044) 1473704916

Author Vitae
Dr. Venkitaraman is Consultant Clinical Oncologist, Suffolk Oncology Centre, Ipswich Hospital NHS, Ipswich, United Kingdom.

The Journal of Supportive Oncology
Volume 9, Issue 4, July-August 2011, Pages 127-128
doi:10.1016/j.suponc.2011.04.006 | Permissions & Reprints

Available online 2 July 2011.

Peer Viewpoint

Does One Size Fit All? Is There a Standard Radiation Dose for Malignant Spinal Cord Compression?

Ramachandran Venkitaraman MD, MRCP, FRCR

^, 

Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).

In this edition of the Journal of Supportive Oncology, Loblaw and Mitera have published a succinct review of trials of radiotherapy (RT) dose schedules for treating malignant spinal cord compression (MSCC). Treatment options for MSCC include surgery and RT, with the latter being the most commonly utilized option as the majority of patients are unfit to undergo surgery. This concise review of RT dose for spinal cord compression sheds light in an area where there are very few randomized controlled trials. Clinicians have historically favored multiple fraction regimens for treating patients with MSCC. The most common regimes are either 20 Gy in five fractions or 30 Gy in 10 fractions, with a single fraction of 8 Gy mainly reserved for patients with a poor performance status. Prospective studies suggest a different set of prognostic factors for deciding the dose of RT in these patients.

The histology of the primary tumor is one of the important predictive factors for outcome. Patients with myeloma, breast, prostate, and thyroid malignancies have a favorable outcome. The survival rate for patients with tumors such as lung, melanoma, and sarcoma is generally dismal.^[1] Mainly, primary tumors that are very sensitive to RT are lymphomas, myeloma, and seminomatous germ-cell tumors, as well as breast and prostate cancers. Gastrointestinal tract cancer, lung cancer, renal tumors, sarcomas, and gynecological tumors are considered to have poor radiosensitivity.

Randomized trials, especially in patients with unfavorable tumor histology, do not show any superiority for fractionated treatments compared to a single fraction of 8 Gy. ^{[2] , [3] and [4]} Single-fraction RT is advantageous in terms of time, cost, resources, and patient comfort. It should be considered as the standard dose for patients with extensive metastatic disease and a life expectancy of less than six months and for less radiosensitive primary tumors such as lung, melanoma, and sarcoma.

In patients with favorable histology, retrospective and nonrandomized evidence suggests a trend toward superiority of the higher fractionation schedules in terms of benefit in local control, with fewer in-field recurrences. ^{[1] , [5] , [6] , [7] and [8]} In the prospective SCORE-1 study, there was a statistically significant improved progression-free survival (72% at 12 months after long-course and 55% after short-course RT, P = 0.034) and local control (12-month local control rate, 77% after long-course and 61% after short-course RT, P = 0.032).5 With the ever-improving systemic treatment options for malignancies and the survival of these patients with metastatic disease showing an incremental increase with each decade, preventing recurrence of spinal cord compression becomes even more important. Long-course RT with doses of 30 Gy in 10 fractions offers no benefit compared to shorter regimens in terms of survival. However, long-course RT appears to improve local control, and there are fewer in-field recurrences, which would be an advantage in patients with favorable histology.^[5] The longer schedule of RT, 30 Gy in 10 fractions, should also be considered in the postoperative setting, subject to recovery from the surgery. There is no practical advantage in offering treatments greater or longer than 30 Gy in 10 fractions in any patient subgroup.^[9]

Similarly, in retrospective studies, for patients with limited metastases who are expected to live longer, survival is associated with tumor type, ambulatory status, slower development of motor deficits, and long-course RT.^[10] The six factors demonstrated on multivariate analysis to be significant for survival outcome by Rades et al1 are primary tumor histology, visceral metastases, other extensive bone metastases, ambulatory status before RT, interval between tumor diagnosis and MSCC, and length of time in developing motor deficits. RT dose does not appear to affect the outcome in patients with low scores on these prognostic systems, while a longer-course RT may be effective in patients scoring highly.1

As recommended in the review article by Loblaw and Mitera, risk stratification of patients with MSCC is essential for deciding the dose of RT. A single fraction of 8 Gy is ideal for patients with poor prognostic factors. Randomized controlled trials of single vs. multifractionated treatments, similar to the SCORAD trial, determine the optimal dose-fractionation schedule of RT for MSCC with favorable prognostic factors.

References [PubMed ID in brackets]

1 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstens, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol,  24 21 (2006), pp. 3388–3393.

2 E. Maranzano, P. Latini, S. Beneventi, L. Marafioti, F. Piro, E. Perrucci and M. Lupattelli, Comparison of two different radiotherapy schedules for spinal cord compression in prostate cancer. Tumori,  84 4 (1998), pp. 472–477.

3 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol,  23 15 (2005), pp. 3358–3365.

4 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial. Radiother Oncol,  93 2 (2009), pp. 174–179.

5 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys,  73 1 (2009), pp. 228–234.

6 D. Rades, P.J. Hoskin, L.J. Stalpers, R. Schulte, P. Poortmans, T. Veninga, J. Dahm-Daphi, N. Obralic, I. Wildfang, R. Bahrehmand, R. Engenhart-Cabilic and S.E. Schild, Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys,  64 5 (2006), pp. 1452–1457.

7 D. Rades, L.J. Stalpers, T. Veninga, V. Rudat, R. Schulte and P.J. Hoskin, Evaluation of functional outcome and local control after radiotherapy for metastatic spinal cord compression in patients with prostate cancer. J Urol,  175 2 (2006), pp. 552–556.

8 D. Rades, T. Veninga, L.J. Stalpers, R. Schulte, P.J. Hoskin, P. Poortmans, S.E. Schild and V. Rudat, Prognostic factors predicting functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord compression in breast cancer patients. Int J Radiat Oncol Biol Phys,  64 1 (2006), pp. 182–188.

9 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study. Cancer,  101 11 (2004), pp. 2687–2692.

10 D. Rades, T. Veninga, L.J. Stalpers, H. Basic, V. Rudat, J.H. Karstens, J. Dunst and S.E. Schild, Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol,  25 1 (2007), pp. 50–56.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Correspondence to: Ramachandran Venkitaraman, MD, MRCP, FRCR, Suffolk Oncology Centre, Ipswich Hospital NHS, Heath Road, Ipswich, IP4 5PD, UK; telephone: (0044) 1473704177; fax: (0044) 1473704916

Author Vitae
Dr. Venkitaraman is Consultant Clinical Oncologist, Suffolk Oncology Centre, Ipswich Hospital NHS, Ipswich, United Kingdom.

The Journal of Supportive Oncology
Volume 9, Issue 4, July-August 2011, Pages 127-128
doi:10.1016/j.suponc.2011.04.006 | Permissions & Reprints

Available online 2 July 2011.

Peer Viewpoint

Does One Size Fit All? Is There a Standard Radiation Dose for Malignant Spinal Cord Compression?

Ramachandran Venkitaraman MD, MRCP, FRCR

^, 

Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).

In this edition of the Journal of Supportive Oncology, Loblaw and Mitera have published a succinct review of trials of radiotherapy (RT) dose schedules for treating malignant spinal cord compression (MSCC). Treatment options for MSCC include surgery and RT, with the latter being the most commonly utilized option as the majority of patients are unfit to undergo surgery. This concise review of RT dose for spinal cord compression sheds light in an area where there are very few randomized controlled trials. Clinicians have historically favored multiple fraction regimens for treating patients with MSCC. The most common regimes are either 20 Gy in five fractions or 30 Gy in 10 fractions, with a single fraction of 8 Gy mainly reserved for patients with a poor performance status. Prospective studies suggest a different set of prognostic factors for deciding the dose of RT in these patients.

The histology of the primary tumor is one of the important predictive factors for outcome. Patients with myeloma, breast, prostate, and thyroid malignancies have a favorable outcome. The survival rate for patients with tumors such as lung, melanoma, and sarcoma is generally dismal.^[1] Mainly, primary tumors that are very sensitive to RT are lymphomas, myeloma, and seminomatous germ-cell tumors, as well as breast and prostate cancers. Gastrointestinal tract cancer, lung cancer, renal tumors, sarcomas, and gynecological tumors are considered to have poor radiosensitivity.

Randomized trials, especially in patients with unfavorable tumor histology, do not show any superiority for fractionated treatments compared to a single fraction of 8 Gy. ^{[2] , [3] and [4]} Single-fraction RT is advantageous in terms of time, cost, resources, and patient comfort. It should be considered as the standard dose for patients with extensive metastatic disease and a life expectancy of less than six months and for less radiosensitive primary tumors such as lung, melanoma, and sarcoma.

In patients with favorable histology, retrospective and nonrandomized evidence suggests a trend toward superiority of the higher fractionation schedules in terms of benefit in local control, with fewer in-field recurrences. ^{[1] , [5] , [6] , [7] and [8]} In the prospective SCORE-1 study, there was a statistically significant improved progression-free survival (72% at 12 months after long-course and 55% after short-course RT, P = 0.034) and local control (12-month local control rate, 77% after long-course and 61% after short-course RT, P = 0.032).5 With the ever-improving systemic treatment options for malignancies and the survival of these patients with metastatic disease showing an incremental increase with each decade, preventing recurrence of spinal cord compression becomes even more important. Long-course RT with doses of 30 Gy in 10 fractions offers no benefit compared to shorter regimens in terms of survival. However, long-course RT appears to improve local control, and there are fewer in-field recurrences, which would be an advantage in patients with favorable histology.^[5] The longer schedule of RT, 30 Gy in 10 fractions, should also be considered in the postoperative setting, subject to recovery from the surgery. There is no practical advantage in offering treatments greater or longer than 30 Gy in 10 fractions in any patient subgroup.^[9]

Similarly, in retrospective studies, for patients with limited metastases who are expected to live longer, survival is associated with tumor type, ambulatory status, slower development of motor deficits, and long-course RT.^[10] The six factors demonstrated on multivariate analysis to be significant for survival outcome by Rades et al1 are primary tumor histology, visceral metastases, other extensive bone metastases, ambulatory status before RT, interval between tumor diagnosis and MSCC, and length of time in developing motor deficits. RT dose does not appear to affect the outcome in patients with low scores on these prognostic systems, while a longer-course RT may be effective in patients scoring highly.1

As recommended in the review article by Loblaw and Mitera, risk stratification of patients with MSCC is essential for deciding the dose of RT. A single fraction of 8 Gy is ideal for patients with poor prognostic factors. Randomized controlled trials of single vs. multifractionated treatments, similar to the SCORAD trial, determine the optimal dose-fractionation schedule of RT for MSCC with favorable prognostic factors.

References [PubMed ID in brackets]

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Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Correspondence to: Ramachandran Venkitaraman, MD, MRCP, FRCR, Suffolk Oncology Centre, Ipswich Hospital NHS, Heath Road, Ipswich, IP4 5PD, UK; telephone: (0044) 1473704177; fax: (0044) 1473704916

Author Vitae
Dr. Venkitaraman is Consultant Clinical Oncologist, Suffolk Oncology Centre, Ipswich Hospital NHS, Ipswich, United Kingdom.