Important News Briefs: New Data Reported in Breast, Renal Cell, Head and Neck, and Lung Cancer

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The 2013 European Cancer Congress (ECC), held September 27 to October 1 in Amsterdam, was jointly sponsored by the European Society of Medical Oncology, the European Cancer Organization, and the European Society of Radiation Oncology. With the Congress theme being “Reinforcing Multidisciplinarity,” ECC 2013 featured 3,176 scientific abstracts, 121 late-breaking abstracts, and hundreds of lectures and special programs. The ASCO Post has covered key presentations with longer news articles, but here we bring our readers short summaries of other abstracts of interest.

Zoledronic Acid in Early Breast Cancer

In the phase III NEOZOTAC trial conducted in 247 early breast cancer patients, the addition of bisphosphonates to neoadjuvant chemotherapy (docetaxel, doxorubicin, cyclophosphamide) did not enhance the rates of pathologic complete response or clinical response, reported Ayoub
, of Leiden University Medical Center in The Netherlands, and colleagues.1 Rates of pathologic complete response were 18% with chemotherapy alone and 18% with chemotherapy plus zoledronic acid.

In premenopausal and perimenopausal women, pathologic complete response rates for chemotherapy alone and chemotherapy plus zoledronic acid were 22% and 19%, respectively, and in postmenopausal women, they were 10% and 17%, respectively. While neither of these differences was statistically significant, the investigators felt more research is needed in postmenopausal women. Survival data were not yet mature.

Bevacizumab Plus Endocrine Therapy for Advanced Breast Cancer

The LEA study failed to demonstrate a statistically significant increase in progression-free survival with the addition of bevacizumab (Avastin) to endocrine therapy as first-line treatment for advanced breast cancer.2 Median progression-free survival was 14.4 months for endocrine therapy alone and 19.3 months for endocrine therapy plus bevacizumab (P = .126)

No differences according to subgroups were observed. Adding bevacizumab as first-line therapy also had no impact on overall survival, which was 52 months in each arm, but overall response rates were almost doubled (41% vs 22%; P < .001).

“Taking into account the higher toxicity with bevacizumab in addition to endocrine therapy, the overall risk-benefit analysis remains unfavorable. The study of this combination by the [Cancer and Leukemia Group B (CALGB)] should be further informative, said Sibylle Loibl, MD, Associate Professor of Gynecology at the University of Frankfurt, Germany, who presented the study.

Dovitinib for Renal Cell Carcinoma

The investigational oral multitargeted tyrosine kinase inhibitor dovitinib had disappointing results as third-line therapy in renal cell carcinoma, failing to meet the primary endpoint of progression-free survival vs sorafenib (Nexavar), according to an interim analysis of an open-label phase III trial.3 Patients enrolled in the trial had shown disease progression despite prior vascular endothelial growth factor (VEGF)/mammalian target of rapamycin (mTOR)-targeted therapies.

The “positives” of the trial are acceptable safety with dovitinib, and that it is a landmark trial for future third-line studies in renal cell carcinoma. Lead author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, said that more effective drugs are needed for patients whose disease progresses after treatment with VEGF-targeted therapies and mTOR inhibitors.

The phase III GOLD trial compared dovitinib vs sorafenib, a drug approved for second-line treatment of renal cell carcinoma. Patients enrolled in the trial had metastatic renal cell carcinoma and received one prior VEGF-targeted therapy and one prior mTOR inhibitor. All patients had shown disease progression within 6 months of their last targeted therapy.

As of March 2011, 570 patients were enrolled; 284 were randomly assigned to dovitinib and 286 to sorafenib. The interim data were from a cutoff of April 2013.

At baseline, about 23% were classified as poor risk according to MSKCC criteria and between 35% and 42% had bone metastasis. Sunitinib (Sutent) was used as prior VEGF therapy in 90% of patients, and everolimus (Afinitor) was the predominant prior mTOR inhibitor (> 85% of patients).

At the time of analysis, 495 patients were off study, mainly due to progressive disease. The primary endpoint of progression-free survival by central review was not met. Median progression-free survival was 3.7 months for dovitinib vs 3.6 months for sorafenib, a nonsignificant difference. Median progression-free survival by investigator assessment was 3.9 months for both arms. Subgroup analysis of progression-free survival showed no significant difference between the two arms. Median overall survival was 11.1 months for dovitinib and 11 months for sorafenib.

Nausea, diarrhea, and vomiting were the most common adverse events with dovitinib. Hypertension, hand/foot syndrome, and alopecia were more common in the sorafenib group.

Formal discussant of this trial, James Larkin, PhD, FRCP, Consultant Medical Oncologist at The Royal Marsden Hospital, London, said the study confirms that sorafenib is a relevant benchmark for new therapies in this setting. However, predictive markers for response are greatly needed.

Everolimus in Papillary Renal Cell Carcinoma

The mTOR inhibitor everolimus showed clinical efficacy for the initial treatment of advanced papillary renal cell carcinoma, according to the phase II results of the RAPTOR trial presented by Bernard J. Escudier, MD, Head of the Immunotherapy Unit at the Institut Gustave Roussy, Villejuif, France.4 RAPTOR is the first prospective study that investigated the impact of a targeted agent, everolimus, in patients with papillary renal cell carcinoma; it is approved for patients who progress after treatment with sunitinib or sorafenib. Papillary carcinomas make up 10% to 15% of renal cell cancers and can develop as individual or multiple tumors, appearing either in the same kidney or in both kidneys.

In the open-label study, 92 treatment-naive patients received everolimus 10 mg/day. The 6-month progression-free survival was 58.7% in the per-protocol analysis, and 34.9% by central review. Progression-free survival was 7.8 months and 3.7 months, respectively. At least half of the patients were alive at 20 months.

Recurrence Score in Rectal Cancer

In patients with rectal cancer treated with surgery, the 12-gene Oncotype DX recurrence score assay may accurately predict risk of recurrence, ­Marlies S. Reimers, MD, a PhD student in the Department of Surgery at Leiden University in The Netherlands, reported at the meeting.5

The 308 stage II and III patients from the Dutch total mesorectal excision trial had been treated with total mesorectal excision surgery alone, without neoadjuvant or adjuvant treatment. Recurrence score was determined for 297 patients. At a median follow-up of 11 years, recurrence score predicted the risk of recurrence (P = .011), the risk of distant recurrence (P = .030), and rectal cancer–specific survival (P = .007).

The effect of the recurrence score was most prominent in stage II rectal cancer and attenuated with more advanced stages. In stage II patients, the 5-year recurrence risk ranged from 12% in the low recurrence score group to 53% in the high recurrence score group; 5-year rectal cancer–specific mortality ranged from 5% to 37%, respectively.

The investigators concluded that the recurrence score may be especially clinically useful in patients with stage II rectal cancer, by identifying high-risk patients who could benefit from adjuvant chemotherapy, and excluding low-risk patients.

Altered Fractionation for Head and Neck Cancer

Compared with standard radiation, the use of altered-fractionation radiotherapy increased overall survival in patients with locally advanced head and neck cancers in a meta-analysis presented by Pierre Blanchard, MD, a radiation oncologist from the Institut Gustave Roussy, Villejuif, France.6 “The improvement in survival is marked for patients in the hyperfractionated regimen, with an absolute benefit of 8.1% at 5 years,” he reported.

Dr. Blanchard and colleagues examined randomized trials comparing standard radiation therapy with altered-fractionation radiotherapy with or without concomitant chemotherapy in patients with local head and neck squamous cell carcinomas. Fractionation was defined as either standard (5 fractions per week for 7 weeks) or altered therapy, which could have been either hyperfractionated (10 fractions per week for 7 weeks resulting in a higher dose); accelerated (same dose given over 6 weeks); or very accelerated (low dose given in about 3 weeks). The researchers collected data from 31 trials representing more than 11,500 patients.

After 7 years of follow-up, the higher dose intensity of altered-fractionation radiotherapy improved outcomes. “The hyperfractionated [regimen] is the most effective in terms of overall survival. Indeed, in this group of trials the risk of death is reduced by 18% by the use of hyperfractionated radiotherapy, with 41% of patients alive at 5 years compared to 33% in the [standard-fractionation radiotherapy] group. While the acute side effects of [altered-fractionation radiotherapy] are increased compared to those experienced by patients on [standard-fractionation radiotherapy], the late side effects are comparable and, overall, side effects are more than compensated for by the significant increase in survival in the [altered-fractionation radiotherapy] group,” Dr. Blanchard said.

Lung Cancer Vaccine as Maintenance

Immunotherapy with an investigational tumor cell vaccine (belagenpumatucel-L [Lucanix]) failed to improve survival vs placebo when used as maintenance therapy in a phase III study of patients with advanced non–small cell lung cancer (NSCLC) without disease progression (responding or stable disease) after chemotherapy.7

“Most tumors use [transforming growth factor] (TGF)-beta to evade the immune system. Activated T- and B-cells are refractory to TGF-beta inhibition,” explained lead author
Giuseppe Giaccone, MD, PhD, Associate Director of Clinical Research at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC (formerly of the National Cancer Institute).

The trial was conducted in eight countries at 73 clinical sites and enrolled 532 patients (42 with stage IIIA and 490 with stage IIIB/IV) who had not shown disease progression on front-line therapy. At 4 to 17 weeks following chemotherapy, patients were randomly assigned in a 1:1 ratio to double-blind therapy with the vaccine or placebo as maintenance therapy.

The vaccine is composed of four different allogeneic NSCLC cell lines genetically modified to block TGF-beta. The cells are irradiated and cryopreserved until the vaccine is used. The vaccine was given as 18 monthly injections followed by two quarterly injections.

At 6 months of follow-up, overall survival was 20.3 months in the vaccine arm vs 17 months in the placebo arm, which was much higher than anticipated for placebo. Median overall survival is typically about 10.4 months for patients with stage IV disease given a chemotherapy doublet, Dr. Giaccone said. In this study, there were patients with stage IIIA and IIIB disease who did better, he added.

An exploratory subgroup analysis showed that patients enrolled within 12 weeks of chemotherapy had a trend toward improved survival in the vaccine arm. “In several subgroups of patients randomized within 12 weeks, the results were positive enough to warrant another study,” Dr. Giaccone noted.

The rate of serious adverse events was low, with only five patients experiencing one of these events. The most common adverse events were local reactions, including injection site reaction, erythema, induration, rash, and local effects.

Patient Selection for Lung Cancer CT Screening

According to a late-breaking abstract, the most efficient use of annual lung cancer computed tomography (CT) screening is in people between the ages of 55 and 80 with at least 30 pack-years of smoking and who quit within 15 years, reported Harry J. de Koning, MD, PhD, Professor of Epidemiology at Erasmus University Medical Center, Rotterdam, The Netherlands.8

Dr. de Koning and colleagues modeled a hypothetical cohort of 100,000 people based on the U.S. National Lung Screening Trial (NLST), which showed a 20% reduction in mortality with CT screening of high-risk populations.

 “If you go above that strategy, you exceed the harms, with more radiation exposure, more overdiagnosis and overtreatment, and higher cost,” he said.

Dr. de Koning and his co-investigators used five different models to estimate the harms and benefits in the study population assuming they were born in 1950 and followed from ages 45 to 90. They evaluated 576 possible scenarios and reported on the 26 considered most efficient using the NLST scenario.

In the study, triennial screening programs reduced lung cancer mortality by 5% to 6%, biennial screening programs by 7% to 10%, and annual screening programs by 11% to 21%.

If screening were limited to the group they identified (aged 55–80; 30 pack-years; quitting within the past 15 years), 19.3% of the cohort would be screened at least once; 287,000 CT screens would be obtained; and 1971 screen-detected cases would be found, 50% of them detected at an early and treatable stage. This would lead to a 14% reduction in lung cancer mortality (avoiding 520 deaths), and 5,500 life-years gained. The conclusion was that 550 screens are needed to avoid one death.

These benefits must be balanced against extending screening to groups with less stringent criteria, which would result in 330,000 CT exams, 66,000 false-positive results, and an estimated overdiagnosis rate of 4% (190 lung cancers), as well as 24 deaths due to radiation exposure. ■

Disclosure: Drs. Loibl, Charehbili, Larkin, and Reimers reported no potential conflicts of interest. Dr. Escudier has served in a consulting or advisory role for AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Dr. Motzer has had a consultant or advisory role with Pfizer and has received research funding from Astellas Pharma, AVEO, GlaxoSmithKline, Novartis, and Pfizer.


1. Charehbili A, Van de Ven S, Liefers GJ, et al: Clinical and pathological response after neoadjuvant chemotherapy with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer. 2013 European Cancer Congress. Abstract 1858. Presented September 29, 2013.

2. Loibl S, De la Haba J, von Minckwitz G, et al: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer. Final analysis of the LEA study. 2013 European Cancer Congress. Abstract 1851. Presented September 28, 2013.

3. Motzer R, Szczylik C, Vogelzang NJ, et al: Phase 3 trial of dovitinib vs sorafenib in patients with metastatic renal cell carcinoma after 1 prior VEGF-pathway targeted and 1 prior mTOR inhibitor therapy. 2013 European Cancer Congress. Presented September 29, 2013. Abstract LBA 34.

4. Escudier B, Bracarda S, Maroto JP, et al: Open-label phase II trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. 2013 European Cancer Congress. Abstract 2706. Presented September 29, 2013.

5. Reimers MS, Kuppen PJK, Lee M, et al: Validation of the 12-gene colon cancer recurrence score assay as a predictor of recurrence risk in stage II and III rectal cancer patients. 2013 European Cancer Congress. Abstract LBA1. Presented September 28, 2012.

6. Blanchard P, Lacas B, Bourhis J, et al: Meta-analysis of radiotherapy in head and neck carcinomas: An update. 2013 European Cancer Congress. Abstract LBA26. Presented September 28, 2013.

7. Giaccone G, Bazhenova L, Nemunaitis J, et al: A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer. 2013 European Cancer Congress. Abstract LBA 2. Presented September 28, 2013.

8. De Koning HJ, Plevritis SK, Mexa R, et al: Benefits and harms of computed lung cancer screening programs for high risk populations—using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide. 2013 European Cancer Congress. Abstract 14. Presented September 30, 2013.