ASTRO Issues Guideline on Definitive and Adjuvant RT for Locally Advanced Non-Small Cell Lung Cancer

“The American Society for Radiation Oncology (ASTRO) is issuing a new guideline, “Definitive and adjuvant radiotherapy in locally advanced non-small cell lung cancer: An American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.” The guideline’s executive summary is published in the May-June issue of Practical Radiation Oncology (PRO), ASTRO’s clinical practice journal. The complete guideline, which cites 35 years of data to help guide current treatment and future research, is available online as an open-access article in PRO. The American Society of Clinical Oncology (ASCO) today issued an endorsement of ASTRO’s guideline.

“ASTRO’s guideline panel included 14 leading lung cancer oncologists in the U.S. and Canada, reviewed 74 studies from English language publications within the PubMed database, published from January 1, 1966 to March 15, 2013. The panel developed five Key Questions on the role of definitive and adjuvant radiation therapy (RT) for locally advanced non-small cell lung cancer (LA NSCLC), which represents nearly one-quarter of all lung cancer patients. In addition to the 74 studies, 27 published clinical practice guideline documents that were relevant to one or more of the five Key Questions were reviewed to ensure the guideline panel obtained all appropriate clinical trial reports.”


Stage I and II NSCLC: Removal of Whole Lung Could Work Better than Removal of Cancerous Lobe Followed by Radiation

“Patients with positive surgical margins after lobectomy and adjuvant radiation for non-small cell lung cancer had an increased risk for death compared with patients who were treated with pneumonectomy without radiation.

“ ‘We have demonstrated that positive margins are not that uncommon and occur in roughly 4% of patients receiving lobectomy for stage I or II non-small cell lung cancer [NSCLC],’ Brian C. Gulack, MD, of Duke University, said during a presentation at the American Association for Thoracic Surgery Annual Meeting. ‘Furthermore, positive margin status is associated with worse overall survival, and among patients with positive margins, adjuvant radiation therapy does not appear to provide a significant long-term survival benefit.’

“Gulack and colleagues analyzed patients with positive margins after lobectomy for stage I and stage II NSCLC from the National Cancer Data Base to determine if adjuvant radiation improved survival. Patients who underwent lobectomy without known induction therapy for NSCLC from 1998 to 2006 were grouped by margin status and assessed based on treatment and outcomes.

“Among 50,010 patients who met study criteria, 3.9% had positive margins after lobectomy. Positive margins were associated with an increased risk for death (adjusted HR = 1.46; 95% CI, 1.39-1.6).”


Adjuvant Chemotherapy Associated with Shorter Survival in LCNEC

“Patients who underwent adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinomas demonstrated poorer 3-year survival than those who did not undergo adjuvant treatment, according to study results presented at the American Association for Thoracic Surgery Annual Meeting.

“ ‘We did not see any particular subset of patients who may benefit from this treatment,’ researcher Pier Luigi Filosso, MD, of the University of Torino in Italy, said during a presentation.

“Filosso and colleagues conducted a retrospective cohort study to determine the impact of adjuvant chemotherapy in patients with resected large cell neuroendocrine carcinomas (LCNEC). The analysis included 400 patients with LCNEC who underwent surgery between 1992 and 2014 at one of 14 institutions worldwide.

“Researchers used the Kaplan-Meier method to estimate OS after resection. Propensity score for the likelihood of receipt of adjuvant chemotherapy was estimated based on patient age, gender, prior malignancy, ECOG performance status, TNM stage and year of surgery.”


NRAS & BRAF Mutational Status May Help Guide Therapy in Melanoma Patients

“A new study is suggesting that it may be important to look at mutational status when determining adjuvant treatments for melanoma patients. Researchers at the University of North Carolina (UNC) School of Medicine are now reporting that NRAS and BRAF mutations in melanoma patients should be identified early, and may need to be taken into consideration when establishing treatment paradigms.

“The results of this study were published online in the April 9, 2015 issue of JAMA Oncology.

“Researchers looked at data from the Genes, Environment, and Melanoma (GEM) Study, which included 912 patients with a median follow-up of 7.6 years. They examined tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status.  They found 13% of the patients had tumors with NRAS mutations, 30% had BRAF mutations, and 57% had neither.

“There was no statistically significant difference in the 5-year survival rates for patients with NRAS or BRAF-mutated melanoma tumors compared with survival in those patients with tumors lacking mutations. However, there were lower 5-year survival rates for patients with higher-risk tumors with mutations. The study suggested the 5-year survival rate was 73% for patients with high-risk NRAS-mutated tumors, 71% for patients with high-risk tumors with BRAF mutations, and 82% for patients with high-risk cancer and lacking either mutation.”


Ipilimumab Improves Survival in High-Risk Stage III Melanoma After Surgery

“Results of an EORTC trial appearing in The Lancet Oncology show that adjuvant Ipilimumab significantly improves recurrence-free survival in patients with completely resected stage III melanoma at high risk of disease recurrence, but that this treatment was also associated with a high rate of immune-related adverse events.

“Prof Alexander M M Eggermont of the Gustave Roussy Cancer Campus and lead author of this study says, ‘Ipilimumab has already been approved as a treatment for patients with advanced melanoma. Our intention with this study was to assess Ipilimumab as an adjuvant treatment for patients with completely resected stage III melanoma at high risk of recurrence. In my experience, this marks both the first clinical trial of an approved drug with an effect on survival in advanced melanoma in the adjuvant setting, and, in this same setting, the first to study an immune checkpoint inhibitor in the adjuvant setting. Our results show that Ipilimumab is active in the adjuvant setting, but the side-effects are considerable.’

“Between 2008 and 2011, the double-blind, phase III EORTC trial 18071 accrued 951 patients who were randomly assigned to receive either Ipilimumab (475 patients) or placebo (476 patients). All patients were included in the intention-to-treat analyses. At a median follow-up of 2.74 years, the median recurrence-free survival was 26.1 months (95% confidence interval (CI) 19.3 – 39.3) in the Ipilimumab group and 17.1 months (95% CI 13.4 – 21.6) in the placebo group (hazard ratio 0.75; 95% CI 0.64 – 0.90; p = 0.0013). The 3-year recurrence-free survival rate was 46.5% (95% CI 41.5 – 51.3) in the Ipilimumab group and 34.8% (30.1 – 39.5) in the placebo group.”


Older Early-Stage NSCLC Patients Benefit From Adjuvant Chemotherapy

“A retrospective study found that early-stage non–small-cell lung cancer (NSCLC) patients over 70 years old derive a similar benefit as younger patients from adjuvant chemotherapy following surgical resection. This suggests that age should not preclude patients from receiving adjuvant chemotherapy.

“ ‘Studies conducted in the last decade have provided evidence that adjuvant chemotherapy after surgical resection improves outcomes for patients with resected stages II and IIIA disease and selected patients with stage I (large tumor size) NSCLC,’ wrote study authors led by Apar Kishor Ganti, MD, of the University of Nebraska Medical Center in Omaha. These studies, however, have not focused specifically on elderly patients, and NSCLC has a median age of 70 years at diagnosis.

“The new study was a population-based retrospective review of 7,593 patients with stage IB to stage III NSCLC who underwent surgical resection; 2,897 (38%) were aged at least 70 years. Results of the study were published online ahead of print in Cancer.

“Among the younger patients, 31.6% received adjuvant chemotherapy, while only 15.3% of the older patients received this treatment (P .0001). Both groups saw changes in rates of adjuvant chemotherapy over time, though of different magnitudes: 9.3% of younger patients diagnosed between 2001 and 2003 received adjuvant chemotherapy, which rose by 27.8% by 2009 to 2011. In older patients, the rate was 4.5% in the earlier period and increased by 16.0%. The most common chemotherapy option used in all patients (64.6%) was carboplatin-based doublets.”


Italian Trial Shows Benefit of Dose-Dense Adjuvant Therapy With Sequential Epirubicin-Cyclophosphamide-Paclitaxel in Early Node-Positive Breast Cancer

“In an Italian 2×2 phase III trial reported in The Lancet, Del Mastro et al found that dose-dense adjuvant therapy with sequential epirubicin, cyclophosphamide, and paclitaxel (EC-P) with or without fluorouracil (5-FU) increased disease-free survival vs standard-interval therapy in early-stage node-positive breast cancer. No benefit of adding 5-FU to EC-P was observed.

“In this open-label trial, 2,091 patients from 81 Italian centers were randomly assigned 1:1:1:1 between April 2003 and July 2006 to receive adjuvant dose-dense chemotherapy every 2 weeks with pegfilgrastim (Neulasta) support with 5-FU plus EC-P (FEC-P, n = 500) or EC-P (n = 502) or standard-interval chemotherapy every 3 weeks with FEC-P (n = 544) or EC-P (n = 545). The primary endpoint was disease-free survival in the intention-to-treat population, with primary comparisons between every-2-week vs every-3-week schedules and FEC-P vs EC-P.

“Overall, patients had a median age of 51 to 53 years, 47% to 55% were postmenopausal, 59% to 63% had lumpectomy, 48% to 52% had T1 tumors, 57% to 64% had one to three positive nodes, 43% to 49% had grade 3 tumors, 21% to 24% were HER2-positive, 77% to 81% were estrogen or progesterone receptor–positive, and 43% to 50% had ≥ 20% Ki67-positive cells.

“The investigators concluded: ‘In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome.’ ”


Radiation after Prostatectomy: Sooner May Be Better

“Important news for men receiving treatment for prostate cancer: Two new studies from the University of Virginia School of Medicine have upended the widely held view that it’s best to delay radiation treatment as long as possible after the removal of the prostate in order to prevent unwanted side effects.

” ‘The common teaching has been, without clear evidence, that urinary incontinence and erectile function are worse when radiation is delivered earlier rather than later, but we didn’t see any protective effect of delayed radiation compared to earlier radiation,’ said radiation oncologist Timothy N. Showalter, MD, of the UVA Cancer Center. ‘It contradicts the clinical principle of delaying radiation as long as possible for the sake of the patient’s side effects. It really speaks against that, and that ought not to be used for a reason to delay radiation.’

“The findings inject hard facts into a debate that has long divided the medical community, with many radiation oncologists preferring adjuvant therapy – radiation given soon after prostate removal to kill off any remaining cancer cells – and many urologists preferring salvage therapy – radiation given later, when prostate-specific antigen tests suggest it’s needed. ‘Urologists tend to prefer to forgo adjuvant radiation therapy, because they fear the side effects, and radiation oncologists tend to prefer offering adjuvant radiation therapy because they fear the risk of metastasis [cancer spreading to other sites in the body],’ Showalter said.”


Puma Biotechnology Initiates Phase II Trial of PB272 in Early Stage HER2-Positive Breast Cancer

“Puma Biotechnology, Inc. PBYI, +2.74% a development stage biopharmaceutical company, announced the initiation of a Phase II trial of Puma’s investigational drug PB272 (neratinib) for the extended adjuvant treatment of breast cancer.

“The 70 patient study will be an open label single arm Phase II trial of PB272 monotherapy administered to patients with HER2-positive early stage breast cancer who have previously received adjuvant treatment with trastuzumab. Patients will receive extended adjuvant treatment with neratinib for a period of one year. Patients will receive primary prophylaxis with high dose loperamide (16 mg per day initially) in order to attempt to reduce the neratinib-related diarrhea. The primary endpoint of the trial is reduction in the incidence and severity of diarrhea.

“ ‘We are pleased to initiate this Phase II trial,’ said Alan H. Auerbach, Chief Executive Officer and President. ‘Because the ExteNET Phase III trial was run prior to the implementation of loperamide prophylaxis in clinical trials of neratinib, in the ExteNET Phase III trial neratinib was administered without loperamide prophylaxis. The results from this Phase II study will give us a better understanding of the safety of neratinib in the extended adjuvant setting with concurrent high dose loperamide administered and, importantly, to what degree the grade 3 neratinib-related diarrhea can be reduced. We anticipate that initial results from this trial should be available by yearend 2015 and would enable us to include this data in our NDA filing for neratinib in the extended adjuvant setting, which is currently anticipated for the first quarter of 2016.’ “