Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.

BACKGROUND: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI). METHODS: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed. FINDINGS: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups. INTERPRETATION: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers. FUNDING: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.

Clinical outcomes and toxicity of proton beam radiation therapy for re-irradiation of locally recurrent breast cancer.

PURPOSE: Repeat radiation therapy (RT) using photons/X-rays for locally recurrent breast cancer results in increased short and long-term toxicity. Proton beam RT (PBRT) can minimize dose to surrounding organs, thereby potentially reducing toxicity. Here, we report the toxicity and clinical outcomes for women who underwent re-irradiation to the chest wall for locally recurrent breast cancer using PBRT. MATERIALS AND METHODS: This was a retrospective study analyzing 16 consecutive patients between 2013 and 2018 with locally recurrent breast cancer who underwent re-irradiation to the chest wall with PBRT. For the recurrent disease, patients underwent maximal safe resection, including salvage mastectomy, wide local excision, or biopsy only per surgeons recommendations. Systemic therapy was used per the recommendation of the medical oncologist. Patients were treated with median dose of 50.4 Cobalt Gray Equivalent (CGyE) in 28 fractions at the time of re-irradiation. Follow-up was calculated from the start of second RT course. Acute toxicities were defined as those occurring during treatment or up to 8 weeks after treatment. Late toxicities were defined as those occurring more than 8 weeks after the completion of therapy. Toxicities were based on CTCAE 4.0. RESULTS: The median age at original diagnosis and at recurrence was 49.8 years and 60.2 years, respectively. The median time between the two RT courses was 10.2 (0.7-20.2) years. The median follow-up time was 18.7 (2.5-35.2) months. No local failures were observed after re-irradiation. One patient developed distant metastasis and ultimately died. Grade 3-4 acute skin toxicity was observed in 5 (31.2%) patients. Four (25%) patients developed chest wall infections during or shortly (2 weeks) after re-irradiation. Late grade 3-4 fibrosis was observed in only 3 (18.8%) patients. Grade 5 toxicities were not observed. Hyperpigmentation was seen in 12 (75%) patients. Pneumonitis, telangiectasia, rib fracture, and lymphedema occurred in 2 (12.5%), 4 (25%), 1 (6.3%), and 1 (6.3%) patients, respectively. CONCLUSIONS: Re-irradiation with PBRT for recurrent breast cancer has acceptable toxicities. There was a high incidence of acute grade 3-4 skin toxicity and infections, which resolved, however, with skin care and antibiotics. Longer follow-up is needed to determine long-term clinical outcomes.

Lessons Learned From Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients.

PURPOSE: Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created. METHODS AND MATERIALS: Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy. RESULTS: Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients. CONCLUSIONS: These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation.

Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers.

BACKGROUND: Patients with multiple primary lung cancers increasingly receive multiple courses of stereotactic body radiotherapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. PATIENTS AND METHODS: We reviewed a prospective lung SBRT database of patients treated for stage I non-small-cell lung cancer between June 2004 and December 2015. RESULTS: A total of 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients who received a single course had a 3-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8-59.3), 3-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade 3 or higher toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4-88.9%], P < .0001 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively) and FFP (85.8% [95% CI, 70.7-93.5], P = .03 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively). Patients receiving synchronous SBRT had similar OS (46.4% [95% CI, 19.3-69.9%], P = .75) and similar FFP (57.5% [95% CI, 25.3-80.0%], P = .17) as single-course patients. There were no significant differences in rates of grade 3 or higher toxicity or of grade 1 or higher toxicity between single-course patients and the other groups. CONCLUSION: Patients who received either synchronous or metachronous SBRT had no significant detriment in OS or toxicity compared to single-course patients. This supports the use of SBRT in patients with multiple primary lung cancers.

The Ioban drape: a simple method to improve finger surgery safety and efficiency.

Surgery involving the fingers can be technically challenging especially when utilizing fluoroscopic imaging. The surgical field is often obscured by the remaining fingers and attempts to position the hand may expose the surgeon and assistants to additional radiation exposure. This paper describes a simple and effective technique to remove the uninvolved fingers from the surgical field allowing for a more efficient operative procedure with less radiation exposure.

Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.

INTRODUCTION: Acute dysphagia is a distressing dose-limiting toxicity occurring frequently during concurrent chemo-radiation or high-dose radiotherapy for lung cancer. It can lead to treatment interruptions and thus jeopardize survival. Although a number of predictive factors have been identified, it is still not clear how these could offer assistance for treatment decision making in daily clinical practice. Therefore, we have developed and validated a nomogram to predict this side-effect. In addition, clinical usefulness was assessed by comparing model predictions to physicians' predictions. MATERIALS AND METHODS: Clinical data from 469 inoperable lung cancer patients, treated with curative intent, were collected prospectively. A prediction model for acute radiation-induced dysphagia was developed. Model performance was evaluated by the c-statistic and assessed using bootstrapping as well as two external datasets. In addition, a prospective study was conducted comparing model to physicians' predictions in 138 patients. RESULTS: The final multivariate model consisted of age, gender, WHO performance status, mean esophageal dose (MED), maximum esophageal dose (MAXED) and overall treatment time (OTT). The c-statistic, assessed by bootstrapping, was 0.77. External validation yielded an AUC of 0.94 on the Ghent data and 0.77 on the Washington University St. Louis data for dysphagia ≥ grade 3. Comparing model predictions to the physicians' predictions resulted in an AUC of 0.75 versus 0.53, respectively. CONCLUSIONS: The proposed model performed well was successfully validated and demonstrated the ability to predict acute severe dysphagia remarkably better than the physicians. Therefore, this model could be used in clinical practice to identify patients at high or low risk.

ACR appropriateness criteria on nonsurgical treatment for non-small-cell lung cancer: poor performance status or palliative intent.

Radiation therapy (RT) plays a major role in the definitive treatment of patients with non-small-cell lung cancer who are unable to tolerate surgery. Radiation therapy alone is used primarily for early-stage (stages I and II) patients. Higher doses of RT (>65 Gy) seem to improve outcomes, and modern techniques such as stereotactic body RT have been very promising. For patients with locally advanced disease (stages IIIA and IIIB), concurrent chemotherapy and RT remains the standard of care. However, many patients cannot tolerate the regimen because of its toxicity. Sequential chemotherapy followed by RT is used in these situations. Radiation therapy alone is used for the rare patient who cannot tolerate the use of any chemotherapy because of comorbid conditions. Palliative external-beam RT is useful for patients with metastatic disease, causing symptoms such as dyspnea, cough, hemoptysis, postobstructive pneumonia, and pain. Hypofractionation has been attempted as a means to provide more rapid and convenient symptom relief, but results from clinical trials are conflicting on whether it is an improvement over standard palliative fractionation. Endobronchial brachytherapy provides relief for patients with endobronchial lesions causing obstruction or hemoptysis. Palliative chemotherapy improves survival and quality of life in patients with metastatic disease compared with best supportive care. Chemotherapy also improves outcomes as a second-line and third-line treatment for patients in whom previous regimens have failed. Biologic therapies such as erlotinib and bevacizumab have been incorporated into every phase of chemotherapy with good results.