Bryan J. Schneider

Definitive and Adjuvant Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline

PURPOSE The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on external-beam radiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Because of its relevance to the American Society of Clinical Oncology (ASCO) membership, ASCO endorsed the guideline after applying a set of procedures and a policy that are used to critically examine and endorse guidelines developed by other guideline development organizations. METHODS The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO expert panel was convened and endorsed the guideline. The ASCO guideline approval body, the Clinical Practice Guideline Committee, approved the final endorsement. RESULTS The recommendations from the ASTRO guideline, published in Practical Radiation Oncology, are clear, thorough, and based on the most relevant scientific evidence. The ASCO Endorsement Panel endorsed the guideline and added qualifying statements. RECOMMENDATIONS For curative-intent treatment of locally advanced NSCLC, concurrent chemoradiotherapy improves local control and overall survival compared with sequential chemotherapy followed by radiation. The standard dose-fractionation of radiation is 60 Gy given in 2-Gy once-daily fractions over 6 weeks. There is no role for the routine use of induction therapy before chemoradiotherapy. Current data fail to support a clear role for consolidation therapy after chemoradiotherapy; however, consolidation therapy remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy. Important questions remain about the ideal concurrent chemotherapy regimen and optimal management of patients with resectable stage III disease.

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-Kit-positive, extensive-stage small-cell lung cancer.

BACKGROUND The prognosis for patients with extensive-stage small-cell lung cancer remains poor. This trial was designed to evaluate irinotecan/cisplatin plus maintenance imatinib in patients with c-Kit-positive disease (the transmembrane receptor c-Kit is the product of the c-KIT protooncogene). PATIENTS AND METHODS Immunohistochemistry for c-Kit was performed before enrollment. Treatment consisted of irinotecan 65 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 on day 1 and every 21 days for 4 cycles. Imatinib was administered at 400 mg twice a day until progression or unacceptable toxicity occurred. RESULTS Fourteen patients were enrolled. Slow accrual led to early study termination. Six patients did not begin treatment with imatinib because of disease progression, persistent toxicity, or referral for radiation therapy. Eight patients had a partial response with irinotecan/cisplatin and received imatinib. The median number of weeks on imatinib was 6.1 (range, 4.1-25.1 weeks). Reasons for imatinib discontinuation included disease progression (n = 7) and persistent neutropenia (n = 1). No objective responses to imatinib were evident, but 3 patients (21%) exhibited stable disease for 12, 15, and 25 weeks. The median progression-free survival was 4.3 months (95% CI, 2.9-4.8 months). The median overall survival was 7.8 months (95% CI, 5.7-10.0 months). The irinotecan/cisplatin regimen was well tolerated (grade 1/2 neutropenia, 29%; anemia, 43%; thrombocytopenia, 14%; and diarrhea, 29%), except in 1 patient with grade 3 vomiting. Imatinib toxicity included grade 1/2 nausea in 50% of the patients, peripheral edema in 75% of the patients, grade 3 fatigue in 13% of the patients, and neutropenia in 13% of the patients. CONCLUSION Despite the selection of tumors expressing c-Kit, imatinib did not appear to delay disease progression after response to chemotherapy. However, this trial was underpowered because of its early termination. Although disease stability with imatinib was evident in 3 patients and the therapy was well tolerated, this approach does not appear to warrant further clinical study.

Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site

The purposes of this study were to evaluate efficacy and toxicity of the combination of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site (CUP).

Phase II Study of Celecoxib and Docetaxel in Non-small Cell Lung Cancer (NSCLC) Patients with Progression after Platinum-Based Therapy

Introduction: To evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy. Methods: Patients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate. Results: Twenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0–25%) and the 6-month survival rate was 59% (95% CI 37–80%). Median survival time was 6.9 months (95% CI, 2.8–15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15–57%) and 1% (95% CI, 0–10%), respectively. The most frequent grade ≥3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial. Conclusions: The addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel.

Non–Small-Cell Lung Cancer: Treatment of Late Stage Disease: Chemotherapeutics and New Frontiers

Systemic therapy should be considered in patients with advanced non-small cell lung cancer (NSCLC) who are no longer amenable to local therapies. Systemic therapy has been shown to improve survival and preserve quality of life in patients with a reasonable performance status. In unselected patients, the standard of care for initial therapy remains platinum-based chemotherapy. At progression, further treatment typically consists of the sequential administration of single-agent therapy, which has also been shown to improve survival and reduce cancer-related symptoms. Molecular biomarkers are essential to guide targeted agents. This analysis requires ample tumor DNA; thus adequate biopsy samples are critical to guide therapeutic options. More biomarkers are currently being validated and may potentially have specific targeted therapy. In the near future, it is likely that rapid multiplexed genotype testing will help reduce the need for large amounts of tumor for analysis and will promote personalized cancer therapy. We review recent changes in the definition of stage IV NSCLC and review current and future systemic therapeutic approaches for patients with advanced disease.

Phase II trial of sunitinib maintenance therapy after platinum-based chemotherapy in patients with extensive-stage small cell lung cancer

Introduction: The prognosis for patients with extensive-stage small cell lung cancer remains poor. This trial was designed to evaluate the efficacy and toxicity of maintenance sunitinib after platinum-etoposide chemotherapy. Methods: Patients who demonstrated objective tumor response or stable disease after four cycles of platinum plus etoposide chemotherapy were eligible. Sunitinib was given at 50 mg daily for 4 weeks of a 6-week cycle until disease progression or unacceptable toxicity. The primary end point was 4-month progression-free survival (PFS) rate from initiation of sunitinib. Results: Sixteen patients were enrolled. Responses to platinum-etoposide were complete response (CR)/partial response (PR)/stable disease (SD) = 3/11/2. The median number of weeks on sunitinib was 4 (range: 1.4–20). Reasons for sunitinib discontinuation were disease progression (50%), toxicity (31%), and patient request (19%). Median PFS from the start of sunitinib was 2.5 months (95% confidence interval [CI], 0.8–3.1). Further accrual would have failed to reach the target PFS rate, so the study was terminated. There were no objective responses to sunitinib, but four patients (25%) had disease stability for 15, 15, 17, and 20 weeks. Median PFS and overall survival from the start of chemotherapy were 6.2 months (95% CI, 4.1–6.5) and 8.2 months (95% CI, 6.2–14.7), respectively. Grade 3 to grade 4 toxicity included thrombocytopenia (25%), fatigue (19%), muscle weakness (13%), and hypothyroidism (6%). Conclusions: Sunitinib did not seem to maintain disease stability after response to chemotherapy. Sunitinib was discontinued in half of patients due to toxicity or request to stop therapy. Although disease stability with sunitinib was noted in four patients, this approach does not seem to warrant further clinical study.

Differentiation between carcinoid and sarcoid with F-18 FDG PET and In-111 pentetreotide.

Abstract: A patient who presented with weight loss and recurrent left lower lobe pneumonia was diagnosed with endobronchial carcinoid. Chest CT scan demonstrated extensive mediastinal and hilar lymphadenopathy suggesting stage IIIB disease, but radionuclide imaging with In-111 pentetreotide and F-18 FDG PET diagnosed 2 distinct pathologic processes based on functional differences between neuroendocrine tumors (expressing somatostatin receptors) and sarcoidosis (intensely FDG-avid). The possible association of carcinoid with sarcoidosis and sarcoid-like reactions in regional lymph nodes should always be considered, and the staging process should include both anatomic and functional imaging and biopsy confirmation of suspected metastatic lesions.

Advances in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by early metastatic spread and responsiveness to initial therapy. The incidence of SCLC has been declining in the United States in parallel with the decreasing prevalence of cigarette smoking. Limited stage disease is potentially curable with chemoradiotherapy followed by cranial irradiation. Extensive stage disease is incurable, but systemic chemotherapy can improve quality of life and prolong survival. Nearly all patients relapse with chemoresistant disease. Molecularly targeted therapy has failed to yield convincing clinical benefits. Nevertheless, many biologically rational strategies, including immune checkpoint inhibition, show promise in ongoing clinical trials.

Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in Patients With Biomarker-Selected Non–Small-Cell Lung Cancer

PURPOSE Overexpression of COX-2 correlates with advanced stage and worse outcomes in non-small-cell lung cancer (NSCLC), possibly as a result of elevated levels of COX-2-dependent prostaglandin E2 (PGE2). Exploratory analyses of studies that used COX-2 inhibitors have demonstrated potentially superior outcome in patients in whom the urinary metabolite of PGE2 (PGE-M) is suppressed. We hypothesized that patients with disease defined by PGE-M suppression would benefit from the addition of apricoxib to second-line docetaxel or pemetrexed. PATIENTS AND METHODS Patients with NSCLC who had disease progression after one line of platinum-based therapy, performance status of 0 to 2, and normal organ function were potentially eligible. Only patients with a ≥ 50% decrease in urinary PGE-M after 5 days of treatment with apricoxib could enroll. Docetaxel 75 mg/m(2) or pemetrexed 500 mg/m(2) once every 21 days per the investigator was administered with apricoxib or placebo 400 mg once per day. The primary end point was progression-free survival (PFS). Exploratory analysis was performed regarding baseline urinary PGE-M and outcomes. RESULTS In all, 101 patients completed screening, and 72 of the 80 who demonstrated ≥ 50% suppression were randomly assigned to apricoxib or placebo. Toxicity was similar between the arms. No improvement in PFS was seen with apricoxib versus placebo. The median PFS for the control arm was 97 days (95% CI, 52 to 193 days) versus 85 days (95% CI, 67 to 142 days) for the experimental arm (P = .91). CONCLUSION Apricoxib did not improve PFS, despite biomarker-driven patient selection.