Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.

BACKGROUND: Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. METHODS: Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. FINDINGS: 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. INTERPRETATION: Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. FUNDING: National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

Evidence for management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).

PURPOSES: This systematic review addressed the following key questions on managing small cell lung cancer (SCLC): the sequence, timing, and dosing characteristics of primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensive-stage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography (PET) for staging; treatment of mixed histology tumors; surgery; and second-line and subsequent-line treatment for relapsed/progressive disease. METHODS: The review methods were defined prospectively in a written protocol. We primarily sought randomized controlled trials that compared the interventions of interest. RESULTS: Robust evidence was lacking for all questions except PCI, for which a patient-level metaanalysis showed that PCI improves survival of SCLC patients who achieved complete response after primary therapy from 15.3 to 20.7% (p = 0.01). The case for concurrent over sequential radiation delivery rests largely on a single multicenter trial. Support for early concurrent therapy comes from one multicenter trial, but two other multicenter trials found no advantage. Metaanalysis did not find significant reductions in 2-year and 3-year mortality rates for early TRTx. Favorable results from a single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. Relevant comparative studies were nonexistent for management of mixed histology disease and surgery for early limited SCLC. PET may be more sensitive in detecting extracranial disease than conventional staging modalities, but studies were of poor quality. CONCLUSIONS: PCI improves survival among those with a complete remission to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components.

Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019.

PURPOSE: There are no published survival data after chemoradiotherapy (chemoRT) in pathologically documented stage IIIB non-small-cell lung cancer. Studies of radiotherapy (RT) alone or chemotherapy followed by RT yield 5-year survivals less than 10%. The Southwest Oncology Group (SWOG) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy, safety, and long-term outcome of replacing postinduction surgery with additional chemoRT. PATIENTS AND METHODS: Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1, T4N2, or N3 stage IIIB non-small-cell lung cancer. They had pulmonary function adequate to withstand combined-modality therapy, identical to the requirements of the previous trial with postchemoRT surgery. Induction therapy was two cycles of cisplatin plus etoposide (PE) concurrent with once-daily thoracic RT (45 Gy). In the absence of progressive disease, RT was completed to 61 Gy, with two additional cycles of cisplatin plus etoposide. RESULTS: Fifty eligible patients were accrued with tumor-node (TN) substage confirmed on central review: 18, T4N0/1; 12, T4N2; and 20, N3. Grade 4 neutropenia was the most common toxicity (32%). Grade 3/4 esophagitis occurred in 12% and 8%. Median follow-up was 52 months, and overall median survival was 15 months (10 to 22, 95% confidence interval). Three- and 5-year survivals were 17% and 15% (5-year T4N0/1, 17%; T4N2, 13%; and N3, 15%). CONCLUSION: Feasibility and long-term survival support the application of these results as a standard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared. These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials.

A case against surgery for most IIIa non-small cell lung cancer.

Stage IIIa non-small cell lung cancer remains categorically a heterogeneous hodgepodge without clear prospective mandates for clinical care. Poor outcome ensues for patients with mediastinal node-positive cancer when treated with surgery alone, but we are unclear how to define subsets that might benefit from surgery. This article reviews significant trials of surgery and chemoradiotherapy, including those using induction chemotherapy for stage III patients. While many continue to believe that chemotherapy without RT may provide equivalent pathologic complete response and survival rates, there is very little apparent difference in survival between patients managed with surgery or those managed to a higher dose of radiotherapy with concurrent chemotherapy (using an established chemotherapy regimen, 2-dimensional radiotherapy treatment planning, and a dose of only 61 Gy). If there is any benefit to surgery in the IIIa as currently staged, the benefit is very small and is counterbalanced by operative risk.

Southwest Oncology Group: two decades of experience in non-small cell lung cancer.

Over the past two decades, studies of the Southwest Oncology Group have consistently reported stable esophagitis rates despite changing scales with concurrent chest radiotherapy and cisplatin/etoposide regimens. Patient selection has perhaps contributed to increased survival over this period. The Southwest Oncology Group has incorporated surgical questions and advanced the field with a steady use of consistent therapies (ie, cisplatin/etoposide plus radiotherapy of 45 Gy [induction therapy] and cisplatin/etoposide plus at least 61 Gy) in potentially operable or unresectable disease. Further studies examining the addition of either docetaxel or novel agents to such regimens are underway.

Outcome of radiation therapy for renal transplant rejection refractory to chemical immunosuppression.

Twenty consecutive patients with kidney graft rejection refractory to chemical immunosuppression were treated with local irradiation to the transplanted renal graft (3 x 1.5 Gy). Ten patients were complete responders (median follow-up: 47 months). Six patients were partial responders and failed after 1-4 months. Four patients did not respond.

Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline.

PURPOSE: The American College of Chest Physicians (ACCP) produced an evidence-based guideline on treatment of patients with small-cell lung cancer (SCLC). Because of the relevance of this guideline to American Society of Clinical Oncology (ASCO) membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. METHODS: The ACCP guideline on the treatment of SCLC was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel updated the literature search, reviewed the content, and considered additional recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements. RECOMMENDATIONS: Surgery is indicated for selected stage I SCLC. Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at http://www.asco.org/endorsements/sclc and http://www.asco.org/guidelineswiki.

National Institutes of Health State-of-the-Science Conference Statement: Symptom management in cancer: pain, depression, and fatigue, July 15-17, 2002.

BACKGROUND: Despite advances in early detection and effective treatment, cancer remains one of the most feared diseases. Among the most common side effects of cancer and treatments for cancer are pain, depression, and fatigue. Although research is producing increasingly hopeful insights into the causes and cures for cancer, efforts to manage the side effects of the disease and its treatments have not kept pace. The challenge that faces us is how to increase awareness of the importance of recognizing and actively addressing cancer-related distress. The National Institutes of Health (NIH) convened a State-of-the-Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue to examine the current state of knowledge regarding the management of pain, depression, and fatigue in individuals with cancer and to identify directions for future research. Specifically, the conference examined how to identify individuals who are at risk for cancer-related pain, depression, and/or fatigue; what treatments work best to address these symptoms when they occur; and what is the best way to deliver interventions across the continuum of care. STATE-OF-THE-SCIENCE PROCESS: A non-advocate, non-Federal, 14-member panel of experts representing the fields of oncology, radiology, psychology, nursing, public health, social work, and epidemiology prepared the statement. In addition, 24 experts in medical oncology, geriatrics, pharmacology, psychology, and neurology presented data to the panel and to the conference audience during the first 1.5 days of the conference. The panel then prepared its statement, addressing the five predetermined questions and drawing on submitted literature, the speakers' presentations, and discussions held at the conference. The statement was presented to the conference audience, followed by a press conference to allow the panel to respond to questions from the media. After its release at the conference, the draft statement was made available on the Internet. The panel's final statement is available at http://consensus.nih.gov. CONCLUSIONS: The panel concluded that the available evidence supports a variety of interventions for treating cancer patients' pain, depression, and fatigue. Clinicians should routinely use brief assessment tools to ask patients about pain, depression, and fatigue and to initiate evidence-based treatments. Assessment should include discussion about common symptoms experienced by cancer patients, and these discussions should continue over the duration of the illness. Impediments to effective symptom management in cancer patients can arise from different sources and interactions among providers, patients and their families, and the health care system. Numerous factors could interfere with adequate symptom management. Among these factors are incomplete effectiveness of some treatments, a lack of sufficient knowledge regarding effective treatment strategies, patient reluctance to report symptoms to caregivers, a belief that such symptoms are simply a part of the cancer experience that must be tolerated, and inadequate coverage and reimbursement for some treatments. Additional research is needed on the definition, occurrence, the treatment of pain, depression, and fatigue, alone and in combination, in adequately funded prospective studies. The panel also concluded that the state of the science in cancer symptom management should be reassessed periodically.

70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808.

PURPOSE: To prospectively evaluate the feasibility of delivering 70 Gy once-daily thoracic radiotherapy (TRT), concurrent with chemotherapy, in the treatment of limited-stage small-cell lung cancer (L-SCLC). MATERIALS AND METHODS: Eligible patients received two cycles of induction paclitaxel (175 mg/m(2) on Day 1) and topotecan (1 mg/m(2) on Days 1-5) with granulocyte colony stimulating factor support, followed by three cycles of carboplatin (area under the curve = 5 on Day 1) and etoposide (100 mg/m(2) on Days 1-3). TRT (70 Gy, 2 Gy/fx/7 weeks) was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered to patients achieving a complete response or good partial response. RESULTS: Ninety percent of patients (57 of 63) proceeded to protocol TRT. There was one treatment-related fatality. Nonhematologic Grade 3/4 toxicities affecting more than 10% of patients, during or after TRT, were dysphagia (16%/5%) and febrile neutropenia (12%/4%). The response rate to all therapy was 92% and the median overall survival is 22.4 months (95% confidence interval 16.1, infinity ). Twenty-eight patients remain alive with a median follow-up of 24.7 months. CONCLUSION: 70 Gy once-daily TRT can be delivered safely in the cooperative group setting for patients with L-SCLC. Initial efficacy data are encouraging. The hypothesis that high-dose once-daily TRT results in comparable or improved survival compared with twice-daily accelerated TRT warrants testing in a Phase III trial.

Lunx is a superior molecular marker for detection of non-small cell lung cancer in peripheral blood [corrected].

The clinical management of non-small cell lung cancer (NSCLC) would benefit greatly by a test that was able to detect small amounts of NSCLC in the peripheral blood. In this report, we used a novel strategy to enrich tumor cells from the peripheral blood of 24 stage I to IV NSCLC patients and determined expression levels for six cancer-associated genes (lunx, muc1, KS1/4, CEA, CK19, and PSE). Using thresholds established at three standard deviations above the mean observed in 15 normal controls, we observed that lunx (10 of 24, 42%), muc1 (5 of 24, 21%), and CK19 (5 of 24, 21%) were overexpressed in 14 of 24 (58%) peripheral blood samples obtained from NSCLC patients. Patients who overexpressed either KS1/4 (n = 2) or PSE (n = 1) also overexpressed either lunx or muc1. Of patients with presumed curable and resectable stage I to II disease (n = 7), at least one marker was overexpressed in three (43%) patients. In advanced stage III to IV patients (n = 17), at least one marker was overexpressed in 11 patients (65%). These results provide evidence that circulating tumor cells can be detected in NSCLC patients by a high throughput molecular technique. Further studies are needed to determine the clinical relevance of gene overexpression.

Dose-volume relationship for acute side effects during high dose conformal radiotherapy for prostate cancer.

PURPOSE: To determine acute and late complications for bladder and rectum and to determine dose-volume correlations. METHODS AND MATERIALS: Sixty-four patients received definitive treatment for prostate cancer between January 1995 and December 1998 using conformal three-dimensional radiotherapy. Doses ranged from 72 to 80Gy. The acute and late side effects were gathered retrospectively, and graded according to Radiotherapy and Oncology Group criteria (RTOG). The patients were divided into two groups: or=76Gy (Group B) and had a mean follow-up of 32 and 22 months, respectively. RESULTS: No grades 3-4 acute, urinary or rectal toxicity was reported. Acute grade 2 rectal complications were seen in 10 and 18% of the patients in Groups A and B, respectively. They were observed at a mean dose of 38Gy. Acute grade 2 urinary symptoms were 33 and 47% for Groups A and B, respectively. They were seen at a mean dose of 43Gy. Acute rectal symptoms were dose-volume related. Patients without diarrhea had a mean rectal volume receiving a dose of 70Gy or more of 8.5 cm(3). However, patients with RTOG 2 diarrhea had a volume of 16.5 cm(3) (P=0.042). No dose-volume relationship for acute bladder symptoms or late complications were seen. Grades 1-2 late rectal and bladder complications were seen in 11 and 8% of the patients, respectively. None required hospital admission or transfusion. CONCLUSION: Radiotherapy to the prostate can be given at 80Gy. No grades 3-4 acute, urinary or rectal toxicity was reported. Acute rectal symptoms are dose-volume related.

Small cell lung cancer: state of the art and future perspectives.

Small cell lung cancer accounts for less than 20% of all lung cancer. The management of this distinct tumor entity differs from the more common non-small cell lung cancer. Primary prevention of smoking exposure remains the most important public health measure. Although small cell lung is an exquisitely chemosensitive disease it remains ultimately fatal for the great majority of patients. Combination chemotherapy regimens have improved response rate and survival of the last three decades. The combination of cisplatin and etoposide has been considered the standard therapy for over a decade. More intensive triplet combination chemotherapy and high-dose chemotherapy have shown improved response rates and survival. Early concomitant and accelerated radiotherapy improves survival in limited stage disease. This review summarizes the current state of the art and future perspectives in detection, staging and standard therapy of small cell lung cancer. Particular emphasis is given to the importance of concomitant and accelerated radiotherapy and consideration of dose-intensive combination chemotherapy regimens.

Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.

The role of radiotherapy and chemotherapy for curative management of medically inoperable and stage III nonsmall cell lung cancer, and radiotherapy for palliation of symptomatic disease.

Radiotherapy has an expanding role in all phases of treatment of nonsmall cell lung cancer. Evolutions in technique, such as three-dimensional conformal radiotherapy, hold the promise for more effective treatment of patients with early stage disease who are not candidates for surgical intervention. Multimodality therapy for patients with locally advanced disease is evolving rapidly, with evidence accruing as to the optimal schedules and doses of radiotherapy and combination chemotherapy. Palliative dose schedules are being refined that maximize patient comfort while providing substantial symptom relief.

Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis.

PURPOSE: In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. MATERIAL AND METHODS: We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. RESULTS: In non-small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non-lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. CONCLUSION: Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Once-daily radiotherapy to > or =59.4 Gy versus twice-daily radiotherapy to > or =45.0 Gy with concurrent chemotherapy for limited-stage small-cell lung cancer: a comparative analysis of toxicities and outcomes.

PURPOSE: The aim of this study was to compare toxicities, disease control, survival outcomes, and patterns of failure between groups of limited-stage small-cell lung cancer patients treated with once-daily versus twice-daily radiotherapy and concurrent chemotherapy. MATERIALS AND METHODS: This single-institution retrospective analysis included a comparison of two of radiotherapy regimens to planned doses of (1) > or =59.4 Gy at 1.8-2.0 Gy per once-daily fraction or (2) > or =45 Gy at 1.5 Gy per twice-daily fractions with concurrent platinum-based chemotherapy. Comparative analyses of toxicities and disease control were performed. RESULTS: A total of 71 patients were included in the present study (17 once-daily, 54 twice-daily). Patient, tumor, staging, and treatment factors were similar between the two treatment groups. Median planned radiotherapy doses were 60 Gy (range 59.4-70.0 Gy) and 45 Gy (range 45-51 Gy) for the once-daily and twice-daily groups, respectively. Acute toxicities were similar between the groups ( approximately 20% grade 3 esophagitis). At a median survival follow-up of 26.2 months (range 3.4-85.5 months), 42 patients had died. The 2-year overall survival estimates were similar at 43% and 49% for the once-daily versus twice-daily groups, respectively. Isolated in-field failures were similar between the two groups ( approximately 17%). CONCLUSION: The present analysis did not detect a statistically significant difference in acute toxicities, disease control, or survival outcomes in limited-stage small-cell lung cancer patients treated with concurrent chemotherapy and once-daily versus twice-daily radiotherapy.