N. Mohammed

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial

Summary Background Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. Methods The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. Findings Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI −3·2% to 13·7%]). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Interpretation Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Funding Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.

BACKGROUND AND PURPOSE A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule. MATERIALS AND METHODS 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed. RESULTS 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0 months and 2 year overall survival was 50%. CONCLUSION These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

Purpose To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

How do lung cancer specialists follow their patients with stage III non-small cell lung cancer (NSCLC) after definitive treatment? - A short report

Although pretreatment evaluations are well defined for the diagnosis of radically treatable NSCLC, we have very little data about the follow-up of these patients after completion of therapy, especially for stage III patients. No documented standards for surveillance were set in the NCCN, ACCP or ESMO guidelines. In order to determine the standard practice patterns of lung specialists, a survey was done. Physicians were asked which tests they do for pretreatment evaluation and also on asymptomatic patients during their post-treatment follow-up. The survey was sent to 192 centres which were part of the EORTC Lung Cancer Group. Thirty-eight centres from 12 different countries replied. Results showed that almost all the centres are doing very similar pretreatment evaluation procedures in stage III NSCLC. In the post-treatment follow-up setting, results were more varied in terms of frequency and type of scans used. The most commonly used test was a computed tomography (CT) of the chest and abdomen at 3 months post-treatment. Positron emission tomography (PET)/CT and magnetic resonance imaging (MRI) of the brain with contrast were done only in symptomatic patients. This audit suggests that one CT scan at 3 months after the end of radical treatment has become a standard with little evidence showing it is better than a chest radiography (CXR). These data should be used to encourage research into molecular parameters or new imaging techniques that could be tested as more sensitive methods of picking up relapse in radically treated stage IIIA patients who has a high relapse rate in the first 12 months.

Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer

BACKGROUND Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I-II non-small cell lung cancer. AIM To determine whether low dose gemcitabine increased event-free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. METHODS Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) weekly gemcitabine. RESULTS Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49-88)years and 67 (63%) were male. 86 (81%) were PS 0-1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p=0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild. CONCLUSION No evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low.

PO-0667: Cardiac toxicity in lung cancer patients after chemo-radiotherapy (CART): a pilot study

Purpose/Objective: To determine if a weekly cone-beam CT (CBCT) is enough to evaluate the entire tumor inclusion and the reproducibility throughout the radiation course treatment in lung cancer. Materials and Methods: Thirty-six lung cancer patients were treated with image-guided radiotherapy (IGRT) on an Elekta Synergy Beam Modulator linear accelerator. The GTV included the tumor and the positive nodes in PET-CT and pathologic analysis. The PTV was configured with the GTV and a margin of 0.7 cm – 1 cm in all directions. In our protocol of lung cancer treatment, prior to each radiotherapy fraction we make one cone-beam CT every day on the first five days of treatment using automated softtissue registration. The positional errors of the reference image in relation to the acquired image (given in terms of translation movements) were obtained. No rotations were permitted. The average of these translational movements in the three axes (x, y, z) was calculated. This average was applied from the sixth day of treatment until the end. Weekly image guidance was registered resulting in at least 10 CBCT scans for each patient. The deviations in the three axes in every weekly CBCT with respect to the average were analyzed (Tx, Ty, Tz) Results: The graphics summarize the result of our analysis. In 29 patients (80.6%) the mean value of the difference between the positional errors compared to the average was: x = (0.19 ± 0.14) cm, y = (0.21 ± 0.14) cm, z = (0.27 ± 0.16) cm. All these values were less than 0.5cm and were considered correct for the suitable treatment of the patients. The shifts in the z axis showed more variability compared to the other axes mainly related to breathing movements. Nevertheless this z axis variability did not influence on the entire tumor inclusion and the set up reproducibility. In the other 7 patients (19.4%) we obtained a greater difference in either axes, and a CBCT more often than once a week was evaluated by the physician. Conclusions: Our preliminary results showed that in most lung cancer patients treated with IGRT, once an average is calculated after the first five days of treatment, a weekly cone-beam CT is enough to evaluate the entire tumor inclusion and the reproducibility throughout the radiation treatment.