Allan Price

Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non–Small-Cell Lung Cancer

PURPOSE To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

European Organisation for Research and Treatment of Cancer Recommendations for Planning and Delivery of High-Dose, High-Precision Radiotherapy for Lung Cancer

PURPOSE To derive recommendations for routine practice and clinical trials for techniques used in high-dose, high-precision thoracic radiotherapy for lung cancer. METHODS A literature search was performed to identify published articles considered both clinically relevant and practical to use. Recommendations were categorized under the following headings: patient selection, patient positioning and immobilization, tumor motion, computed tomography and [18F]fluorodeoxyglucose-positron emission technology scanning, generating target volumes, radiotherapy treatment planning, treatment delivery, and scoring of response and toxicity. The American College of Chest Physicians grading of recommendations was used. RESULTS Recommendations were identified for each of the recommendation categories. Although most of the recommended techniques have not been evaluated in multicenter clinical trials, their use in high-precision thoracic radiotherapy and stereotactic body radiotherapy (SBRT) appears to be justified on the basis of available evidence. CONCLUSION Recommendations to facilitate the clinical implementation of high-precision conformal radiotherapy and SBRT for lung tumors were identified from the literature. Some techniques that are considered investigational at present were also highlighted.

Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer

PURPOSE Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. PATIENTS AND METHODS Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. RESULTS Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. CONCLUSION Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.

Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.

PURPOSE Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. PATIENTS AND METHODS Cohorts of NSCLC patients currently smoking > or = 10 cigarettes per day for > or = 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. RESULTS Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 microg/mL for 150 mg and 300 mg, respectively. CONCLUSION The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases : a phase II study of the EORTC Lung Cancer Group (08965)

This study was performed to evaluate the activity of single-agent temozolomide in two groups of chemotherapy-naïve non-small cell lung cancer (NSCLC) patients, with (12 patients) and without (13 patients) brain metastases (BM). Patients in both groups were treated with temozolomide 200 mg/m(2)/day, administered orally for 5 consecutive days of a 28-day cycle. Treatment was continued for up to six cycles, disease progression or unacceptable toxicity. The median number of received cycles was only one in the group with and two in the group without BM, and early disease progression was the main reason for treatment discontinuation. Toxicity was moderate-in the group of patients with BM, the most frequently observed grade 3 or 4 side-effects included thrombocytopenia (17%), granulocytopenia (17%), lethargy (17%); other neurological (17%) and other genitourinary toxicity (17%). Patients without BM experienced anaemia (15%), thrombocytopenia (23%), nausea (15%) and lethargy (15%). This trial was designed according to Simon one-sample two-stage testing procedure and both groups of patients were assessed separately. No objective response was observed in either group and the study was closed after the first step of accrual with the conclusion of a lack of therapeutic activity of single-agent temozolomide in patients with stage IV NSCLC.

International comparisons of survival from lung cancer: pitfalls and warnings.

Population-based survival data can provide valuable comparative data on outcome but should be interpreted with caution. Differences in data collection and analysis, patient and tumor characteristics and treatment options can have an impact on reported results. Ideally, data from the whole population, including clinical-only diagnoses, should be reported and the methods of case identification described. The relative survival rates should preferably be given. Data on patient characteristics such as age, sex, ethnicity and socioeconomic deprivation should be described, together with tumor details such as pathology and clinical stage. Whenever possible, details on the use of treatments should be reported.

Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer

PURPOSE Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). RESULTS The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). CONCLUSION In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

Variations in Target Volume Definition for Postoperative Radiotherapy in Stage III Non–Small-Cell Lung Cancer: Analysis of an International Contouring Study

PURPOSE Postoperative radiotherapy (PORT) in patients with completely resected non-small-cell lung cancer with mediastinal involvement is controversial because of the failure of earlier trials to demonstrate a survival benefit. Improved techniques may reduce toxicity, but the treatment fields used in routine practice have not been well studied. We studied routine target volumes used by international experts and evaluated the impact of a contouring protocol developed for a new prospective study, the Lung Adjuvant Radiotherapy Trial (Lung ART). METHODS AND MATERIALS Seventeen thoracic radiation oncologists were invited to contour their routine clinical target volumes (CTV) for 2 representative patients using a validated CD-ROM-based contouring program. Subsequently, the Lung ART study protocol was provided, and both cases were contoured again. Variations in target volumes and their dosimetric impact were analyzed. RESULTS Routine CTVs were received for each case from 10 clinicians, whereas six provided both routine and protocol CTVs for each case. Routine CTVs varied up to threefold between clinicians, but use of the Lung ART protocol significantly decreased variations. Routine CTVs in a postlobectomy patient resulted in V(20) values ranging from 12.7% to 54.0%, and Lung ART protocol CTVs resulted in values of 20.6% to 29.2%. Similar results were seen for other toxicity parameters and in the postpneumectomy patient. With the exception of upper paratracheal nodes, protocol contouring improved coverage of the required nodal stations. CONCLUSION Even among experts, significant interclinician variations are observed in PORT fields. Inasmuch as contouring variations can confound the interpretation of PORT results, mandatory quality assurance procedures have been incorporated into the current Lung ART study.

What Is the Role of Radiotherapy in Malignant Pleural Mesothelioma

OBJECTIVE A review of the evidence supporting the use of radiotherapy in patients with mesothelioma was performed. METHODS Relevant publications were searched for on Medline. RESULTS In a Medline search on radiotherapy and mesothelioma, 611 hits were obtained. A limited number of prospective phase II trials of radiotherapy as part of trimodality protocols for early disease and in the palliation of pain were found, along with three small randomized controlled trials of port-site prophylaxis. CONCLUSION No randomized data exist to support the use of radiotherapy after radical surgery, although there are a large number of publications describing its use as an integral part of therapy, including seven phase II studies. One ongoing trial is randomizing patients to radiotherapy or not after extrapleural pneumonectomy. None of these studies provided any assessment of radiotherapy independent of the other modalities investigated, nor did any formally assess intensity-modulated radiotherapy. There have been several reports of excessive toxicity with this technique, and its use should be limited to phase I studies until the basis of this toxicity is better understood. Three trials have looked at port-site prophylaxis, one supporting its use and two showing no evidence of benefit. Two studies addressed pain control prospectively, one showing definite but short-lived benefits. Implications. Radiotherapy is widely used in treating mesothelioma with little supporting evidence. More randomized trials are required to justify this use in all three common settings for its use.

Acute radiation pneumonitis after postmastectomy irradiation: Effect of fraction size

Prior to 1982 the standard radiation tissue absorbed dose administered to the chest wall following mastectomy was 40.0-42.5 Gy in 10 alternate day fractions over 4 weeks. From 1982 the standard maximum dose was 45.0 Gy administered in 20 daily fractions over 4 weeks. On review of the records of the 770 patients treated between 1979 and 1984, 19 (2.5%) had symptoms of acute radiation pneumonitis, 7/484 (1.4%) treated by the earlier technique and 12/286 (4.2%) by the later technique (X2 = 4.56, P less than 0.05). The mean 4 cm depth doses on the chest wall were 33.98 Gy and 36.84 Gy respectively in the earlier and later populations (t = 5.06, P less than 0.001) and 33.62 Gy and 38.30 Gy in those developing acute pneumonitis. Comparison of these two schedules gives an alpha/beta ratio of 8.5 Gy. It is suggested that the sparing of symptomatic acute reactions in human lung by smaller doses per fraction may be less than currently believed.