Andrea Bezjak

Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases.

PURPOSE To compare pain relief among various dose-fractionation schedules of localized radiotherapy (RT) in the treatment of painful bone metastases. METHODS AND MATERIALS A systematic search for randomized trials of localized RT on bone metastases using different dose fractionations was performed using Medline (1966 to February 2001) and other sources. The primary outcomes of interest were complete and overall pain relief. The studies were divided into three groups: comparisons of doses given as a single fraction, single vs. multiple fractions, and comparisons of doses given as multiple fractions. The complete and overall pain responses for studies comparing single vs. multiple fractions were pooled. Exploratory analyses of the dose-response relationship, using the biologic effective dose (alpha/beta = 10), were performed using results from all three groups of trials. RESULTS Two trials comparing single vs. single, eight trials comparing single vs. multiple, and six trials comparing multiple vs. multiple fractions were included. The complete and overall response rates from studies comparing single-fraction RT (median 8 Gy, range 8-10 Gy) against multifraction RT (median 20 Gy in 5 fractions, range 20 Gy in 5 fractions to 30 Gy in 10 fractions) were homogeneous and allowed pooling of data. Of 3260 randomized patients in seven studies, 539 (33.4%) of 1613 and 523 (32.3%) of 1618 patients achieved a complete response after single and multifraction RT, respectively, giving a risk ratio of 1.03 (95% confidence interval 0.94-1.14; p = 0.5). The overall response rate was in favor of single-fraction RT (1011 [62.1%] of 1629) compared with multifraction (958 [58.7%] of 1631; risk ratio 1.05, 95% confidence interval 1.00-1.11, p = 0.04), reaching statistical significance. However, when the analysis was restricted to evaluated patients alone, the overall response rates were similar for single fraction and multifraction RT, at 1011 (72.7%) of 1391 and 958 (72.5%) of 1321, respectively (risk ratio 1.00; p = 0.9). Exploratory analyses by biologic effective dose did not reveal any dose-response relationship among the fractionation schedules used (single 8 Gy to 40 Gy in 15 fractions). Of the other results and observations reported in the trials, only the re-irradiation rates were consistently different between the treatment arms (more frequent re-irradiation in lower dose arms among trials reporting re-irradiation rates). CONCLUSION Meta-analysis of reported randomized trials shows no significant difference in complete and overall pain relief between single and multifraction palliative RT for bone metastases. No dose-response relationship could be detected by including data from the multifraction vs. multifraction trials. Additional data are needed to evaluate the role of re-irradiation and the impact of RT on other treatment end points such as quality of life.

Neurocognitive Function and Progression in Patients With Brain Metastases Treated With Whole-Brain Radiation and Motexafin Gadolinium: Results of a Randomized Phase III Trial

PURPOSE To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. RESULTS Four hundred one patients were enrolled (251 with non-small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P =.062) and improved neurologic function as assessed by a blinded events review committee (P =.048). CONCLUSION Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

PURPOSE This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.

PURPOSE This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain. RESULTS Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01). CONCLUSION Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.

Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group

PURPOSE Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patients quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. PATIENTS AND METHODS Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. RESULTS Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. CONCLUSION Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.

A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial

7022 Background: In phase II studies, erlotinib has shown single agent activity in a number of tumor types, including NSCLC. NCIC CTG BR.21 is a randomized, placebo-controlled trial undertaken to determine if the Epidermal Growth Factor Receptor (EGFR) inhibitor erlotinib (Tarceva) prolongs survival in NSCLC patients after 1st or 2nd line chemotherapy. METHODS Eligibility criteria included stage IIIB/IV NSCLC, PS 0-3, 1-2 chemotherapy regimens (at least 1 combination regimen if < 70 yrs). Patients were stratified by center, PS (0,1 v 2,3), response to chemo (CR, PR v SD v PD), number of prior regimens (1 v 2), platinum (yes v no), and were randomized 2:1 to receive erlotinib 150 mg po/day or placebo. The 10 endpoint was survival with 20 endpoints of progression free survival (PFS), response, toxicity and QOL. RESULTS From Nov/01-Feb/03, 731 pts entered the study (median age 61y; 64% male; 67% PS 0,1). 50% had received 2 prior regimens, 93% had received platinum and 37% prior taxanes. Patient characteristics were well balanced. Overall response to erlotinib was 8.9% (95% CI: 6.6-12.0%, p < 0.001), median duration 34.2 wks. Statistically significant and clinically relevant differences were observed for overall survival and PFS. The planned primary QOL analysis, time to deterioration of patient reported symptoms (TTDS), showed statistically and clinically meaningful benefit for patients randomized to erlotinib. Rash and diarrhea were the most frequent symptoms; 5% of patients discontinued erlotinib for toxicity compared to 2% of patients on placebo. CONCLUSION This is the first randomized trial to confirm that a Her1/EGFR inhibitor prolongs survival after 1st or 2nd line chemotherapy for NSCLC. [Figure: see text] [Table: see text].

Trimodality Therapy With Induction Chemotherapy Followed by Extrapleural Pneumonectomy and Adjuvant High-Dose Hemithoracic Radiation for Malignant Pleural Mesothelioma

PURPOSE Malignant pleural mesothelioma (MPM) remains associated with poor outcome. We examined the results of trimodality therapy with cisplatin-based chemotherapy followed by extrapleural pneumonectomy (EPP) and adjuvant high-dose (50 to 60 Gy) hemithoracic radiation therapy for MPM. PATIENTS AND METHODS We conducted a retrospective review of all patients prospectively evaluated for trimodality therapy protocol between January 2001 and December 2007 in our institution. RESULTS A total of 60 patients were suitable candidates. Histology was epithelioid (n = 44) or biphasic (n = 16). Chemotherapy regimens included cisplatin/vinorelbine (n = 26), cisplatin/pemetrexed (n = 24), cisplatin/raltitrexed (n = 6), or cisplatin/gemcitabine (n = 4). EPP was performed in 45 patients, and hemithoracic radiation therapy to at least 50 Gy was administered postoperatively to 30 patients. Completion of the trimodality therapy in the absence of mediastinal node involvement was associated with the best survival (median survival of 59 months v <or= 14 months in the remaining patients, P = .0003). The type of induction chemotherapy had no significant impact on survival. Pathologic nodal status remained a significant predictor of poor survival despite completion of the trimodality therapy. After completion of the protocol, the 5-year disease-free survival was 53% for patients with N0 disease, reaching 75% in patients with ypT1-2N0 and 45% in patients with ypT3-4N0. CONCLUSION This large, single-center experience with induction chemotherapy followed by EPP and adjuvant high-dose hemithoracic radiation for MPM shows that half of the patients are able to complete this protocol. The results are encouraging for patients with N0 disease. However, N2 disease remains a major factor impacting on survival, despite completion of the entire trimodality regimen.

Function and Health Status Outcomes in a Randomized Trial Comparing Preoperative and Postoperative Radiotherapy in Extremity Soft Tissue Sarcoma

PURPOSE Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described. PATIENTS AND METHODS One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery. RESULTS One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment. CONCLUSION The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.

Palliative Thoracic Radiotherapy for Lung Cancer: A Systematic Review

PURPOSE The optimal dose of radiotherapy (RT) to palliate symptomatic advanced lung cancer is unclear. We systematically reviewed randomized controlled trials (RCTs) of palliative thoracic RT. METHODS RCTs comparing two or more dose fractionation schedules were reviewed using the random-effects model of a freely available information management system. The relative risk and 95% CI for each outcome were presented in Forrest plots. Exploratory analysis comparing dose schedules after conversion to the time-adjusted biologically equivalent dose (BED) was performed to investigate for a dose-response relationship. RESULTS A total of 13 RCTs involving 3,473 randomly assigned patients were identified. Outcomes included symptom palliation, overall survival, toxicity, and reirradiation rate. For symptom control in assessable patients, lower-dose (LD) RT was comparable with higher-dose (HD), except for the total symptom score (TSS): 65.4% of LD and 77.1% of HD patients had improved TSS (P = .003). Greater likelihood of symptom improvement was seen with schedules of 35 Gy(10) versus lower BED. At 1 year after HD and LD RT, 26.5% versus 21.7% of patients were alive, respectively (P = .002). Sensitivity analysis suggests this survival improvement was seen with 35 Gy(10) BED schedules compared with LDs. Physician-assessed dysphagia was significantly greater in the HD arm (20.5% v 14.9%; P = .01), and the likelihood of reirradiation was 1.2-fold higher after LD RT. CONCLUSION No significant differences were observed for specific symptom-control end points, although improvement in survival favored HD RT. Consideration of palliative thoracic RT of at least 35 Gy(10) BED may therefore be warranted, but must be weighed against increased toxicity and greater time investment.

Palliative Effect of Chemotherapy: Objective Tumor Response Is Associated With Symptom Improvement in Patients With Metastatic Breast Cancer

PURPOSE Because one of the goals of chemotherapy for metastatic breast cancer is to provide symptom palliation, we were interested in identifying the relationship between tumor shrinkage and improvement in disease-related symptoms. PATIENTS AND METHODS Three hundred patients enrolled onto a randomized trial of metastatic breast cancer formed the basis of our study. The nine most common baseline symptoms were identified and followed. Changes from baseline (improvement, stable, worsening) were defined using patient responses to a quality-of-life (QoL) questionnaire (the European Organization for Research and Treatment of Cancer EORTC QLQ-C30) as well as using graded toxicity data collected on case report forms (CRFs). The association between symptom improvement and tumor response was assessed using a linear trend test via a logistic regression model. RESULTS The most commonly reported baseline symptoms were cancer pain in 38% (CRF data) and 81% of patients (QoL data) and tiredness in 26% (CRF data) and 89% (QoL data) of patients. Three symptoms-cancer pain, shortness of breath, and abnormal mood-showed a significant relationship between improvement and objective response, using both CRF and QoL assessments. Constipation, anorexia, and nausea showed a similar trend when QoL data were used but not when CRF information was used. The converse was seen for lethargy. There was no correlation between symptom change and response for cough and insomnia. CONCLUSION For some symptoms, we found a significant association between symptom improvement and objective tumor regression. In these cases, symptom improvement was greatest in those patients who had complete or partial responses, followed by those with stable disease and then those with progressive disease. Further work in this area will be useful in determining the surrogate value of objective tumor response in identifying the efficacy of palliative chemotherapy.