Joseph L. Pater

Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial

BACKGROUND External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS After stratification by tumour size (< or = 10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS Median follow-up was 3.3 years (range 0.27-5.6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5-30], p=0.01). Tumour size and anatomical site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment (p=0.0481). INTERPRETATION Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomical site of the tumour.

Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial.

The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP).

Psychometric properties and responsiveness of the EORTC Quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer

The QLQ-C30, a health-related quality of life questionnaire developed for use in patients with cancer, has been previously validated in patients with lung cancer and head and neck cancer. In this study, further validation was carried out for 535 patients, including patients with breast cancer (n=143) and ovarian cancer (n=111) for whom there is no previously published validation, as well as patients with lung cancer (n=121). All patients were entered in one of two trials of anti-emetics to prevent chemotherapy-induced emesis. The QLQ-C30 was completed before chemotherapy and on day 8 after chemotherapy. The factor structure in patients with breast and ovarian cancer was similar to that previously described. Interdomain correlations, in the entire group, were strongest for the physical and role function domains and the fatigue, pain and global quality of life.domains before and after chemotherapy. In addition, after chemotherapy, social function was also strongly correlated with fatigue and global quality of life. These correlations were not always of equal strength in the breast, ovarian and lung groups, suggesting that there may be differences between these groups. The responsiveness of the QLQ-C30 in the presence of widely metastatic, as compared with locoregional, disease showed changes in the expected directions (i.e., diminished function in physical and social role functions and in global quality of life, with greater fatigue and pain in patients with metastatic disease). Eight days after chemotherapy, decreases were seen in physical, role and social functioning and in global quality of life, and there was greater fatigue, nausea and vomiting compared with before chemotherapy. Patients with breast cancer had better physical, role and social functioning, and less fatigue and pain than patients with ovarian cancer. This result is expected, since many of the patients with breast cancer had early stage disease, whereas those with ovarian cancer had advanced stage disease. Mean scores for patients with lung cancer were between the other two groups, in keeping with the mixture of early and advanced stage disease in these patients. There was a strong correlation between ECOG performance status scores and several domains of the QLQ-C30; these were all in the expected directions. The results of this study confirm those in earlier studies on patients with lung cancer, and provide new information on patients with breast and ovarian cancer. In addition, the QLQ-C30 is responsive to the effects of chemotherapy and of metastatic disease.

Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis

Background— Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events. Methods and Results— We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID. From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16 070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen (P=0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events (P for interaction=0.034). Conclusions— We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.

Quality of life scores: An independent prognostic variable in a general population of cancer patients receiving chemotherapy

This report examines the prognostic associations between QOL scores measured by the EORTC QLQ-C30 and survival in a large heterogeneous population of cancer patients. Eight hundred and fifty-one cancer patients who were to receive chemotherapy were enrolled in two National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) antiemetic trials. All patients completed the EORTC QLQ-C30 immediately prior to their first chemotherapy. Survival data were available and obtained for 474 of 639 patients (74%). Coxs proportional hazards model was used to assess the independent impact of QOL and demographic variables on survival. Presence of metastatic disease, diagnosis of lung or ovarian cancer, ECOG performance status, global quality of life and emotional functioning were significantly associated with survival. Global QOL was predictive in all patients, in subgroups of patients with metastatic disease, with breast and lung cancer and other tumour types. In patients with low global quality of life scores, patients with low emotional functioning ratings lived longer than did patients with high emotional functioning ratings. Patients with high global QOL live significantly longer than do patients with low global QOL. The relationship between emotional functioning in patients with low global QOL and survival needs confirmation.

Enrollment of Older Patients in Cancer Treatment Trials in Canada: Why is Age a Barrier?

PURPOSE To evaluate the enrollment of older patients (>/= 65 years) in Canadian cancer treatment trials and compare accrual of older patients in Canada and the United States. PATIENTS AND METHODS A retrospective analysis of the number of older patients enrolled in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) treatment trials between 1993 and 1996 was performed. These rates were compared with the corresponding rates in the general population of patients who were >/= 65 years old and had cancer, obtained from Statistics Canada, and those published by the Southwest Oncology Group (SWOG) in the United States. RESULTS Between 1993 and 1996, 4,174 patients were enrolled onto 69 NCIC CTG trials of 16 tumor types. Older patients accounted for 22% of trial enrollees, compared with 58% of the Canadian population with cancer. This discrepancy existed in all cancer types except for multiple myeloma. The percentages of older patients enrolled were also analyzed by study type: 15% in adjuvant trials, 25% in metastatic trials, 29% in investigational new drug trials, 24% in phase I trials, and 21% in supportive care trials. The overall proportion of older patients enrolled onto Canadian trials (22%) was slightly lower than that in SWOG trials (25%). CONCLUSION Age remains a barrier for accrual onto cancer treatment trials, even when reimbursement is not an issue. Strategies to overcome this barrier, including the implementation of trials specifically tailored to patients aged >/= 65 years, are prudent in light of our aging population.

Assessment of Quality of Life in MA.17: A Randomized, Placebo-Controlled Trial of Letrozole After 5 Years of Tamoxifen in Postmenopausal Women

PURPOSE To evaluate the impact of letrozole compared with placebo after adjuvant tamoxifen on quality of life (QOL) in the MA.17 trial. METHODS Patients completed the Short Form 36-item Health Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL) at baseline, 6 months, and annually. Mean change scores from baseline were compared between groups for summary measures and domains. A response analysis compared the proportion of patients who demonstrated an important change in QOL. RESULTS Of 5,187 randomly assigned women in the trial, 3,612 (69.9%) participated in the QOL substudy: 1,799 were allocated to placebo and 1,813 were allocated to letrozole. No differences were seen between groups in mean change scores from baseline for the SF-36 physical and mental component summary scores at 6, 12, 24, and 36 months. Small (< 0.2 standard deviations) but statistically significant differences in mean change scores from baseline were seen for the SF-36 domains of physical functioning (12 months), bodily pain (6 months) and vitality (6 and 12 months), and the MENQOL vasomotor (6, 12, and 24 months) and sexual domains (12 and 24 months). On the response analysis, a significant difference was seen between groups for the bodily pain domain (percentage of patients reporting a worsening of QOL, 47% placebo v 51% letrozole; P = .009) and the vasomotor domain (22% placebo v 29% letrozole; P = .001). CONCLUSION Letrozole did not have an adverse impact on overall QOL. Small effects were seen in some domains consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis.

Effect of postchemotherapy nausea and vomiting on health-related quality of life

Abstract The purpose was to measure the effects of postchemotherapy nausea and vomiting (PCNV) on health-related quality of life (HQL) in patients receiving either moderately or highly emetogenic chemotherapy. The study sample consisted of 832 chemotherapy-naive patients with cancer who received either moderately or highly emetogenic chemotherapy as part of multicenter trials of new antiemetics. The patients completed the self-report European Organization for Research and Cancer (EORTC) core Quality of Life Questionnaire (QLQ-C30) before chemotherapy (baseline) and 1 week (day 8) and 2–4 weeks after chemotherapy. They also completed a self-report nausea and vomiting (NV) diary for 5–7 days after chemotherapy. To determine the effects of PCNV on HQL, the change in scores between the baseline and day 8 HQL assessments was calculated for each domain and symptom in the QLQ-C30 and compared in four subgroups of patients: those with both nausea and vomiting, those with nausea but no vomiting, those with no nausea but with vomiting, and those with neither nausea nor vomiting. The group with both nausea and vomiting showed statistically significantly worse physical, cognitive and social functioning, global quality of life, fatigue, anorexia, insomnia and dyspnea as compared to the group with neither nausea nor vomiting (0.0001<P<0.05). Patients with only nausea but no vomiting tended to have less worsening in functioning and symptoms than those having both nausea and vomiting. Increased severity of vomiting (>2 episodes) was associated with worsening of only global quality of life and anorexia as compared with 1–2 episodes of vomiting (0.0001<P<0.01). By 2–4 weeks after chemotherapy all HQL scores had either returned to their baseline levels or were better than baseline. PCNV adversely affects several quality-of-life domains, but patients with only nausea experience less disruption than do those with both nausea and vomiting. Patients with 1–2 episodes of vomiting experience almost the same degree of disruption of HQL as do patients with more than 2 episodes of vomiting.

Effect of daily etidronate on the osteolysis of multiple myeloma.

Progressive bone disease in multiple myeloma frequently leads to osteolysis, bone resorption, pathologic fractures, vertebral compression, and hypercalcemia. We conducted a double-blind study in 173 newly diagnosed multiple myeloma patients of etidronate disodium (EHDP), a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity. The patients were randomly assigned to receive oral EHDP 5 mg/kg/d or placebo until death or discontinuation due to intolerance or refusal. The extent of vertebral deformity was measured by a vertebral index as well as height. The frequency of pathologic fractures, hypercalcemia, and bone pain was regularly assessed, as well as size and number of osteolytic lesions. All patients received melphalan and prednisone daily for 4 days every 4 weeks as the primary chemotherapy for their disease. Although the repeated measures analysis showed a significant height loss, there was no difference between treatment arms (P = .98). There was no significant difference in bone pain, episodes of hypercalcemia, or development of pathologic fractures. Patients on EHDP showed less deterioration in their vertebral index, but this difference only approached statistical significance (P = .07). We conclude that EHDP therapy used in this dosage schedule does not have a clinically significant impact in multiple myeloma.

Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors

PURPOSE We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. PATIENTS AND METHODS A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institutes Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. RESULTS The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. CONCLUSION This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.