Raghu Rajan

Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer

BackgroundEighty percent of all breast cancers and almost 90% of breast cancer deaths occur among post-menopausal women. We used a nested case control design to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer occurrence among women over 65 years of age. The cyclooxygenase (COX)-2 enzyme is expressed more in breast cancers than in normal breast tissue. COX-2 inhibition may have a role in breast cancer prevention.MethodsIn the Canadian province of Quebec, physician services are covered through a governmental insurance plan. Medication costs are covered for those ≥ 65 years of age and a publicly funded screening program for breast cancer targets all women 50 years of age or older. We obtained encrypted data from these insurance databases on all women ≥ 65 years of age who filled a prescription for COX-2 inhibitors, non-selective NSAIDs (ns-NSAIDs), aspirin, or acetaminophen between January 1998 and December 2002. Cases were defined as those women who have undergone mammography between April 2001 and June 2002 and had a diagnosis of breast cancer within six months following mammography. Controls included those who have undergone mammography between April 2001 and June 2002 without a diagnosis of any cancer during the six months following mammography. The exposure of interest, frequent NSAID use, was defined as use of ns-NSAIDs and/or COX-2 inhibitors for ≥ 90 days during the year prior to mammography. Frequent use served as a convenient proxy for long term chronic use.ResultsWe identified 1,090 cases and 44,990 controls. Cases were older and more likely to have breast cancer risk factors. Logistic regression models adjusting for potential confounders showed that frequent use of ns-NSAIDs and/or COX-2 inhibitors was associated with a lower risk of breast cancer (OR: 0.75, 95% confidence interval 0.64–0.89). Results were similar for COX-2 inhibitors (0.81, 0.68–0.97) and ns-NSAIDs (0.65, 0.43–0.99), when assessed separately. Frequent use of aspirin at doses > 100 mg/day in the year prior to mammography was also associated with a lower risk of breast cancer (0.75, 0.64–0.89). However, use of aspirin at doses ≤ 100 mg/day did not have any association with breast cancer (0.91, 0.71–1.16).ConclusionWomen who use NSAIDs or doses of aspirin > 100 mg frequently may have a lower risk of breast cancer.

Phase III Multi-Institutional Trial of Adjuvant Chemotherapy With Paclitaxel, Estramustine, and Oral Etoposide Combined With Long-Term Androgen Suppression Therapy and Radiotherapy Versus Long-Term Androgen Suppression Plus Radiotherapy Alone for High-Risk Prostate Cancer: Preliminary Toxicity Analysis of RTOG 99-02

PURPOSE Long-term androgen suppression plus radiotherapy (AS+RT) is standard treatment of high-risk prostate cancer. A randomized trial, Radiation Therapy Oncology Group trial 9902, was undertaken to determine whether adjuvant chemotherapy with paclitaxel, estramustine, and etoposide (TEE) plus AS+RT would improve disease outcomes with acceptable toxicity. METHODS AND MATERIALS High-risk (prostate-specific antigen 20-100 ng/mL and Gleason score >or=7; or Stage T2 or greater, Gleason score 8, prostate-specific antigen level <100 ng/mL) nonmetastatic prostate cancer patients were randomized to AS+RT (Arm 1) vs. AS+RT plus four cycles of TEE (Arm 2). TEE was delivered 4 weeks after RT. AS continued for 2 years for both treatment arms. RT began after 8 weeks of AS began. RESULTS The Radiation Therapy Oncology Group 9902 trial opened January 11, 2000. Excess thromboembolic toxicity was noted, leading to study closure October 4, 2004. A total of 397 patients were accrued, and the data for 381 were analyzable. An acute and long-term toxicity analysis was performed. The worst overall toxicities during treatment were increased for Arm 2. Of the 192 patients, 136 (71%) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 (37%) of 189 patients on Arm 1. Statistically significant increases in hematologic toxicity (p < 0.0001) and gastrointestinal toxicity (p = 0.017) but not genitourinary toxicity (p = 0.07) were noted during treatment. Two Grade 5 complications related to neutropenic infection occurred in Arm 2. Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2. At 2 and 3 years after therapy completion, excess long-term toxicity was not observed in Arm 2. CONCLUSION TEE was associated with significantly increased toxicity during treatment. The toxicity profiles did not differ at 2 and 3 years after therapy. Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer.

Very low-dose warfarin prophylaxis to prevent thromboembolism in women with metastatic breast cancer receiving chemotherapy: an economic evaluation.

PURPOSE A recent double-blind, randomized trial demonstrated that very low-dose warfarin (VLDW) reduced the incidence of venous thromboembolism (VTE) without increasing the rate of bleeding in women with metastatic breast cancer receiving chemotherapy. We have evaluated the economic impact on the health care system of using VLDW in such patients. METHODS The records of patients entered onto the trial and a simultaneous, fully allocated, costing model for a tertiary care hospital in Hamilton, Canada were used to determine the difference in costs associated with the care of patients with and without VLDW. RESULTS The cost of providing VLDW was

Human papillomavirus testing with Pap triage for cervical cancer prevention in Canada: a cost-effectiveness analysis

21,854 (Canadian dollars) per 100 patients. This therapy led to a reduction in costs of

A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: Final results of radiation therapy oncology group phase 3 randomized trial NRG oncology RTOG 9902

24,297 per 100 patients, thus saving the health care system

Bladder conservation treatment in the elderly population: results and prognostic factors of muscle-invasive bladder cancer.

2,443 per 100 patients. In the sensitivity analysis, VLDW prophylaxis still did not increase health care costs unless the cost of VLDW was greatly increased, the cost of treating thromboembolic episodes was markedly reduced, or the incidence of either VTE or bleeding with VLDW was increased above the rates observed in the trial. CONCLUSION We conclude that for women receiving chemotherapy for metastatic breast cancer, the benefits of VLDW can be realized without increased health care costs.

Tolerance of radiotherapy and chemotherapy in elderly patients with bladder cancer.

BackgroundRecently published results from a large randomized trial (Canadian Cervical Cancer Screening Trial study group) suggest that human papillomavirus testing followed by Pap smear-based triage for human papillomavirus positive women may be an effective way to screen women for cervical cancer. We determined the potential cost-effectiveness of including human papillomavirus tests for cervical cancer screening for Canada and three provinces: Alberta, Newfoundland and Ontario.MethodsWe developed four Markov decision models using data from relevant Canadian and provincial studies and databases. The models were used to determine the number of false positive test results, cancers, lifetime costs and life-expectancy for 27 different screening strategies that varied by age to begin screening (18 or 25 years), screening interval (one, two, three, or five years) and whether the currently recommended strategy (screening every year from age 18 until 21 and then every three years afterwards with conventional Paps) was conducted prior to age 25. Strategies were compared using incremental cost-effectiveness ratios.ResultsScreening strategies beginning at age 18 were associated with a substantial increase in the number of false-positive test results but only small differences in the number of cancers compared to the same strategy conducted beginning at age 25. Strategies of human papillomavirus testing first, followed by triage with Pap smears were associated with lower costs and greater increases in life-expectancy than the currently recommended screening strategy in Canada.ConclusionA strategy of human papillomavirus testing beginning at age 25, with Pap triage for women with positive human papillomavirus results may be more effective at reducing cervical cancer at a lower cost than the current recommended strategy for screening in Canada.

Breast cancer stage at time of detection in women with systemic lupus erythematosus

PURPOSE Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

Contemporary outcome and management of patients who had an aborted cystectomy due to unresectable bladder cancer

Objectives:To report the long-term results of bladder conservation strategies in elderly patients with muscle-invasive bladder cancer and evaluate the different factors affecting locoregional control and patient survival. Methods:We reviewed the records of 39 elderly patients aged 70 or older, treated with curative intent with radiotherapy, with or without chemotherapy after transurethral resection of bladder for T2-T4aN0 carcinoma of the bladder. Twenty-seven men and 12 women were identified with a median age of 78 (range 70–87). Sixteen of the patients had a previous history of superficial bladder cancer. Twenty-five patients had T2 lesions, 13 patients had T3 lesions, and 1 patient had T4a lesion. The majority of patients were unsuitable for surgery because of medical reasons (67%), whereas the others refused radical cystectomy (33%). Patients were treated with radical radiation therapy with or without chemotherapy. Results:At a median follow-up time of 35.5 months for patients at risk, the 5-year overall survival is 28.9% for all stages, 31.9% for T2 lesions, and 26.8% for T3-T4a lesions. Significant prognostic factors for overall survival on univariate analysis were performance status and age. Five-year cause-specific survival is 37.5% for all stages, 41.5% for T2 lesions, and 34.7% for T3-T4a lesions. No significant prognostic factors for cause-specific survival were indentified on univariate analysis. Toxicity was acceptable. Conclusion:Younger age and good performance status were favorable prognostic factors for overall survival. Bladder conservation strategies achieved satisfactory results and were well-tolerated in this elderly population with invasive bladder cancer.

An international cohort study of cancer in systemic lupus erythematosus.

Bladder-sparing radiotherapy with concurrent chemotherapy may be a reasonable alternative to cystectomy in patients with invasive bladder cancer. The purpose of this study was to determine the tolerance of combined treatment in elderly patients. In this retrospective study, the records of patients 70 or more years of age with stage T2-T4a, N0, M0 disease who were treated with bladder-sparing regimens between 1985 and 2000 were examined for toxicity. Of 149 consecutive patients treated for cancer of the bladder, 14 patients met eligibility criteria. The median age was 79 years. At a median follow-up of 17 months, the median survival was 19 months. All patients had at least mild toxicity, with 6 of 14 patients having grade III to IV toxicity. Grade III to IV toxicities included one patient with grade IV neutropenia, three with grade III gastrointestinal toxicities, one patient with grade III urinary frequency, one patient with grade IV ureteral obstruction who required stent placement, and one episode of hydration-induced grade III heart failure. Two of 14 patients stopped chemotherapy and 5 patients required dose reductions for toxicity. The observed rates of toxicity compare favorably with studies of bladder-sparing therapy in patients with median ages less than 70 years. Our study shows that bladder-sparing radiotherapy with concurrent chemotherapy is feasible in patients 70 or more years of age, and should be considered for such patients if they are inoperable or strongly wish to avoid cystectomy.