Adjuvant therapy with raltitrexed in patients with colorectal cancer intolerant of 5-fluorouracil: British Columbia Cancer Agency experience.

BACKGROUND: Severe 5-FU toxicity in adjuvant therapy of colorectal cancer may require change of therapy. We retrospectively explored the safety and efficacy of adjuvant raltitrexed in patients intolerant of 5-FU. METHODS: Over a 5 year period, patients who received 5-FU and subsequent raltitrexed therapy were identified. RESULTS: There were 44 patients, (39 stage III). Median number of prior 5-FU cycles was 2. Three year relapse free and overall survival proportions for stage III patients were 70.8% and 83.6%, respectively. CONCLUSIONS: Raltitrexed adjuvant therapy can be given safely and effectively in patients where further 5-FU is contraindicated.

CHOP-R therapy overcomes the adverse prognostic influence of BCL-2 expression in diffuse large B-cell lymphoma.

BCL-2 protein expression correlates with shorter survival in patients with diffuse large B cell lymphoma (DLBCL) who are treated with CHOP chemotherapy. We report a retrospective analysis of the prognostic significance of BCL-2 status in patients who received CHOP with the addition of rituximab (CHOP-R) for DLBCL. Patients over 15 years of age with de novo, HIV negative DLBCL, without CNS involvement, and known BCL-2 protein status were identified from the BCCA Lymphoid Cancer Database. BCL-2 tumour positivity was defined as over 50% of tumour cells with BCL-2 protein expression. 140 patients who received CHOP-R were analysed. The majority (59%) of patients were over 60 years of age. Disease stage distribution was limited (22%) and advanced (78%). BCL-2 protein expression was observed in 90 (64%) cases. IPI score was similar in both BCL-2 positive and negative cases. Median follow-up time for living patients is 40 months. BCL-2 status did not predict for either progression-free or overall survival. IPI score was predictive for progression-free survival but not overall survival. The addition of rituximab to CHOP chemotherapy negates the adverse prognostic influence of BCL-2 protein expression on progression free and overall survival in DLBCL.

Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.

PURPOSE: For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). METHODS: We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with "B" symptoms or bulky [> 10 cm] disease) DLBCL. RESULTS: A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002) and overall survival (risk ratio, 0.40; 95% CI, 0.27 to 0.61, P < .0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and overall survival (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001). The benefit of treatment in the postrituximab era was present regardless of age. CONCLUSION: The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.

Curative treatment for esophageal cancer: Vancouver Island Cancer Centre experience from 1993 to 1998.

OBJECTIVES: To review outcomes after curative treatment for esophageal cancer in the Vancouver Island Cancer Centre from 1993 to 1998. Curative treatments included esophagectomy alone, and chemoradiotherapy with "selective surgery" for patients with post-treatment-positive endoscopic biopsy or less than 75% regression on computed axial tomography scan, or with resectable local recurrence. METHODS: Patients undergoing esophagectomy alone, or primary chemoradiotherapy and "selective surgery" were reviewed. This was a retrospective, nonrandomized, institutional experience. Surgical complication, relief of dysphagia, disease-specific survival rates and prognostic factors were analyzed. RESULTS: Nineteen patients underwent esophagectomy alone. A total of 56 patients underwent primary chemoradiotherapy, of whom 16 had "selective surgery". Relief of dysphagia was similar in both groups of esophagectomy patients. Exploration for "selective surgery" was performed in 12 patients after their first postchemo-radiotherapy endoscopy (two patients had unresectable disease), and in seven for relapse, one of whom died intraoperatively. Overall, the mortality rate due to surgery was 3%. Chemoradiotherapy was not associated with more frequent serious surgical complications. For patients who underwent esophagectomy alone and those who underwent chemoradiotherapy plus selective surgery, the median survival times were 12.9 and 16.4 months, respectively, and the three-year survival rates were 21% and 37%, respectively. Seventeen of 25 patients who underwent chemoradiotherapy and who survived more than two years have not required selective surgery. For the two groups of patients combined, no single prognostic factor for survival was significant in multivariate analysis, but for patients who underwent chemoradiotherapy plus selective surgery, negative endoscopic biopsy was highly significant. CONCLUSIONS: Surgical complication and disease-specific survival rates after primary chemoradiotherapy with selective surgery compare favourably with esophagectomy alone in the curative treatment of esophageal cancer. A prospective, randomized trial is necessary for the definitive evaluation of the strategy of chemoradiotherapy and selective surgery.

Raltitrexed: optimism and reality.

BACKGROUND: Raltitrexed was developed as a direct and specific inhibitor of thymidylate synthase. Early clinical trials showed similar activity to 5-fluorouracil (5-FU), mainly in metastatic colorectal cancer (MCRC). METHODS: Pharmacokinetics are summarized and Phase III adjuvant and MCRC trials of raltitrexed are reviewed. RESULTS: Response rates and overall survival with raltitrexed in MCRC are equivalent to 5-FU. Pooled analysis showed relapse free survival was 1 month longer with 5-FU compared with raltitrexed. Grade 3+ toxicity rates with raltitrexed compare favorably with 5-FU. Unexpectedly, however, treatment-related mortality (TRM) was greater with raltitrexed, mainly due to protocol violations. TRM was also greater in the adjuvant trial, leading to its discontinuation. In spite of excess TRM, much of which could have been avoided, overall survival was the same as with 5-FU. Quality of life was variously reported as better or inferior to 5-FU. CONCLUSION: The simple once every 3 week regimen of raltitrexed has not fulfilled its promise. Meanwhile, the field change in MCRC management has left little space for raltitrexed. Withdrawal of the sponsor's support has left raltitrexed without the level of continuing investigation afforded to 5-FU. The use of raltitrexed in Canada is limited to patients exhibiting intolerance - mucosal, hematological and cardiac - to 5-FU.

Clinical activity of celecoxib in metastatic malignant melanoma.

Cyclo-oxygenase-2 has been demonstrated in primary and metastatic melanoma suggesting that it may have a functional role and be a potential therapeutic target. Celecoxib, which was approved by Health Canada for familial adenomatous polyposis coli, was offered to 27 patients with surgically incurable recurrent melanoma, 87 percent of whom had stage M1c disease. In this case series, 6 patients had received prior systemic therapy and one had prior CancerVax. Tumor regressions were seen in 7 patients (2 complete regressions, 2 partial regressions, and 3 mixed stable/partial response). For all patients, median overall survival time from first incurable metastasis was 31.9 months, and median times to progressive disease and death from start of celecoxib were 4.3 months and 10.4 months, respectively. Further clinical evaluation of celecoxib in melanoma is warranted.

Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.

BACKGROUND: The British Columbia randomized radiation trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal patients with lymph node-positive breast cancer treated by modified radical mastectomy and adjuvant chemotherapy. Three hundred eighteen patients were assigned to receive no further therapy or radiation therapy (37.5 Gy in 16 fractions). Previous analysis at the 15-year follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival but that improvement in overall survival was of only borderline statistical significance. We report the analysis of data from the 20-year follow-up. METHODS: Survival was analyzed by the Kaplan-Meier method. Relative risk estimates were calculated by the Wald test from the proportional hazards regression model. All statistical tests were two-sided. RESULTS: At the 20 year follow up (median follow up for live patients: 249 months) chemotherapy and radiation therapy, compared with chemotherapy alone, were associated with a statistically significant improvement in all end points analyzed, including survival free of isolated locoregional recurrences (74% versus 90%, respectively; relative risk [RR] = 0.36, 95% confidence interval [CI] = 0.18 to 0.71; P = .002), systemic relapse-free survival (31% versus 48%; RR = 0.66, 95% CI = 0.49 to 0.88; P = .004), breast cancer-free survival (48% versus 30%; RR = 0.63, 95% CI = 0.47 to 0.83; P = .001), event-free survival (35% versus 25%; RR = 0.70, 95% CI = 0.54 to 0.92; P = .009), breast cancer-specific survival (53% versus 38%; RR = 0.67, 95% CI = 0.49 to 0.90; P = .008), and, in contrast to the 15-year follow-up results, overall survival (47% versus 37%; RR = 0.73, 95% CI = 0.55 to 0.98; P = .03). Long-term toxicities, including cardiac deaths (1.8% versus 0.6%), were minimal for both arms. CONCLUSION: For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.