Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

On the need for biopsy confirmation at suspected first recurrence of cancer.

At the time of suspected first recurrence of cancer, it is unclear whether biopsy confirmation is routinely performed, although this is a very common clinical situation. First, 20 oncologists were surveyed to ascertain the pattern of practice in our community. A questionnaire with hypothetical typical cases suspected of having recurrent cancer was distributed. Second, eligibility criteria were reviewed from investigational protocols from the National Cancer Institute (NCI) and the Eastern Cooperative Oncology Group to see whether confirmation of recurrence was specifically required in these research studies. Third, 64 cases from our own practice were reviewed retrospectively to determine our patterns and results in performing biopsies to document suspected recurrence. Finally, criteria were developed that might suggest the need for biopsy confirmation of recurrence and then retrospectively tested against our cases. There was no clear consensus among oncologists regarding the need for tissue confirmation in patients with solid tumor with suspected recurrences, although rebiopsy was routinely requested for recurrent lymphoma. Published Eastern Cooperative Oncology Group and NCI protocols reviewed did not require biopsy proof specifically of recurrence. Retrospective review of our own cases suggested that, in the absence of one of the proposed indicators, the risk of making an erroneous diagnosis without biopsy confirmation is low. It is suggested that biopsy is not routinely necessary for confirmation of recurrence in all cases of suspected recurrent solid tumors, but criteria are proposed that would help to reduce the possibility of misdiagnosis when biopsy of suspected recurrence is not performed.

Phase II Trial of Docetaxel and Carboplatin in Patients With Advanced Squamous Carcinoma of the Esophagus (E2298): A Trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Occasional complete responses have been reported in patients with squamous-cell carcinoma of the esophagus treated with carboplatin, and the inferior outcomes seen in early studies might have been the result of underdosing using BSA calculations. Docetaxel was reported to have single-agent activity in squamous-cell carcinoma of the esophagus, with a 50% response rate in a pilot study performed in South Africa. Thus, ECOG investigated the potential role of combination carboplatin using AUC-based dosing and docetaxel in patients with squamous-cell carcinoma of the esophagus. PATIENTS AND METHODS: ECOG 2298 was a multicenter, international, phase II clinical study of docetaxel and carboplatin in patients with histologically confirmed, measurable squamous-cell carcinoma of the esophagus. Docetaxel 75 mg/m(2) was infused over 1 hour on day 1 of each cycle. The carboplatin dose was calculated to an AUC of 6 and infused over 15-30 minutes immediately after the docetaxel. The regimen was repeated every 3 weeks for a total of 6 cycles or until disease progression occurred or unacceptable toxicity developed. RESULTS: A total of 32 patients were accrued, mostly men (78%) with a median age of 64 (range, 41-86). Half the patients were black and half were white. Five patients were not evaluable due to protocol violations. Of the remaining 27 patients, one (3%) achieved a complete clinical response. Four others (13%) achieved partial responses. Thirteen (41%) had stable disease and 9 (28%) had progression of disease. Overall objective response rate was 15.6% (95% CI 5.9% to 36%). The most common grade 3 and 4 toxicities were leukopenia (25/32=78%) and neutropenia (27/32=84%). Most nonhematologic toxicities were infrequent and ≤ grade 3; however, two patients experienced grade 5 toxicities; one died of bowel obstruction and another died of infection with grade 4 neutropenia. CONCLUSIONS: The high toxicity and poor efficacy shown in this study suggest that the combination of carboplatin and docetaxel in squamous-cell carcinoma of the esophagus should not be investigated further. Newer agents need to be investigated in this malignancy.

The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families.

The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation >or=10% using the Myriad II model and a DNA sample available, were studied. Individuals without deleterious point mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should be confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence >or=10%.

Breast cancer in the very young patient: a multidisciplinary case presentation.

A case is presented that exemplifies many issues and controversies in the diagnosis and treatment of breast cancer in the very young. This woman was 22 years of age at diagnosis; she initially underwent breast-conservation therapy and adjuvant chemotherapy, retained fertility, had a subsequent uncomplicated pregnancy and delivery, and 7 years later developed a local recurrence in the breast. The discussion addresses risk factors, diagnosis, and treatment of breast cancer in the young; the impact of treatment on fertility; implications regarding pregnancy, and the management of local recurrence after breast conservation.