Adjuvant CTX Research Articles

Tumor microsatellite-instability status to predict benefit of adjuvant chemotherapy for stage III colon cancer

4046 Background: Microsatellite instability (MSI) is an alternative pathway to colon cancer pathogenesis and may be categorized by the degree of MSI exhibited as MSI-high (MSI-H), MSI-low (MSI-L) or microsatellite stable (MSS). The aim of this study was to determine the prognostic impact MSI status on survival in stage III colon cancer. Methods: A total of 197 patients who received curative resection of stage III colon cancer from 1991 through 2002 were identified. Records of these patients were retrospectively evaluated to determine chemotherapy (CTx) use and vital status. DNA extracted from paraffin embedded tumor specimens was amplified by polymerase chain reaction using a panel of 7 markers. MSI-H was defined as instability in >40% of markers and low as instability in >0% but <40% of markers. Overall survival based on MSI and CTx status was compared using Kaplan-Meier analysis and the log-rank test and Cox multiple regression to adjust for covariates. Results: Median follow-up was 5.4 years. There were 25 (13%) MSI-H, 38 (19%) MSI-L and 134 (68%) MSS patients. Median age was 56 years (MSI-H), 65 years (MSI-L) and 62 years (MSS). 5-fluorouracil adjuvant CTx was completed in 135 (69%), not completed in 36 (18%) and unknown in 26 (13%) patients. Tumors were left sided in 56% of the cohort, 72% among MSI-H, 60% among MSI-L, 51% among MSS. 5-year overall survival after adjuvant CTx ranged 71–82% and was not significantly different among the groups. Completion of CTx improved survival among MSS, HR 0.18 (95% confidence [CI] 0.07–0.42, p<0.0001), but not among MSI- H, HR 0.83 (95% CI 0.19–3.60, p=0.79), with an intermediate effect among MSI-L, HR 0.36 (95% CI 0.09–1.47, p=0.0562). The effect of completing adjuvant CTx persisted after adjustment for age, sex, stage (IIIA, B, C), and histology, RR 0.19 (95% CI 0.089–0.41, p<0.0001), RR 0.059 (95% CI 0.009–0.39, p=0.003), RR 0.26 (95% CI 0.01–13.3, p=0.31) for MSS, MSI-L, and MSI-H, respectively. Conclusions: 5-fluorouracil based adjuvant chemotherapy did not affect overall survival in patients with stage III colon cancer who are MSI-H due to a high baseline survival rate without adjuvant therapy. Adjuvant chemotherapy did improve survival in patients who are MSS and an intermediate effect was seen in paitents who are MSI-L. No significant financial relationships to disclose.

Survival improvement by systemic chemotherapy in adult patients with recurrent glioblastoma multiforme treated with two courses of radiotherapy

1578 Background: We evaluated the added value of systemic chemotherapy (CTx) in adult patients with recurrent supratentorial glioblastoma multiforme (GBM) selected to receive local re-treatment (administered as a 2nd course of radiotherapy, RTx). Methods: Retrospective comparison of two patient cohorts treated subsequently during different time periods. All patients had histologically confirmed recurrent GBM. Minimum recurrence-free interval was 4 months. The first cohort (n=26) had surgical resection and standard postoperative external beam RTx followed by a second course of external beam RTx for recurrence (median cumulative dose 102 Gy). None of these patients ever received CTx during the whole course of disease. The more recently treated cohort (after 1999) of 19 patients also had surgical resection and 2 courses of external beam RTx (median cumulative dose 90 Gy). After primary local treatment, 9 of these patients had adjuvant nitrosourea-based CTx. At recurrence, all 19 patients received temozolomide 150–200 mg/m2/day for five days every 4 weeks in addition to RTx. Results: The cohort without CTx had less favorable baseline characteristics, because of their significantly lower median KPS at recurrence (70 vs. 90%, p<0.01) and shorter interval between primary diagnosis and recurrence (12 vs. 16 months, p<0.05). However, these patients were non-significantly younger (median age 44 vs. 50 years, p>0.05). The percentage of patients with secondary GBM was similar (21 vs. 23%, p>0.5). Median survival from re-irradiation was significantly better in the RTx plus CTx group, 9 vs. 5 months (p<0.05). In multivariate analysis, prognosis was significantly improved by CTx. Importantly, there was also an advantage when overall survival from first diagnosis was evaluated, median 24 vs. 19 months (p<0.05). Conclusion: The current data suggest that re-irradiation plus temozolomide is better than re-irradiation alone. CTx led to a prolongation of overall survival from first diagnosis by 5 months. The most intensively treated, prognostically favourable de-novo GBM patients had surgical resection, 2 courses of RTx and 2 different systemic CTx regimens. [Table: see text]

Rates and predictors of adjuvant chemotherapy use in older breast cancer patients with hormone receptor-negative disease

6020 Background: For women with hormone receptor-negative (HR-) breast cancer, chemotherapy (CTX) is the only adjuvant systemic treatment option, since hormonal therapies are largely ineffective in this patient subgroup. Older women are less likely than younger women to receive adjuvant CTX, although age alone is not a contraindication to treatment. Our objective was to identify predictors of adjuvant CTX use in older US women with HR-negative breast cancer, using population-based cancer registry data linked with Medicare claims. Methods: We identified all first primary breast cancers reported to the SEER cancer registries from 1992 through 1999. We included women age 66 and older with non-metastatic, HR- breast cancer. Chemotherapy use within 6 months of diagnosis was identified in Medicare claims. Results: Of 45,701 women diagnosed with Stage I-Stage III breast cancer, 5,081 (11%) had HR- disease. Overall, 31% of the HR- cohort received chemotherapy within 6 months of diagnosis. Adjuvant CTX use increased over time, and was negatively associated with age at diagnosis. In multivariate analysis, age remained a strong predictor of adjuvant CTX use. Women under 75 were at least 4 times more likely to receive CTX than those age 75 and older. Large tumor size, poorly differentiated tumor cells, and lymph node involvement increased the odds of receiving CTX, while greater comorbidity and lower socioeconomic status decreased these odds. Controlling for other factors, the association between year of diagnosis and adjuvant CTX was not significant. Conclusions: Among older women with HR- breast cancer, receipt of adjuvant CTX is strongly correlated with age and prognosis. Although use of adjuvant CTX increased during the 1990s, this trend was attenuated after adjusting for other factors. Further analyses will examine trends in the use specific adjuvant CTX agents, as well as CTX toxicities, in this patient population. No significant financial relationships to disclose.

Changes in survival and time to progression in metastatic breast cancer (MBC) patients enrolled into clinical trials from 1983 to 2001

634 Background: Despite the widespread perception that the availability of new drugs improves prognosis in MBC, survival gains were rarely reported in randomised clinical trials of 1st line chemotherapy (CTX) with last generation agents. We evaluated the survival of MBC patients enrolled into trials conducted by the GONO during a 20 year period, to detect any improvement potentially attributable to the use of newer drugs. Methods: Between 1983 and 2001, 790 patients were entered into 6 consecutive trials of CTX coordinated by the data center at the National Cancer Research Institute in Genoa, Italy (2 phase II and 4 randomised phase III). In trials started after 1994, a taxane was part of the CTX regimen. This analysis was limited to 640 patients, as patients metastatic ab initio were excluded. Five cohorts of patients according to 3-yr periods of diagnosis of relapse were identified. Kaplan-Meier estimates of overall survival (OS) and time to progression (PFS) were computed from enrolment, and compared by the log rank test. Multivariate PH models were used to adjust for differences in baseline factors, including age, nodal and receptor status, adjuvant CTX, relapse free survival, metastatic site and PS. Results: The following differences in baseline characteristics in the 5 cohorts were observed: the proportion of patients pretreatead with adjuvant anthracyclines increased from 4% to 26%; that of patients with a RFS>5 years increased from 19% to 33% and the proportion of patients with dominant visceral disease increased from 57% to 74%. Median PFS was 306 days, 294 days, 237 days, 328 days and 348 days in cohorts 1983–86, 87–89, 92–94, 95–97 and 98–2001, respectively (p < 0.0001). Median OS in the same cohorts was 546 days, 522 days, 584 days, 793 days and 713 days, respectively (p < 0.0001). These data were confirmed in multivariate analyses, when prognostic variables were adjusted for. Conclusions: It appears that the prognosis of MBC patients enrolled in CTX clinical trials since 1995 is significantly improved as compared to patients enrolled during 1983–94. A possible role of drugs introduced in the '90s is suggested. No significant financial relationships to disclose.

Changes in survival and time to progression in metastatic breast cancer (MBC) patients enrolled into clinical trials from 1983 to 2001

634 Background: Despite the widespread perception that the availability of new drugs improves prognosis in MBC, survival gains were rarely reported in randomised clinical trials of 1st line chemotherapy (CTX) with last generation agents. We evaluated the survival of MBC patients enrolled into trials conducted by the GONO during a 20 year period, to detect any improvement potentially attributable to the use of newer drugs. Methods: Between 1983 and 2001, 790 patients were entered into 6 consecutive trials of CTX coordinated by the data center at the National Cancer Research Institute in Genoa, Italy (2 phase II and 4 randomised phase III). In trials started after 1994, a taxane was part of the CTX regimen. This analysis was limited to 640 patients, as patients metastatic ab initio were excluded. Five cohorts of patients according to 3-yr periods of diagnosis of relapse were identified. Kaplan-Meier estimates of overall survival (OS) and time to progression (PFS) were computed from enrolment, and compared by the log rank test. Multivariate PH models were used to adjust for differences in baseline factors, including age, nodal and receptor status, adjuvant CTX, relapse free survival, metastatic site and PS. Results: The following differences in baseline characteristics in the 5 cohorts were observed: the proportion of patients pretreatead with adjuvant anthracyclines increased from 4% to 26%; that of patients with a RFS>5 years increased from 19% to 33% and the proportion of patients with dominant visceral disease increased from 57% to 74%. Median PFS was 306 days, 294 days, 237 days, 328 days and 348 days in cohorts 1983–86, 87–89, 92–94, 95–97 and 98–2001, respectively (p < 0.0001). Median OS in the same cohorts was 546 days, 522 days, 584 days, 793 days and 713 days, respectively (p < 0.0001). These data were confirmed in multivariate analyses, when prognostic variables were adjusted for. Conclusions: It appears that the prognosis of MBC patients enrolled in CTX clinical trials since 1995 is significantly improved as compared to patients enrolled during 1983–94. A possible role of drugs introduced in the '90s is suggested. No significant financial relationships to disclose.

Squamous cell carcinoma of the anal margin

To define the optimal treatment of patients with squamous cell carcinoma (SCCA) of the anal margin. Nineteen patients treated with curative intent by radiotherapy (RT) alone or combined with adjuvant chemotherapy (CTX) between 1979 and June 2000 were analyzed. The pertinent literature was reviewed and discussed as it related to our experience. Local control after RT or RT and CTX was observed in all 19 patients (100%). One T1 patient developed inguinal lymph node metastases and subsequently died secondary to regional and distant disease. This patient did not receive elective inguinal node RT; the lymph nodes of the other 18 patients in this analysis were irradiated. Four patients died of intercurrent disease at 25, 29, 37, and 113 months after RT, respectively. The remaining 14 patients were alive and disease-free from 52 to 143 months after treatment. No patient suffered a severe complication or required a diverting colostomy or an abdominoperineal resection (APR) after treatment. Review of the literature reveals that the probability of cure is similar after RT alone or combined with CTX compared with surgery. Therefore, the choice of treatment depends on the anticipated functional result. Patients with SCCA of the anal margin have a high likelihood of cure with sphincter preservation after RT or RT and CTX. Patients with well to moderately differentiated T1 tumors may undergo excision if it can be accomplished without compromising the sphincter. The remainder are treated with RT. Adjuvant CTX is indicated for those with T3-T4 tumors and/or involved regional nodes.

Preoperative chemoradiotherapy for localized pancreatic carcinoma: A perspective

The role of chemotherapy (CTX) in the treatment of localized adenocarcinoma of the pancreas must be enhanced if current results are to be surpassed. It is postulated that histologic response to various chemotherapeutic agents may offer an assessable endpoint intermediate to and perhaps as or more meaningful than survival analysis. A history of trials assessing the value of adjuvant preoperative and postoperative chemotherapy and radiation therapy (RT) is provided. Experiences with histologic assessment of treatment response are reviewed. There has been no clear benefit from adjuvant CTX, either when delivered with RT or as postoperative maintenance. Imaging tests were much less sensitive than histologic grading in determining responses (7% vs. 71% partial responses) of patients with resected pancreatic cancers previously treated with RT/CTX. This suggests that standard imaging assessments of pancreatic carcinoma response to chemotherapy and radiation therapy may be inaccurate. Preresectional delivery of chemotherapeutic agents with RT allows response rates to be quantified histologically. This method of response analysis, being much more sensitive than analysis by computed tomographic scanning, may allow the more rapid development of improved chemotherapeutic programs for this malignancy.