Jeffrey L. Berenberg

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study

AbstractPurpose: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. Patients and Methods: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. Results: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p=0.45) and overall survival (p=0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins >1 cm, had superior survival compared to cases not meeting these requirements (p<0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). Conclusion: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

DPYD Variants as Predictors of 5-fluorouracil Toxicity in Adjuvant Colon Cancer Treatment (NCCTG N0147)

BACKGROUND Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. METHODS We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. RESULTS In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). CONCLUSION In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.

Patient and Tumor Characteristics and BRAF and KRAS Mutations in Colon Cancer, NCCTG/Alliance N0147

BACKGROUND KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. METHODS Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. RESULTS KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF (V600E) mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF (V600E) mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. CONCLUSIONS Specific patient and tumor characteristics are associated with KRAS and BRAF (V600E) mutations.

Surviving and Thriving With Cancer Using a Web-Based Health Behavior Change Intervention: Randomized Controlled Trial

Background Given the substantial improvements in cancer screening and cancer treatment in the United States, millions of adult cancer survivors live for years following their initial cancer diagnosis and treatment. However, latent side effects can occur and some symptoms can be alleviated or managed effectively via changes in lifestyle behaviors. Objective The purpose of this study was to test the effectiveness of a six-week Web-based multiple health behavior change program for adult survivors. Methods Participants (n=352) were recruited from oncology clinics, a tumor registry, as well as through online mechanisms, such as Facebook and the Association of Cancer Online Resources (ACOR). Cancer survivors were eligible if they had completed their primary cancer treatment from 4 weeks to 5 years before enrollment. Participants were randomly assigned to the Web-based program or a delayed-treatment control condition. Results In total, 303 survivors completed the follow-up survey (six months after completion of the baseline survey) and participants in the Web-based intervention condition had significantly greater reductions in insomnia and greater increases in minutes per week of vigorous exercise and stretching compared to controls. There were no significant changes in fruit and vegetable consumption or other outcomes. Conclusions The Web-based intervention impacted insomnia and exercise; however, a majority of the sample met or exceeded national recommendations for health behaviors and were not suffering from depression or fatigue at baseline. Thus, the survivors were very healthy and well-adjusted upon entry and their ability to make substantial health behavior changes may have been limited. Future work is discussed, with emphasis placed on ways in which Web-based interventions can be more specifically analyzed for benefit, such as in regard to social networking. Trial Registration Clinicaltrials.gov NCT00962494; http://www.clinicaltrials.gov/ct2/show/NCT00962494 (Archived by WebCite at http://www.webcitation.org/6NIv8Dc6Q).

Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.

Stepwise development of a cancer care delivery research study to evaluate the prevalence of virus infections in cancer patients

Background: SWOG initiated a cancer care delivery research study of virus infection rates among newly diagnosed cancer patients. This study will inform viral screening guidelines in oncology clinics. Methods: In a first step ‘vanguard’ phase, we evaluated the feasibility of multiple study procedures. Site investigators were surveyed to obtain feedback on study implementation. Results: Much higher enrollment occurred at sites where all physicians participated and viral testing was performed as routine practice. These procedures will be required going forward. Additional protocol changes based on site investigator input were implemented. Conclusion: This multistep protocol design process illustrates how cancer care delivery research studies can adapt to real-world strategies and procedures that exist at community clinics where the predominance of cancer patients are treated.

Cancer Clinical Trials in Hawaiâi: Whoâs Being Represented

Background: Representation of diverse ethnic/racial groups is critically important in the development of cancer prevention and treatment strategies. However, representation of diverse ethnic/racial groups has yet to be fully realized, especially among historically disadvantaged minority groups. Ethnic minority groups account for about 75% of Hawai‘i’s population; approximately 55% of the state’s population self-identify as Asian (with the most predominant ethnic/racial groups being Japanese, Filipino, Chinese, and Korean) and approximately 24% as Native Hawaiian/Pacific Islander. Such diversity provided researchers a unique opportunity to characterize the demographic profile of cancer prevention and treatment trials conducted in Hawai ‘i. Methods: In the current study, the gender and ethnic/racial distribution of four national cancer prevention trials and 178 treatment trials conducted in Hawai‘i from 1992 to 2004 were characterized. Results: Native Hawaiian men were significantly less likely to participate in both cancer prevention and treatment trials than Native Hawaiian women. In addition, Native Hawaiian men and women had the lowest proportion of participation in cancer clinical trials in comparison to White and Asian American men and women. Conclusions: Our findings identify gender and ethnic/racial differences in the participation of cancer clinical trial participants in the state of Hawai‘i. This serves as an important indicator for the need of future research to specifically investigate the relationship of culture and other factors on participation. Such research may inform promotional strategies that increase trial participation, with the hopeful prospect of decreasing cancer incidence and increasing quality of life for those diagnosed with cancer.

Abstract B26: Cancer prevention clinical trials: Assessing for disparities in recruitment in Hawaii

A key concern of clinical trials of cancer is improving the participation rates of minority populations that are often underrepresented and have high rates of disease. In particular, identifying the underlying factors that contribute to the underrepresentation of minorities is essential for developing improved recruitment strategies—this is especially important for prevention trials of cancer that may ultimately translate to reducing the burden of disease in the population. To identify disparities in cancer prevention trials in Hawaii, we compared participation rates across racial/ethnic groups for breast and prostate cancer prevention trials. We then examined the methods of recruitment for each trial. The following four prevention trials were included in our assessment: the Breast Cancer Prevention Trial (BCPT), the Prostate Cancer Prevention Trial (PCPT), and the Study of Tamoxifen and Raloxifene (STAR). We identified gender differences in the participation rates of Native Hawaiians. Among 272 female participants in the STAR and BCPT trials, 10.3% (n = 28) were Native Hawaiian. In contrast, among 213 male participants in the SELECT and PCPT studies, only 5.2% (n = 11) were Native Hawaiian. The ethnic breakdown of the state during the approximate time of recruitment (2000) was as follows: African American 2.4%, Caucasian 24.3%, Chinese 7.4%, Filipino 16.5%, Hawaiian 19.8%, Japanese 18.9%, Korean 2.4%, Other ethnicities 8.4% (US Census, 2000). In these trials differing recruitment strategies were used. For example, in the SELECT trial a targeted direct mailing campaign to men 50 years of age or older (27.6% of sample), whereas in the STAR trial physician referral was the primary source of participation (59.0%). While these analyses do not speak to what specific strategies were most beneficial for a given racial/ethnic group, it is important to note that there was a higher likelihood of recruiting Native Hawaiian women when they were referred to the trial by their physician. Understanding the importance of the relationship between the study participant and the referral agent is just one strategy that will be examined in our future work. Researchers attempting to recruit African Americans at a rate of 20% for clinical trials (Cook at al., 2005) found that a diligent effort aimed at expanding the eligibility recruitment for African American men and the provision of more resources to particularly target this group were strategies that helped decrease disparities in recruitment. Given the multi‐ethnic and multi‐cultural nature of Hawai9i there are a wide range of practices and beliefs that need to be considered and incorporated in clinical trial recruitment. Our ultimate goal is to improve the participation rates of Native Hawaiians in clinical trials of cancer prevention. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B26.