Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713.

BACKGROUND: Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer. PATIENTS AND METHODS: Patient eligibility: stage II to III biopsy-proven, KRAS-wt rectal adenocarcinoma; no bowel obstruction; adequate hematologic, hepatic and renal function; performance status of 0 to 2. Target enrollment: 80 patients. TREATMENT: induction chemotherapy with wCAPOX (weekly capecitabine and oxaliplatin) and cetuximab followed by the same regimen concurrent with radiation (omitting day 15 oxaliplatin). If fewer than 7 pCRs were observed at planned interim analysis after 40 patients received all therapy, the study would close. Eighty eligible patients would provide 90% power given a true pCR rate > 35% at a significance of 0.04. The regimen would lack future interest if pCR probability was ≤ 20%. RESULTS: Between February 2009 and April 2013, 83 patients registered. Four were ineligible and 4 not treated, leaving 75 evaluable for clinical outcomes and toxicity, of whom 65 had surgery. Of 75 patients, 20 had pCR (27%; 95% confidence interval [CI], 17%-38%); 19 (25%) had microscopic cancer; 36 (48%) had minor/no response (including 10 without surgery). Three-year disease-free survival was 73% (95% CI, 63%-83%). CONCLUSION: Our trial did not meet the pCR target of 35%. Toxicity was generally acceptable. This regimen cannot be recommended outside the clinical trial setting.

Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.

PURPOSE: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. EXPERIMENTAL DESIGN: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). CONCLUSION: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.

Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304).

BACKGROUND: Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS: The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS: There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS: Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.

Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection.

PURPOSE: Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. PATIENTS AND METHODS: In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. RESULTS: Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. CONCLUSION: Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.

Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008.

Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans.

Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144.

PURPOSE: Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens. PATIENTS AND METHODS: After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery. RESULTS: Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3. CONCLUSION: All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.

Locally advanced prostate cancer treated with concomitant radiation and 5-fluorouracil: Southwest Oncology Group Study 9024.

PURPOSE: Radiation is considered the standard treatment for locally advanced (T3 and T4) prostate cancer but cure with radiation alone is infrequent. Studies have shown that adding androgen ablation improves the results but there is still much room for improvement. We performed a phase II multi-institutional study to explore the feasibility of concomitant chemoradiotherapy. MATERIALS AND METHODS: Eligible patients had prostate cancer with clinical evidence of invasion through the prostatic capsule or into the seminal vesicles without evidence of nodal or distant metastasis. Prior prostatectomy was not allowed and patients could not be candidates for surgical resection due to medical reasons or refusal of surgery. Radiation consisted of 7,020 cGy in 39 fractions. Continuous infusion 5-fluorouracil at a dose of 200 mg/m2 daily was started on day 1 and continued 7 days weekly until the last day of radiation. RESULTS: All 30 eligible patients were evaluated for toxicity. Diarrhea was the most common toxicity with grade 3 and 4 diarrhea in 2 and 1 patients, respectively. The only other grade 4 toxicity was hemorrhagic cystitis in 1 patient. There was 1 incident each of grade 3 stomatitis, congestive heart failure, edema, proctitis and hematuria. No patient with grade 3 or 4 toxicity required treatment delay. Ten patients (33%) achieved a negative biopsy and 13 (43%) achieved prostate specific antigen less than 1.0 ng/ml. Six patients (20%) achieved a complete response, defined as negative biopsy and prostate specific antigen less than 1.0 (95% CI 8 to 39). Patients without any biopsies or without prostate specific antigen followup were assumed to be nonresponders. CONCLUSIONS: Toxicity was acceptable. The modest response rate indicates that better chemotherapy that improves local and systemic failure is necessary to improve the results. This study confirms the feasibility of a combined chemoradiotherapy approach.

Report from the Radiation Oncology Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2003.

To achieve the ultimate goal of cancer treatment, which is 100% cancer control with negligible toxicity, the therapeutic window must be enlarged, allowing for higher doses of beneficial treatments with reduced toxicity. The advent of image- and metabolism-guided therapy offers the best opportunity to date for combining modern radiation targeting and imaging techniques. Indeed, for the first time, it is reasonable to locally target metastatic disease with the goal of sterilization. Combining these focal radiation techniques with novel targeted antiproliferative agents and full-dose classic cytotoxic chemotherapy will become more effective as we learn to use these compounds in a less systemically toxic manner and as radiation fields become more defined. In addition, increasing numbers of biologic modifiers of normal tissue response are becoming available, and they suggest great promise for decreasing the normal tissue toxicity resulting from both radiation and chemotherapy treatments. Thus, radiation metastectomy for gross metastases, used together with systemic control of micrometastatic disease, may yield improved survival rates. This hypothesis is ready for testing in cancers of the breast, prostate, colon, and in sarcomas. Enlarging the therapeutic window is a major goal that would allow for an increasingly favorable therapeutic gain.

Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation.

PURPOSE: Radiation therapy has recently emerged as a pivotal modality in the management of completely resected, high-risk gastric cancer. The recently published results of the Intergroup 0116 Gastric Surgical Adjuvant Trial randomized high-risk (T3,4 and/or node positive), completely resected gastric or gastroesophageal adenocarcinomas to receive either observation alone or radiochemotherapy after complete resection. Radiochemotherapy produced significant improvements in relapse-free (p < 0.0001) and overall survival (p = 0.01). Radiation oncologists must now clearly comprehend the principles governing the rationale supporting this therapy to apply it to those afflicted with this disease. This paper represents a consensus report reviewing data supporting radiotherapy, important clinical and anatomic issues related to radiotherapy, and details of the practical application of radiation therapy to commonly occurring clinical presentations. Supportive therapy during and after radiochemotherapy is also discussed.