Stephen K. Williamson

A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer

PURPOSE Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study.

PURPOSE The Southwest Oncology Group (SWOG) conducted a randomized comparison of cisplatin plus fluorouracil (5-FU) and carboplatin plus 5-FU versus single-agent methotrexate (MTX) in patients with recurrent and metastatic squamous-cell carcinoma (SCC) of the head and neck. The primary objective was to compare separately the response rates of each combination regimen to standard weekly MTX. PATIENTS AND METHODS Two hundred seventy-seven patients diagnosed with SCC of the head and neck were randomized to one of three treatments: (1) cisplatin 100 mg/m2 intravenously (IV) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days; (2) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days; and (3) MTX 40 mg/m2 IV given weekly. RESULTS All three treatment regimens were well tolerated. However, both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX (P = .001). Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens. The complete and partial response rates were 32% for cisplatin plus 5-FU, 21% for carboplatin plus 5-FU, and 10% for MTX. The comparison of cisplatin plus 5-FU to MTX was statistically significant (P less than .001), and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance (P = .05). Median response durations and median survival times were similar for all three treatment groups. Logistic regression models showed that only treatment assigned was associated significantly with response (P = .001). Cox proportional hazards models indicated that only performance status was associated significantly with survival (P less than .01). CONCLUSIONS We conclude that combination chemotherapy resulted in improved response rates but was associated with an increased toxicity and no improvement in overall survival. Therefore, new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified.

Randomized Controlled Trial of Reduced-Dose Bolus Fluorouracil Plus Leucovorin and Irinotecan or Infused Fluorouracil Plus Leucovorin and Oxaliplatin in Patients With Previously Untreated Metastatic Colorectal Cancer: A North American Intergroup Trial

PURPOSE Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade > or = 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. PATIENTS AND METHODS The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. RESULTS Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. CONCLUSION FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics

PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.

Pharmacogenetic Predictors of Adverse Events and Response to Chemotherapy in Metastatic Colorectal Cancer: Results From North American Gastrointestinal Intergroup Trial N9741

PURPOSE With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. PATIENTS AND METHODS Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. RESULTS All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. CONCLUSION This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.

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.

Phase III Trial of Paclitaxel Plus Carboplatin With or Without Tirapazamine in Advanced Non–Small-Cell Lung Cancer: Southwest Oncology Group Trial S0003

PURPOSE Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m(2) in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine. RESULTS Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003). CONCLUSION The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.

Tirapazamine: a novel agent targeting hypoxic tumor cells.

Background: Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and most anticancer drugs. Tirapazamine (TPZ) is a newer class of cytotoxic drugs with selective toxicity towards hypoxic mammalian cells. Objective: This article reviews the mechanism of action, toxicity and antitumor activity of the drug and provides insights into factors that may have contributed to the disappointing results in some of the Phase III trials. It also identifies the need to explore dependable markers of tumor hypoxia and limit future trials of this agent to patients who have significant populations of hypoxic tumor cells. Methods: We reviewed all clinical trials published to date and present a summary of the results. There are also several ongoing studies, the results of which are pending and may yet impact the clinical use of the drug. Results/conclusion: Despite the very promising results obtained in various preclinical studies and early-Phase clinical trials, several Phase III trials have failed to demonstrate any survival benefit of adding TPZ to chemotherapy or radiation therapy in non-small cell lung cancer or head and neck cancer. Several clinical trials have yet to be completed and reported.

Lower Osteopontin Plasma Levels Are Associated With Superior Outcomes in Advanced Non–Small-Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy: SWOG Study S0003

PURPOSE S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol. PATIENTS AND METHODS Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens. RESULTS Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively). CONCLUSION Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.

Mutant DNA in Plasma of Lung Cancer Patients: Potential for Monitoring Response to Therapy

Abstract: The hypothesis tested was that mutant tumor DNA shed into plasma would show predictive value for monitoring response to therapy in non‐small cell lung carcinoma patients. Pretreatment plasma specimens from 25 patients on a phase I trial were evaluated, 12 with paired posttreatment specimens, and 138 patients on the Southwest Oncology Group S0003 trial, 38 with paired posttreatment specimens, for the presence of K‐RAS mutations. Thirteen tumor specimens from the phase I trial patients and seven tumor specimens from S0003 patients were also available for comparative analysis of K‐RAS mutations in tumor tissue and plasma. All patients were treated similarly with paclitaxel, and carboplatin chemotherapy. DNA was extracted and mutational analyses performed using an RFLP‐PCR assay. K‐RAS mutations were found in plasma DNA in 5/25 of the phase I patients (20%). Median survival was 10 months in all patients, 11.4 months in the wild‐type K‐RAS group, and 3.3 months in the mutant K‐RAS group (P= 0.056). Point mutations in plasma DNA were identical to mutations found in the tumors, confirming the tumor as the source. In two patients with K‐RAS mutations pretreatment, posttreatment plasmas were evaluated: a patient with clinical progressive disease retained the mutant DNA, while in a patient with a complete response (CR), the K‐RAS mutation was no longer detectable. In an ongoing analysis of S0003 patients, to date, K‐RAS mutations have been found in the plasma of 14 patients (10.1%). In 42 matched pre‐ and posttreatment specimens from both phase I and S0003 trials, four patients had K‐RAS mutations pretreatment that were not detectable posttreatment. Of these, two had a clinical CR or partial response, and the other two had stable disease. It was concluded that detection of tumor DNA in plasma is feasible using molecular techniques and that this approach shows promise for monitoring patient response to therapy.