BACKGROUND

Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil.

METHODS

Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts.

RESULTS

A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively.

CONCLUSIONS

Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial.

BACKGROUND

The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC).

METHODS

A retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade>> or =1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan-Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose.

RESULTS

Of 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients.

CONCLUSIONS

This retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.

The International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) investigators have now completed two large systematic reviews of adjuvant therapy trials in colon cancer. The IMPACT 1 study pooled data from three separate trials each comparing the efficacy of 5-fluorouracil (5-FU)/leucovorin with observation alone as adjuvant treatment for 1,526 patients with Dukes' B or C colon cancer. The results showed that treatment with 5-FU/leucovorin significantly reduced mortality by 22% (P = .029) and events such as relapse, second tumor, or death by 35% (P < .0001) after 3 years of follow-up. The side effects associated with 5-FU/leucovorin were clinically acceptable. The IMPACT 1 study also showed a clear benefit of adjuvant treatment for patients with Dukes' C colon cancer, but not for stage-B patients. After up to 10 years of follow-up, 5-FU/leucovorin significantly reduced mortality by 30% for patients with Dukes' C disease (P = .003), but only reduced mortality by 8% in patients with Dukes' B colon cancer (P = .658). The aim of the IMPACT 2 study was to determine whether 5-FU/leucovorin is an effective adjuvant treatment for patients with Dukes' B2 colon cancer. Results were pooled from five separate trials that randomized 1,016 patients. After a median of 5.75 years of follow-up, B2 patients receiving 5-FU/leucovorin did not have a significant increase in overall survival or event-free survival. At 5 years, the hazard ratio for overall survival was 0.86 (90% confidence interval, 0.68 to 1.07) and for event-free survival was 0.83 (90% confidence interval, 0.72 to 1.07). 5-Fluorouracil/leucovorin was not recommended as a standard adjuvant treatment for all patients with Dukes' B2 colon cancer.

BACKGROUND

The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC).

METHODS

Patients were assigned to oxaliplatin, leucovorin and 5-FU for 12 cycles (group A, FOLFOX6) or oxaliplatin and capecitabine for eight cycles (group B, CAPOX). Primary endpoint was disease-free survival (DFS). Tumors were classified as mismatch repair proficient (pMMR) or deficient (dMMR) according to MLH1, PMS2, MSH2 and MSH6 protein expression. KRAS exon two and BRAF V600E mutational status were also assessed.

RESULTS

Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5-83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9-83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4-89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one-two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions.

CONCLUSIONS

No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size.

BACKGROUND

ANZCTR 12610000509066 . Date of Registration: June 21, 2010.

BACKGROUND

The purpose of this study was to identify clinical and pathological parameters to improve prediction of disease-free survival (DFS) and overall survival (OS) in patients treated with neoadjuvant chemoradiotherapy for rectal cancer.

METHODS

Between July 1995 and May 2007, 148 patients with primary rectal adenocarcinoma received neoadjuvant chemoradiotherapy followed by mesorectal excision. Preoperative treatment included various protocols, UFT and leucovorin (28%) and oxaliplatin-based chemotherapy (72%). Clinical and pathological variables were evaluated in relation to patient outcomes.

RESULTS

Thirteen percent of patients achieved a complete pathologic response. No response or minimal response as defined by Dworak (Tumor Regression Grade 0/1) was observed in 30 patients (20%). At a median follow-up of 37 months, the 3-year DFS and OS were 64% and 83%, respectively. Pre-treatment serum carcinoembryonic antigen (CEA) level </= 2.5 ng/ml was associated with higher DFS (74 vs. 53%; p = 0.018), higher complete pathologic responses (21 vs. 9%; p = 0.05), and less recurrences (24 vs. 44%; p = 0.014).

CONCLUSIONS

The data suggest that a CEA level </= 2.5 ng/ml might be a predictor not only of tumor response, as has been suggested before, but also of DFS. This finding could be useful in the future to predict individual risk and to develop more aggressive or alternative strategies.

BACKGROUND

Despite early scepticism, several studies of systemic adjuvant 5-fluorouracil (5-FU)-based chemotherapy demonstrated significant benefits in high-risk colon cancer. As many clinical investigations have since been conducted in this setting, a comprehensive literature review was undertaken to clarify the role of adjuvant therapy in the treatment of colorectal cancer.

METHODS

Current and future adjuvant treatment approaches in colorectal cancer were reviewed, and differences in the present-day North American and European practices were highlighted.

CONCLUSIONS

5-FU plus leucovorin for six months is generally considered the 'standard' adjuvant treatment in Dukes' stage C (stage II) colon cancer. Large-scale international trials of other strategies are required to provide further advances in treatment outcome. Following the lead of the USA Intergroup trials, a recently initiated cooperative effort, the Pan-European Trials in Adjuvant Colon Cancer (PETACC), may serve as a European model for such investigations. In T3 and/or lymph-node positive rectal cancer, postoperative (chemo)radiotherapy in the USA is considered the adjuvant treatment of choice. However, most European investigators have advocated for preoperative intensive short-course irradiation instead. Randomized trials in this area are ongoing. In the near future, new drugs for the treatment of colorectal cancer may lead to tailored therapies.

OBJECTIVE

To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer.

METHODS

Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival.

RESULTS

All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%.

CONCLUSIONS

UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.

OBJECTIVE

To evaluate prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the reduction of chemotherapy-induced oral mucositis.

METHODS

Twenty patients with stage IV squamous cell carcinoma of head and neck were studied. Two-cycles (periods) of identical doses of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) chemotherapy with cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d, leucovorin 90 mg/m2/d by 96-hour continuous intravenous infusion every 3 weeks were given to each patient. After PFL chemotherapy, GM-CSF 4 micrograms/kg subcutaneously from days 5 to 14 or no therapy was given by a randomized self-controlled crossover study design. Oral mucositis was graded with modified Radiation Therapy Oncology Group criteria.

RESULTS

In the first cycle of PFL chemotherapy, GM-CSF significantly reduced the incidence, mean duration, and mean area under the curve (AUC) of severe oral gross mucositis (grade>> or = 3) compared with no therapy. These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade>> or = 2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy.

CONCLUSIONS

GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy.

OBJECTIVE

Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis.

METHODS

Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events.

RESULTS

In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001).

CONCLUSIONS

The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.

Understanding the relationship between chemical structure and biological properties of folate analogs, particularly their interactions with the target enzymes, transport proteins and folate-metabolizing enzyme, folylpolyglutamate synthetase (FPGS), has enabled the rational design and development of the selective thymidylate synthase (TS) inhibitors with folate-based structures for clinical uses. These compounds specifically inhibit TS devoid of concomitant effects at other loci, unlike 5-fluorouracil (5-FU). ZD1694 ('Tomudex') was designed as a non-nephrotoxic and highly active analog of N10-propargyl-5,8-dideazafolic acid (CB3717), which is a potent TS inhibitor but had unacceptable nephrotoxicity caused by its poor water solubility. The potent cytotoxic activity of ZD1694 is dependent upon active uptake into cells via the reduced folate carrier (RFC), and subsequent rapid and extensive metabolism to polyglutamate forms inside cells. Marked enhancement of the TS inhibitory activity has been noted as the glutamate chain is elongated. Polyglutamation is critical to the biological activity of ZD1694 against tumor and normal proliferating tissues. The retentive property of ZD1694 polyglutamates inside cells led to a single, infrequent administration schedule in clinical studies. ZD1694 has completed phase I and phase II evaluation with activity observed in several tumor types, particularly in colorectal cancer with a 26% objective response rate. A recent European phase III study of ZD1694, randomized against a 5-FU plus leucovorin regimen, demonstrated an equivalent response rate for advanced colorectal cancer (complete or partial responses; 20 versus 17%) and less toxicity than seen with the latter regimen. The newer selective TS inhibitors, which retain potency for TS inhibition but are not substrates for RFC and/or FPGS, are currently under clinical evaluation. These classes of compound may have benefits for circumvention of resistance by virtue of alterations in these protein functions and for the management of toxicity.

BACKGROUND

Early relapse in colorectal cancer (CRC) patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage) and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes.

METHODS

Six gene polymorphisms functional in drug-metabolism - GSTP1 Ile105Val, ABCB1 Ile1145Ile, MTHFR Ala222Val, TYMS double (2R) or triple (3R) tandem repeat - and DNA-repair genes - ERCC2 Lys751Gln and XRCC1 Arg399Gln - were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0) or III (any T N1 and 2 M0) and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU) and leucovorin (LV). The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated.

RESULTS

In this study, the distributions of GSTP1 (P = 0.003), ABCB1 (P = 0.001), TYMS (P < 0.0001), ERCC2 (P < 0.0001) and XRCC1 (P = 0.006) genotypes in the Asian population, with the exception of MTHFR (P = 0.081), differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype ERCC2 2251A>C (P = 0.006), tumor invasion depth (P = 0.025), lymph node metastasis (P = 0.011) and cancer stage (P = 0.008) were significantly correlated with early relapse. Patients carrying the ERCC2 2251AC or2251CC genotypes had a significantly increased risk of early relapse (OR = 3.294, 95% CI, 1.272-8.532).

CONCLUSIONS

We suggest that ERCC2 2251A>C alleles may be genetic predictors of early CRC relapse.

BACKGROUND

Patients with advanced pancreatic cancer failing gemcitabine-based first-line chemotherapy are still in relatively good clinical conditions and may still require second-line chemotherapy, which is frequently administered in daily clinical practice given to without solid scientific support.

METHODS

A retrospective survey was carried out including 40 patients with stage III or IV gemcitabine-refractory pancreatic carcinoma. Patients received standard FOLFIRI regimen biweekly until progression or unacceptable toxicity. Response evaluation criteria in solid tumors and National Cancer Institute common toxicity criteria were employed respectively for response and toxicity assessment.

RESULTS

Six partial responses (15%) and 14 stabilizations of disease (35%) were recorded for a tumor growth control rate of 50%. The median time to progression was 3.7 (range, 1-6.5 months), and median overall survival was 6 months (range, 2-8.2 months). A stabilization of performance status and a subjective improvement of cancer-related symptoms were recorded in 21 patients (52.5%). No correlation has been found between length of time to progression during first-line chemotherapy and length of that reported in the second-line setting or objective response. Grade 3-4 diarrhea and mucositis was observed in 15% and 10% of cases, respectively.

CONCLUSIONS

Data presented in this article demonstrate that the second-line FOLFIRI regimen are able to induce an objective response in a relatively small fraction of patients with gemcitabine-refractory adenocarcinoma of the pancreas. The use of second-line chemotherapy should be carefully proposed to patients with good performance status or those who had a good response to first-line therapy.

BACKGROUND

The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma.

METHODS

Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m(2) as a 60-min infusion on day 1, leucovorin 400 mg/m(2) as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m(2) as a 46-h infusion and irinotecan 90 mg/m(2), repeated on day 3, at the end of the 5-FU infusion, every 2 weeks.

RESULTS

Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1-53). Grade 3-4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3-4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%.

CONCLUSIONS

The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.

Salvage therapy for relapsed large-cell lymphoma (LCL) is more effective in patients with minimal disease, suggesting that early detection of relapse might increase the chance of long-term survival. To determine whether current follow-up procedures are effective in identifying preclinical disease, we analyzed patterns of relapse in 139 LCL patients who achieved a complete remission (CR) with high/moderate-dose methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M/m-BACOD). The timing and results of all posttreatment follow-up tests were examined in the 36 patients who relapsed from complete remission (CR) and 46 controls who remain in CR. Despite conscientious posttreatment follow-up, only two of the 36 relapses (6%) were detected before the development of symptoms. Sixty-seven percent of patients relapsed in new disease sites (42% in new and old sites, and 25% in new sites only). Consistent with this observation, the tests most sensitive to clinical relapse were those not targeted to specific sites of disease: gallium scan (sensitivity, 90%), physical examination (80%), and lactate dehydrogenase (LDH) (65%). Of screening tests performed, only LDH was successful in detecting preclinical relapse, with a sensitivity of 42% and specificity of 85% for impending symptomatic relapse. These results indicate that conventional screening was ineffective in detecting preclinical relapse in LCL patients. We recommend prospective evaluation of a strategy that (1) screens with a frequency appropriate to a patient's risk of relapse, (2) uses sensitive test(s) not targeted to specific sites, and (3) limits aggressive screening to those high-risk patients eligible for potentially curative salvage therapy.

BACKGROUND

Methylenetetrahydrofolate reductase is a pivotal enzyme in folate metabolism and 5-fluorouracil (5-FU) cytotoxicity. Two common single-nucleotide polymorphisms (SNPs), MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), reduce enzyme activity. Initially, these SNPs were claimed to predict clinical efficacy, but further studies have yielded contradictory results. We tested whether these two polymorphisms are determinants of clinical outcome in a large patient group with a long follow-up time.

METHODS

We included 331 patients who had been treated with adjuvant 5-FU/leucovorin chemotherapy after intended curative resection between 1997 and 2003. Clinical data, including relapse rates, overall survival, and tumor stage, were collected. DNA was extracted from formalin-fixed tumor tissue and analyzed for the MTHFR 677C>T and 1298A>C SNPs with real-time PCR.

RESULTS

The MTHFR 677C>T and 1298A>C polymorphisms were not associated with survival or relapse-free survival (P>> 0.2). The 677 CC genotype was associated to toxicity (odds ratio = 1.83, P = 0.01).

CONCLUSIONS

The MTHFR 677C>T and 1298A>C polymorphisms probably do not predict efficacy of adjuvant 5-FU treatment in colorectal cancer after complete resection; however, the 677C>T polymorphism may be associated with lower toxicity in 5-FU treatment. Implementation of SNP analysis for these polymorphisms for individualized treatment is premature.

OBJECTIVE

Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients.

METHODS

Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively.

RESULTS

Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy.

CONCLUSIONS

There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive.

OBJECTIVE

To compare the time to deterioration in health-related quality of life (HRQoL) in patients with previously untreated metastatic colorectal cancer receiving a 5-fluorouracil (5-FU)-based chemotherapy regimen with or without the addition of bevacizumab (BV) in two randomized, placebo-controlled studies.

METHODS

Prespecified HRQoL endpoints in the phase II (Study 2192) and phase III (Study 2107) studies were time to deterioration in HRQoL, measured by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Colorectal Cancer Subscale (CCS), Trial Outcome Index (TOI-C), and FACT-C total score. Time to deterioration in HRQoL was evaluated for patients with baseline and postbaseline assessments, using the stratified log-rank test.

RESULTS

In the pivotal phase III trial, HRQoL baseline and postbaseline CCS scores were available for 127 patients receiving irinotecan, 5-FU, and leucovorin (LV) (IFL) and 122 patients receiving IFL plus BV. The time to deterioration in HRQoL did not differ significantly between treatment groups as measured by the CCS, TOI-C, or FACT-C total score. In the phase II study, baseline and postbaseline CCS scores were available for 77 and 89 patients receiving 5-FU and LV and 5-FU and LV plus BV, respectively. In that study, the time to deterioration in HRQoL was similar between groups as measured by the CCS and TOI-C scores, but was significantly longer in the 5-FU and LV plus BV arm than in the 5-FU and LV plus placebo arm for the FACT-C total score.

CONCLUSIONS

When added to 5-FU chemotherapy, BV significantly prolonged overall survival and progression-free survival without compromising HRQoL.

BACKGROUND

Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer.

METHODS

G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m(2), irinotecan 80 mg/m(2), leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m(2) bolus followed by infusional 5-FU 600 mg/m(2) over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m(2) bolus, followed by cisplatin 50 to 75 mg/m(2), and then infusional 5-FU 600 mg/m(2) over 8 hours.

RESULTS

Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months.

CONCLUSIONS

Adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative to switching to different drug classes for treatment of relapsed/resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

OBJECTIVE

To evaluate the economic burden of colorectal cancer (CRC) treatment on the healthcare system as treatment costs have risen 340-fold during the past 5 years.

METHODS

Nationwide registry.

METHODS

Patients with CRC (N = 421) were selected from an observational prospective patient registry of US oncology clinics. The 8 most commonly prescribed regimens were identified. Standard dosing schedules were set for these regimens based on a literature review and expert CRC oncologist input. Each chemotherapeutic regimen was broken down into its component agents, and regimen costs were calculated by summing the costs of each agent per regimen. Price-per-milligram costs were calculated from Health Care Financing Administration Common Procedural Coding System codes for specific drugs. Patient population, temporal, and regional trends were studied among standard regimens.

RESULTS

The most common regimens were 5-fluorouracil-leucovorin calcium (5-FU/LV) (147 patients [34.9%]), fluorouracil-leucovorin-irinotecan hydrochloride (FOLFIRI) (111 patients [26.4%]), and fluorouracil-leucovorin-oxaliplatin (103 patients [24.5%]). The remaining 60 patients (14.3%) received irinotecan, capecitabine, and oxaliplatin; oxaliplatin; irinotecan in combination with oxaliplatin; or a miscellaneous regimen. The largest cost differential for 6 cycles of planned treatment was $35,971 between FOLFIRI ($36,999) and 5-FU/LV ($1028). On a per-week basis, treatment costs may differ by more than 91 times. Patient utilization of growth factors, ancillary medications, and monoclonal antibodies added significant costs.

CONCLUSIONS

The costs of CRC regimens varied considerably. Trends in treatment regimens have changed notably over time, with newer agents and supportive drugs adding substantially to treatment costs.

The treatment of metastatic colorectal cancer (mCRC) has changed dramatically from the 1980s, when only fluorouracil (5-FU) was available for treatment and the median survival was at best 12 months, to a time when mCRC is considered more of a chronic disease in which the median survival is now reported in excess of 2 years. This review traces the evolution of treatment in this setting, including studies of single-agent vs combination treatment with 5-FU/leucovorin, irinotecan, oxaliplatin, and capecitabine, comparisons of simultaneous and sequential regimens, and the role of targeted agents such as bevacizumab, cetuximab, and panitumumab.

OBJECTIVE

This prospective randomized trial was performed to compare the effectiveness of intravenous vinorelbine tartrate with intravenous fluorouracil and leucovorin (5-FU/LV) on the primary end points of survival, quality of life (QOL), and relief of cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). Secondary end points included tumor response rates and time to treatment failure. In addition, the safety of both treatment regimens was evaluated in this multicenter study.

METHODS

Two hundred sixteen patients with stage IV NSCLC were enrolled onto this study from 18 centers. Vinorelbine was administered at a dose of 30 mg/m2/wk. 5-FU/LV was administered at a dose of 425 mg/m2 and 20 mg/m2, respectively, for 5 consecutive days every 4 weeks. Patients with progressive disease or toxicity were removed from study while responding and stable patients were continued on therapy.

RESULTS

The median survival time of patients who received vinorelbine was 30 weeks, with 25% of patients alive at 1 year, compared with a median survival time of 22 weeks and 16% of patients alive at 1 year for those treated with 5-FU/LV (P = .03, log-rank test). This improvement in survival was associated with a higher objective response rate (12% v 3%) and time to treatment failure (10 weeks v 8 weeks) for vinorelbine versus 5-FU/LV. The dose-limiting toxicity of vinorelbine was granulocytopenia, with 54% of patients experiencing grade 3/4 granulocytopenia. Nonhematologic toxicity of vinorelbine was generally grade 1 or 2. The most common grade 3 toxicities were related to injection-site reactions.

CONCLUSIONS

This trial confirms the efficacy of vinorelbine in patients with advanced NSCLC. The clinical activity and relatively favorable toxicity profile of this agent make it a reasonable and useful treatment option in the management of patients with this disease.

OBJECTIVE

Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery.

METHODS

After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m and leucovorin 20 mg/m in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists.

RESULTS

Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1-60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute--Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths.

CONCLUSIONS

In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).