Bevacizumab in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in patients with metastatic colorectal cancer who were previously treated with oxaliplatin-containing regimens: a multicenter observational cohort study (TCTG 2nd-BV study)

The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6?months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3?months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8?months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6?months (95% CI, 17.6-25.6) and 16.5?months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade ≥3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU.     

Systemic therapy for metastatic colorectal cancer: current options, current evidence.

Combination chemotherapy regimens including irinotecan and oxaliplatin markedly improve response rate and prolong median survival over fluorouracil with leucovorin (FU/LV), and have supplanted FU/LV as the standard systemic approach for metastatic colorectal cancer. The recent availability of five active chemotherapeutic agents has doubled the median overall survival for metastatic colorectal cancer from 10 to 20 months, and though the optimal strategy for incorporation of all drugs is still unclear, current data support the use of chemotherapy doublets in first-line rather than sequential single-agent therapy. Multidrug regimens increase both response rate and the proportion of patients able to undergo potentially curative resection. In addition, as many as 20% to 30% of patients never receive second-line chemotherapy. When used as single agents, bolus and infusional FU/LV and capecitabine are similarly effective but have differing toxicity. Chemotherapy combinations that incorporate infusion of FU are less toxic and more effective than those using bolus FU dosing. Capecitabine is under study as an alternative dosing method for use in combination regimens; however, the optimal dose has not been defined and final safety and efficacy outcomes are being addressed in ongoing phase II and III investigations. Three combinations have shown excellent first-line efficacy in phase III trials--IFL with bevacizumab, FOLFOX, and FOLFIRI--but neither of these combinations is clearly superior. Sound clinical judgment must continue to guide treatment decisions while we await data regarding the optimal combination and sequence of fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab.     

Carboplatin/5-fluorouracil as an Alternative to Cisplatin/5-Fluorouracil for Metastatic and Recurrent Head and NeckSquamous Cell Carcinoma and Nasopharyngeal Carcinoma

Background: Palliative chemotherapy with cisplatin/5-fluorouracil (5FU) is the commonest regimen employedfor metastatic and recurrent head and neck squamous cell carcinoma (SCCHN) and nasopharyngeal carcinoma(NPC). However, this regimen is cumbersome requiring 5 days of admission to hospital. Carboplatin/5FU maybe an alternative regimen without compromising survival and response rates. This study aimed to comparethe efficacy and toxicity of carboplatin/5FU regimen with the cisplatin/5FU regimen. Materials and Methods:This retrospective study looked at patients who had palliative chemotherapy with either cisplatin/5FU orcarboplatin/5FU for metastatic and recurrent SCCHN and NPC. It included patients who were treated atUKMMC from 1st January 2004 to 31st December 2009 with either palliative IV cispaltin 75 mg/m2 D1 only plusIV 5FU 750 mg/m2 D1-5 infusion or IV Carboplatin AUC 5 D1 only plus IV 5FU 500 mg/m2 D1-2 infusion plus IV5FU 500 mg/m2 D1-2 bolus. The specific objectives were to determine the efficacy of palliative chemotherapy interms of overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS)and to evaluate the toxicities of both regimens. Results: A total of 41 patients were eligible for this study. Therewere 17 in the cisplatin/5FU arm and 24 in the carboplatin/5FU arm. The ORR was 17.7 % for cisplatin/5FUarm and 37.5 % for carboplatin/5FU arm (p-value=0.304). The median PFS was 7 months for cisplatin/5FU and9 months for carboplatin/5FU (p-value=1.015). The median OS was 10 months for cisplatin/5FU arm and 12months for carboplatin/5FU arm (p-value=0.110). There were 6 treatment-related deaths (6/41=14.6%), four inthe carboplatin/5FU arm (4/24=16.7%) and 2 in the cisplatin/5FU arm (2/17=11.8%). Grade 3 and 4 hematologictoxicity was also more common with carboplatin/5FU group, this difference being predominantly due to grade3-4 granulocytopenia (41.6% vs. 0), grade 3-4 anemia (37.5% vs. 0) and grade 3-4 thrombocytopenia (16.6%vs. 0). Conclusions: Carboplatin/5FU is not inferior to cisplatin/5FU with regard to its efficacy. However, therewas a high rate of treatment-related deaths with both regimens. A better alternative needs to be considered.     

Phase II study of a triplet regimen in advanced colorectal cancer using methotrexate, oxaliplatin and 5-fluorouracil

Building upon the concept of schedule-specific biochemical modulation of 5-fluorouracil (FU), which alternates bolus and continuous infusion (CI) FU, we have incorporated oxaliplatin (l-OHP) following the bolus part of the regimen to explore the activity of this new combination. Patients with advanced, untreated, measurable colorectal cancer received sequential methotrexate (MTX) (days 1 and 15)-->l-OHP+FU (days 2 and 16) (200, 85 and 600 mg m(-2), respectively) followed by 3 weeks of CI FU (200 mg m(-2) day(-1)) given from day 29 to 50, modulated by weekly leucovorin (LV) (20 mg m(-2)). After 1 week of rest, the second cycle was started. The treatment was continued until progression or patient's refusal. According to the intention-to-treat analysis on all 46 patients accrued, the response rate was 42% (95% CL=28-55%), with three complete responses and 16 partial responses. The median overall survival was 15.9 months and the median progression-free survival 6.9 months. Toxicity was very mild, with the bolus part of the regimen more toxic than the infusional part (24 vs 7% of grade III-IV, respectively). This new combination of MTX -->l-OHP-FU followed by FU CI is well tolerated, feasible and produces activity results similar to other more simple, but more toxic, regimens. Pros and cons of the different fluoropyrimidines-l-OHP combinations are discussed.     

Irinotecan in the treatment of colorectal cancer

Irinotecan, a water-soluble, semisynthetic derivative of camptothecin, is a key component of first- and second-line treatment regimens for metastatic colorectal cancer (CRC). In the first-line treatment of metastatic CRC, the results of two prospective, multicenter phase III trials have shown that the combination of irinotecan with bolus or infusional 5-fluorouracil (5FU)/leucovorin (LV) can significantly prolong survival compared with 5FU/LV alone, with a manageable side effects profile. In addition, irinotecan-based regimens, with or without oxaliplatin, may improve resectability of metastases and further increase patient survival. Studies of irinotecan in the first-line setting in combination with newer agents, such as bevacizumab, have shown impressive overall survival. In the second-line setting, irinotecan has demonstrated efficacy superior to that of best supportive care. Initial studies of irinotecan plus bolus 5FU/LV, and the preliminary results from trials of irinotecan plus infusional 5FU/LV in the adjuvant setting, have been disappointing; however, for the largest trial, the Pan-European Trial in Adjuvant Colon Cancer, results with sufficient follow-up are pending. Irinotecan has an acceptable tolerability profile and is not associated with cumulative toxicities in patients with metastatic CRC; regimens containing irinotecan extend treatment duration and improve survival. New regimens and adjunctive therapies are being explored to reduce the incidence of common complications of irinotecan treatment, such as diarrhea and neutropenia.     

The Efficacy and Safety of Modified Docetaxel,Cisplatin, and 5-Fluorouracil Vs. Epirubicin,Oxaliplatin, and Capecitabine Regimen in the Advanced Gastric Cancer: A Randomized Controlled Clinical Trial

Introduction: One of the major challenges of advanced gastric cancer treatment is the lack of a standard regimen for patients. However, several clinical trials have shown that modified docetaxel, cisplatin, and 5-fluorouracil (m-DCF) and epirubicin, oxaliplatin, and capecitabine (EOX) regimens are superior to other regimens. Methods: This randomized, single-center clinical trial was performed on 40 patients with advanced gastric cancer. The first group received the m-DCF regimen as follows: docetaxel (40 mg/m2) on the first day; cisplatin (40 mg/m2) on the first and second days; and 5-fluorouracil (400 mg/m2) from the first to fourth day. The second group received the EOX regimen, including epirubicin (50 mg/m2) and oxaliplatin (130 mg/m2) i.v on the first day and capecitabine at a twice-daily dose of 625 mg/m2 p.o for 21 days. Treatment was applied every three weeks for a total of eight cycles in both groups. In each group, the overall and progression-free survival rates and toxicity were assessed. Results: A total of 40 patients were enrolled in this study (21 samples in the m-DCF group and 19 samples in the EOX group), 62.5% of whom were male. The median survival rate was 14.00 (95% CI: 11.82-16.18) months in the m-DCF group and 15.00 (95% CI: 9.56-20.43) months in the EOX group; however, differences between the groups were not significant. The progression-free survival rate was higher in the EOX group, although there was no significant difference between the two groups. Also, there was no significant difference regarding the side effects (e.g., toxicity) or need for supportive care between the groups. Conclusion: It seems that both m-DCF and EOX regimens are similar in terms of survival and toxicity and are recommended as first-line treatment for advanced gastric cancer with respect to the patient’s status.     

Möglichkeiten der systemischen Therapie in metastasierten Stadien des Magenkarzinoms

Recently published results from several phase III trials have significantly increased the therapeutic options in the treatment of metastatic stomach cancer: The continuous infusion of 5-FU can be replaced by capecitabine, and cisplatin can be replaced by oxaliplatin in both cases without impairing efficacy. According to the results of the REAL-2 trial, the combination of epirubicin, oxaliplatin and capecitabine (EOX) achieved superior results for overall survival compared to epirubicin, cisplatin und 5-FU (ECF) (9.9 versus 11.2 months, HR 0.8). However, the question of whether an optimal first line therapy should include a triplet regimen or the sequential use of doublets is a matter of debate. The combination of irinotecan and 5-FU may serve as an alternative to platinum-containing regimens in patients where, due to co-morbidity, a platinum-free regimen is preferred. The 3-drug combination of docetaxel, 5-FU and cisplatin (DCF) demonstrated a statistically significant survival benefit compared to the 2-drug combination of 5-FU and cisplatin in a randomized phase III trial, although results were limited by a particularly significant hematological toxicity, which prevents its application in the large group of elderly patients with gastric cancer. Direct randomized phase III comparisons of DCF with other 3-drug combinations, such as EOX are still missing.     

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.     

Status of treatment for advanced gastric carcinoma

Gastric cancer is the second most common cause of cancer death worldwide. Advanced gastric cancer is incurable. The most widely investigated single-agent chemotherapy is 5-fluorouracil (5-FU), with partial response rates up to 20%. Pilot phase II studies investigating combinations of 5-FU, anthracyclines, mitomycin, methotrexate, and platinums achieved higher response rates; however, the response rates declined in subsequent larger trials. Furthermore, toxicity was substantially higher in confirmatory trials, emphasizing the need to develop well-tolerated regimens prior to multi-institutional testing. Although phase III studies of combination regimens have not achieved a clear worldwide standard, the regimen of epirubicin, cisplatin, and continuous-infusion 5-FU achieved a survival benefit, possibly through the increased activity of infusional 5-FU combined with cisplatin. The taxanes, irinotecan and oxaliplatin, have recently shown important activity in gastric cancer. Patient accrual to a phase III trial comparing a docetaxel-based combination regimen with the regimen of cisplatin and 5-FU has completed accrual. Whether patients with adenocarcinomas of the proximal stomach and gastroesophageal junction will have the same response rates to these new agents as did patients with classical body and distal gastric cancers is unknown. It is anticipated that the development of these active new agents will ultimately improve survival for patients with advanced gastric cancer.     

Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.     

Comparing cytotoxic backbones for first‐line trastuzumab‐containing regimens in human epidermal growth factor receptor 2‐positive advanced oesophagogastric cancer: A meta‐analysis

According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5‐fluorouracil (5‐FU) is standard first‐line treatment for human epidermal growth factor receptor 2 (HER2)‐positive advanced oesophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab‐based cytotoxic backbone regimens compared to the standard ToGA regimen using meta‐analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first‐line trastuzumab‐based regimens for HER2‐positive oesophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in situ hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab‐based regimens to the ToGA regimen. Hazard ratios (HRs) and 95% confidence intervals (95%CI) were calculated by extraction of the published Kaplan‐Meier curves. Incidence counts and toxicity sample‐sizes were extracted for adverse events and compared using single‐arm proportion meta‐analysis in R. Fifteen studies (N = 557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5‐FU (median OS = 20.7 months) versus ToGA (16.0 months, HR = 0.75, 95% CI = 0.59–0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S‐1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand‐foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S‐1 can substitute capecitabine or 5‐FU when specific toxicities are encountered.     

Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205).

PURPOSE: To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. PATIENTS AND METHODS: A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. RESULTS: At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P <.001) and longer progression-free survival than did FU alone (P <.001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. CONCLUSION: Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.     

Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer.

PURPOSE: N-(phosphonacetyl)-L-aspartic acid (PALA) is a pyrimidine synthesis inhibitor that modulates fluorouracil (FU) cytotoxicity. Two previous studies of patients with colorectal carcinoma documented complete response (CR) and partial response (PR) rates of 40% and 43% using weekly low-dose PALA followed by a 24-hour FU infusion. We investigated whether comparable results could be obtained with biochemical modulation by low-dose PALA using bolus instead of infusional FU. PATIENTS AND METHODS: Forty-five patients without prior chemotherapy who had advanced colorectal carcinoma were treated with PALA 250 mg/m2 followed 24 hours later by bolus FU at three dose levels, 600, 700, 800 mg/m2, repeated weekly for 6 weeks followed by a 2-week break. RESULTS: The CR and PR rate was 15 of 43 patients or 35% (95% confidence interval [CI], 21% to 49%), with an overall median survival of 18 months. Grade 3 or 4 diarrhea was the major toxicity observed in 24% of patients receiving FU at 700 mg/m2 and in 43% of patients receiving 800 mg/m2. Hematologic toxicity was observed only with an FU dose of 800 mg/m2, and 29% (four of 14) of patients developed grade 4 leukopenia. We also noted the development of ascites in six patients, mild hyperbilirubinemia in 16 patients, and a decreased albumin level in 22 patients; these abnormalities occurred more frequently in responding patients. CONCLUSIONS: The observed response rate, median survival, and toxicity in this study are similar to those obtained with PALA plus infusional FU and with other methods of FU modulation. Larger phase III studies are needed to compare bolus FU/PALA regimens with other PALA and non-PALA-containing combinations. Our future focus will be attenuate this regimen's toxicity while maintaining or improving its response rates and survival.     

Infusional cisplatin plus cyclophosphamide in advanced ovarian cancer

Twenty-one patients with previously untreated advanced ovarian cancer received a two-drug regimen of cisplatin delivered as a systemic infusion at 20 mg/m2/d for 5 days concomitant with oral cyclophosphamide 150 mg/d in divided doses. Courses were repeated at 3- to 4-week intervals. Responses were observed in 14 of 19 evaluable patients (74%) with three complete responses (one pathologically confirmed at second-look laparotomy) and 11 partial responses. Median time to disease progression in the responders was 12 months (range, 4 to 24 months with four patients maintaining remission at 11, 13, 14, and 19 months). The median survival for the entire group was 12 months (range, 1 to 64 months). A higher-than-expected frequency of nephrotoxicity (38%) and neurotoxicity (24%) was observed, suggesting that infusional cisplatin may lead to cumulative adverse effects and necessitate limiting the number of courses delivered in this fashion. Forty-three percent of patients received less than four courses of therapy related to these two categories of toxicity. The therapeutic effect of infusional cisplatin may be comparable to previous reports of bolus schedules in ovarian cancer when employed in combination with cyclophosphamide but the non-hematologic toxicities are substantial.     

Chemotherapy for metastatic gastric cancer in Japan

Until the 1990s, there were no chemotherapy regimens with old-generation anticancer agents showing a survival benefit over 5-fluorouracil (FU) alone, and standard chemotherapy for metastatic gastric cancer had not been established. In the late 1990s, several new active agents were developed and some phase III trials with these agents were conducted; the new agent S-1 showed noninferiority to 5-FU in these trials. S-1 plus cisplatin is the first doublet chemotherapy to have shown a survival benefit over monotherapy with S-1. It has been demonstrated that capecitabine and oxaliplatin (OHP) can replace 5-FU and cisplatin (CDDP), offering more convenient treatment options. Thus, combination chemotherapy with an oral fluoropyrimidine (S-1 or capecitabine) and platinum (CDDP or OHP) has been recognized as standard chemotherapy for metastatic gastric cancer all over the world. However, it can be said that none of these new combination chemotherapies have shown remarkable progress from 5-FU plus cisplatin regimens. It is expected that triplet chemotherapy with a taxane; the use of molecular targeting agents; and the establishment of treatment strategies including second line chemotherapy, will lead to remarkable progress in personalized medicine in the near future.     

A short-term infusion regimen of Cisplatin, 5-Fluorouracil and L-folinic Acid in advanced head and neck-carcinoma

Treatment of advanced head and neck cancer is still a matter of controversy. Although current chemotherapy regimens are able to induce high response rates, they have not shown improved survival. We employed a combination of cisplatin (CDDP), 5-fluorouracil (5FU) and 1-folinic acid (1-FA) in a 6-hour infusion schedule easy to administer on an outpatient basis. 49 patients have been included to date. The treatment plan consists of 5-FU (375 mg/m(2)) plus 1-FA (100 mg/m(2)) in a 4-hour i.v. infusion followed by a 2-hour i.v. administration of CDDP (20 mg/m(2)). This therapy was repeated for five consecutive days and recycled every 3-4 weeks. Out of 46 evaluable patients there were 6 complete responses (CR) and 23 partial responses (PR) for an overall response rate of 63%. Overall survival was 10.2 months (mean). Untreated patients had a higher probability of response as well as patients with naso-oropharyngeal primary tumor. Toxicity was generally mild with leukopenia, anemia and vomiting being the most frequent side effects. In conclusion, this combination appears well tolerated and active in the palliation of advanced head and neck cancer. However we think that increasing dose intensity of standard regimens and experimental new therapeutic approaches are needed to improve the clinical outcome of this disease.     

Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study.

PURPOSE: Concurrent chemoradiotherapy is the standard of care for locally advanced cervix cancer; the optimal chemotherapy regimen is not yet defined. This trial was designed to compare the outcome of protracted venous infusion (PVI) fluorouracil (FU) with standard weekly cisplatin and concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes were eligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, and high- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT. RESULTS: The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk [RR] unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm. CONCLUSION: In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.     

Experience with chemotherapy for advanced pancreatic carcinoma

The effectiveness of different regimens of chemotherapy for advanced pancreatic cancer was compared in 74 cases (1995-1999). 5-fluorouracil (5FU), adriamycin and mitomycin C (FAM) were given to 12 patients, 5FU alone--23, 5FU plus leukovorin--29, and gemcitabine alone--10. Metastases to the liver were detected in 42 (57%) patients. Partial response (40) was registered in: FAM--1 (8%); 5FU--1 (4%); 5FU + leukovorin--3 (10%); gemcitabine--3 (30%). Mean duration (40) was 5.4; 4; 6.1 and 9 months, respectively. Stabilization was recorded in 17 (23%), mean duration--4.4 months; tumor progression--49 (66%). Toxic side-effects of all the regimens were insignificant. Mean survival rates following FAM, 5FU, 5FU + leukovorin were 4.4; 4.2 and 5.6 months, respectively, while that for gemcitabine varied 3-24 months (on average--7.9 months). Survival in patients responsive to chemotherapy was 9.8; remaining patients--4.7 (p (0.05). Chemotherapy for advanced pancreatic carcinoma is a measure of palliation; its use was followed by a 20% increase in survival. Gemcitabine treatment appeared most effective.     

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.     

Capecitabine in the treatment of advanced gastric cancer

Although the role of systemic chemotherapy has been established for the treatment of advanced gastric cancer, the prognosis of these patients remains poor, with a median overall survival of less than 1 year. Based on the results of several randomized Phase III trials, 5-fluorouracil continuous infusion plus cisplatin, with or without epirubicin, has become the global reference regimen for this patient population. However, treatment with fluorouracil infusion requires either frequent hospitalizations or the use of a central venous access device, harboring potential complications. Capecitabine, a tumor-activating oral prodrug of fluorouracil, may be more advantageous in terms of patient convenience, safety and efficacy. Two recent randomized Phase III trials have shown that capecitabine could replace infusional fluorouracil in cisplatin-based regimens. Furthermore, Phase II trials have shown that many other capecitabine-based doublet or triplet chemotherapy regimens incorporating newer cytotoxic agents are active and well tolerated. Many promising biological agents are now being tested in Phase III trials, incorporating capecitabine combinations as control arms, in patients with advanced gastric cancer.