Combined intravenous and intraperitoneal chemotherapy with fluorouracil + leucovorin vs fluorouracil + levamisole for adjuvant therapy of resected colon carcinoma.

Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leucovorin (LV) has been established as effective adjuvant treatment for patients with stage III colon cancer. Among several other promising treatment strategies in resected colon cancer, intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole, the present randomized study was initiated. A total of 241 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned to ''standard therapy'' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m(-2) plus FU 350 mg m(-2), both administered intravenously (days 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage II disease, no significant difference was noted between the two arms after a median follow-up time of 4 years (range 2.5-6 years). Among 196 eligible patients with stage III disease, however, a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival (P = 0.0014) and a survival advantage (P = 0.0005), with an estimated 43% reduction in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, combined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement (9 vs 25 patients in the FU/levamisole arm; P = 0.005). Treatment-associated side-effects were infrequent and generally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage III colon carcinoma.     

Chemoradiotherapy and adjuvant chemotherapy for rectal cancer

Local recurrence is an important factor in determining the outcome of patients after surgery for rectal cancer, and various attempts have been made to reduce the local recurrence rate. Randomized controlled trials have shown that radiotherapy combined with total mesorectal excision can reduce the local recurrence rate in rectal cancer patients who undergo curative surgery. Chemoradiotherapy is more effective in achieving local control than radiotherapy alone, and preoperative chemoradiotherapy is superior to postoperative chemoradiotherapy in terms of adverse events. Recent advances have led to the identification of potential therapeutic targets such as epidermal growth factor receptor, vascular endothelial growth factor, and endothelial receptors. These new agents have been used in combination with conventional chemoradiotherapy, and higher pathological complete response rates have been reported for such combinations in comparison with conventional regimens. With regard to lateral node dissection, a recent study showed that postoperative chemoradiotherapy was more effective in reducing the local recurrence rate than lateral node dissection. As for adjuvant chemotherapy, one randomized controlled trial showed that patients who received uracil and tegafur as adjuvant therapy had significantly prolonged relapse-free survival times and overall survival times. As well, one metaanalysis has shown the efficacy of oral uracil-tegafur as adjuvant chemotherapy for rectal cancer.     

直肠癌同步放化疗与辅助化疗

辅助及新辅助治疗是直肠癌最重要的综合治疗手段,新辅助同步放化疗和术后辅助化疗在直肠癌治疗中起着至关重要的作用。一些新的化疗和靶向药物的出现可以进一步改善直肠癌的治疗效果。     

西咪替丁辅助治疗直肠癌的临床应用研究

为探讨西咪替丁辅助治疗直肠癌的临床价值,将行直肠癌根治术患者60例随机分为对照组和西咪替丁治疗组各30例.治疗组术前1周开始服用西咪替丁0.2 g,4次/d;术后1～7d继续应用西咪替丁静脉推注0.4 g,2次/d;术后第8天后继续服用西咪替丁0.2 g,4次/d ,持续2年.对照组与治疗组术均应用CF/5-FU辅助化疗6个疗程,统计治疗组和对照组的5年累积生存率并进行统计学分析.西咪替丁治疗组中位生存期56个月,5年累积生存率为20.5%;对照组中位生存期50.5个月,5年累积生存率为34.0%.两组5年累积生存率差异无统计学意义（χ^2=2.892,P=0.089）.初步研究结果提示,西咪替丁辅助治疗直肠癌未能明显提高直肠癌患者的术后生存率.     

Feasibility of weekday-on/weekend-off oral UFT/Leucovorin schedule as postoperative adjuvant chemotherapy for colorectal cancer

Two phase III studies revealed an oral UFT/Leucovorin (LV) regimen, in which the drugs are taken for 28 consecutive days every 35 days, which proved to be equivalent to an infusional 5-fluorouracil/LV regimen for metastatic colorectal cancer (CRC). The weekday-on/weekend-off schedule for UFT, which is taken for 5 consecutive days followed by 2 drug-free days,has been reported to be safe and to have good feasibility. In the present study, we investigated the weekday-on/weekend-off schedule for UFT/LV in 54 patients with CRC. The median administration period was 8 months. Ten patients (19%) showed grade 2 or more severe adverse reactions. One of them had grade 3 diarrhea and anorexia. Grade 2 anemia was observed in 9 cases (19%) and grade 2 leucopenia was in 2 cases (4%). Myelotoxicity was mild. These results suggested that the adverse reactions in the weekday-on/weekend-off schedule for UFT/LV are less severe than the conventional UFT/LV schedule reported previously. Antitumor effects and survival benefits of the two schedules should be evaluated by a phase III study.     

Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.     

Postoperative adjuvant chemotherapy and pelvic radiotherapy for resected rectal cancer

Conclusions Although postoperative pelvic radiotherapy reduces the incidence of locoregional recurrence in patients with resected rectal cancer, this does not result in any improvement in disease-free or overall survival. These results are consistent with the findings of NSABP R-01, in which postoperative radiotherapy without chemotherapy failed to affect disease-free or overall survival.     

Evaluation of levamisole as an adjuvant to chemotherapy for treatment of ANLL

Levamisole is a synthetic, orally administered, relatively nontoxic compound with immunorestorative ability. Levamisole was tested in this study of 60 adults with acute nonlymphocytic leukemia (ANLL) to determine if augmentation of response rate or duration, or survival over that obtained with a standard chemotherapy regimen alone would result. The chemotherapy regimens for all patients consisted of daunorubicin and cytosine arabinoside for induction and consolidation, methotrexate with citrovorum factor reversal in a cytoreductive phase, and late intensification with thioguanine and cytosine arabinoside. The first 30 patients received chemotherapy alone; a second group of 30 patients were scheduled to receive levamisole in addition to chemotherapy. Levamisole, 45 mg/m2, was administered orally twice daily for three consecutive days each week beginning one week after the initiation of induction chemotherapy and continuing until relapse. No significant difference emerged between the two groups with respect to remission rate, time to achieve remission, postrelapse survival, or total survival. However, a trend towards improved postcomplete remission survival (P = 0.072) was noted in the levamisole group, and patients who received levamisole had a significantly greater reinduction rate after relapse (P = 0.019).     

Adjuvant levamisole and fluorouracil in high risk colorectal cancer patients

Adjuvant chemotherapy in colorectal cancer patients is aimed at decreasing the relapse rate of the disease and increasing the disease-free and the overall survival of the patients. In a prospective study we evaluated the efficacy of 5-FU plus levamisole as an aduvant therapy for 153 patients with Dukes' B-2 or C colon or rectal cancer following a curative-intended surgery. Adjuvant chemotherapy was started within 4 to 6 weeks following the operation. Combination of 5-FU 375 mg/m(2)/day was given intravenously over 15-20 min for 5 consecutive days, every month for 1 year. Levamisole 50 mg t.i.d. was administered orally during the first 3 days of each course of chemotherapy. Rectal cancer patients were also irradiated to the tumor bed and pelvic lymphatics. The dose intensities (DI) of 5-FU and levamisole in our study were 432.6 mg/m(2)/w and 103.8 mg/m(2)/w, respectively. Failure analysis in Dukes' B and C patients showed that the rectum accounted for 47.5% of the relapses, of which only 3 cases were in the vicinity of the resected area. Almost half of the failures were observed within the year of adjuvant treatment. The liver was the most common site for first relapse (50%). The 3-year disease-free survival of Dukes' B-2 patients group was 84%, compared with 64% in Dukes' C. The main toxic manifestations were diarrhea, nausea and vomiting, weakness and mucositis. No dose reduction was needed. Our protocol, using lower DI of levamisole yielded similar results with a lower rate of toxicity than other common protocols.     

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE: To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS: For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS: Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS: Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.     

Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer

The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored.     

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer

Background

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated.

Patients and methods

Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens—arm A, 3 courses of fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m² (FEC) followed by 3 courses of docetaxel 100 mg/m² (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC.

Results

Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient.

Conclusion

The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.     

Late mortality and levamisole adjuvant therapy in colorectal cancer.

Beginning in 1975, 78 patients with resected stage B and C colorectal carcinoma were randomly assigned (2:1) to receive either levamisole 2.5 mg kg-1 day-1 given for 2 days every week for 18 months or placebo therapy in the same schedule. Pretreatment characteristics (age, gender, disease site, CEA and stage) and the pattern of follow-up were similar in both groups. For the first 5 years following randomisation, relapse-free survival and overall survival were similar in the two treatment groups. Subsequently, excess late mortality was associated with levamisole group assignment. Consequently, overall survival was somewhat greater in the placebo group than in the levamisole group, 68% vs 38% (P < 0.08). For patients surviving 5 years from randomisation, subsequent survival favoured placebo over levamisole (100% vs 57%; P < 0.03). The absolute numbers of deaths were 27 in the levamisole group (19 definitely cancer related) and seven in the group placebo (five definitely cancer related). This long-term result seen with a more intensive adjuvant levamisole dose and schedule suggests: (1) other levamisole adjuvant trials in patients with colorectal cancer should be examined for long-term outcome; (2) future trials utilising the even higher levamisole dosage required for clinical immunomodulation should proceed cautiously.     

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.     

Perioperative adjuvant chemotherapy vs postoperative chemotherapy for one year

Summary Our first series started in January 1965. The experimental group (507 cases) received one single, short adjuvant chemotherapy course (cyclophosphamide 5 mg/kg/day for six days, starting immediately after mastectomy). The randomized control group had 519 cases. The 15-year relapse-free rates were 53.70% and 38.09% respectively.Our second series started in March 1977. Now all patients receive one single, short adjuvant chemotherapy course (a multidrug course). Cases with histologically proven axillary metastases are then randomized to a new experimental group with chemotherapy continued for one year, and a control group. The series is still open.Compared with the historical control group without any chemotherapy, the new experimental group fared extremely well. Compared with the new, randomized control group with a short adjuvant course, however, the gain seems only moderate. The side effects of the two schedules for a single, short adjuvant chemotherapy course were practically negligible. The side effects of the continued chemotherapy for one year were considerable, and for some patients not tolerable. Nausea and vomiting tended to increase in severity and duration from course to course.Our tentative conclusions are: one single, short adjuvant chemotherapy course immediately after mastectomy may be recommended to all patients. It does increase the cure rate, and the side effects are acceptable. Extension of adjuvant chemotherapy to treatment for one year is still experimental, and should be restricted to high-risk groups. Further cost-benefit analysis of such an extension is needed.writing committee for the Scandinavian Adjuvant Chemotherapy Study Group     

Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer.

PURPOSE: Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer. PATIENTS AND METHODS: After surgery, patients were randomly assigned to CIFU 250 mg/m(2)/d for 56 days every 9 weeks for three cycles or FU 425 mg/m(2) and LV 20 mg/m(2) daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS). RESULTS: The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively. CONCLUSION: CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.