Platinum-Based Chemotherapy Followed by Radiation Therapy of Locally Advanced Nasopharyngeal Cancer a Retrospective Analysis of 39 Cases

A retrospective analysis was performed of 39 patients with locally advanced nasopharyngeal cancer treated with combined chemotherapy and radiation therapy during the last five years, at our departments. There were 26 men and 13 women with median age 55 (24-75) years. Histology was squamous cell carcinoma in 6 patients and undifferentiated carcinoma in the remaining 33 patients. Induction chemotherapy consisted of either regimen A (cisplatin 100mg/m² day 1, 5-FU 1000mg/m² days 2-6 as continuous infusion, bleomycin 15 mg days 15 and 29 i.m., mitomycin 4mg/m² day 22 and hydroxyurea 1 000mg/m² daily days 23-27) or regimen B (carboplatin 300mg/m² day 1, 5-FU 1 000mg/m²days 1-5 as continous infusion and methotrexate 1.2g/m² day 14 with leucovorin rescue). After completion of induction chemotherapy 13 patients (33%) had complete remission (CR) and 19 (49%) partial remission (PR). The CR rate was increased after radiation therapy to 72%. Survival rates were 88% at 12 and 78% at 24 months. Median time to progression was 29.5 months. In conclusion, induction chemotherapy with a platinum-based regimen followed by radiation therapy achieved a high rate of local control. If the treatment also prolongs survival must, however, be studied by randomized trials.     

Nordic 5-fluorouracil/leucovorin bolus schedule combined with oxaliplatin (Nordic FLOX) as first-line treatment of metastatic colorectal cancer

This study combined oxaliplatin with the Nordic bolus schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. Twenty-seven patients were treated every second week with oxaliplatin 85 mg/m² as a 2-h infusion on day 1, followed by a 3-min bolus injection with 5-FU 500 mg/m² and 30 min later a bolus injection with FA 60 mg/m² given on days 1 and 2. Seventeen patients achieved a complete (n=2) or partial (n=15) response, leading to a confirmed response rate of 63% (95% CI 45-81%). The estimated median times to progression and survival were 8.9 and 18.7 months, respectively. Neutropenia grade 3-4 toxicity was seen in 63% of patients, neuropathy grade 3 in one patient and grade 2 in 12 patients. Oxaliplatin combined with the bolus Nordic schedule of 5-FU/FA (Nordic FLOX) appears to be well tolerated, effective and feasible as first-line treatment of metastatic colorectal cancer yielding results comparable with those obtained by more complex schedules.     

GP、PF及TPF方案化疗联合调强适形放疗治疗鼻咽癌的临床疗效

背景与目的：诱导化疗联合放疗及辅助化疗治疗鼻咽癌的疗效目前尚未明确,本研究旨在比较GP（吉西他滨+顺铂）方案、PF（顺铂+氟尿嘧啶）方案及TPF（多西他赛+顺铂+氟尿嘧啶）方案化疗联合调强适形放疗（intensity-modulated radiotherapy,IMRT）在无远处转移鼻咽癌患者中的临床疗效。方法：本研究回顾性分析了2009年1月—2010年12月期间在复旦大学附属肿瘤医院放疗科接受诱导化疗联合IMRT及辅助化疗的134例无远处转移鼻咽癌患者。GP组（吉西他滨1 000 mg/m2,第1、8天+顺铂25 mg/m²,第1~3天）、PF组（顺铂25 mg/m²,第1~3天+氟尿嘧啶500 mg/m²,第1~5天,持续静脉滴注）及TPF组（多西他赛75 mg/m²,第1天+顺铂25 mg/m²,第1~3天+氟尿嘧啶500 mg/m²,第1~5天,持续静脉滴注）分别纳入55、20和59例患者。诱导化疗每21 d重复,2~3个疗程后行IMRT。原发灶及阳性淋巴结的大体肿瘤靶区（gross tumor volume,GTV）的处方剂量分别为（66.0~70.4）Gy/（30~32）次和66.0 Gy/（30~32）次。放疗结束28 d后行辅助化疗2~3个疗程,方案与之前接受的诱导化疗方案相同。随访并比较3组不同的诱导化疗联合放疗及辅助化疗方案的患者5年总生存期（overall survival,OS）、无病生存期（disease-free survival,DFS）及局部无复发生存期（local recurrence-free survival, LRFS）情况。结果：GP组、PF组和TPF组的5年OS率分别为91.9%、75.1%和90.8%,5年LRFS率分别为95.8%、82.3%和96%。GP组的5年OS率（P=0.041）高于PF组,TPF组的5年LRFS率高于PF组（P=0.043）。TPF组和GP组间生存曲线差异无统计学意义。结论：GP方案诱导化疗联合IMRT及辅助化疗治疗无远处转移鼻咽癌的临床疗效可能优于PF方案,尚待大样本数据验证。三药联合的TPF方案并未优于GP方案。可考虑展开Ⅲ期临床试验评价GP方案诱导化疗在无远处转移初治鼻咽癌人群中的疗效。     

A phase II study of oxaliplatin with low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) as first line therapy for patients with advanced gastric cancer

To determine the activity and toxicities of a low dose leucovorin (ldLV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin administered fortnightly (modified FOLFOX-4), as a first-line therapy for patients with advanced gastric cancer. Patients were treated with cycles of oxaliplatin 85 mg/m² on day 1 plus LV 20 mg/m², followed by 5-FU a 400 mg/m² bolus and a 22 hour continuous infusion of 600 mg/m² 5-FU on days 1 - 2 every two week intervals. Forty-five patients were enrolled in this study. Forty-two patients were assessable for response. One of the 42 patients demonstrated complete response, and 20 partial responses, and overall response rate of 50%. The median time to progression and overall survival time were 7.7 months (95% CI: 3.6 - 11.9 months) and 11.2 months (95% CI: 9.1 - 13.3 months), respectively. Major hematologic toxicities included grade 1 - 2 anemia (39.7%), neutropenia (30.4%) and grade 3 - 4 neutropenia (10.9%). Twelve cycles were associated with neutropenic fever. The most common non-hematological toxicities were grade 2 nausea/vomiting (20%). There was no treatment related death. The modified FOLFOX-4 regimen was found to be a safe and effective first line therapy in advanced gastric cancer.     

A Phase I Study of Escalating Interferon Alpha-2A Combined with 5-Fluorouracil and Leucovorin in Patients with Gastrointestinal Malignancies

On the basis of preclinical data showing synergy between 5-fluorouracil (5-FU), leucovorin (LV) and IFN-alpha-2a, a phase I study was carried out to determine the maximum tolerable dose (MTD) of IFN-alpha-2a with this combination in patients with gastrointestinal malignancies. The treatment consisted of 370 mg/m² 5-FU and 200 mg/m², LV on days 1 to 5, and IFN-alpha-2a on days 1 to 5 of the first week of chemotherapy and on days 1, 3, 5 of each subsequent week, on a 28-day cycle. Six patients with colorectal, 3 with pancreas, 2 with oesophagus, 2 with hepatocellular and one with gastric cancer were treated. At level III (5 × lo⁶ U/m²) all patients experienced grade 3 or 4 toxicity during the first 56 days of treatment and the MTD was declared level II. Grade 3 toxicity comprised of anorexia, mucositis, diarrhoea, and fatigue; in one instance, grade 4 neutropenia occurred. Ten patients were evaluable for response, one patient with an oesophageal cancer had a minor response and one patient with rectal cancer and liver metastases had a radiological complete response lasting 3 months. The recommended dose for this schedule in phase TI studies is 5-FU 370 mg/m², LV 200 mg/m², and IFN-alpha-2a 4 × 10⁶ U/m².     

Randomized Phase II Study of a Combination of Cisplatin (DDP), 5-Fluorouracil (5-FU), and Allopurinol (HPP) Versus 5-FU in Advanced Colorectal Carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group Study

In order to improve the therapeutic index of fluorouracil (5-FU), it has been combined with cisplatin (DDP) as synergistic agent and with allopurinol (HPP) as toxicity modulator. Patients with measurable colorectal carcinoma, previously untreated by chemotherapy, were randomized to receive either 5-FU alone 500 mg/m² push iv days 1-5 or HPP 3 300 mg po, days 1-5, 5-FU 800 mg/m² push iv, days 3-5 and DDP 50 mg/m² d6. Treatment was repeated every 4 weeks. Of 104 patients randomized, 82 were evaluable for response and survival. Six partial responses were seen in each treatment group (15%) and the median survival time was 7 months. Hematologic toxicities were comparable in both treatment groups, with a mean nadir white blood cell count of 3500/ vs. 3800/mm³ and a mean nadir platelet count of 148,000/ vs. 203,000/mm³ for HPP-5-FU-DDP and 5-FU, respectively. This study suggests that the addition of both HPP and DDP does not improve the activity of 5-FU.     

Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction.[8] This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m² over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m² bolus, followed by infusional 5-FU 600 mg/m² over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m² bolus, followed by cisplatin 50-75 mg/m² over 30 minutes and then infusional 5-FU 600 mg/m² over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m² inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.     

Treatment of Advanced Gastric Cancer with a Modified Regimen of Etoposide/Leucovorin/5-Fluorouracil

The efficacy and toxicity of a combination of etoposide 100 mg/m²/day iv on day 2-4, leucovorin 300 mg/m²/day iv, and 5-FU 500 mg/m² day iv on day 1-5 every 4 weeks were assessed in 21 patients with advanced gastric cancer with measurable or evaluable diseases. Eight patients had an objective response, including 3 in CR. The overall response rate was 38.1% (95% CI 33.4-42.8%). Five of 8 patients who exhibited locally advanced and unresectable diseases had an objective response (2 CR, 3 PR). The response rate in patients with metastatic disease was 23.0% (95% CI 14.4-31.6%). The median progression-free interval and overall survival time were 7 and 10 months, respectively. The most frequent side effect was alopecia (Gr I/II 71.4%). No treatment-related death occurred. Modified ELF is a relatively effective and tolerable combination regimen for advanced gastric cancer and can be safely administered to elderly patients and patients with systemic diseases.     

A Phase I Trial of Protracted 5-Fluorouracil Infusion and Oral Calcium Leucovorin

This phase I study of 36 patients was performed to identify the maximal tolerated dose of oral calcium leucovorin (CLV) that could be concomitantly administered with protracted 5-fluorouracil (5-FU) infusion (greater than 30 days). Administration of CLV in very small doses (5 mg p.o. q8h) with 5-FU, 200-300 mg/m²/day, resulted in excessive toxicity requiring treatment interruption in all patients. Subsequent reduction in the dose of 5-FU to 100 mg/ m² / day with simultaneous administration of CLV, 5 mg p.o. q8h, decreased the toxicity and allowed for protracted administration of the combination. In subsequent patients the dose of oral CLV was increased to 22.5 mg p.o. q8h, which resulted in treatment-limiting toxicity in the majority of patients. Toxicity consisted almost exclusively of mucositis. No mye-losuppression or significant organ toxicity was observed. We conclude that even low doses of oral CLV potentiate the biological effect of infusion 5-FU. If the combination is to be given on a protracted basis, 5-FU must be administered at a much smaller dosage than has been traditionally utilized.     

Double Modulation of 5-Fluorouracil in the Treatment of Advanced Colorectal Carcinoma: Report of a Trial with Sequential Methotrexate, Intravenous (Loading Dose) Folinic Acid, 5-Fluorouracil, and a Literature Review

5-Fluorouracil (5-FU) modulation with either folinic acid (FA) or methotrexate (MTX) has improved 5-FU's potential cytoreductivity. We combined MTX and FA with 5-FU to further augment 5-FU's cytoreductivity. Patients (n = 34) with advanced colorectal carcinoma were first given intravenous MTX (escalated from 30 mg/m2 to 70 mg/m²). FA (100 mg/m²) was infused 17-24 hr later, followed by 5-FU (600 mg/m²). Oral rescue doses of FA were begun 24 hr after MTX. Patients were treated every 2 weeks. No previously treated patient (n = 6) responded. Eight of the remaining 28 (29%) (95% confidence interval, 15-47%) patients achieved a PR. Median survival was 9.3 months. Toxicity (primarily gastrointestinal) necessitated dosage modification in 10 patients (29%). These results, in addition to a literature review, reveal that the manipulation of 5-FU by two modulating agents does not improve the response rate seen with single-agent modulation.     

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

Unresectable adenocarcinoma of the pancreas: patterns of failure and treatment results

We retrospectively reviewed the outcome of 36 consecutive patients seen in our department with nonmetastatic unresectable adenocarcinoma of the pancreas. There were 28 men and 8 women with a mean age of 63.7 years (range, 43-78 years). Radiation therapy (RT) was given to all patients. 5-Fluorouracil (5-FU) was given as a bolus (500-1000 mg/m²/day) during the first and last weeks of RT in 22 patients, whereas continuous 5-FU (225 mg/m²/day) was given to 3 patients. The median survival for all patients was 10 months. Overall survival for all patients at 1 and 3 years was 47.2% and 19.1%, respectively. The pancreas, peritoneum, liver, and lungs were components of failure in 66.7%, 33.3%, 14.8%, and 14.8%, respectively. Local control was a major problem in patients treated for unresectable pancreatic cancer. The results of this study confirm the dismal prognosis of these patients.     

A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract

Purpose: Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase (DPD). It allows for oral dosing of 5-fluorouracil (5-FU), which may potentially improve the antitumor activity of 5-FU when delivered concurrently with radiotherapy while avoiding the inconvenience and morbidity of continuous infusion (CI) 5-FU. We addressed the safety of oral eniluracil/5-FU combined with radiation therapy and determined the profile of dose-limiting toxicities and recommended Phase II dose (RPTD) in patients with pancreatic and hepatobiliary cancers. Methods and Materials: Patients with resectable or locally advanced pancreatic and biliary cancer received eniluracil (starting at 6.0 mg/m² q12h)/5-FU (starting at 0.6 mg/m² q12h). Eniluracil/5-FU were given concurrently with preoperative radiation to 4500 cGy followed by 540 cGy by reduced fields. Surgery was considered 4 weeks after completion of therapy. Results: Thirteen patients were enrolled. Chemoradiotherapy was completed in all patients. The MTD was not reached and, thus, the RPTD of eniluracil/5-FU was determined to be 10 mg/m² q12h/1 mg/m² q12h. Two patients with locally advanced disease had a 30-45 percent cross-sectional tumor reduction, one of which underwent margin-negative resection. Two of 5 patients with pancreatic cancer, and 1 of 3 patients with cholangiocarcinoma, with underwent exploratory surgery had margin-negative resections. One patient had a pathologic complete response (pCR). Patient 5-FU plasma exposure increased slightly from Day 8 to Day 31. Conclusion: Preoperative chemoradiation with oral eniluracil/5-FU is feasible, well tolerated, and potentially effective in the neoadjuvant setting. Further investigation of oral fluoropyrimidines as radiosensitizers for pancreaticobiliary malignancies is warranted.     

Hydroxyurea May Increase the Activity of Fluorouracil plus Folinic Acid in Advanced Gastrointestinal Cancer: Phase II Study

In a phase II trial, 36 patients with advanced gastrointestinal cancer were treated with: folinic acid (FA) 500 mg/m² in a 2-hr intravenous (IV) infusion, 5-fluorouracil (5-FU) 600 mg/m² as an IV push injection 1 hr after FA, and hydroxyurea (HU) 35 mg/kg/day given p.o. in three administrations (every 8 hr) 6 hr after 5-FU. Cycles consisted of six weekly treatments for 6 weeks, followed by a 2-week rest period. Thirty-three patients were evaluable for response and 36 for toxicity; 73% had previous chemotherapy. The response rate was 30% (CR + PR), the median duration of response was 21 weeks (range 5-36), and time to failure was 17 weeks (range 3-51). The response in patients previously exposed to chemotherapy was 29% and 44% in chemotherapy-naive patients. The median survival for all entered patients was 28 weeks (range 6-54). The most common toxicity was gastrointestinal: diarrhea 22/36 (61%), mucositis 15/36(42%), and nausea and vomiting 15/36(42%); hematological toxicity was mild. We conclude that HU can potentiate the activity of 5-FU plus FA in advanced gastrointestinal cancer; in particular, HU can restore the activity of 5-FU in patients previously exposed to chemotherapy.     

Fluorouracil and High-dose Leucovorin with Radiotherapy as Adjuvant Therapy for Rectal Cancer: Results of a Phase II Study

The purpose of this phase II study was to evaluate the efficacy and toxicity of fluorouracil and high-dose leucovorin (5-FU/LV) with pelvic irradiation as adjuvant therapy for patients with macroscopical resected rectal or recto-sigmoid cancer. Following surgery for stages II-III primary (52) or recurrent rectal cancer (4), 56 patients received 8 cycles of 5-FU/LV and pelvic irradiation. 5-FU doses were 200 mgr/m² for cycles 2-3 and 300 mgr/m² for cycles 1 and 4-8. LV doses remained fixed at 200 mgr/m². Pelvic radiation was started in the third week, between the first and second cycle. The total dose was 50.4 Gy. No severe complications had been recorded. The incidence of grade 3 diarrhea was 19%. Three patients presented leukopenia grade 3 (5%). In 44 patients (78%) the planned treatment could be administered. The median follow-up was 40 months (range 22-66). Seven patients had a local relapse (13%) and 6 developed distant metastasis (10%). The 3-year disease-free survival was 72% and the overall survival was 76%. These preliminary results show that combined post-operative 5-FU/LV and pelvic radiotherapy are well tolerated and present a reasonable local control and survival rates. This adjuvant treatment should be evaluated in randomized trials.     

Second line chemotherapy with 5 fluorouracil and vinorelbine in anthracycline and taxane pretreated patients with metastatic breast cancer

Purpose. 5-Fluorouracil (5-FU) and Vinorelbine (Vin) are active in the second line therapy of metastatic breast cancer (MBC). We conducted a multi-institutional phase II study to assess the activity of the combination of 5-FU and Vin in anthracycline and taxane pretreated patients with MBC. Patients and Methods. Patients with MBC previously treated with anthracyclines and taxanes, who had measurable or evaluable disease, were treated with folinic acid 200 mg/m² IV, 5-FU 400 mg/m² IV bolus, and 5-FU 600 mg/m² continuous infusion over 24 hours on days 1, 2, 15, and 16 and Vin 25 mg/m² on days 1 and 15 of a 28-day cycle, for six cycles. Response rate, time to disease progression, overall survival, and toxicity were evaluated. Results. Thirty-eight patients were enrolled and 35 were evaluable for response. Grade III and IV neutropenia was seen in four and three patients, respectively. At a median follow-up of 19.5 months, 33 patients have progressed, 14 during treatment and 19 during the follow-up period, and 23 have died for an overall survival of 12.3 months. The time to progression was six months. Eight patients had a partial response and 14 had stable disease for a clinical benefit rate of 63%. Conclusion. The combination of 5-FU and Vin is well tolerated and is a good option for the palliative care of patients with MBC.     

Protracted Continuous Infusion of 5-Fluorouracil in Combination with Doxorubicin, Vincristine, and Oral Cyclophospharnide in Advanced Breast Cancer

Several studies suggest that protracted continuous Infusion constitutes an important way to optimize the dose and the efficacy of 5-fluorouracil (5-FU) in metastatic cancer. Eighty-three women aged 27-76 (median age 55) with metastatic breast cancer were treated every 4 weeks with a continuous ambulatory venous infusion of 5-FU 350 mg/m²/day and oral cyclophosphamide 100 mg/m²/day over 15 days. The continuous therapy was associated with a weekly administration of vincristine (0.8 mg/m²) and doxorubicin (15 mg/m²) on day 1, day 8, and day 15. Cycles were repeated every 28 days. Thirty-four patients were treated in first-line metastatic chemotherapy and 49 in second-line. Toxicities included: mucositis (grade ≤ 2) 23%, diarrhea (grade ≤ 2) 7%, a hand-foot syndrome (grade ≤ 2) 9%, alopecia (grade 3) 21%, neurological (grade ≤ 2) 4%, grade 3 and 4 leukopenia 29%, and grade 3 and 4 thrombopenia 8%. Heart toxicity was only 3%. Catheter infection was observed in 1 case and 7 patients experienced thrombosis. The overall objective response rate (OR) was 48% and the complete response rate was 23%. The median duration of response was 10 months. The median survival was 16 months. Activity was better in naive than pretreated women (respectively, 55% and 42% of OR, p = 0.21). Analysis of responses according to the metastatic sites shows the pronounced efficacy on soft tissus diseases (skin recurrences 42%, lymph nodes 52%), and also in visceral metastases (hepatic 36%, lung 34%).     

5-Fluorouracil and High-Dose Calcium Leucovorin for Hepatocellular Carcinoma: A Phase II Trial

A phase II trial of 5-fluorouracil (5-FU) [250450 mg/m^2/day × 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m²/day × 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.     

A phase II study of modified deGramont 5-fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer

Purpose: To evaluate the toxicity and efficacy of a modified deGramont regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with advanced colorectal cancer who have progressed on at least one but not more than two prior chemotherapy regimens. Patients and Methods: Patients with stage 4 colorectal cancer were treated with oxaliplatin 85 mg/m² by a 2-hour intravenous infusion, followed by leucovorin 500 mg/m² by a 2-hour intravenous infusion, followed by 5-FU 400 mg/m² by bolus injection, followed by 5-FU 2.4 g/m² administered by a 46-hour continuous infusion. Cycles were administered every 2 weeks. Results: Seventy patients were treated and 68 patients had previously received irinotecan. Eleven percent of patients had a partial response, 33% of CEA-evaluable patients had a ≥50% drop in their CEA level. The median time to progression was 6.2 months, and the median overall survival was 8.7 months. Toxicity was mild to moderate, as 14% of patients experienced grade 3 or 4 neutropenia and 3% of patients experienced grade 3 neuropathy. Conclusion: The modified deGramont regimen of 5-FU, leucovorin, and oxaliplatin is tolerable and is associated with a modest degree of antitumor activity in patients who have progressed on both 5-FU and irinotecan.     

A dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients’ median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0–1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m² on day 1 and at escalating doses on day 8, starting from 100 mg/m² with increments of 10 mg/m² ; cisplatin was administered at a fixed dose of 80 mg/m² on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. Results: At the dose of CPT-11 120 mg/m² , three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m² on day 1 and 110 mg/m² on day 8 in combination with CDDP 80 mg/m² on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). Conclusion: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy; further investigation is warranted to define its precise role in the second-line setting.