Sequential combination of 5-fluorouracil, cis-platinum and irradiation. 1. Advanced head and neck cancers

Based on the synergistic action of 5-fluorouracil (5-FUra), cis-dichlorodiamminoplatinum(II) (cis-DDP) and gamma-rays, which was suggested in experiments on murine tumours, a sequential treatment combining irradiation and chemotherapy for human solid tumours known to be resistant to conventional treatments has been developed. A pilot study was carried out on 30 patients with recurring head and neck cancers previously treated by radiotherapy and surgery. The good tolerance and the initial results justified applying this protocol to previously untreated cases. The second study involved 40 patients with stage III and IV tumours. After 3 cycles of combined radio- and chemotherapy followed by a conventional radiotherapy, 78% were good responders (51% in complete remission). Oropharynx and oral cavity, without base of tongue, have a 51% actuarial survival at 3 years when they achieved an early complete remission.     

Cisplatin schedule in combination with gemcitabine in unresectable non-small cell lung cancer

Gemcitabine (on days 1, 8, and 15)-cisplatin (on day 15) combinations were used to treat 9 patients with unresectable non-small cell lung cancer to study efficacy and safety. Gemcitabine 1,000 mg/m2 was administered on days 1, 8, and 15 of a 28-day cycle. Cisplatin 60-65 mg/m2 was administered on day 15 of a 28-day cycle. Three cycles were planned per patient. The nine patients received 25 cycles of chemotherapy. Objective response rates was 55% (complete response 11% and partial response 44%). Stable disease was 33%, and progressive disease was 11%. Seven of 9 patients received the planned 3 cycles of therapy. Two patients received only 2 cycles, due to progressive disease (1 patient), and ulcerative colitis (1 patient). Grade 3 leukopenia was 22%, and grade 3 neutropenia was 11%. No grade 4 hematological toxicities were observed. Grade 3 anorexia was 11%, and grade 3 skin rash which occurred in the first cycle 22%. Our data show less toxicity and no significant difference in response rates, so the administration of cisplatin on day 15 seemed to be a useful and safe regimen.     

Sequential chemo-radiotherapy in non-small cell lung cancer

Locally advanced non-small cell lung cancer (NSCLC) stage IIIA/IIIB represents approximately 30% of NSCLC and still has a poor prognosis. In this article we give a short review on several randomized phase III trials that showed a slight but significant survival benefit for sequential chemo-radiotherapy in the treatment of locally advanced NSCLC.     

不能手术切除的非小细胞肺癌集束电极射频治疗的初步探讨

目的：探讨应用集束电极射频(radiofrequency ablation；RFA)治疗不能手术切除的非小细胞肺癌的可行性和近期疗效。方法：在CT引导下经皮肺穿刺或术中直视下RFA治疗不能手术切除的非小细胞肺癌，随访观察治疗近期效果、中位生存期、1年生存率、2年生存率及围手术期并发症。结果：86例患共92个肿瘤病灶用RFA治疗，术后并发气胸16例，随访5～36个月。治疗后1个月41．86％的KPS评分改善。16例出现局部复发，其中9例患再次RFA。中位生存时问为14个月，1年生存率为78．15％，2年生存率为46．88％。结论：RFA治疗不能手术的非小细胞肺癌创伤小，可重复治疗，安全可靠．局部治疗效果较好。     

Cisplatin, continuous-infusion 5-fluorouracil, and intermediate-dose methotrexate in the treatment of unresectable non-small cell carcinoma of the lung.

Forty-one patients with unresectable non-small cell carcinoma of the lung (NSCCL) were treated with cisplatin 20 mg/m2/d for 5 days as a daily bolus injection, 5-fluorouracil 800 mg/m2/d by continuous infusion for 5 days, and intermediate-dose methotrexate 200 mg/m2 on days 15 and 22 of a 28-day cycle (PFM). One complete and 23 partial responses were observed, yielding an overall response rate of 60%. There was no significant difference in response rates based on histologic subtype or extent of disease (locally unresectable versus metastatic). Median duration of response was 6 months, and the median survival of all patients was 10 months. Two patients with unresectable disease at presentation became resectable after chemotherapy and remain disease-free at 46+ and 53+ months. Toxicity was modest, with oral mucositis the major adverse effect. Clinically important neutropenia was uncommon. PFM is an active regimen in NSCCL and deserves further study in the "neoadjuvant" setting.     

Postoperative irradiation in non-small cell lung cancer

A growing body of evidence suggests that postoperative irradiation for non-small cell lung cancer may cause life-threatening toxicity and, when the risk of local-regional recurrence is low, the toxicity of irradiation may outweight the benefit. However, many of these studies used outdated, even crude techniques. Although these techniques may be responsible for a significant amount of the toxicity reported in these studies, essentially no randomized or high-quality retrospective study has shown a survival benefit for postoperative irradiation for patients with N0 or N1 disease. The situation for N2 tumors is more positive. Taken as a whole, the available data suggest that, as a worst-case scenario, the net effect of adjuvant irradiation is neutral (with neither a net survival decrement nor a net advantage). As a best-case scenario, postoperative irradiation may improve the chance for long-term survival in patients with N2 tumors.     

Treatment of advanced non-small cell lung cancer with cisplatin, 5-fluorouracil, and mitomycin C

Thirty patients with advanced non-small cell lung cancer (NSCLC) were treated with cisplatin (P), mitomycin C (M), and 5-fluorouracil (5-FU) chemotherapy. Twelve patients (40%) achieved major responses to therapy (11 partial, one regression). The median duration of partial response was 20 weeks. Median survival for the entire group was 29 weeks. Toxicity with this combination was moderate, with myelosuppression being the most significant toxic effect. Acute hematologic toxicity was generally mild, with 74% of patients having a leukocyte nadir greater than or equal to 2000/microliter and 67% with a platelet count nadir of greater than or equal to 100,000/microliter. There were, however, two toxic deaths during periods of treatment-induced cytopenia, 40% of patients developed significant anemia necessitating blood transfusions, and 33% had episodes of prolonged neutropenia. Nonhematologic toxicities were generally mild, although one patient developed a cardiac arrest of unclear etiology during day 4 of cycle 3 of treatment and died, for a total treatment mortality rate of 10% (three of 30). This drug combination produced a response rate comparable to those noted with other two or three drug cisplatin-based regimens in NSCLC but does not appear to offer any substantial advantage given its moderate toxicity, short duration of response, and necessity for substantial hospitalization.     

化疗间期序贯应用厄洛替尼治疗晚期非小细胞肺癌的临床观察

目的　评价化疗后序贯给予厄洛替尼在晚期非小细胞肺癌（ＮＳＣＬＣ）中的客观缓解率和毒副反应。方法　初治或复治的局部晚期或晚期ＮＳＣＬＣ患者共３９例,初治患者２５例采用ＧＣ方案化疗,复治患者１４例方案为多西他赛或培美曲塞,化疗间歇期序贯给予厄洛替尼（１５０ｍｇ／天,ｄ１５～ｄ２８）,２８天为１周期。连用６周期,直至疾病进展或毒副反应不能耐受。结果　３９例患者至随访结束时共完成化疗１３５个周期,平均化疗３４６个周期。所有患者均可进行疗效评价,其中获ＰＲ９例（初治７例）,ＳＤ２３例（初治１４例）,ＰＤ７例（初治２例）。总体客观缓解率（ＲＲ）为２３１％,其中初治ＲＲ为２８.０％（７／２５）,复治ＲＲ１４.３％（２／１４）,总体疾病控制率（ＤＣＲ）为８２.１％,初治患者为９２.０％,复治患者６４.３％。主要不良反应为皮疹和血液系统毒性。结论　化疗序贯厄洛替尼治疗ＮＳＣＬＣ近期疗效较好,毒副反应可耐受,远期疗效有待进一步观察。     

Hypofractionated irradiation for non-small cell lung cancer

Large radiation fractions are an effective way of killing tumour cells but have generally been avoided in curative treatment of patients because of concerns of a disproportionate increase in late normal tissue toxicity. Radiobiological modelling of the effect of radiation on lung tumours and late-reacting normal tissues, which are more sensitive to large radiation fractions, has been undertaken. The biological effect of radiation on tumours is increased as the overall treatment time is shortened but this is not true for late-reacting normal tissue. Sample data are shown in which the relative increases in radiation effect on the tumour and late-reacting normal tissues are similar after hypofractionation. A favourable therapeutic ratio can be achieved because the bulk of normal tissue will receive a lower dose of radiation at a lower dose per fraction than the tumour, especially with current techniques where the volume of normal tissue irradiated can be sharply reduced. The clinical evidence confirms that lung toxicity is volume-dependent. It is the small Stage I and II tumours which are most likely to benefit from hypofractionated regimens, as the volumes to be treated are smaller and they have a lower incidence of distant metastases. Patients with Stage III tumours with favourable prognostic factors are nowadays treated with combined chemotherapy and radiotherapy and so for this group more conservative hypofractionation regimens are being explored. However, more advanced tumours may be treated with hypofractionation to lower total doses to achieve palliation and a modest degree of survival benefit.     

Phase II study of weekly 5-fluorouracil,cisplatin and vinblastine in advanced non-small cell lung cancer

The scheduling of chemotherapeutic agents may be important in optimising their antitumour actions. This has been explored in non-Hodgkin lymphoma, osteogenic sarcoma and bladder cancer with improved results using intensive, weekly dosing schemas. We began a phase II study of cisplatin, 5-fluorouracil and vinblastine in non-small cell lung cancer (NSCLC) on a weekly schedule. 38 patients with advanced or metastatic NSCLC were entered; 32 are evaluable for response. 11 patients were treated with 5-fluorouracil 1.5 g/m² and vinblastine 4 mg/m² by 24-h continuous infusion, and cisplatin 30 mg/m² over 30 min, 6–8 h after the start of the infusion. Because of prohibitive myelotoxicity, the next 27 patients received 5-fluorouracil 1.2 g/m² and vinblastine 3 mg/m². None had had prior chemotherapy while 6 had had previous radiation therapy. Myelosuppression was the predominant toxic effect. Other side-effects included neuropathy, diarrhoea, mucositis, nausea and vomiting. 32 patients are evaluable for response: there have been 14 partial remissions (44%). Responses have occurred chiefly in lung and lymph nodes. The median survival on this study is 7 months, and responders did not live longer than non-responders. While this regimen is well tolerated by the majority of patients and has a response rate comparable to other active regimens identified in single institution studies, survival does not appear to be enhanced. We conclude that the schedule manipulation described here does not enhance the therapeutic index of these drugs in NSCLC.     

Schedule-dependent synergism of vinorelbine and 5-fluorouracil/UFT against non-small cell lung cancer

Elderly patients with advanced non-small cell lung cancer (NSCLC) require chemotherapy that is effective and minimally toxic. We evaluated the activity of a combination of vinorelbine and 5-fluorouracil (5-FU)/UFT (a fixed combination of tegafur and uracil) in vitro and in vivo to establish a rationale for clinical use. The cytotoxic activities of various combinations of vinorelbine and 5-FU, the active metabolite of tegafur, were analyzed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazlium bromide (MTT) assay and isobologram technique in vitro, using 3 NSCLC cell lines (A549, PC14, and Ma10). Sequential exposure to vinorelbine followed by 5-FU showed additive or synergistic activity against all 3 NSCLC cell lines tested. The reverse sequence showed no synergism. Antitumor activity and survival prolongation after treatment with different combinations of vinorelbine and UFT were evaluated in nude mice bearing PC14 xenografts. Treatment with vinorelbine before UFT was associated with higher antitumor activity, less toxicity, and longer survival than the reverse sequence. To clarify the underlying mechanism by which the combination exerts the synergistic effects, the expression of thymidylate synthase (TS) was assessed by Western blot analysis in vitro and by immunohistochemical analysis in an animal model. Vinorelbine suppressed the 5-FU-induced increase in TS protein in A549 cells. In PC14 tumor tissues of animal models, TS expression in cancer cells was suppressed by vinorelbine. Our data suggest that treatment with vinorelbine injection before oral UFT may have synergistic activity against NSCLC. This synergistic activity may be attributed to increased chemosensitivity to UFT caused by vinorelbine-induced suppression of TS.     

Evaluation of chemotherapy of unresectable non-small cell lung cancer]

For this evaluation, a comparison was made of survival of 34 patients with non-small cell lung cancer who had undergone chemotherapy (Group B) with that of 38 patients without this chemotherapy (Group A). Group B had received neither radiotherapy for primary lesions nor bronchial artery infusion of anticancer drugs, and the chemotherapeutic regimen was CDDP + VDS or CDDP + VDS + MMC chemotherapy. MST of this group was significantly longer than that of Group A (4.5 months vs 7.3 months. P less than 0.01), but the PS features of the two groups differed significantly. A comparison was thus made of survival for PS 1-2 cases in both groups (Group A: 17 cases, Group B: 27 cases). MST of group A and B were 6.8 and 9.8 months, respectively (P less than 0.05). The efficacy of the treatment for prolonging survival in terms of age, sex, PS, histology, T factor, N factor and M factor was evaluated by multivariate analysis using the proportional hazard model of Cox. The results obtained indicated the chemotherapy significantly prolonged survival.     

Concomitant 5-fluorouracil infusion and high-dose radiation for stage III non-small cell lung cancer

Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.     

Alpha interferon-2b, leucovorin, and 5-fluorouracil (ALF) in non-small cell lung cancer

Eighteen patients with non-small cell lung cancer (NSCLC) who had previously received no systemic chemotherapy, were treated on this phase II study with interferon-alfa-2b 8 MU tiw, leucovorin 500 mg/m2 IVPB over 2 hours and 5-Fluorouracil 500 mg/m2 i.v. for 6 weeks followed by a 2-week rest. There were was no rest period for interferon. Median age of patients on this study was 63 years. Fatigue, nausea, and diarrhea were the most common toxicities. There were no grade IV toxicities and no treatment-related deaths. Seven partial responses (39%) with median duration of 4.5 months were seen. An additional patient has had stable disease/minor response for 12+ months. Median survival is 10 months. ALF has activity in NSCLC.     

Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer.

BACKGROUND. Cisplatin and 5-fluorouracil have noted synergy in preclinical systems. The authors combined methotrexate with infusional cisplatin and 5-fluorouracil in an attempt to produce a regimen with improved activity in advanced NSCLC. METHODS. Twenty-six ambulatory patients with previously untreated non-small cell lung cancer were treated with continuous-infusion cisplatin (25 mg/m2/day for 5 days), 5-fluorouracil (800 mg/m2/day for 5 days), and intermediate-dose methotrexate (200 mg/m2 on days 15, 22), followed by leucovorin rescue (PFM regimen). RESULTS. Patients received a median of four cycles of therapy. Two patients had a complete response, and 10 had a partial response (overall response rate, 46.2% or 12 of 26). The median time to treatment failure was 22.5 weeks; the median survival was 55 weeks from the start of chemotherapy. There were no toxic deaths attributed to chemotherapy. Thrombocytopenia was the only Grade 4 toxicity (27%). Grade 1/4 and 2/4 peripheral neuropathy occurred in 17 of 26 patients (66%) and was associated with a cumulative cisplatin dose of more than 300 mg/m2. CONCLUSIONS. PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy.     

Negative phase II study of 5-fluorouracil with high-dose leucovorin in non-small cell lung cancer

Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater than or equal to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.     

Combination therapy with vinorelbine and gemcitabine in unresectable non-small cell lung cancer

Vinorelbine (VNR) and gemcitabine (GEM) were used in combination to treat 10 patients with unresectable non-small cell lung cancer to study the efficacy, safety, possibility of out-patient administration, and improvement of subjective symptoms. One course of treatment consisted of i.v. drip infusion of VNR at 25 mg/m2 followed by i.v. drip infusion of GEM at 1,000 mg/m2 on day 1 and day 8. This course was repeated more than twice, as a rule, at 3-week intervals. In 10 patients registered from November 1999 to March 2000, we observed PR in 5, SD in 4 and PD in 1. The response rate was 50%. PS was improved in 5 out of 6 patients with PS 1 or worse. All 4 patients with subjective symptoms reported improvement. Adverse effects of leukopenia of grade 3 or more occurred in 50% of patients and neutropenia in 80%. By dose reduction, we could administer 7.1 courses to each patient on average. Non-hematological toxicities, excluding eruption of grade 3 which occurred in the first course and made it impossible to continue the treatment, were phlebitis in 40% of patients, anorexia in 30% (only grades 1 and 2) and transient drug fever (only grade 1) in 50%. All were tractable, and no lung toxicity occurred. Antibiotic chemotherapy could be performed in 7 patients on an outpatient basis. Combination therapy with VNR and GEM also seemed to be a safe and useful treatment on an outpatient basis.     

Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer

A pilot study was conducted using a combination of cisplatin (70 mg/m2 i.v., day 1), etoposide (60 mg/m2 i.v., days 1 through 5), continuous-infusion 5-fluorouracil (800 mg/m2 i.v., days 1 through 5), and allopurinol (600 mg p.o., days 1 through 7). Treatment was repeated every 3-4 weeks. Ten patients with metastatic non-small cell lung cancer were treated. Significant toxicities were observed, including electrocardiographic changes simulating acute myocardial infarction in three patients. There was no objective response, therefore the study was closed early according to its design.