Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer

We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. Weekly i.v. paclitaxel (60 mg/m2; 3-h infusion) plus concurrent chest RT (60 Gy over 6 weeks) was delivered for 6 weeks. Twenty-nine patients were evaluable for response. Three patients achieved a complete response (10%), and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68-96%). One patient progressed during the therapy, and three patients had stable disease. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (37%). One patient died of pneumonia after completion of therapy. Additional grade > or =3 toxicities included pneumonitis (12%) and neutropenia (6%). One patient had a grade 3 hypersensitivity reaction. The median overall survival duration for all 33 patients who entered the study was 20 months, and 1-, 2-, and 3-year overall survival rates were 60.6%, 33.3%, and 18.2%, respectively. The median progression-free survival duration for all 33 patients was 10.7 months, and 1-, 2-, and 3-year progression-free survival rates were 39.4%, 12.1%, and 6.1%, respectively. Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.     

Adjuvant chemotherapy and radiation therapy for elimination of residual microscopic non-small cell lung cancer

This study determined if patients with residual microscopic non-small cell lung cancer (NSCLC) following lung resection treated with combination chemotherapy and radiation realize prolonged survival. Ten men with microscopic NSCLC following resection were given chemotherapy and radiation therapy. Four (40%) of the ten patients were disease-free at 45 months and fully functional. Only two (20%) of the patients died of recurrent lung cancer. Of patients who died of lung cancer, recurrence occurred within five months of treatment and death occurred within one year. The findings suggest combination chemotherapy and radiation therapy delay or prevent recurrence from residual microscopic NSCLC following lung resection.     

吉西他滨联合卡铂作为诱导方案治疗老年不可手术的非小细胞肺癌

Objective:The purpose of this study was to evaluate the efficacy and safety of gemcitabine (GEM) and carboplatin (CBP) used as induction regimen in the treatment of elderly patients with locally advanced unresectable non-small cell lung cancer (NSCLC). Methods: Seventy-eight cases of elderly patients have been cytologically and pathologically confirmed with locally advanced unresectable NSCLC, the age of the patients ranged from 65 to 75 years. The patients were treated with the combined regimen of gemcitabine and cisplatin. GEM 1000 mg/m2 intravenously injected by drip on the 1st, 8th day and the dosage of CBP was AUC 4 that was used on the 1st day, 21 days apart to each cycle, most patients received 2 cycles. Treatment response was evaluated according to the criteria of RECIST (Response Evaluation Criteria in Solid Tumor), the side effect of the regimen was judged based on WHO criteria. Results: Seventy-eight patients were evaluated and received a total of 156 cycles chemotherapy. There were no complete regression that could be observed, but 32 cases had partial regression (PR), 37 cases with no change (NC) and 9 cases with progression disease (PD). The overall response rate was 41.0%. The main side effects were hematological toxicity. Conclusion: The GC regimen could be used as induction treatment for elderly patients with locally advanced unresectable NSCLC, and the regimen could be well tolerated and is safe in terms of side effects.     

Alternating chemotherapy in advanced non-small cell lung cancer: a phase II study

Fifty-three patients with advanced non-small cell lung cancer (NSCLC) were treated with alternating two-drug schedules cisplatin/vindesine and ifosfamide/mitomycin. Objective response (complete and partial response) was obtained in 31% (confidence limits 18.6-44%) of patients. The median duration of response was 26 weeks. The median survival was 25 weeks, with 24% of patients alive at 1 year. The toxicity was acceptable. The still poor antitumor activity of the chemotherapy schedules used and the lack of non-cross-resistance are factors that could explain the low antitumor activity of alternating chemotherapy.     

Complex and controversial issues in locally advanced non-small cell lung carcinoma

Locally advanced non-small cell lung carcinoma (NSCLC) presents enormous challenges to clinicians and researchers. Because of the absence of metastatic disease, it is a potentially curable condition, greatly differentiating it from stage IV NSCLC. The median and actuarial survival rates are poor, though clearly improved in the past decade, and clearly better than several other types of locally advanced malignancies (e.g., pancreatic cancer, glioblastoma). As demonstrated in Table I, the combination of chemotherapy and radiotherapy has earned the designation of "standard of care" for most good-performance-status patients with locally advanced NSCLC. It is likely that improvements in radiotherapy have also contributed to the enhanced survival and local control rates in this disease. With concurrent chemoradiotherapy, the majority of patients can receive a substantial local response (Fig. 1). Many achieve durable local control, only to succumb to eventual distant metastatic failure. There remains much room for improvement, and there are several avenues for clinical and translational research that offer promise. These include new systemic chemotherapy options (and newer ways of combining these drugs with radiotherapy), improvements in radiotherapy fractionation and dose intensity, methods of protection from chemoradiotherapy toxicity, specific therapies to prevent brain metastatic failure, and the integration of biologically targeted molecules into chemoradiation programs. This article summarizes the advances in the treatment of locally advanced NSCLC over the past several decades and explores some of the many remaining controversies and areas for future investigation.     

Long-term survival results for patients with locally advanced, initially unresectable non-small cell lung cancer treated with aggressive concurrent chemoradiation

The present study was performed to investigate whether modes of voluntary contraction have an influence on an appearance of the premovement silent period (PSP) and components of the premovement cortical potentials. The EMG and the EEG were simultaneously recorded in an isometric ballistic contraction for exerting rapidly an elbow extension force and in a ballistic contraction for fast extending an elbow joint. The prime mover in the 2 contraction modes was the triceps brachii muscle. The frequency of the PSP was significantly higher in the isometric ballistic contraction than in the ballistic contraction (P < 0.01). The duration of the PSP was significantly longer in the isometric ballistic contraction than in the ballistic contraction (P < 0.01). In the isometric ballistic contraction, the 3 premovement cortical potentials (FNP, SNP and TNP) were identified. However, in the ballistic contraction the TNP did not appear. The PSP occurred in the phase of the TNP. The results obtained suggest that the PSP and the TNP are related to a more forceful contraction with faster rates of contraction, rather than only to speed of muscular contraction.     

Cytostatic treatment of patients with advanced non-small cell lung cancer

Complications of patellar resurfacing in total knee arthroplasty have rekindled the interest of many surgeons in patellar retention. In a prospective study 20 randomly selected patients of 40 underwent patellar resurfacing in combination with their total knee arthroplasty. The other 20 patients were left with an unresurfaced patella. Within 24 months of follow-up, the advantages of patellar resurfacing could be seen according to the Knee Society Score. Especially in advanced osteoarthritis of the knee joint, the patients achieved better scores in climbing stairs and in function. The superior functional results are arguments for patellar resurfacing, at least in knees with advanced osteoarthritis.     

Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews

OBJECTIVE: To determine how patients with lung cancer value the trade off between the survival benefit of chemotherapy and its toxicities. DESIGN: Scripted interviews that included three hypothetical scenarios. Each scenario described the same patient with metastatic non-small cell lung cancer with an expected survival of 4 months without treatment. Subjects were asked to indicate the minimum survival benefit required to accept the side effects of chemotherapy in the first two scenarios (mild toxicity and severe toxicity). In the third scenario, subjects were asked to choose between chemotherapy and supportive care when the benefit of chemotherapy was either to prolong life by 3 months or to palliate symptoms. SUBJECTS: 81 patients previously treated with cis-platinum based chemotherapy for advanced non-small cell lung cancer. MAIN OUTCOME MEASURE: Survival threshold for accepting chemotherapy. RESULTS: The minimum survival threshold for accepting the toxicity of chemotherapy varied widely in patients. Several patients would accept chemotherapy for a survival benefit of 1 week, while others would not choose chemotherapy even for a survival benefit of 24 months. The median survival threshold for accepting chemotherapy was 4.5 months for mild toxicity and 9 months for severe toxicity. When given the choice between supportive care and chemotherapy only 18 (22%) patients chose chemotherapy for a survival benefit of 3 months; 55 (68%) patients chose chemotherapy if it substantially reduced symptoms without prolonging life. CONCLUSIONS: Patients' willingness to accept chemotherapy for the treatment of metastatic lung cancer varies widely. Many would not choose chemotherapy for its likely survival benefit of 3 months but would if it improved quality of life. The conflict between these patients' preferences and the care they previously received has several explanations, one being that some patients had not received the treatment they would have chosen had they been fully informed.     

Ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma

We evaluated the efficacy and toxicity of the novel combination of ifosfamide (IFX) and vinorelbine (VNB) as first-line chemotherapy in patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Between March 1993 and November 1994, 44 patients (17 stage IIIB; 27 stage IV) received a regimen consisting of IFX, 2 g/m2 in a 1-h infusion, days 1-3; mesna, 400 mg/m2 in an i.v. bolus at hours 0 and 4 and 800 mg orally at hour 8, days 1-3; and VNB, 35 mg/ m2 in a 20-min infusion, days 1 and 15. During the first course only, a half dose of VNB (17.5 mg/m2) was administered on days 8 and 22. Courses were repeated every 28 days. Forty patients were fully evaluable for response, and 44 were assessable for toxicity. Objective regression was recorded in 13 of 40 patients (33%). No patient achieved a complete response. Thirteen patients presented a partial response (33%); 17 (42%) had no change; and progressive disease was observed in 10 (25%). The median duration of response was 10 months, and the median time to treatment failure for the whole group was 4 months. Median survival was 11 months. The dose-limiting toxic effect was myelosuppression. Leukopenia occurred in 25 patients (57%) and was grade 3 or 4 in 8 patients (18%). Twelve patients (27%) developed peripheral neurotoxicity, while five had mild IFX-induced CNS toxicity. Phlebitis was observed in 15 of 30 patients (50%) who did not have central implantable venous systems. The IFX-VNB combination exhibited an activity against NSCLC that was among the highest reported for non-cisplatin-containing regimens, with a toxicity profile that was easily managed.     

Intraarterial chemotherapy combined with radiation therapy for advanced cancer of the uterine cervix

The results of intraarterial chemotherapy (IACT) combined with definitive radiation therapy for 23 advanced and bulky carcinomas of uterine cervix are reported. IA-CT with cisplatin 50 mg and doxorubicin 30 mg was administered by one shot method in bilateral internal iliac arteries. The protocol consisted of one to three treatment session every 3 weeks. Nine of eleven patients with clinical stage III achieved a complete local response (82%), and the 3- and 5-year survival in these cases were 72% and 72%, respectively. These results were superior to the response (58%), 3- and 5-year survivals (68%, 58%) obtained in 19 patients treated mainly with radiation therapy alone. The side effect of grade 2 and 3 for the intestine, such as ileus and hemorrhagic colitis, was noted in 3 patients (15%). In addition, 3 of 8 patients with radical surgery and postoperative radiation therapy after IA-CT developed insufficient fracture of pelvic bone. These complications accompanied by IA-CT combined with radiation therapy and/or surgery increased slightly, compared with that by the previous therapy without IA-CT, but were not critical. The results suggest that IA-CT following radiation therapy is effective to improve the prognosis of patients with Stage III cervical cancer.     

Hyperfractionated accelerated radiation therapy for non-small cell lung cancer: clinical phase I/II trial

PURPOSE: In an attempt to improve local control and survival of nonsmall cell lung cancer (NSCLC), hyperfractionated accelerated radiation therapy (HART) was carried out as a clinical phase I/II trial. METHODS AND MATERIALS: HART was delivered by 1.1 Gy/fraction, three fractions per day with intervals of 4 h and five treatment days per week. The clinical tumors were irradiated to 74.3 Gy (72.6-75.9)/66-69 fx, 33 days (29-40) (not corrected for lung density), and the subclinical lesions, to 50.0 Gy (48.4-50.6)/44-46 fx, 33 days (29-40). Sixty-nine patients with NSCLC were enrolled in this study. Nine patients were withdrawn from the study during HART due to different reasons. Sixty patients formed the study for outcome analyses. They were 57 males and 3 females with median age of 61 years (21-77). There were 41 cases of squamous cell carcinoma, 15 cases of adenocarcinoma, and 4 cases of large cell carcinoma. Overall, favorable patients (KPS > or = 70, weight loss < 5% and Stages I, II, IIIa) accounted for 73% (44 of 60) of all patients. Forty-four patients (73%) received adjuvant chemotherapy (DDP + VP16) with median cycles of 1.8 before and/or after HART. In order to compare the outcome of HART with conventional irradiation, 50 NSCLC patients treated by conventional fractionated irradiation (CFI) during the same period were chosen as the basis to evaluate relative effects of HART. They derived from the control group of another clinical trial of hyperfractionated irradiation for NSCLC in the same department. They received median tumor dose of 63.9 Gy (62.8-65.0)/34 fx (32-36), 48 days (45-53). RESULTS: 1. Acute and late complications: (a) In HART, 87% of patients (52 cases) developed acute radiation esophagitis: Grade 1-2, 46 cases (77%) and Grade 3, 6 cases (10%), at 2.5 weeks (2-3.5 weeks) after HART began. Five patients with Grade 3 esophagitis had their HART interrupted for <7 days. In CFI, esophagitis was much less (44%,p < 0.05) with 38% of Grade 1-2 and 6% of Grade 3. (b) In HART, acute pulmonary symptoms (RTOG Grade 1-2) occurred in 17% (10 cases), and acute radiation pneumonitis (Grade 3), in 8% (5 cases), while in CFI, they were 24% and 2% (p > 0.05), respectively. Late lung fibrosis (RTOG Grade 1-2) appeared in 20% (12 cases), whereas 18% in CFI (p > 0.05). (c), No other severe acute or late complications have been observed so far in HART. 2. Immediate response. In HART, 20% of patients (12 cases) achieved CR, 60% (36 cases), PR and 20% (12 cases), NR or PD. In CFI, the above three percentages were 10, 28, and 62%, respectively (p < 0.001). 3. Follow-up. The 1-, 2-, and 3-year actuarial survivals were 72, 47, and 28% for HART, and 60, 18, and 6% for CFI, respectively (p < 0.001). Better local control was seen in HART than in CFI with 1-, 2-, and 3-year local control rates being 71, 44, 29%, and 60, 20, and 5%, respectively (p = 0.001). Distant metastases developed less in HART than in CFI. The 1-, 2-, and 3-year distant metastasis rates were 23, 36, and 50% in HART, but 30, 48, and 80% in CFI (p = 0.021). CONCLUSION: 1. HART could be tolerated by most of the favorable NSCLC patients. The predominant complication was acute esophagitis. No other severe acute or late complications have been observed so far. 2. HART resulted in better survivals and local controls, and less distant metastases than CFI.     

Efficacy of neoadjuvant chemotherapy in primary non-small cell lung cancer

PURPOSE: To examine the changes in ciliary body thickness after topical application of pilocarpine, cyclopentolate hydrochloride, and PhXA41, a prostaglandin F2alpha analog. METHOD: We used high-frequency Humphrey UBM840 ultrasound biomicroscope to examine 36 healthy young Japanese subjects. RESULTS: The mean ciliary body thickness increased from 0.67 +/- 0.07 mm to 0.073 +/- 0.08 mm (P < .01) after application of 2% pilocarpine; 1% cyclopentolate hydrochloride and 0.005% PhXA41 decreased the mean ciliary body thickness from 0.75 +/- 0.07 mm to 0.69 +/- 0.05 mm (P < .05) and from 0.78 +/- 0.06 mm to 0.75 +/- 0.06 mm (P < .01), respectively. CONCLUSIONS: Our ultrasound study clearly indicates that pilocarpine increased comparative thickness of the ciliary body by 8.3%, whereas PhXA41 decreased comparative thickness by 3.3% in a manner similar to cyclopentolate hydrochloride.     

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.     

调强放疗结合腔内放疗同步化疗治疗中晚期宫颈癌的临床观察

目的 研究调强放疗、腔内治疗并同步化疗治疗中晚期(IIB-ⅢB)宫颈癌的疗效及毒副反应.方法 选择宫颈癌患者60例,随机分为调强组(调强放疗,腔内放疗结合同步化疗,30例),常规组(常规四野箱式外照射,腔内放疗结合同步化疗,30例).治疗方法:调强组给予56～60 Gy剂量,常规组予50～54 Gy盆腔照射.腔内放疗:A点给予5 Gy/次,2次/周,共6～8次.所有病人接受多西他赛和顺铂同步化疗,每3周一次,共3个疗程.比较临床疗效和急性、晚期毒副反应.结果 两组病人资料类似.中位随访时间是47个月.调强组与常规组的1,2,3年生存率分别为90.0%,86.7%,80.0%以及86.7%,70.0%,60.0%;两组比较差异没有显著性(P>0.05).调强组中有7例(23.33%)患者复发,常规组有17例(56.67%)复发,两组比较差异有统计学意义(P＜0.05).常规组中3,4级急性和晚期消化道反应和泌尿道反应的发生率比调强组高,差异有统计学意义(P＜0.05).血液骨髓毒副反应的比较,两组结果相似.结论 调强放疗结合腔内放疗并同步多西他赛、顺铂化疗,是治疗局部晚期宫颈癌有效的方法.     

Phase II study of liarozole in advanced non-small cell lung cancer

The aim of this phase II study was to investigate the efficacy and tolerability of liarozole, a novel benzimidazole derivative, in non-small cell lung cancer (NSCLC). Liarozole 300 mg twice daily orally was evaluated in 14 patients with stage IIIB and IV NSCLC. 8 patients had received prior treatment with chemotherapy and/or radiotherapy. WHO toxicity grading and response criteria were used. Liarozole was well tolerated. Grade 2 toxicities included alopecia (1 patient), dermatological toxicity (5 patients), dry mouth (2 patients) and nausea and vomiting (2 patients). Leukocytosis was seen in 5 patients, including 2 cases with an elevated white cell count pretreatment. Liarozole was discontinued in 1 patient who developed intolerable progressive pruritus associated with an erythematous rash. No objective tumour response was seen, all 14 patients developing progressive disease within 4 months of commencing treatment. Liarozole was well tolerated but was ineffective as single agent therapy in the management of NSCLC. The side-effect profile was compatible with inhibition of retinoic acid degradation.     

Long-term remission after brachytherapy with external irradiation for locally advanced lung cancer

Three cases are reported who received brachytherapy with external irradiation for inoperable lung cancer and have shown long-term remission. The diseases were adenoid cystic carcinoma, recurrent adenocarcinoma and squamous cell carcinoma. The associated symptoms were severe cough and dyspnea in all 3 cases. They received 60 Gy of external irradiation. After an interval of 2 weeks, 6 Gy at a radius of 1 cm from the center of the source was delivered by iridium-192. They received 2-4 fractions at 1-week intervals. On termination of brachytherapy, complete response was observed in all cases. In 1 case, bronchial stenosis due to radiation-induced fibrosis was observed, but was successfully treated by bronchial stent. Cough and dyspnea disappeared, and all patients have been rendered asymptomatic for the last 2 years. Local disease was well controlled in 2 cases; however, minimal local recurrence was observed after a 2-year follow-up in 1 case.