Accelerated-interrupted radiation therapy given concurrently with chemotherapy for locally advanced non-small cell lung cancer

PURPOSE: To evaluate the efficacy of multidrug chemotherapy combined with accelerated radiation therapy in the treatment of localized but unresectable non-small cell lung cancer. PATIENTS AND METHODS: Between September 1990 and February 1993, 35 patients with Stage III (15 IIIA & 20 IIIB) non-small cell lung cancer were entered on a protocol using combined accelerated radiation therapy and chemotherapy. Radiation therapy consisted of 55.6 Gy in 30 fractions (1.8 Gy bid for 5 consecutive days given in 3 weeks [total of 15 days], every other week). Chemotherapy consisted of cisplatin (10 mg/m2), vinblastine (4 mg/m2), 6-thioguanine (40 mg bid), and 5-fluorouracil (400 mg/m2 as continuous infusion) given concomitantly with radiation therapy. Approximately 3 weeks following completion of radiation therapy, two cycles of consolidation chemotherapy were given, consisting of two doses of cisplatin (120 mg/m2) 4 weeks apart and six doses of vinblastine (4 mg/m2) given on two consecutive days every other week for 3 weeks. RESULTS: Six patients were still alive at last follow-up; for them the median follow-up time is 47 months (range, 39-55.8). The median survival time is 17.5 months. The 1-, 2-, 3- and 4.5-year survival rates are 69%, 37%, 20% and 17%, respectively. Overall response rate is 63%, with 51.5% partial response and 11.5% complete response rates. Esophagitis occurred as follows: Grade 4 = 0, Grade 3 = 1, Grade 2 = 6, and Grade 1 = 13. No patient developed Grade 3 or 4 acute respiratory toxicity. Significant hematologic toxicity occurred as follows: 37% Grade 3 and 31% Grade 4 leukopenia. Radiation pneumonitis occurred in two patients. DISCUSSION: The regimen tested in this protocol appears to be very well tolerated with minimal pulmonary or esophageal toxicity. This, coupled with the shortened course of radiation therapy and the ability to deliver the combined radiation and chemotherapy portion of the treatment on an outpatient basis most of the time, has made multi-modality treatment for this malignancy much easier and more convenient for patients. In addition, the favorable survival in this group of patients with locally advanced disease is very encouraging and warrants further study.     

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.     

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.     

Phase II study of 3-hour infusion of paclitaxel in previously untreated non-small cell lung cancer

Paclitaxel has clinical activity in non-small cell lung cancer, with response rates of 21 and 24% in a 24-h infusion. Recent clinical studies have shown that a 3-h infusion of the drug with premedication did not result in hypersensitivity reactions, and that neutropenia was milder in the 3-h than in the 24-h schedule. In this Phase II study, we tried to evaluate the efficacy and toxicity of paclitaxel given over 3 h in patients with previously untreated, unresectable stage III or IV non-small cell lung cancer. In addition, we attempted to investigate the pharmacokinetics and pharmacodynamics of the drug. Paclitaxel was administered i.v. over 3 h at a dose of 210 mg/m2 every 3 weeks with premedication of dexamethasone, ranitidine, and diphenhydramine. Heparinized blood samples were obtained from 12 patients for pharmacokinetic studies. Twenty-three (38%) of 60 assessable patients achieved a partial response, with a median duration of 3.2 (range, 2.3-11.1) months. The median survival for all patients was 11.2 months, and the 1-year survival rate was 48%. Thirty (50%) patients developed grade 4 neutropenia. Nonhematological toxicities were mild, except for pulmonary toxicity in one (1.7%) patient who required mechanical ventilatory support for 4 days. The duration of the paclitaxel concentration above 0.1 microM correlated well with the percentage of decrease in the absolute neutrophil count. In conclusion, a 3-h infusion of paclitaxel was safe and probably not less effective than a 24-h infusion.     

Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer

We report the immunological and clinical results of a phase II trial with intravenously administered highly purified endotoxin (Salmonella abortus equi) in patients with advanced cancer. 15 patients with non-small cell lung cancer and 27 with colorectal cancer were entered into the study. 37 evaluable patients received at least four injections of endotoxin (4 ng/kg body weight) and 1600 mg ibuprofen orally in 2-week intervals. Transient renal (WHO grade 0-1) and hepatic (WHO grade 0-4) toxicities occurred in several patients. Constitutional side-effects such as fever, chills and hypotension could not be prevented completely by pretreatment with ibuprofen. 3 patients in the colorectal cancer group demonstrated objective responses (1 complete remission (CR), 2 partial remission (PR)). The complete remission has been maintained for more than 3 years, while the partial remissions were stable for 7 and 8 months, respectively. Only marginal antitumour effects were seen in the lung cancer group. Tolerance of the macrophage system to the stimulatory effect of endotoxin, as measured by human necrosis factor alpha (TNF-alpha) release into serum, built up after the first administration and remained at a steady-state level after each subsequent injection. In constrast, rising CD4:CD8 ratio and release of tumour necrosis factor beta (TNF-beta) indicated the continuing activation of the lymphocyte system by repetitive injections of endotoxin.     

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.     

An early phase II trial combining cisplatin and carboplatin in advanced non-small cell lung cancer

We conducted an early phase II trial in advanced non-small cell lung cancer (NSCLC) to evaluate response efficacy of a combination of Cisplatin (CDDP) and Carboplatin (CBDCA). The twenty-six patients in the study had had no previous treatment. They received a sequential administration of 300 mg/m2 CBDCA and 80 mg/m2 CDDP with approximately 3,500 ml of hydration on day 1 every 4 weeks. All patients were evaluable for response and toxicity. Ten (38.5%) of all assessable patients achieved a partial response (95% confidence interval, 19.8-57.2%). Response rates for patients with stage III A, III B and IV- disease were 40.0 (2/5), 70.0 (7/10) and 9.1% (1/11), respectively. Response rates for patients with squamous cell carcinoma, adenocarcinoma and large cell carcinoma were 35.7 (5/14), 45.5 (5/11) and 0.0% (0/1), respectively. The median survival time (MST) of all patients was 11 months. The MST for patients with stage III disease was 14 months; for those with stage IV disease it was 7 months. The MST for responding patients was 15 months and for not responding patients 5 months. Major toxicities were hematologic and gastrointestinal, and the dose-limiting factor was thrombocytopenia. This combination chemotherapy was effective against NSCLC with tolerable toxicities. Further trials are warranted to determine the efficacy of the combination chemotherapy.     

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer: results of a multicentre, phase II trial

The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.     

Phase II study of all-trans-retinoic acid and alpha-interferon in patients with advanced non-small cell lung cancer

Between April 1993 and June 1994, 29 patients (pts) with unresectable, locally advanced, or metastatic non-small cell lung cancer were treated with a combination of p.o. trans-retinoic acid (TRA), 150 mg/m2/day, in three divided doses and s.c. IFN-alpha, 3 x 10(6) units/day. The age range was 41-80 years (median, 63 years). The Eastern Cooperative Oncology Group performance status was 0-1 (24 pts) and 2 (5 pts). Pts had advanced disease, refractory to conventional therapy (5 stage IIIB and 24 stage IV). Twenty-one pts had adenocarcinoma, six had squamous cell carcinoma, and two had large cell carcinoma. Only 3 pts completed 8 weeks of treatment, requiring neither interruption nor dose modification. Fatigue occurred in 88% of pts. A syndrome complex consisting of dry oral and nasal mucosa, recurrent sinus infections, and epistaxis occurred in 64% of pts. Grade II/III dermatitis was seen in 52%. Severe scrotal dermatitis was seen in 7 pts (47% of 15 males). Hypertriglyceridemia was moderate/severe in 11 pts, and 3 pts required gemfibrozil for levels up to 1660 mg/dl. Hematological toxicity was not encountered, and none of the pts had leukocytosis. One pt died with complications of myocardial infarction while on TRA/IFN-alpha. Twenty-five pts had more than 2 weeks of treatment and are evaluable for response; two pts died early with complications of cancer, and two pts declined to continue after only 3 and 5 days of treatment. Final assessment of response was by accepted clinical and radiological criteria at 8 weeks. There have been four objective responses: complete response, 2 (18+ and 17 months) and partial response, 2 (7 and 14 months). Responses were observed in all histologies. Combined differentiation treatment with TRA/IFN-alpha has modest but objective activity in non-small cell lung cancer. Toxicity is considerable. Additional studies to elucidate the biological basis of TRA/IFN-alpha and to define prognostic parameters predicting response are needed.     

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

A phase I/II study of paclitaxel (TAXOL) and concurrent radiotherapy in advanced nonsmall cell lung cancer

OBJECTIVE: Polymerase chain reaction amplification of a portion of the RhC/c/E/e gene could lead to a rapid, accurate determination of fetal RhC/c/E status. The purpose of this study was to evaluate the accuracy of this technique by testing for the first time a large number of deoxyribonucleic acid samples derived from individuals whose RhC/c/E status was established by standard serologic methods. We also evaluated the potential clinical utility of polymerase chain reaction to ascertain fetal antigen status. STUDY DESIGN: Samples were obtained from Centre d'Etude du Polymorphisme Humain families used for studies of genetic variation (n = 655). Deoxyribonucleic acid was extracted by standard techniques. With few modifications, published primers and reaction conditions were used. Samples were digested with restriction enzymes yielding characteristic electrophoresis patterns for RhC/c/E. Clinical utility was assessed by review of all patients evaluated for erythrocyte sensitization. RESULTS: RhC-positive (n = 479), RhC-negative (n = 176), Rhc-positive (n = 524), Rhc-negative (n = 131), RhE-positive (n = 131) and RhE-negative (n = 524) samples were evaluated. The sensitivity of RhC/ c and E typing by polymerase chain reaction was 98.3%, 98.1%, and 96.9%, respectively. The specificity of polymerase chain reaction for identifying the RhC/c/E antigens was 91.5%, 94.7%, and 99.2%, respectively. CONCLUSIONS: Although it would appear that use of polymerase chain reaction to establish RhC/c/E type could aid in evaluation of RhC/c/E sensitization, we are concerned about the instances of antigen-positive individuals characterized as antigen negative. Further study is necessary to determine if this reflects a polymorphism, mutation, a data coding error, or a combination. The Centre d'Etude du Polymorphisme Humain database is known to contain such errors at a rate that may surpass the error rate of our testing. A second molecular technique could be used to achieve better accuracy in the ascertainment of Rh C/c/E type. On the basis of a review of our patient population, molecular deoxyribonucleic acid techniques now available could aid the management of erythrocyte sensitization in pregnancy in > 96% of cases.     

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.     

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.     

Phase II trial of raltitrexed ('Tomudex') in advanced small-cell lung cancer

Raltitrexed, a thymidylate synthase inhibitor, was given to 21 patients with advanced small-cell lung cancer, at a dose of 3 mg m(-2) as a 15-min intravenous infusion at 21-day intervals. All of the patients had extensive disease and 17 had received prior therapy. Patients with disease refractory to primary chemotherapy were excluded. Forty-one treatment cycles were given (median two, range one to four). The drug was well tolerated. No objective tumour response was documented. The patients had chemoresistant disease, as shown by a response in only one of ten patients who went on to receive alternative cytotoxic regimens. We conclude that raltitrexed given in this schedule is inactive as second line therapy for small-cell lung cancer.     

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.     

Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial

The ability of rats to learn the location of a hidden platform in a swim maze was compared in animals with excitotoxic lesions of the anterior or posterior (retrosplenial) cingulate cortex or radiofrequency lesions of the cingulum bundle or fimbria-fornix. Performance of this allocentric spatial task was unaffected by the posterior cingulate cortex lesions, while anterior cingulate cortex damage produced only a mild acquisition deficit. Transection of the fornix and lesions of the cingulum bundle produced similar patterns of impairment on initial acquisition, but the cingulum bundle lesions had less effect on reversal of the task. The results from the water maze, and from a subsequent T-maze alternation task, indicate that cingulum bundle lesions can produce a spatial deficit that is similar, but milder, to that observed after fornix transection. The results of the excitotoxic lesions suggest that previous studies examining conventional cingulate lesions may have been influenced by damage to adjacent fibre tracts, such as the cingulum bundle.