Phase II study of neoadjuvant chemotherapy in patients with surgically-proven, unresectable stage III non-small cell lung cancer.

BACKGROUND: The aim of this study was to assess whether patients with truly unresectable (bulky extracapsular N2, T4 for tracheobronchial angle or mediastinal organ invasion) stage III non-small cell lung cancer (NSCLC), as proven by cervical mediastinoscopy supplemented or not by left anterior mediastinoscopy and fiberoptic bronchoscopy or thoracotomy, could become resectable after induction cisplatin-containing chemotherapy. In addition, we studied the value of preoperatory magnetic resonance imaging (MRI), in evaluating the probability of achieving a radical resection after neoadjuvant chemotherapy. PATIENTS AND METHODS: Sixteen consecutive untreated stage III NSCLC patients were enrolled in the study. All the patients received two cycles of combination chemotherapy including cisplatin 100-120 mg/m2 intravenously (i.v.) days 1 and 22 and vinorelbine 30 mg/m2 i.v. days 1, 8, 15, 22 and 28 or vinblastine 5 mg/m2 i.v. days 1, 8, 15, 22 and 28. Thoracotomy was planned, after chemotherapy, for all non-progressive patients. No other treatment after surgery was devised following radical resection and patients with residual disease after surgery received standard post-operative radiotherapy. Response to treatment was evaluated by thorax CT and MRI two weeks after the last administration of chemotherapy. RESULTS: The overall complete resection rate was 38% (6 out of 16 patients). MRI was predictive of complete resectability in 80% of cases. In fact, 6 patients judged resectable were completely resected, 3 patients judged unresectable underwent only explorative thoracotomy or incomplete resection while MRI was unpredictive only in one case. The most important chemotherapy-related toxicity was hematological: eight patients (50%) had grades III-IV leukopenia. CONCLUSION: These results indicate that preoperative second generation cisplatin-based chemotherapy can make resectable truly unresectable stage III NSCLC patients in only 38% of cases and that MRI is a reliable tool for assessment of radical resection probability after neoadjuvant chemotherapy.

Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP).

BACKGROUND: The cisplatin-doxorubicin combination has shown moderate activity in malignant pleural mesothelioma (MPM; objective response, 25%), and preclinical studies suggest that interferons (IFNs) may have an antiproliferative effect on mesothelioma cell lines with a marked increase in cisplatin cytotoxicity. Therefore, the combined chemoimmunotherapy regimen is an worthwhile approach to evaluate in a Phase II trial. METHODS: From December 1995 to June 1999, 37 previously untreated patients with MPM were treated with cisplatin 60 mg/m(2) intravenously on Day 1 plus doxorubicin 60 mg/m(2), recycled every 3-4 weeks and IFN-alpha-2b, 3 x 10((6)) international units subcutaneously 3 times a week for a total of 6 courses or until progression. Inclusion criteria were histologic diagnosis of MPM and measurable disease defined by computed tomography scan or magnetic resonance imaging. RESULTS: Thirty-four patients were assessable for toxicity and 35 for efficacy according to World Health Organization criteria. One hundred thirty-five courses were administered with a median of 4 cycles per patients. Seventy-six percent of patient presented at least 1 episode of severe myelosuppression (Grade 3 and 4). Severe anemia and thrombocytopenia occurred in 30% and 24% of patients, respectively. Sixty percent of patients presented constitutional symptoms. In the 35 patients assessable for response, the overall response rate was 29% (95% confidence interval, 15-47%). The median duration of response was 8.4 months. With a median follow-up of 19.6 months, the median survival was 9.3 months. One- and 2-year survival was 45% and 34%, respectively. CONCLUSIONS: This combined regimen has definite activity in MPM. However, toxicity, particularly myelosuppression and fatigue, is not negligible and may limit its application.

The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer.

Brain is the most common site of metastatic spread in small-cell lung cancer (SCLC). Approximately 10% of SCLC patients have brain metastases (BM) already at diagnosis and an additional 40% will develop central nervous system (CNS) involvement during their disease course. Although whole brain radiotherapy and corticosteroids is considered the treatment of choice, accumulating evidence suggests that systemic chemotherapy may also play an important role. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with recent clinical observations of frequent BM responses with systemic chemotherapy. During the last decade, several reports about the effect of systemic chemotherapy on BM from SCLC have been published. Pooled data from five studies report 66% response rate (RR) in 64 patients with initial BM. In addition, an average RR of 36% is derived from five studies including 135 patients with delayed BM treated with systemic single agent chemotherapy. Among new drugs with activity in patients with SCLC brain metastases, camptothecin analog topotecan is one of the most promising with a 52% RR. Although whole brain radiation remains the standard treatment of established BM in SCLC there is an emerging role for systemic chemotherapy, particularly with the use of new active drugs as part of combined modality treatments.

The combination of etoposide and cisplatin in non-small-cell lung cancer (NSCLC).

The role of chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has been a subject of debate for many years. Only recently, cisplatin-based combination chemotherapy has been demonstrated to yield a small but definite survival benefit and to improve symptoms, performance status and quality of life in a substantial proportion of advanced NSCLC patients. The cisplatin-etoposide (PE) regimen was developed in the early 1980s and has been one of the standard chemotherapy programs most extensively used in the clinical practice until a few years ago. More recently, several randomized trials have compared the efficacy of new cisplatin-containing combination chemotherapies including Paclitaxel or Gemcitabine with that of PE or PE-like regimens. Preliminary results are encouraging, indicating a small benefit in favor of the last generation of regimens which might therefore replace PE as 'gold standards' in the treatment of advanced NSCLC. However, the costs of these last generation regimens is higher and the entity of the benefit small. Therefore, PE chemotherapy can still be an option in selected situations.

Induction chemotherapy followed by concurrent standard radiotherapy and daily low-dose cisplatin in locally advanced non-small-cell lung cancer.

Both induction chemotherapy and concurrent low-dose cisplatin have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study was designed to investigate activity and feasibility of a novel chemoradiation regimen consisting of induction chemotherapy followed by standard radiotherapy and concurrent daily low-dose cisplatin. Previously untreated patients with histologically/cytologically proven unresectable stage IIIA/B NSCLC were eligible. Induction chemotherapy consisted of vinblastine 5 mg m(-2) intravenously (i.v.) on days 1, 8, 15, 22 and 29, and cisplatin 100 mg m(-2) i.v. on days 1 and 22 followed by continuous radiotherapy (60 Gy in 30 fractions) given concurrently with daily cisplatin at a dose of 5 mg m(-2) i.v. Thirty-two patients were enrolled. Major toxicity during induction chemotherapy was haematological: grade III-IV leukopenia was observed in 31% and grade II anaemia in 16% of the patients. The most common severe toxicity during concurrent chemoradiation consisted of grade III leukopenia (21% of the patients); grade III oesophagitis occurred in only two patients and pulmonary toxicity in one patient who died of this complication. Eighteen of 32 patients (56%, 95% CI 38-73%) had a major response (11 partial response, seven complete response). With a median follow-up of 38.4 months, the median survival was 12.5 months and the actuarial survival rates at 1, 2 and 3 years were 52%, 26% and 19% respectively. The median event-free survival was 8.3 months with a probability of 40%, 23% and 20% at 1, 2 and 3 years respectively. Induction chemotherapy followed by concurrent daily low-dose cisplatin and thoracic irradiation, in patients with locally advanced NSCLC, is active and feasible with minimal non-haematological toxicity. Long-term survival results are promising and appear to be similar to those of more toxic chemoradiation regimens, warranting further testing of this novel chemoradiation strategy.

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study.

We have recently reported high clinical activity against advanced colorectal cancer of a regimen-alternating bolus FUra, modulated by methotrexate (MTX), and continuous infusion FUra, modulated by 6-s-leucovorin (6-s-LV). Considering the low toxicity of the bolus part of this regimen and our recent in vitro finding of a strong synergism between bolus FUra and natural-beta-IFN (n-beta-IFN), this cytokine was incorporated in the bolus part of our treatment programme. Fifty-six patients with untreated, advanced, measurable colorectal cancer were treated with two biweekly cycles of FUra bolus (600 mg m(-2)), modulated by MTX (24 h earlier, 200 mg m(-2)), and n-beta-IFN (3 x 10(6) IU i.m. every 12 h, starting at the time of FUra administration for four doses), alternating with a 3-week continuous infusion of FUra (200 mg m(-2) daily), modulated by 6-s-LV (20 mg m(-2) weekly bolus). After a 1-week rest, the whole cycle (8 weeks) was repeated if indicated. A total of 5 complete and 17 partial responses were obtained (response rate, 41%; 95% confidence limits, 28-55%) in 54 assessable patients. After a median follow-up time of 36 months, five patients are still alive. Overall, the median time to treatment failure was 6.4 months. The median duration of survival was 15.0 months. There was one treatment-related death after a course of MTX --> bolus FUra/n-beta-IFN and grade III-IV toxicity occurred in 18% of the patients. As the addition of n-beta-IFN results in high toxicity, whereas the efficacy seems to be similar to that of the same regimen without the cytokine, our groups are currently randomizing the original regimen, without IFN, against standard modulated bolus FUra.

Management of malignant pleural effusions.

Malignant pleural effusions (MPEs) represent a common complication of advanced malignancies. However, adequate palliation of this highly symptomatic accompaniment to cancer can be achieved in most patients by adopting the appropriate therapy. Several options are available for the treatment of MPE. Systemic therapy may control the effusion in patients whose underlying malignancy is sensitive to anti-cancer agents. Repeated thoracocentesis can be appropriate for patients with limited life expectancy or slowly recurrent effusions. In the majority of the remaining cases the treatment of choice is pleurodesis with sclerosing agents administered via tube thoracostomy. Controversy still exists as to which drug produces the best results: talc and bleomycin appear to be among the most cost-effective agents. The debate over the best agent to be used for pleurodesis refers to the difficulty in comparing results of studies using different eligibility criteria, response assessment and end-points. This article describes the various treatments which have been reported in the literature to play a role in the management of MPEs. It is also aimed at providing guidelines in allocating patients to appropriate treatments.

Alternating bolus and continuous infusion 5-fluorouracil: a strategy to overcome resistance to this fluoropyrimidine in advanced colorectal cancer patients.

Focusing our effort on the importance of FUra scheduling we have tested the hypothesis that pulse and continuous infusion (CI) of the fluoropyrimidine have different mechanisms of cytotoxicity. Our initial approach was to compare the mechanism of resistance of a cell line resistant to a short term exposure to FUra (HCT-8/FU4hR) to that of a cell line resistant to a prolonged exposure to the fluoropyrimidine (HCT-8/FU7dR). Cytotoxicity studies showed that HCT-8/FU4hR cells were still sensitive to FUra given as a 7-d exposure, suggesting different mechanisms of resistance. Indeed, rapid recovery of TS activity after drug removal was evident in the HTC-8/FU7dR cell line while HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS inhibition by FUra and duration of inhibition after FUra removal. In contrast, labelling studies with [3H-6]FUra(4 h exposure, 100 microM) showed that the incorporation of the fluoropyrimidine into RNA is significantly decreased in HCT-8/FU4hR cells as compared to parental HCT-8 cells. Given the lack of cross resistance between the two schedules in vitro, a pilot trial was done on patients with colorectal cancer refractory to bolus FUra. On 15 patients failing after FUra+LV or FUra alone 1 PR, 3 MR, 3 SD and 8 P were observed, confirming a certain degree of activity of CI FUra in patients clinically resistant to bolus FUra. Based on this rationale, a phase II trial of schedule-oriented biochemical modulation of FUra in advanced colorectal cancer patients was conducted, employing a hybrid regimen of 2 biweekly cycles of FUra bolus (600 mg/sqm), preceeded by (24 h interval) methotrexate, 200 mg/sqm (in order to maximize the RNA effect of the drug) alternating with Fura continuous infusion, 200 mg/sqm daily for 3 weeks, modulated by leucovorin, 20 mg/sqm weekly bolus (in order to maximize the DNA effect). Thirty-three consecutive patients (median ECOG PS 1) with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study, from February 1992 to August 1993. Three complete and 13 partial responses were obtained among these 33 patients (RR = 48%, 95% confidence limits, 31-66%). After a median follow-up time of 23 months, 16 patients are still alive. The median progression free survival and overall survival were 9.6 and 20.8 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3% and vomiting 3% for the bolus part and 21%, 3% and 6% respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen. In conclusion, this experimental and clinical project has generated a novel regimen of schedule oriented biochemical modulation that is twice as active and half as toxic compared to bolus FU+LV given with either the daily x 5 or the weekly schedule. This high clinical activity is very encouraging, especially considering that 1) consecutive patients were entered, 2) the responses were independently reviewed, 3) the progression free survival and survival were much longer than those actually reported for this disease, 4) the toxicity of the program, in particular the bolus regimen, was relatively low allowing further intensification.

Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer.

Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.

Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil.

We have recently demonstrated that continuous-infusion (CI) 5-fluorouracil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m2 per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) or FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU + LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU + LV.

Phase II study of 5-fluorouracil plus leucovorin and interferon alpha 2b in advanced colorectal cancer.

15 untreated patients with advanced measurable colorectal cancer along with other 29 patients in progression after failing first line chemotherapy with fluoropyrimidines received 5-fluorouracil (5FU) 500 mg/m2 given as a weekly bolus at mid-infusion of leucovorin (LV), 500 mg/m2 administered intravenously over 2 h and interferon alpha 2b (IFN) 3 x 10(6) U given intramuscularly every other day. All patients had their previous chemotherapy at least 4 weeks prior to 5FU-LV-IFN. 5 patients discontinued the three drug regimen due to toxicity (intense weakness, fever and influenza-like symptoms in 4 patients; diarrhoea in 1 patient) however no grade IV toxicity was observed. IFN administration was reduced to twice/weekly in 5 patients due to influenza-like symptoms. 1 complete response and 5 partial responses were observed (13.6% response rate); the complete response was obtained in a patient resistant to 5FU: the response rate was only twice as much in untreated patients (3/15 patients, 20%) compared with that in patients previously treated with fluoropyrimidines (3/29 patients, 10.3%). Therefore, modulation of 5FU with LV plus IFN at the doses and schedules employed in this study may rarely overcome clinical resistance to the fluoropyrimidine and the addition of IFN does not appear to enhance the activity of 5FU plus LV.