Patterns of CT lung injury and toxicity after stereotactic radiotherapy delivered with helical tomotherapy in early stage medically inoperable NSCLC.

OBJECTIVE: To evaluate toxicity and patterns of radiologic lung injury on CT images after hypofractionated image-guided stereotactic body radiotherapy (SBRT) delivered with helical tomotherapy (HT) in medically early stage inoperable non-small-cell lung cancer (NSCLC). METHODS: 28 elderly patients (31 lesions) with compromised pulmonary reserve were deemed inoperable and enrolled to undergo SBRT. Patterns of lung injury based on CT appearance were assessed at baseline and during follow up. Acute (6 months or less) and late (more than 6 months) events were classified as radiation pneumonitis and radiation fibrosis (RF), respectively. RESULTS: After a median follow-up of 12 months (range, 4-20 months), 31 and 25 lesions were examined for acute and late injuries, respectively. Among the former group, 25 (80.6%) patients showed no radiological changes. The CT appearance of RF revealed modified conventional, mass-like and scar-like patterns in three, four and three lesions, respectively. No evidence of late lung injury was demonstrated in 15 lesions. Five patients developed clinical pneumonitis (four patients, grade 2 and one patient, grade 3, respectively), and none of whom had CT findings at 3 months post-treatment. No instance of symptomatic RF was detected. The tumour response rate was 84% (complete response + partial response). Local control was 83% at 1 year. CONCLUSION: Our findings show that HT-SBRT can be considered an effective treatment with a mild toxicity profile in medically inoperable patients with early stage NSCLC. No specific pattern of lung injury was demonstrated. ADVANCES IN KNOWLEDGE: Our study is among the few showing that HT-SBRT represents a safe and effective option in patients with early stage medically inoperable NSCLC, and that it is not associated with a specific pattern of lung injury.

Small cell lung cancer.

Small cell lung cancer accounts for 13-15% of all lung cancer worldwide. There has been a decrease in the number of cases, with no clear explanation, except probably to changing in smoking habits in the last two decades. In the early eighties, it became clear that SCLC was an extremely sensitive tumor as to radiation as to chemotheraputic agents. With cisplatinum etoposide combinations or cyclophosphamide, anthracycline and vincristine/etyoposide regimens responses were observed in 50-70%, with 20-30% complete remissions in extensive disease. For limited stage patients chemotherapy associated with thoracic radiation was able to produce a cure rate of 10-20%. The addition of prophylactic brain irradiation to limited stage cases has reduced mortality by a factor of nearly 5%. But despite these early good results no breakthrough came later on, and in the last decade or so, we are still facing this plateau. New agents have recently been included in the therapeutic armamentarium, such as gemcitabine, irinotecan, paclitaxel. This fact has allowed many patients to receive a relatively active second line therapy, but the overall survival remains unchanged. Targeted therapies are undergoing some evaluations, but the data are too premature and so far quite discouraging. At the present time there is a urgent need to improve clinical research in this somehow forgotten disease.

Oral vinorelbine given as monotherapy to advanced, elderly NSCLC patients: a multicentre phase II trial.

Vinorelbine intravenously (i.v.) demonstrated its efficacy and tolerability in advanced non-small cell lung cancer (NSCLC) patients, including elderly subjects. Since vinorelbine is now available as an oral formulation this phase II open study was designed to evaluate its activity and tolerability in advanced, elderly NSCLC patients. A total of 56 chemonaive patients were recruited from April 2001 through to March 2002. The dosage schedule, already tested in younger NSCLC patients, was 60 mg/m(2)once a week for three weeks (first cycle), followed by 80 mg/m(2) once a week until disease progression or development of unacceptable toxicity. A limited sampling scheme was used for performing pharmacokinetic analysis on 52 of 56 patients enrolled in the study. Treatment was well tolerated with grade 3/4 neutropenia in 11/17 patients (20/30%) and febrile neutropenia in 1 (2%). Six partial responses (11%) and 25 stable disease responses were recorded, with a disease control rate of 55%. Median overall survival was 8.2 months (95% Confidence Interval (CI) [6.2-11.3]). The clinical benefit response rate was 31% on 32 evaluable patients. Pharmacokinetic profiles appeared quite similar to the historical profiles recorded following i.v. administration. Oral vinorelbine appears to be a reasonable alternative to i.v. vinorelbine, both in terms of activity and tolerability, in advanced, elderly NSCLC patients.

EDU-CARE, a randomised, multicentre, parallel group study on education and quality of life in COPD.

Chronic obstructive pulmonary disease (COPD) represents one of the main causes of morbidity and mortality in the western world. Unfortunately, its therapy is largely palliative, the key aims of treatment being to reduce exacerbations, minimise symptoms, and improve patients' ability to perform their usual daily activities. In the absence of true disease-modifying treatments, the concept of rehabilitation has become important. In addition, it has been shown that educational and self-management programmes may play a role in the general treatment of COPD patients. This study was promoted by the Italian Association of Hospital Pulmonologists (AIPO) with the aim to verify changes and improvements induced by an educational programme validated by AIPO in patients with COPD. Edu-Care is a 6-month, multicentre, randomised, controlled, parallel-group study. In addition to treatment within the usual therapeutic schemes for COPD, patients were randomised to either the 'Educational' group, i.e. to receive a formal and structured educational programme, or the 'Normal General Advice' group, i.e. to receive the usual general advice given by general practitioners on life-style and on the disease's risk factors and treatment. A number of evaluations were performed: pulmonary function test, walking distance, quality of life, locus of control, register of number of exacerbations and hospital admissions. To date, of the 1,230 patients enrolled interim data are available from 1,003 patients. Males represent 85% of the study population. Smoking habit is quite a common status (21%). In the year prior to enrolment 34% of patients had one exacerbation, 49% 2-3 exacerbations, and 17% more than 3 exacerbations. Seventy-two percent of patients were not hospitalised over the year prior to enroLlment, while 22% were hospitalised once and 6% had more than 2 hospitalisations. Edu-Care is the first large study aimed to evaluate the efficacy of an educational programme for patients with COPD. AIPO wishes to make a contribution to this important field. This is the reason why Edu-Care includes a very large number of patients in numerous Italian centres throughout northern and southern Italy.

Low dose spiral computed tomography.

Low dose spiral computed tomography is the best tool we have today to detect early lung cancer. The author describes the technique of image intake and the advantages in thoracic oncology.

Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study.

AIMS AND BACKGROUND: The polychemotherapeutic regimen PEV (cisplatin, epidoxorubicin and vindesine) + lonidamine proved to be valid in terms of activity and efficacy in the treatment of patients with advanced, previously untreated non-small cell lung carcinoma. The goal of the study was to verify whether a different dose of lonidamine, together with an increase in cisplatin and epidoxorubicin compared to the standard regimen, is able to improve the activity and efficacy of PEV without increasing toxicity. PATIENTS AND METHODS: Thirty-one patients were treated with cisplatin (80 mg/m2/i.v.), epidoxorubicin (70 mg/m2/i.v.) and vindesine (3 mg/m2/i.v.) every 28 days for 6 courses in combination with lonidamine (600 mg/day on days 1 and 2 of each course followed by 450 mg/day until progression of disease or intolerance). All the patients were monitored for clinical response, median duration of response and survival and for toxicity. RESULTS: The clinical response in the 29 assessable patients was: 41.4% partial remission, 48.3% stable disease, and 10.3% progression of disease. The median duration of response was 8.5 months (range, 4-26+) and median survival was 12 months (range, 4-26+). Survival was above the median in 15 stage IIIb patients, and 2 patients were long survivors at 26+ months. The toxicity of PEV + lonidamine was mild; there were no toxic deaths nor acute toxicity of grade 4 according to the WHO scoring system. CONCLUSIONS: Our polychemotherapeutic regimen proved to be valid in terms of activity and efficacy, and a further dose increase in single chemotherapeutic agents as well as lonidamine could therefore be justified.

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.

The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force.

AIMS: To evaluate the efficacy and treatment compliance in elderly patients with advanced non-small cell lung cancer (NSCLC) of two chemotherapeutic agents with mild toxicity, 153 previously untreated patients aged over 70 years were randomized to receive lonidamine (450 mg daily p.o. until progression), vindesine (3 mg/m2/daily i.v. weekly for 4 weeks and then every 2 weeks until progression), the combination of the two drugs at the same dose and schedule, or supportive therapy only in a four-arm factorial randomized trial. METHODS: 126 patients were included in the final analysis. Their median age was 75 years. Forty percent had stage IV disease and 60% stage III. Most patients were males (85%) and the majority had squamous histology (68%). RESULTS: Among 104 patients evaluable for response there were only 3 PRs (1/30 in the lonidamine arm and 2/33 in the lonidamine + vindesine arm). Overall, 8.7% and 9.5% of the patients, respectively, progressed or died early, before response evaluation; another 9.4% refused treatment continuation because of poor compliance with the study protocol. Eighty-five patients were fully evaluable for toxicity, which was generally mild. Leukopenia grade 1-3 was found in less than 30% of patients treated with vindesine or vindesine + lonidamine. The most common complaints associated with lonidamine treatment were myalgia (70% of patients), fatigue (55% and 83% of patients treated with lonidamine or lonidamine + vindesine, respectively) and testicular pain in nearly 40% of cases. The overall median survival was 170 days, with no significant impact on survival of either lonidamine or vindesine. CONCLUSIONS: The low response rate and survival together with the poor treatment compliance, even in the presence of mild toxicity, do not support the usefulness of these "gentle" chemotherapies in elderly NSCLC patients. The standard management of advanced NSCLC in elderly patients remains to be defined. Specifically designed studies to address this issue are warranted.

Cisplatin-vindesine-mitomycin (MVP) vs cisplatin-ifosfamide-vinorelbine (PIN) vs carboplatin-vinorelbine (CaN) in patients with advanced non-small-cell lung cancer (NSCLC): a FONICAP randomized phase II study. Italian Lung Cancer Task Force (FONICAP).

In the present multicentre randomized phase II trial, the activity and toxicity of three platinum-based combination regimens for the treatment of advanced non-small-cell lung cancer (NSCLC) were evaluated. The three regimens were: MVP (mitomycin-C 6 mg m(-2) on day 1, vindesine 3 mg m(-2) on days 1 and 15, and cisplatin 80 mg m(-2) on day 1 every 28 days), PIN (cisplatin 80 mg m(-2) day 1, ifosfamide 3 g m(-2) day 1 and vinorelbine 25 mg m(-2) day 1 and 8 every 21 days) and CaN (carboplatin 350 mg m(-2) day 1 and vinorelbine 25 mg m(-2) days 1 and 8 every 28 days). A total of 140 chemotherapy-naive patients entered the study; 49 patients were treated with MVP, 48 with PIN and 43 with CaN. Sixty-seven per cent of the patients had stage IV disease. Response rates, calculated on an 'intention to treat' basis, were as follows: MVP, 14.3% (95% CI 5.94-27.2%); PIN, 16.7% (95% CI 7.4-30.2%); and CaN, 14% (95% CI 5.3-27.9%). The overall median survivals were 256, 269 and 243 days for patients treated with MVP, PIN and CaN respectively. Myelosuppression was the most frequent toxicity: grade 3-4 leucopenia was observed in 14.3%, 25% and 18.6% of patients treated with MVP, PIN and CaN respectively. This multicentre phase II randomized trial shows that MVP, PIN and CaN can be administered on an outpatient basis with acceptable toxicities. Unfortunately, the three regimens showed an activity significantly lower than that reported in previous single-institution phase II trials.

Evaluation of response to chemotherapy in patients affected with non-small cell lung cancer by means of three tumour markers elaborated by discriminant analysis.

Chemotherapy is the most effective treatment for inoperable patients (70%) affected with non-small cell lung cancer (NSCLC). The early detection of tumour progression is mandative in order to promptly shift these patients towards salvage or supportive therapy. The present authors investigated the clinical value of a panel of tumour markers, elaborated by means of discriminant analysis, as a follow-up indicator for the detection of tumour progression. The serum levels of tissue polypeptide antigen (TPA), CYFRA-21.1, neuron-specific enolase (NSE) and carcino-embryonic antigen (CEA) were determined before chemotherapy and after three cycles of treatment. Discriminant analysis generated a formula (canonic variable) which correctly classified the 87.8% of the 74 subjects (86.1% of the 36 progressive diseases and 89.5% of 38 non-progressive diseases). This approach produces an algorithm able to calculate a progression score in NSCLC patients which can be helpful for following-up care and therapy control of these patients.

Validation of an algorithm able to differentiate small-cell lung cancer (SCLC) from non-small-cell lung cancer (NSCLC) patients by means of a tumour marker panel: analysis of the errors.

By means of a mathematical score previously generated by discriminant analysis on 90 lung cancer patients, a new and larger group of 261 subjects [209 with non-small-cell lung cancer (NSCLC) and 52 with small-cell lung cancer (SCLC)] was analysed to confirm the ability of the method to distinguish between these two types of cancers. The score, which included the serum neuron-specific enolase (NSE) and CYFRA-21.1 levels, permitted correct classification of 93% of the patients. When the misclassifications were analysed in detail, the most frequent errors were associated with limited disease SCLC with low NSE levels and with advanced NSCLC with high NSE levels. This demonstrates the importance of the marker in correctly categorizing patients.

Combined treatment with thymosin-alpha1 and low-dose interferon-alpha after ifosfamide in non-small cell lung cancer: a phase-II controlled trial.

22 patients with advanced non-small-cell lung cancer were randomized to receive chemotherapy (ifosfamide) or chemotherapy followed by thymosin alpha1 + low-dose IFNalpha. Chemo-immunotherapy induced an enhanced response rate compared with chemotherapy alone (33% and 10% respectively). Although these differences were not significant, the difference in time to progression was (p=0.0059). CD4+, CD8+ and NK cell counts were significantly depressed after two cycles of chemotherapy, while no difference in cell count were seen in chemo-immunotherapy treated patients. Hematologic toxicity was reduced by the immunotherapy, with no grade 3/4 toxicity seen compared to 50% in patients treated with chemotherapy alone.

Lonidamine plus cyclophosphamide in the treatment of adanced non-small cell lung cancer in the elderly: a phase II study.

AIM AND BACKGROUND: The aim of this Phase II trial was to verify the therapeutic activity and tolerability of chemotherapy with lonidamine (LND) plus cyclophosphamide (CTX) in advanced non-small cell lung cancer (NSCLC) in the elderly. The rationale of the combination is reported. CTX showed mild toxicity, with a 12% objective response (OR) in monochemotherapy; LND potentiated the in vitro antiproliferative activity of alkylating agents, mainly CTX, without increasing myelotoxicity, particularly important in the elderly. METHODS: The schedule consisted of CTX, 600 mg/m2/i.v. on day 1 every 21 days for 6 cycles; LND, 450 mg/die/p.o. from day 1 to progression. RESULTS: Between November 1990 and April 1991, 41 patients with stage III-IV NSCLC were enrolled; 35 were assessable for response. Median age was 73 years (range, 71-79 years); 13 patients (32%) presented stage III A, 20 (49%) stage III b, and 8 (19%) stage IV disease. Cardiovascular conditions and/or chronic respiratory failure contraindicated surgical treatment in stage III A patients. Of enrolled patients, 14.6% experienced PR, 48.8% SD and 14.6% dropped out of the study. Median time to progression was 4 months (range, 2-9 months) and median survival 9 months (range 3-45 months). No patient showed WHO grade IV LND-related toxicity. In 1 patient (2.5%), LND was discontinued after 5 therapy cycles due to WHO grade III myalgia; in 80% of patients, LND oral dosage was reduced to 300 mg/day due to WHO grade II myalgia, and 20% of patients completed treatment with the full dose. CONCLUSIONS: CTX plus LND can be considered a well tolerated therapeutic approach in the elderly with NSCLC with good PS and good liver, renal and cardiac conditions, but 14.6% PR is a slightly better result as compared with 12% PR obtainable with CTX alone as reported in the literature, even though most patients presented with advanced disease and no specific toxic effect was observed. Therefore, a confirmatory randomized trial (CTX vs CTS plus LND) would hardly be useful.

Mitomycin-ifosfamide-cisplatinum (MIP) vs MIP-interferon vs cisplatinum-carboplatin in metastatic non-small-cell lung cancer: a FONICAP randomised phase II study. Italian Lung Cancer Task Force.

The FONICAP group is screening, with randomised phase II studies, the activity of new chemotherapy programmes for advanced non-small-cell lung cancer (NSCLC) looking for regimens with > 30% activity. In the present study, three regimens were tested: MIP (mitomycin 6 mg m-2, ifosfamide 3 g m-2, cisplatinum 80 mg m-2 on day 1 every 28 days); MIP-IFN (MIP and interferon alpha-2b 3 MU s.c. three times a week); and PC (cisplatinum 60 mg m-2 and carboplatin 400 mg m-2 on day 1 every 28 days). Overall 93 chemotherapy-naive patients were enrolled: 23 received MIP, 27 received MIP-IFN and 43 received PC. Eighty per cent of the patients had stage IV and 20% stage IIIb disease (positive pleural effusion or supraclavicular nodes). Response rates were as follows: MIP = 9% (95% CI 1-28%), MIP-IFN = 7% (95% CI 1-24%) and PC = 14% (95% CI 5-28%). The overall median survival was 183 days. Grade III-IV leucopenia was observed in 36% of patients treated with MIP-IFN vs 10% in the other two arms, and thrombocytopenia grade III-IV was reported in nearly 10% of patients overall. In conclusion, (1) all three regimens investigated have poor activity (< 30%); (2) when tested in multicentre randomised phase II trials, MIP displays lower activity than in phase II trials; (3) PC has similar activity to other platinum-containing regimens; (4) randomised phase II studies are a reliable and quick method of determining the anti-tumour activity of novel chemotherapeutic regimens in NSCLC.

Comparative analysis of CEA and SCC serum markers with IAP in human lung cancer.

Serum levels of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and immunosuppressive acidic protein (IAP) were measured in 37 patients with lung cancers, in 24 with non-cancer pulmonary diseases and in 24 normal controls We evaluated the sensitivity, specificity and accuracy of these three markers alone and combined. The highest specificity was observed for SCC (83.3%) and the highest sensitivity for IAP (94.6%). The best accuracy was obtained with the combined determination of CEA and SCC. In cancer and non-cancer pulmonary diseases the best correlation was observed between CEA and SCC (r = 0.30 in cancer and r = 0.45 in non-cancer pulmonary diseases). Although the IAP test is not specific in the detection of lung cancer, its use may be helpful in monitoring the acute phase reactions that occur very frequently in this malignancy.

Etoposide v etoposide and cisplatin in the treatment of advanced non-small cell lung cancer: a FONICAP randomized study.

A multicenter Italian Cooperative Study Group (FONICAP) conducted a prospective, randomized trial comparing cisplatin and etoposide (VP-16) with single-agent etoposide. The national study accrued 216 patients with measurable or evaluable non-small cell lung cancer (NSCLC) with either unresectable stage III, or distant metastasis (stage IV). One hundred patients were evaluable for response in the single-agent arm, and 93 in the two-drug combination arm. The overall response rates for the etoposide group and cisplatin/etoposide (VP-16) group were 7% and 26%, respectively (P less than 0.005). Five patients (5.6%) in the combination arm and 1 (1%) in the single agent arm had a complete response. The overall median survival was 236 days for the two-drug arm and 178 days on the single-drug arm (P = 0.2). Treatment-related toxicity (nausea and vomiting, leukopenia, anemia, hearing-loss, peripheral neuropathy, serum creatinine elevation) was significantly more pronounced in the combined arm. The addition of cisplatin to etoposide gave a small non-statistically significant improvement in terms of performance status and thoracic symptoms.