A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer.

From April 1985 to September 1988, 128 patients with advanced non-small-cell lung cancer (NSCLC) were enrolled in a prospective randomized trial evaluating chemotherapy (arm A) versus best supportive care (arm B). Chemotherapy consisted of cyclophosphamide 500 mg/m2 intravenously (IV) day 1, epirubicin 50 mg/m2 IV day 1, and cisplatin 80 mg/m2 IV day 1 (CE'P regimen) alternating every 4 weeks with methotrexate 30 mg/m2 IV day 1, etoposide 200 mg/m2 IV day 1, and lomustine (CCNU) 70 mg/m2 orally day 1 (MEC' regimen) until progression. Of the 123 patients (62 treated and 61 controls) eligible for survival, 115 were fully evaluable for response (58 treated and 57 controls). Response rates were 21% partial response, 53% stable disease, and 26% progressive disease in arm A, and 47% stable disease and 53% progressive disease in arm B. Median survival was 34.3 weeks (range, 4.3 to 218.6+ weeks) in arm A versus 21.1 weeks (range, 4.3 to 188.6 weeks) in arm B; the difference was not significant at P = .153 (Mantel-Cox). Subgroups of patients retrospectively analyzed by age, performance status, stage M0/M1, and weight loss or not showed no significant difference in survival. Poor-risk patients (at least two of the following: poor performance status, stage M1, weight loss) of arm A survived significantly longer than poor-risk patients of arm B (23.6 weeks v 12.4 weeks, Mantel-Cox P = .008); a significant difference in survival was also observed between nonsquamous cell patients of arm A and those of arm B (median survival, 38.6 weeks v 16.7 weeks; Mantel-Cox P = .041). Toxicity on the chemotherapy arm was hematologic (World Health Organization [WHO] grade greater than 3) in 12% of CE'P and in 13% of MEC' courses and gastroenteric (WHO grade greater than 3) in 24% of CE'P courses and in 8% of MEC' courses. Our alternating treatment was not significantly superior to supportive care. It is likely that certain subgroups of the NSCLC category may have an advantage with chemotherapy.

Teniposide as single drug therapy for elderly patients affected by small cell lung cancer.

From January 1987 to December 1990, 26/105 previously untreated patients affected by small cell lung cancer (SCLC), not suitable for intensive SCLC treatment since 19 of them were older than 70 years and 7 suffered from severe chronic diseases, received induction therapy consisting of teniposide alone, 60 mg/m2 on days 1-5, every 3 weeks until disease progression. After a minimum of two courses, 24 patients were evaluable for response: 13 with limited disease (LD) and 11 with extensive disease (ED) (2 patients were unevaluable: 1 early death and 1 protocol violation). Response rate, by disease stage, was: in the 13 LD, 1 complete response (CR), 8 partial responses (PR), 2 minor responses and 2 failures; in the 11 ED, 1 CR, 4 PR and 6 failures. The overall response rate was 58% (14/24) (95% confidence limits = 38-78%), comprising 8% CR and 50% PR. Median duration of response was 7 months (range 2-32). Median overall duration of survival was 9 months (range 1.5-36+). Toxicity was haematological WHO grade III in 13% of courses delivered, whereas no further important side-effects were recorded, excluding alopecia, which was common. Teniposide used alone appeared a safe and effective palliative treatment for poor-risk patients; the major limitation was the low CR rate.

Symptomatic, stage IV, non-small-cell lung cancer (NSCLC): response, toxicity, performance status change and symptom relief in patients treated with cisplatin, vinblastine and mitomycin-C.

In a series of 46 symptomatic patients with metastatic, stage IV, non-small-cell lung cancer (NSCLC), we used a three-drug combination with cisplatin (120 mg/m2), vinblastine (6 mg/m2) and mitomycin-C (6 mg/m2) (PVM), repeated every 3 weeks. After two courses, we observed that none of the patients had achieved a complete response; 33% (15/46) had partial response (95% confidence limits: 19.2-46.8); 39% (18/46), stable disease and 28% (13/46), progressive disease. Median response duration was 14.0 weeks (range, 4-36.7), median time to progression 22.4 weeks (range, 7-44.4), and median survival time 26.4 weeks (range, 1-103). WHO grade III-IV myelotoxicity occurred in 15.2% of the courses administered, affecting 39.5% of patients, and severe nephrotoxicity was observed in 9.3% of patients. No toxic death occurred. The post-treatment KPS score increased in 7 patients with partial response (47%), 4 with stable disease (22%) and 1 with progressive disease (8%), while it decreased in 3 patients with partial response (20%), 3 with stable disease (17%) and 10 with progressive disease (77%). In all, KPS increased in 12/46 cases (26%). However, no statistically significant difference was observed when the KPS score before and after treatment was compared in the total group of patients or when it was compared in the total group of patients or when it was compared in responders and in non-responders. After chemotherapy, there was complete disappearance of at least one symptom in 27.1% of cases and improvement in 27.1%. Overall, major symptom control occurred in 54.3% of cases, with a median palliation time lasting 10 weeks (range, 4-32). Patients with partial remission and stable disease achieved symptomatic palliation in 90% and 55.5% of cases, respectively. When we compared the palliation rate between responders and non-responders, a significant difference was noted (Chi-square test: P < 0.05). Although our schedule did not produce a higher objective response rate and the KPS score was not significantly improved, the symptom palliation appeared worthwhile considering the highly unfavourable prognosis of the patients investigated.

Chemotherapeutic treatment in unresectable nonsmall cell lung-cancer (nsclc) - a further attempt to modulate Cisplatin, vinblastine and mitomycin-C (pvm) schedule.

Searching for a more appropriate PVM (cisplatin, vinblastine and mitomycin-C) schedule against NSCLC, we treated 62 patients with unresectable NSCLC (49 males and 13 females), with the following regimen: high-dose cisplatin, 120 mg/m(2) i.v., day 1; common-dose vinblastine, 6 mg/m(2) i.v., day 1, and low-dose-mitomycin-C, 6 mg/m(2) i.v., day 1, repeated every 3 weeks, until progression or tolerance. Following a minimum of 2 courses, responses, by extent of disease, were as follows: in 16 patients with stage IIIB: 2 CR, 5 PR (total response rate, 44%), 8 SD and 1 PD; in 42 patients with stage IV: no CR, 15 PR (total response rate, 33%), 18 SD and 13 PD. Overall response rate was 35% with (95%) confidence limit range 23%-47%. In all the series, median duration of response was 17 weeks (range, 4-98 wks) and median time to progression 26 weeks (range, 7-111 wks). Drug related toxicity was WHO grade III and IV, leucopenia: in 30% and 11% of patients, thrombocytopenia in 27% and 10% of patients, respectively. Twelve patients (19%) developed severe anemia requiring transfusions. Three out of 5 patients dismissed treatment due to irreversible nephrotoxicity. No pulmonary toxic effect was recorded and no drug related death occurred. Fifty out of 62 patients (81%) received full doses as scheduled and 12 (19%) required cisplatin-dose reduction alone from 30% to 50%. Median duration of survival, in overall patients, was 27 weeks (range, 2-144 wks). Our results were in line with those of literature; this schedule with low-dose mitomycin-C and a single-dose vinblastine per course, seemed well feasible and safe. However, we recommend a cisplatin dose reduction to 80-90 mg/m(2) to optimise this schedule.

First line chemotherapy in patients with brain metastases from non-small and small cell lung cancer.

In this study we evaluated the role of systemic chemotherapy in 23 previously untreated patients with brain metastases from both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In NSCLC group, 2 patients out of 14 had a brain response after treatment (1 complete and 1 partial response). In the group of 9 patients with SCLC, we observed 5 brain responses (3 complete and 2 partial responses). Brain responses were in accordance with extracranial responses although this appeared more clearly in SCLC than in NSCLC patients.

Factors influencing response to second-line treatment with teniposide (VM26) in patients with progressive small cell lung cancer (SCLC).

Twenty-eight patients with small cell lung cancer (SCLC), 12 with limited (LD) and 16 with extensive (ED) disease, 22 of them relapsed to first-line treatment and 6 not responsive, were treated with a single-agent second-line treatment consisting of teniposide (VM26) 60 mg/m2, i.v. on days 1 to 5, every three weeks, until progression. After a minimum of two courses, we observed no complete response, 7 (LD/ED = 4/3) partial responses (25%), 4 (LD/ED = 2/2) minor responses (14%), and 17 (LD/ED = 6/11) with no change (61%). Median duration of response (partial plus minor) was 3.5 months (range 1-8). Median duration of survival, from VM26 administration, was in LD 6 months (range 2.5-11), in ED 3 months (range 1.5-6) and in all patients 4 months (1.5-11). Correlating the 11 responses with major prognostic variables present in the patients, we observed that KPS > 70, few initial courses of PL/VP16 and response to first-line treatment were significant determinants for successful salvage treatment. This study suggests the need to consider detailed patient characteristics of exposure to previous treatment before prompting new drug phase II studies on SCLC.

Teniposide (VM26) as second-line treatment for small cell lung cancer.

Twenty-six out of 53 patients with small cell lung cancer (SCLC) who relapsed or progressed following a first treatment (induction plus maintenance), were treated by a second-line chemotherapy consisting of: Teniposide (VM26), 60 mg/m2 i.v., days 1-5, every 3 weeks until further progression. The response rate obtained in 24 evaluable patients was: 7 (29%) partial response, 4 (17%) minor response, 8 stable disease, 5 progressive disease and 2 patients with early death. In the whole group, median survival time from the start of VM26 treatment, was 4 months (range 1-11). These data were compared to the median survival (1.5 months, range 1-7) of the remaining 27 patients, the control group, who at the time of progression did not receive further treatment. The difference between survivals was statistically significant (Log-rank test: p less than 0.05). According to these data VM26 seemed to be active, but larger studies better focused on all clinical variables are needed before firm conclusions can be drawn.

Small cell lung cancer (SCLC): a randomized trial of cyclophosphamide, adriamycin, vincristine plus etoposide (CAV-E) or teniposide (CAV-T) as induction treatment, followed in complete responders by alpha-interferon or no treatment, as maintenance therapy.

In this phase III, double-random study, we compared CAV-E to CAV-T combination as induction treatment (1st randomization) for SCLC. Subsequently, patients achieving a complete response (CR) were randomized again (2nd randomization) to receive maintenance treatment with alpha-IFN or no treatment. From June 1990 to June 1992, 75 untreated patients were enrolled in this trial. After stratification according to limited disease (LD) or extensive disease (ED), patients were randomized to receive the following treatment: cyclophosphamide 1000 mg/m2, adriamycin 50 mg/m2, vincristine 2 mg, day 1 i.v., plus etoposide (E) 100 mg/m2 (CAV-E: arm-A) or teniposide (T) 60 mg/m2 on day 2, 3, 4 i.v., every 3 weeks (CAV-T: arm-B). LD patients after 3 cycles of treatment received chest radiotherapy and 2 further cycles, whereas ED patients received 5 consecutive cycles. Patients who achieved a CR entered the 2nd randomization receiving a-IFN (3 x 10(6) I.U., i.m. daily x 9 months) or no treatment. A second-line treatment with carboplatin 300 mg/m2 plus E (if T was initially used) or T (if E was initially used) was also scheduled for patients achieving less than CR to induction treatment. Preliminary results are as follows: 75 patients were randomized, 72 were eligible for survival (arm-A = 37 and arm-B = 35) and 60 were fully evaluable for response (arm-A = 34 and arm-B = 26). In patients with LD the overall response rate was 79% (CR 21%) in arm-A vs 92% (CR 50%) in arm-B. In patients with ED, the overall response rate was 80% (CR 33%) in arm-A vs 84% (CR 7%) in arm-B. At a mean observation time of about 1 year (range 1-25 months), median survival of LD patients was 15 months in arm-A and 13 months in arm-B (Chi-square = 1.55; p > 0.05); in ED patients survival was 10.8 months and 8 months respectively (Chi-square = 2.88; p > 0.05). Cumulative survival probability was identical (12 months) in all patients of both arms. Toxicity was mainly haematologic and gastrointestinal: WHO grade 3-4 myelosuppression and vomiting were observed in 20% and 11% respectively, of cycles delivered in arm-A, compared to 19% and 8%, respectively, of cycles in arm-B. Two septic deaths occurred with CAV-T, while 1 patient discontinued treatment due to persistent myelosuppression with CAV-E. After the first and second-line treatment 20 patients showed a CR.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessing quality of life in patients with cancer: a comparison of a visual-analogue and a categorical model.

A simple instrument for self-assessment of quality of life (QL) in patients with cancer was elaborated using a linear analogue scale (LAS). The instrument was based on five questions, exploring different functional areas; the same questions were also addressed in a parallel format, where problems were seen from an opposite point of view (positive/negative). The LAS was given to 222 patients, for a total of 372 tests collected. Internal consistency was satisfactory (Cronbach's alpha = 0.75); QL score was significantly correlated to parameters of disease. Concordance between scales, as judged by comparison of parallel formats, was statistically significant but poor. A questionnaire was then elaborated with similar items, based on a categorical scale. A direct comparison between LAS and our questionnaire was made on a group of 41 patients. Internal consistency was poor for the LAS (alpha = 0.58) and good for the questionnaire (alpha = 0.93); Spearman's rank correlation coefficients were disappointing for the LAS and good for the questionnaire; the questionnaire was judged reliable in 82.9% of cases, the LAS in 29.3% only; the questionnaire score, and not the LAS score, was significantly correlated with PS and disease status. In conclusion, many patients appeared unable to correctly interpret the visual-analogue scale; the categorical scale was more immediate and correctly understood by the large majority of patients; the correlation between score and important parameters of QL was maintained, and internal consistency was excellent, indicating a satisfactory reliability of this instrument.

A phase II study with teniposide (VM26) in patients with progressed or relapsed small cell lung cancer (SCLC).

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m2, i.v. days 1-5, every 3 weeks until further progression. The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P less than 0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P less than 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.

Advanced epithelial ovarian cancer: no difference in survival rate between exploratory laparotomy and inadequate debulking surgery as treatment approach before chemotherapy.

In this study we have retrospectively evaluated 40 untreated patients with stage III-IV (FIGO) epithelial ovarian cancer. Sixteen patients had received, as initial treatment, inadequate surgical removal of the tumor with bulky residue (BR) of disease and 24 had had an exploratory laparotomy (EL) only. Subsequently, both groups received equivalent chemotherapy consisting of AC combination (adriamycin, cyclophosphamide) in 25 patients. Following surgery plus chemotherapy the two groups achieved a similar high remission rate (BR patients: 73% with AC scheme and 80% with PEC scheme; EL patients: 57% with AC and 100% with PEC). Furthermore, when all responsive patients were surgically re-explored, there was a pathologically complete remission in 5/12 BR patients and in 4/10 EL patients. Median survival was 20 months (range 3-50) in BR patients and 16 months (range 3-31) in EL patients. The statistical comparison between the two groups showed no significance; similarly, there was no significant difference in comparing AC-treated with PEC-treated patients. These data show that in poor risk patients with advanced ovarian carcinoma, inadequate surgery with BR is not prognostically superior to EL alone; therefore, chemotherapy as first treatment approach could be a valid alternative to surgery in such cases.

Moderate chemo-radiotherapy in non-small cell lung cancer: results in 21 patients with advanced disease and low performance status.

Twenty-one patients with advanced non-small cell lung cancer and low performance status (Karnofsky: 40-60) were treated with moderate doses of chemo-radiotherapy. Seven patients (33%) had partial response and a median survival time of 10 months; 5 patients (24%) had stable disease and a median survival time of 5 months; 9 patients (43%) had progression of disease and a median survival time of 6 months. Median survival time for the whole group was 7 months. Toxicity related to treatment was minimal and posttreatment performance status was: stable in 10 patients and improved in 5 responsive patients. We conclude that this therapeutic strategy has some efficacy in this category of patients although it failed to show substantial benefit in terms of survival.

Results of a combined chemo-radiotherapeutic program in 61 patients affected by small cell lung cancer.

Sixty-one patients affected by small cell lung cancer (SCLC) entered in the study. Eighteen had limited disease and 43 extensive disease. Treatment consisted of: induction chemotherapy with 3 courses of CAV (cyclophosphamide, adriamycin, vincristine) in limited disease patients or 2 courses of CAV plus 2 courses of DDP-VP16 (cisplatin, etoposide) in extensive disease patients, followed by chest radiotherapy and CNS prophylaxis in responsive patients. Subsequently, responders and stable patients received maintenance chemotherapy by the alternation of cycles of CAV, DDP-VP16 and C'MP (CCNU, methotrexate, procarbazine), which lasted 1 year or until relapse. Four of 17 limited disease patients (23%) obtained a CR and 11 (65%) a PR; their median survival was 11 months (range, 2+-36+). One of the 7 extensive disease patients (3%) achieved a CR and 19 (51%) a PR; their median survival was 6 months (range, 1-22). Median duration of response was 12 months for CR and 5 months for PR. Responders (CR and PR) survived 11.5 months versus 3.5 months for failures (P less than 0.05); 3/61 (5%) showed long-term survival, in the absence of disease. The overall median survival was 7 months (range, 1-36+). The main toxic effects were myelosuppression and vomiting (WHO grade 3). From our results, this program does not offer further substantial gains in patients with SCLC.

Analgesia with epidural calcitonin in cancer patients.

We evaluated the analgesic effect of salmon calcitonin (sCT) on 14 patients with intractable cancer pain. The drug was administered by epidural infusion (4-8 bolus administrations in 48 h); the dosage was 100 IU/48 h in 5 patients and 400 IU/48 h in 9 patients. Significant, although limited, pain relief and nocturnal pain relief were obtained; the requirement for conventional analgesic drugs was substantially reduced. The treatment was well tolerated and no side effect was recorded. However, only in 3/14 patients did pain relief result in improvement of mobility, with two patients becoming able to ambulate; no patient experienced absence of pain. In general, the treatment produced only limited benefit and subsequent morphine treatment was required in all instances. Widespread use of epidural sCT in intractable cancer pain is not justified as a routine procedure and more substantial evidence is required to support the clinical utility of such an approach.

Etoposide and mitomycin-C in pretreated metastatic breast cancer.

Twenty-five patients with metastatic breast cancer in progression after prior chemotherapy +/- hormonotherapy were treated with etoposide 50 mg/m2 i.v. days 1 to 5 every 21 days and mitomycin-C 10 mg/m2 i.v. day 1 every 42 days. A partial response (PR) occurred in 10 patients with an overall response rate of 40% (47% when only the 21 patients evaluable after 3 courses or more were considered). The median duration of PR was 10.5 months (range 3-31). The soft tissue metastatic sites were the most responsive. Toxicity was mild.

Phase II trial with alternating two drug schedules, CAP/MEC', for advanced (stage III Mo/M1) non-small-cell lung cancer.

Sixty-eight evaluable patients with advanced squamous cell carcinoma (48), large cell carcinoma (2) and adenocarcinoma (18) of the lung were treated with a six-drug regimen delivering two monthly alternated combinations. The combinations were cisplatin, adriamycin and cyclophosphamide (CAP) and methotrexate, etoposide and CCNU (MEC'). Following a minimum of two courses, the overall response rate was 22% (confidence limits, 12% to 32%) (15/68, 2 complete responses and 13 partial responses); 47% (32/68) had stable disease and 31% (21/68) had progressive disease. The responses lasted a median of 3 months (range, 1-15 months). The actuarial median survival was 11 months in responsive patients, 10 months in stable disease patients, and 5 months in progressive patients. The overall median survival obtained was 9 months (range, 2-28+ months). Toxicity was minimal, and subjective tolerance of the treatment appeared good. However, this alternating program did not improve response rate or survival.

Lymphangitic carcinomas of the lung as presentation of prostatic cancer. A case report.

Lymphangitic carcinomatosis of the lung is a late and often fatal manifestation of cancer. We describe a case of a biopsy-proved pulmonary lymphangitic carcinomatosis in an asymptomatic 61-year-old man. The pulmonary picture proved to be the initial sign of a prostatic cancer. Therapy with LH-RH analogues and antiandrogens achieved a complete clearance of lung involvement.

Involvement of the central nervous system in non-Hodgkin's lymphoma.

Fifteen of 146 (10%) adult patients with non-Hodgkin's lymphoma showed clinical and pathologic evidence of involvement of the central nervous system (CNS): in 6 patients, the CNS lymphoma was present at the onset of disease, in 3 of them it was the only sign detected. In the remaining 9 cases, CNS involvement appeared during the course of systemic disease. In all cases symptoms related to infiltration of the CNS were associated with advanced disease (stage IV); bone marrow or bone involvement was found in 9 patients (60%). The histologic subtypes were mostly of high-grade malignancy according to the Kiel classification: immunoblastic (3), centroblastic (3), Burkitt type (2), lymphoblastic (1), LP immunocytoma in polymorphic variant (3), unclassifiable (3). The prominent signs and symptoms of CNS lymphoma are listed: the cranial nerve palsies are the most common finding. The principal means of detecting CNS involvement are discussed: cerebrospinal fluid cytology, brain scan and CAT scan were the most useful diagnostic procedures. The reported data allow identification of patients at high risk of CNS lymphoma: this includes histologies of high-grade malignancy, advanced stage of disease, and bone marrow or bone infiltration. Therefore, either intensive systemic chemotherapy or CNS prophylaxis are recommended for patients with high risk of CNS disease.

Assessment of liver and spleen involvement in Hodgkin's disease.

Prognosis and proper treatment in Hodgkin's disease (HD) are strictly related to staging accuracy: liver and spleen involvement is of particular importance in this regard. We have evaluated, in 113 consecutive patients, the accuracy of clinical parameters to detect histologically documented HD involvement by comparing hepatosplenomegaly, liver function tests, liver and spleen scan, inspection of liver and spleen surface at laparoscopy with histologic findings. Our data suggest that of all the parameters studied, laparoscopy has the highest sensitivity and specificity values (about 100%). Laparoscopy may precede laparotomy as a staging procedure in HD and may give, in patients not submitted to laparotomy whatever the reasons, very reliable information.

[The inoperable non-microcytoma lung cancer. Results of chemotherapeutic and chemoradiotherapeutic treatment]. / Il carcinoma polmonare non-microcitoma, inoperabile. Risultati del trattamento chemioterapico e chemioradioterapico.

The cases of 36 patients with inoperable non-small cell lung cancers and similar anatomoclinical features were retrospectively analysed on the basis of treatment received (21 combined chemical and radiation therapy, 15 chemotherapy). The results showed 7 PR (partial response) 5 S (stable) 9 P (progression) in the group given combined chemical and radiation treatment; 2 PR, 7 S and 6 P in the group given chemotherapy alone. The patients with the best Performance Status produced the best PR figures (6/9) and the longest mean survival (10 months). Analysis of 9 patients in each group indicated that the length of survival is not affected by the timing or doses of drug treatment. Altogether the data support the view that no treatment has any influence on the prognosis for inoperable lung cancers.