The role of chemotherapy in non-small cell lung cancer: the community perspective.

In the past decade, several drugs have been identified that possess activity in treating non-small cell lung cancer (NSCLC). The combination of mitomycin C, vinblastine, and cisplatin (MVP) was studied in 56 previously untreated patients with advanced NSCLC in Bridgeport Hospital from 1981 to 1984. In a selected patient population, 73% of 52 evaluable patients had complete (four patients) or partial (34 patients) responses. Response rate was 88% in epidermoid carcinoma, 70% in adenocarcinoma, and 50% in undifferentiated carcinoma. Median survival was 10 months in responding patients v 4 months in nonresponders. Performance status was the most important factor predictive of prolonged survival. MVP cannot be recommended for patients with poor performance status but may offer worthwhile palliation to patients with advanced NSCLC. Active drug combinations must now be studied as part of a multidisciplinary approach to the primary management of patients with clinically localized NSCLC.

Treatment of multiple myeloma: a randomized study of three different regimens.

The results of an Italian multicentric trial for treatment of symptomatic Multiple Myeloma (MM) are reported. One hundred and thirty-three previously untreated patients were singled out at random for three different chemotherapy schedules: Melphalan plus Prednisone (M.P.) X 6 monthly cycles; Vincristine plus Melphalan plus Cyclophosphamide plus Prednisone (VMCP) X 6 monthly cycles; Peptichemio, Cyclophosphamide, BCNU. Drugs in this latter schedule were administered sequentially, for a period of six months. Criteria for response, progression and relapse were those of the Southwestern Oncology Group. Fifteen patients in MP chemotherapy (35%) and 20 patients in VCMP chemotherapy (46%) achieved an objective response (decrease of at least 50% in the synthesis index of Monoclonal Component (M.C.], while only 3 out of the other 21 patients assigned to the third schedule responded to treatment. No significant differences were noted in the survival curves in either of the three treatment groups. The 38 responding patients did not receive maintenance therapy; no significant difference was found in remission duration between patients in MP and VCMP arms, with a median duration of 16 months for the whole group. No statistical difference was observed between survival and remission curves of patients with a 'response' (M. spike reduction greater than 75%) and those with 'improvement' (M. spike reduction between 75 and 50%). The authors conclude that the inclusion of Vintristine in a combination chemotherapy does not produce clear survival benefits; a longer induction period (12 cycles) could allow a better differentiation between MP and VMCP regimens.

Combination chemotherapy in the management of ovarian germ cell malignancies.

Twenty-four patients with ovarian germ cell malignancies received combination chemotherapy in the present series. Fifteen patients received intensive vincristine, actinomycin-D, and cyclophosphamide therapy for 12 to 18 courses, and 13 are alive and free of disease 34 to 86 months later. One patient with a stage III pure endodermal sinus tumor and one patient with a stage III mixed germ cell tumor composed predominantly of endodermal sinus tumor elements failed vincristine, actinomycin-D, and cyclophosphamide therapy, but each transiently responded to cis-diamminedichloroplatinum, vinblastine, and bleomycin therapy. Nine patients subsequently were treated on a new protocol that used the intensive vincristine, actinomycin-D, and cyclophosphamide regimen for five to six courses for all stage I ovarian germ cell malignancies and cis-diamminedichloroplatinum, vinblastine, and bleomycin therapy for advanced stage tumors containing endodermal sinus tumor. Each patient on the new protocol is alive and free of disease 14 to 26 months later. Short-term intensive vincristine, actinomycin-D, and cyclophosphamide therapy is recommended for all stage I ovarian germ cell malignancies requiring adjuvant chemotherapy. Preservation of ovarian and reproductive function is appropriate in the present group of patients. Vincristine, actinomycin-D, and cyclophosphamide therapy is also recommended for biomarker negative advanced stage ovarian germ cell malignancies. Cis-diamminedichloroplatinum, vinblastine, and bleomycin therapy is recommended for advanced stage biomarker positive ovarian germ cell malignancies. Serial alpha-fetoprotein (AFP) titers accurately reflect the status of endodermal sinus tumor elements and may be used as a guide to discontinue treatment for patients with pure endodermal sinus tumor malignancies, obviating the need for second-look surgery.

Pharmacokinetics of peptichemio in myeloma patients: release of m-L-sarcolysin in vivo and in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each of which contains the alkylating residue m-[di(2-chloroethyl)amino]-L-phenylalanine (L-mSL). The fate of PTC was investigated in eight patients with multiple myeloma after intravenous infusion of the drug. The quantitative analysis of the plasma samples was performed by liquid chromatography with fluorometric detection. L-mSL was rapidly released from the peptides and reached its maximal plasma concentration at the end of the infusion. Its median elimination half-life was 1.73 (range, 0.72-2.41) h. It was possible to follow the concentration of only one of the peptides, L-mSL-L-Arg(NO2)-L-Nval.OEt, during and shortly after the infusion of PTC. The stability of L-mSL and the peptides was studied in buffer solution (pH 7.3), plasma, and blood. The stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min. We conclude that L-mSL plays an important role in the mechanism of action of PTC.

Peptichemio induction therapy in myelomatosis.

Fifteen patients with multiple myeloma, two of whom had plasma cell leukemia, were treated between May 1974 and December 1978. Peptichemio was administered intravenously at doses of 40-80 mg/48 h, courses including 4-17 administrations in association with moderate doses of prednisone (15-50 mg/day) and androstanes at high dosages (250 mg weekly). In two patients PTC was associated with vincristine (VCR) administered on the first day of the course. Eight patients were previously untreated, four had been resistant to melphalan (MPH) and/or cyclophosphamide (CTX), and three had been treated irregularly with one or both of these alkylating agents. The criteria of response to therapy are reported. Out of a total of 15 PTC courses administered we obtained 13 responses, eight complete and five partial; no response was achieved in the other two patients. In the four patients who were resistant to MPH and/or CTX we obtained three responses, which were maintained with the same alkylating agent to which they had been resistant previously. The time needed to obtain a response in 90% of the patients was 6 weeks. Peptichemio was shown to be effective in patients in an advanced stage of the disease, in patients with light-chain myeloma and in those with plasma cell leukemia. The association of VCR potentiated the antitumor effect, but also increased the myelotoxicity. The PTC treatment was well tolerated. It is suggested that PTC be used in induction treatment of myelomatosis and in patients resistant to traditional alkylating agents.

Treatment of neoplasia of the bladder with topical application of a synthetic peptide complex preparation: preliminary results.

Preliminary results are reported on the endo-vesical use of a complex of synthetic peptides ('Peptichemio') in 15 patients suffering from bladder neoplasia who were judged to be beyond surgery or radiotherapy. The agent was introduced into bladder in 20 mg doses diluted in 50 ml of 5% glucose and retained for approximately 30 minutes. Treatment was repeated every 5 to 7 days. The disappearance of the neoplastic mass in 13% of the cases and its reduction in a further 53% encourage the continued use of the preparation in local regional therapy of bladder neoplasia, and the findings help to establish treatment times and doses. For the moment, the authors recommend increasing the interval between treatments to 10 days or more once the neoplastic mass has been reduced or disappeared.

High dose peptichemio in pretreated neuroblastoma.

The aim of this study was to evaluate the antitumor effect and toxicity of a single course of Peptichemio at high dose (450 mg/sq m) given to children with neuroblastoma resistant to first line treatment or at relapse. A total of 28 children were treated. Seven children showed partial response, 4 minor response, 8 had stable disease, and in 8 the tumor progressed. The principal toxic effect was myelosuppression. Hemorrhagic enteritis with liver failure and toxic death occurred in 1 patient. High dose Peptichemio can be administered with tolerable toxicity, inducing tumor regression in one third of previously treated patients.

Alternating intravenous courses of melphalan and peptichemio in high-risk multiple myeloma (preliminary results).

Six patients with high-risk multiple myeloma and one patient with primary amyloidosis were treated with a melphalan-peptichemio-prednisone association (PMP). The response trend seems promising, also in view of the low regimen bone marrow toxicity, but further studies could better evaluate the optimal PMP scheduling and peptichemio side effects.

Differing response rates and survival between squamous and non-squamous non-small cell lung cancer. Comparison of CAP versus MAP.

One hundred and thirty patients with advanced non-small cell lung cancer were treated in a randomized study with either CAP (cyclophosphamide, doxorubicin, and cisplatin) or MAP (mitomycin C, doxorubicin, and cisplatin). Among all patients, regardless of cell type, the regression rate was slightly higher for MAP (46%) than CAP (34%) but no differences were detected in time to progression and overall survival. However, differences were apparent by treatment when patients were divided into two groups: squamous cell (SQC) and non-squamous cell (non-SQC). MAP, compared to CAP, was associated with a significantly superior regression rate (60% vs. 33%), time to progression, and overall survival in SQC. On the other hand, CAP, compared to MAP, was associated with a significantly longer overall survival in non-SQC. This apparent difference among subtypes of non-small cell lung cancer in response to chemotherapy regimens differing only in one drug, if confirmed, will need to be kept in mind in designing future studies.

Clinical aspects of ovarian tumors of low malignant potential.

A review of 21 cases of ovarian tumors of low-malignant potential diagnosed in our department over a period of 13 years was undertaken. Ninety percent of the patients presented with stage I disease. The average age at diagnosis (45 years) was younger than commonly found in patients with invasive epithelial cancer. Three patients received postoperative chemotherapy, and all of those were evaluated by second-look laparotomy. One of our patients with stage Ic serous tumor recurred with lung metastases. In two other patients with mucinous tumors, mucocele of the appendix was found. The five year survival in this series was 100%. Our study emphasizes the need for a prospective study to evaluate the value of adjuvant therapy in the various stages of these ovarian neoplasms.

Combination of cyclophosphamide, adriamycin and platinum (CAP) versus 5-fluorouracil, adriamycin and cyclophosphamide (FAC) as primary treatment in metastatic breast cancer: results of a prospective randomized study.

Based on favorable results we reported earlier with the CAP regimen in breast cancer (CAP vs CMFVP), the present study compared the CAP with the FAC regimen, which is so far one of the most active adriamycin containing chemotherapy regimens in breast cancer. The aim of the study was to find the optimal first line treatment and possibly evaluate the role of cis platinum in breast cancer chemotherapy. The CAP schedule consisted of cyclophosphamide 200 mg/m2 i.v. days 1, 3 and 5, adriamycin 40 mg/m2 i.v. day 1, and platinum 30 mg/m2 i.v. day 1, 3 and 5. The FAC schedule included 5-FU 500 mg/m2 days 1 and 8, adriamycin 50 mg/m2 day 1, and cyclophosphamide 500 mg/m2 day 1. One hundred and twenty-six previously untreated patients received greater than 2 cycles and were evaluated. In the CAP arm 15 complete (26%) and 24 partial remissions were observed, resulting in a 67% overall response rate (39/58). The response in soft tissue and visceral organs was notable (78% - 22/28, 71% - 15/21) with an important complete response rate (32%). In the FAC arm there was an overall response in 41% (28/68) of patients, with 8 complete (12%) and 20 partial responses. The difference in overall response, complete response, and response in soft tissue and visceral organs, was statistically significant in favor of the CAP arm (P less than 0.005). Concerning bone metastases there was no difference between the two schedules in response rate, nor in the median remission duration (CAP 11, FAC 10 months). In spite of a somewhat longer median survival in the CAP group, the difference (13 months vs 9 months) was not statistically significant (P = 0.10). Toxicity was moderate and tolerable in both regimens with more pronounced myelosuppression and vomiting in the CAP group. Compared with the FAC schedule the platinum containing combination chemotherapy (CAP) showed higher antitumor activity with no reflection on remission duration and survival.

Cyclophosphamide, adriamycin and platinum (CAP) combination chemotherapy, a new effective approach in the treatment of disseminated breast cancer. Preliminary report.

The prospective controlled Phase III clinical trial tested the therapeutic value of the cis-platinum-adriamycin-cyclophosphamide combination (CAP), compared with the combination including cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFVP), in untreated metastatic breast cancer. One hundred and twenty-three patients (greater than 2 cycles) were evaluated: 61 on the CAP, and 62 on the CMFVP schedule. An objective response (CR + PR) to CAP combination chemotherapy was achieved in 72% of patients (43/61), with a high rate (36%) of complete remissions. In terms of metastatic site, the response rate appeared to be particularly high in soft tissue and visceral organ (lung, liver) metastases. In the CMFVP group, an objective response was noted in 26 of 62 patients (42%), with 16% complete remissions. The difference in overall therapeutic response - and in the complete remission rate as well - was statistically significant to the advantage of the CAP regimen (P less than 0.01). The duration of remissions was 6-28 + months (means = 14) for the CAP, and 4-15 + months (mean = 9) for the CMFVP schedule. Toxic side effects were more pronounced in the CAP group, particularly myelosuppression, with anemia prevailing. Side effects of CMFVP treatment were moderate. In 39 CMFVP previously treated cases, CAP was administered as second-line treatment, and an objective response was observed in 51% of cases (20/39). Results of this controlled trial showed the advantage of the CAP combination chemotherapy in the treatment of metastatic breast cancer.

Cisplatin (P) versus cyclophosphamide, adriamycin and cisplatin (CAP) for stage III-IV epithelial ovarian carcinoma: a prospective randomized trial.

In 1982 a randomized trial was started to compare a cisplatin-containing polychemotherapy (CAP: cyclophosphamide - CPA 750 mg/m2, adriamycin - ADM 50 mg/m2, cisplatin - P 50 mg/m2 on day 1 every 21 days) with full-dose cisplatin as single agent (P 60 mg/m2/day on days 1 and 2 every 28 days) in 44 patients undergoing exploratory laparotomy or debulking surgery for stage III-IV epithelial ovarian carcinoma with residual disease greater than 5 cm. The response was evaluated at second-look surgery with random biopsies and peritoneal washing. On the basis of the final results the authors underline some data which, although merely indicative (because of the small number of patients) appear to be worth considering since they are in accordance with the latest reports: a) similar response rate (CR + PR = 47%) to first-line treatment in the two groups; b) the CAP treatment may achieve a longer median duration of CRs than the P treatment (20 versus 11 months); c) overall survival seems similar in the two groups of patients (19 versus 18 months), whereas the survival of CRs seems longer in the CAP treated patients (greater than 32 versus 25 months). The authors also discuss some observations on a possible salvage therapy.

cis-platinum-based alternating non-cross-resistant chemotherapy as a first-line treatment in metastatic breast cancer. A phase II study.

Exposure to multiple non-cross-resistant drugs should increase cell kill and the chance of achieving more complete and partial responses. Our earlier study in breast cancer showed that second-line CAP (cyclophosphamide, adriamycin, cis-platinum) treatment was not cross-resistant to the CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisolone) regimen and produced a 51% response rate. These facts initiated a phase II study which used an alternating CMFVP/CAP regimen. Altogether, 49 patients entered the study and 45 were evaluated (greater than 2 cycles). The CMFVP regimen consisted of cyclophosphamide (200 mg/m2 on days 1, 2, 3, 4 and 5), methotrexate (30 mg/m2 on days 2 and 4), 5-fluorouracil (500 mg/m2 on days 1, 3 and 5), vincristine (1.4 mg/m2 on days 1 and 5), and prednisolone (40 mg p.o. on days 1-5), and was alternated with the CAP schedule (300 mg/m2 cyclophosphamide on days 1, 3 and 5, 50 mg/m2 adriamycin on day 1, and 30 mg/m2 cis-platinum on days 1, 3 and 5). Overall response was high, and 37 patients out of 45 responded (82%), with a 28% CR rate (13/45). A particularly high response rate was observed in soft tissues (86%, 18/21) and visceral organs (84%, 16/19). Only 1 patient progressed (3%). The duration of remission was 4-21+ months (median, 12 months). Six of 13 CR patients were still disease free 15 months after the treatment was stopped. The duration of survival was 5-25+ months (median, 15+ months). Toxicity was moderate (myelosuppression in 53% of patients, mainly grade I-II; stomatitis in 11%, except for 100% alopecia and 90% nausea and vomiting). One drug-related death (bone marrow aplasia) was recorded. The high antitumorigenic activity of the alternating regimen used is encouraging and may call for a randomized study for the ultimate evaluation of this treatment approach.

Update in cancer chemotherapy, Part III: Lung cancer, Part 1.

An update in cancer chemotherapy that deals with the various therapies of lung cancer is described. At present, the stage of the disease and cell type are the major factors that determine the treatment. Important differences in the biological behavior and response to treatment exist between small cell and non-small cell cancers. The small cell type is sensitive to many chemotherapeutic agents. Differences in response to chemotherapy and survival have been less among the non-small cell types.The treatment of non-small cell carcinomas including squamous cell, large cell, and adenocarcinoma are reviewed in Part I of this paper. Small cell lung cancer will be described in Part II, which will be published in a future issue of the journal.

[Experience with chemotherapy in peritoneal carcinosis]. / Esperienze di chemioterapia nella carcinosi peritoneale.

5-FU i.v. and Ptc i.v. and intraperitoneally were used to treat 8 patients in the Ancona Oncology Centre suffering from metastatic peritoneal carcinosis. Tolerance was generally good and where side-effects were observed they were the same as those habitually encountered in patients treated with 5-FU and Ptc. Ascitic effusion disappeared or reduced by more than 50% in almost all cases. General condition thus improved.

[The chordoma. Description of 2 clinical cases and results of oncolytic chemotherapy]. / Il cordoma. Descrizione di due casi clinici e risultati della chemioterapia oncolitica.

Only seven hundred cases of chordoma approximatively are reported in medical literature from 1850 to date. We now describe two cases recently observed at our Medical Division, one of sacro-coccigeal chordoma and the other developed from clivus of Blumenbach. Their peculiarities are briefly discussed and compared with a rapid revision of the literature on this argument. The results of antiblastic therapy are presented and its opportunity in addition to Roentgenologic and surgical therapy is discussed.

[Results of a pilot study of hyaluronidase as an adjunct to cytostatic therapy in malignant diseases]. / Ergebnisse einer Pilotstudie mit Hyaluronidase als Zusatz zur zytostatischen Therapie bei malignen Erkrankungen.

46 patients (17 myelomas, 11 malignant lymphomas, 8 mammary carcinomas, 7 head and neck carcinomas, 2 gastrointestinal carcinomas and 1 ovarian carcinoma) were treated with Permease prepared of bovine testes by Sanabo. 7500 i.u. were given either intramuscular one hour before cytostatic chemotherapy or intraperitoneally with cytostatic agents. There were 2 cases of local irritation on the site of injection and 1 case of reversible anaphylactoid reaction. Results achieved in patients treated with the same chemotherapy in spite of resistance, but with addition of Permease: myeloma CR 2/9, subjective improvement 7/9; 5 patients expired, median observation time: 13 months; non-Hodgkin-lymphomas CR 2/5, PR 2/5; 2 patients expired, median observation time: 9 months; breast cancer PR 2/4, 2 patients expired, median observation time: 5 months, 1 patient with Morbus Hodgkin CR, expired after 24 months. The other patients who received systemic treatment had either primary chemotherapy with addition of Permease, or chemotherapy was altered because of resistance against the prior therapy before Permease was applied. Intraperitoneal application of Permease together with cytostatic agents, usually not used for local therapy because of high rate of irritation like cis-platin, was well tolerated. Complete regression of ascites was achieved in all cases. In 1 of the 4 patients duration of remission was 7 months. Hypotheses concerning the mechanism of action of hyaluronidase in malignant diseases are discussed. The effectiveness of Permease might be related to resistance phenomenon of tumor cells or to alteration of pharmacokinetics of cytostatic agents.