Disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operative Group for Neuroblastoma.

PURPOSE: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. PATIENTS AND METHODS: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. RESULTS: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. CONCLUSION: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol.

In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P<0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.

Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial.

BACKGROUND: Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. METHODS: Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. FINDINGS: With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. INTERPRETATION: Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.

Comparison of the cytotoxic activity of melphalan with L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine in human tumour cell lines and primary cultures of tumour cells from patients.

m-L-sarcolysin (m-L-SL) is an isomer of melphalan (Mel) with the di(2-chloroethyl) amino group being substituted in the meta position of phenylalanine. By covalent conjugation of amino acids to m-L-SL, a peptide complex consisting of six m-L-SL-based oligopeptides known as peptichemio (PTC) was developed previously. In the present study, the cytotoxic activity pattern of the different oligopeptides of PTC was investigated in ten human tumour cell lines representing different mechanisms of cytotoxic drug resistance using the fluorometric microculture cytotoxicity assay (FMCA). In the cell line panel, L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine (P2) was the most active oligopeptide, showing slightly lower mean IC50 values (2.6 vs 3.9 and 4.1 microg ml(-1)) than Mel and m-L-SL. The other five oligopeptides were less active than Mel. All active oligopeptides showed mechanistic similarity to Mel as judged by the correlation analysis of the cell line panel log IC50 values (R > or = 0.90), although P2 appeared to be less sensitive to GSH-mediated drug resistance. The relative activity of Mel and P2 was found to be related to degree of proliferation, P2 being more active towards low-proliferating cell lines. P2 and Mel were then further characterized in 49 fresh human tumour samples. In these samples P2 was considerably more active than Mel and showed a higher relative solid tumour activity (2.7 to 4.5-fold). However, the correlation of log IC50s between P2 and Mel in patient cells was high (R = 0.79), indicating a similar mechanism of action in this tumour model too. Cross-resistance with other standard drugs was lower for P2 than Mel. The results show that P2 is the most potent component of PTC and demonstrates a favourable activity profile compared with Mel. These data suggest that further investigation of P2 as a potential anti-tumour agent is warranted.

An observation on combined use of chemotherapy and traditional Chinese medicine to relieve cancer pain.

We have treated 50 patients with stage III, VI malignant tumors confirmed by pathology. The patients were divided into two groups. One group was treated by combination of chemotherapy and traditional Chinese medicine (treatment group); the other only by chemotherapy (control group). The effect of cancer treatment was evaluated according to the criteria of WHO. The results showed that the effective rate was 80% in treatment group and 52% in control group. The pain relieving rate was 68% in treatment group and 40% in control group (P < 0.01). This fact demonstrates that the application of traditional Chinese medicine can invigorate blood circulation, eliminate blood stasis, soften hardness and dissolve the mass, nourish blood and increase vigor. This kind of application can not only enhance the effect of cancer treatment but also increase the cancer pain relieving rate.

A prognostic index for multiple myeloma.

The current prognostic systems have failed to identify multiple myeloma (MM) patients who require aggressive therapy. These staging systems do not reliably distinguish patients with different prognoses. This paper explores the possibility of improving the prognostic forecast in MM by considering some clinical characteristics at diagnosis together with response to first-line chemotherapy. A total of 231 patients were prospectively randomised in a multicentre trial to no therapy vs melphalan + prednisone (MP) for stage I, MP in stage II, and MP vs peptichemio, vincristine and prednisone for stage III. The clinical features of these groups were evaluated for prognostic variables predictive of overall survival by means of univariate and multivariate analysis. The independently significant variables were incorporated into a model that identified three groups of patients with different risks of death and different overall survival. Three variables retained statistical significance: the staging system proposed by the British Medical Research Council, a composite parameter integrating the percentage of bone marrow plasma cells with cytological features of the infiltrating elements (plasma cell vs plasmablast), and response to 6 months of first-line chemotherapy. These three variables led the proposal of a scoring system able to identify three different risk classes (with median overall survival of 52, 28 and 13 months respectively) and to estimate individual patient prognosis more flexibly. The proposed risk classes, drawn from both diagnostic and therapeutic parameters, are thought to be a clinical and investigational instrument for separating MM patients into comparable groups, for selecting the best available therapy and for evaluating response with respect to the disease of each new patient.

Experience with poorly myelosuppressive chemotherapy schedules for advanced myeloma. The Cooperative Group of Study and Treatment of Multiple Myeloma.

In a multicentre study, 83 patients with advanced and previously uniformly treated multiple myeloma (MM) were randomised between cyclophosphamide (600 mg m-2) and epirubicin (70 mg m-2), administered every 3 weeks for three courses and both associated with prednisone and interferon-alpha2b. Both regimens were administered on an outpatient basis and had low haematological toxicity. Clinical results were similar. Overall response rate (43%) and median response and survival (5.9 and 14.1 months respectively) compare well with those obtained with more aggressive chemotherapy schedules.

Effect of alternating combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide for small cell lung cancer on hematopoietic progenitors in the peripheral blood.

The effects of a combination chemotherapy (CAV-PVP) consisting of cyclophosphamide, doxorubicin, hydrochloride (dox) and vincristine (CAV) alternating with cisplatin and etoposide (PVP) on peripheral blood hematopoietic progenitor cells (PBHPs) were studied in five patients with small cell lung cancer (SCLC). The kinetics of the CFU-GM levels were different during the CAV and PVP phases. None of the five patients displayed a rebound increase in the level of peripheral blood CFU-GM during the CAV phase. In contrast, all five patients displayed a rebound increase in peripheral blood CFU-GM levels during the PVP phase of the alternative combination chemotherapy (3-5 weeks after the initiation of PVP regimen). These findings indicate the optimal timing for leukapheresis to obtain PBHPs in SCLC patients which have been treated with an alternating combination chemotherapy consisting of CAV-PVP.

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.

Standard-dose and high-dose peptichemio and cisplatin in children with disseminated poor-risk neuroblastoma: two studies by the Italian Cooperative Group for Neuroblastoma.

PURPOSE: The objective of the present study was to determine whether an increase in the intensity of therapy improves outcome for children with disseminated poor-risk neuroblastoma. PATIENTS AND METHODS: From January 1982 through November 1989, 181 children 1 year or older with newly diagnosed disseminated neuroblastoma were entered onto two consecutive studies of the Italian Cooperative Group for Neuroblastoma (ICGNB): 75 (study NB82) were enrolled from 1982 to 1984 and were treated with standard-dose (SD) chemotherapy, and 106 (study NB85) were enrolled from 1985 to 1989 and received high-dose (HD) chemotherapy. In both treatment protocols, induction therapy included peptichemio and cisplatin (at SD or HD, respectively) and removal of the primary tumor. In study NB82, children who achieved complete or partial tumor regression received SD consolidation therapy, and in study NB85 they received three cycles of HD chemotherapy (3cCT) or one cycle of myeloablative therapy (MAT) followed by autologous bone marrow transplantation (ABMT). RESULTS: Compared with group NB82, the NB85 group had significantly fewer failures (no tumor response or disease progression) after administration of peptichemio (9% v 31%; P < .01), had more complete responses (CRs) and partial responses (PRs) both after treatment with cisplatin (60% v 43%; P = .01) and after surgery (76% v 57%; P < .01), and was more likely to have achieved complete excision of the primary tumor (70% v 46%; P < .01). Overall survival (OS) and progression-free survival (PFS) at 5 years were 11% and 9% in NB82, and 27% and 18% in NB85 (P < .01 for both); however, in NB85, relapses occurred even after 5 years of CR, so that PFS curves converge approximately 7 years after diagnosis. Median survival time was 14 months in NB82 and 24 months in NB85. Children in the NB85 group who after achievement of CR were consolidated with 3cCT had a 5-year PFS of 24% compared with 32% of those treated with MAT followed by ABMT (P = .5). CONCLUSION: Intensified therapy improves response rate and prolongs survival of children with disseminated neuroblastoma, although its impact on the eventual cure rate remains to be established.

Recombinant interferon-alpha 2A as maintenance treatment for patients with advanced stage chronic lymphocytic leukemia responding to chemotherapy.

Forty-five patients suffering from advanced B-CLL were randomized to receive interferon-alpha (IFN alpha) or no treatment after achieving complete remission or partial response, following a chemotherapy protocol called MiNa. The two groups were fully comparable in terms of clinical characteristics and level of response obtained by chemotherapy. IFN alpha was given at a dose of 3 megaunits three times a week intramuscularly for 1 year. The IFN-treated patient group showed a significantly longer duration of response and a less frequent incidence of infections as compared to the no treatment group. A minority of patients who had had partial response to chemotherapy obtained complete remission while on therapy with IFN alpha. Toxicity was mild and patient compliance was excellent. We conclude that IFN alpha may have a role as maintenance therapy in CLL for patients responding to chemotherapy.

Expression of p170 protein in multiple myeloma: a clinical study.

The expression of the p170 multidrug resistance protein by bone marrow plasma cells (BMPC) was assessed at clinical presentation in 53 patients with multiple myeloma (MM) using the C219 monoclonal antibody. Twenty-two of the 53 (41 per cent) patients had variable aliquots (1-60 per cent, median = 6 per cent) of p170+ BMPC by immunocytochemistry. Five of 10 patients studied using bivariate flow cytometry had both diploid and hyperdiploid (DNA index ranged from 1.2 to 1.5) BMPC with hyperdiploid clones having significantly greater p170 expression than diploid ones. Of the 37 patients evaluated for a response, 20 (54 per cent) had responded to induction chemotherapy. The presence of p170+ BMPC was a negative indicator for achieving response. The response rate was 75 per cent for p170- and 25 per cent for p170+ cases (p < 0.01), with no difference on the basis of treatment schedule (melphalan and prednisone, 24 patients; peptichemio, vincristine and prednisone, 13 patients). No difference in response and survival duration was found between p170+ and p170- patients. In six of nine patients studied both at diagnosis and following induction chemotherapy the p170+ BMPC% increased irrespective of the type of treatment or outcome.

Long-term results of a randomized trial comparing cisplatin with cisplatin and cyclophosphamide with cisplatin, cyclophosphamide, and adriamycin in advanced ovarian cancer. GICOG (Gruppo Interregionale Cooperativo Oncologico Ginecologia), Italy.

We report the long-term results of a randomized trial comparing cisplatin (P) with cisplatin and cyclophosphamide (CP) with cisplatin, cyclophosphamide, and adriamycin (CAP) in advanced ovarian cancer. Overall, this update confirms previously published data on 529 cases. Median survival times for the three treatments--CAP, CP, and P--are, respectively, 23, 20, and 19 months. The differences among the three arms are still nonsignificant and the estimated percentage survival at 7 years and confidence limits are, respectively, 21.7 (14.9-28.4), 17.0 (11.0-22.9), and 12.2 (6.9-17.4). According to the results of the Cox regression model on prognostic factors, higher grading, a larger residual tumor size, and performance status less than 80 (Karnovsky) all were independently associated with a poorer outcome, while a serous histotype was related to a better prognosis. The other variables (age, stage, center, type of surgery) initially included in the model did not appear to be significantly related to prognosis. The implications of these long-terms results relative to the application of combination chemotherapy with CAP or CP are discussed.

Bilateral breast involvement in a 71-year-old white man with lambda light chain disease. Regression after a new chemotherapy combination. A case report.

A rare case of lambda light chain disease with bilateral breast involvement is described. A complete regression after a new chemotherapy combination (peptichemio + teniposide + dexamethasone) was obtained. A previous treatment with prednisone + melphalan was ineffective.

Lung cancer: a review of current therapeutic modalities.

This article describes the current approach to the systematic management of both small cell and non-small cell lung cancer (NSCLC). The treatment of stages I, II, and IIIa NSCLC is surgical resection. Although adjuvant chemotherapy in stage I disease offers no survival benefit, the role of adjuvant chemotherapy in stage II and IIIa NSCLC remains controversial. Results of pilot studies using neoadjuvant chemotherapy in stage IIIa NSCLC are encouraging and data from ongoing randomized trials are awaited with interest. For locally advanced NSCLC, chest irradiation remains the standard of care. However, the addition of systemic chemotherapy holds promise. The impact of cisplatin-based regimens on overall survival in stage IV NSCLC remains disappointing. The introduction of newer agents, such as 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), a topoisomerase-I inhibitor, has shown early favorable results. Chemotherapy is the most important therapeutic modality in the management of small cell lung cancer because of this cancer's propensity for early dissemination. In limited stage small cell lung cancer, chest radiotherapy, particularly if used early and concurrently with chemotherapy, may improve survival, but at the expense of increased toxicity. The role of prophylactic brain irradiation remains controversial in limited-stage disease. Chemotherapy is also the most important treatment modality in extensive-stage disease, but its role is only palliative. Radiotherapy is reserved primarily for disease-related complications in patients in whom chemotherapy has failed.

Combined modality therapy for small cell lung cancer.

Small cell carcinoma is one of the solid cancers for which chemotherapy is effective and can prolong the survival of patients. There is a general agreement that the standard regimen is PVP (cisplatin/etoposide) or alternating PVP-CAV (cyclophosphamide/doxorubicin/vincristine) therapy, replacing CAV, which had been considered standard. For the improvement of the treatment results of small cell carcinoma combined modality therapy including radiotherapy and/or surgery is essential, especially against limited disease. The effect of prophylactic cranial irradiation is obscure, because of the relapse to other sites of organs and the late complications of brain radiation. The present status of combined modality therapy for small cell carcinoma is reviewed and the future essential trials are discussed.