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Background and Objective: Sequential treatment with the addition of high-dose therapy (HDT) and peripheral blood progenitor cell (PBPC) rescue has been reported to be active as front-line therapy in aggressive non-Hodgkin's lymphoma (NHL) with bone marrow (BM) involvement. We designed an intensive sequential therapy as front-line therapy in this subset of patients and conducted a phase II study., Design and Methods: Patients with aggressive non-Hodgkin's lymphoma and BM involvement at diagnosis received 8 weeks of VACOP-B chemotherapy as induction therapy. The second phase included high-dose cyclophosphamide (HDCY) (7 g/m(2)) with granulocyte colony-stimulating factor (G-CSF) followed by leukaphereses. The third phase included HDT according to the BEAM protocol or melphalan (140 mg/m(2)) plus total body irradiation (8 Gy in a single dose)., Results: Forty patients were included in the study. According to the intention-to-treat, after VACOP-B, 11 (27.5%) and 22 (55%) patients achieved complete remission (CR) and partial remission (PR), respectively. Thirty-four received HDCY. After HDCY, 18 patients (45%) were in CR and 13 (32.5%) in PR. Twenty-nine underwent HDT plus peripheral blood cell rescue (PBPC) rescue. At the completion of treatment 29 patients (72.5%) were in CR, and 3 patients (7.5%) in PR. The actuarial 3-year overall survival, disease free survival and failure free survival are 48%, 55% and 40%, respectively. Overall severe toxicity was 7.5%., Interpretation and Conclusions: This phase II study suggests that the intensified treatment described is feasible and active in aggressive NHL with BM involvement. A randomized trial is now underway to test this approach.

Background: Adoptive immunotherapy (AI) of cancer, based upon the injection of in vitro manipulated autologous lymphocytes is still in an experimental phase. Our group started different clinical trials of AI in early 1990, and, at present, some specific targets for this approach seem to have been identified., Patients and Methods: 296 patients with solid tumors (melanoma, kidney carcinoma, non-small-cell lung cancer, mesothelioma, neoplastic pleural effusion, and liver cancer) were treated with either locoregional or systemic adoptive immunotherapy (AI) using both LAK and TIL cells in combination with s.c. rIL-2., Results: The surgery/AI combination resulted in good clinical results, characterized by enhanced survival and long lasting disease free periods in a significant number of patients., Conclusions: AI seems to be efficacious in the treatment of melanoma, lung and hepatic cancers. Further studies will expand the application of the treatment to other malignancies.

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.

We report our experience of high-dose cyclophosphamide (HDCY) followed by high-dose therapy (HDT) and peripheral blood progenitor cell (PBPC) autografting in patients with diffuse, intermediate and high-grade non-Hodgkin's lymphomas who have failed conventional treatment. From 1991 to 1996, 54 consecutive patients pre-treated with a median of two chemotherapy lines entered the study. Eighteen patients (33%) were still responders to conventional chemotherapy (sensitive relapse), and 20 patients (37%) were in partial response (PR) after chemotherapy (CT). Sixteen patients (30%) were resistant to conventional CT either at presentation (non responder) or in relapse (resistant relapse). Thirty-nine patients had bone marrow involved by disease and fifteen had an hypoplastic marrow following conventional treatment. Patients received HDCY (7gr/m2) and G-CSF or GM-CSF in order to collect PBPC. Median collected CD34+ cells was 12.3 x 10(6)/Kg (range 0.7-197). After HDT (BEAM or Melphalan + TBI) 50 patients underwent PBPC autografting. According to intention to treat, 44 (81%) of 54 patients achieved complete remission (CR) (50% after HDCY and 31% after HDT). Procedure related death occurred in 6 patients (11%), one after HDCY and 5 after autografting. Twenty-nine (66%) of 44 patients are still in CR, 7 to 63 months (median 27 months) after the procedure. Three-year probability of survival, disease-free survival and progression-free survival are 63%, 64% and 52% respectively. In conclusion, HDCY is an effective procedure not only in mobilizing PBPC, but also in reducing tumour burden. HDT with PBPC support may further improve the outcome in this category of high-risk non-Hodgkin's lymphomas.

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-alpha2a), for patients with metastatic melanoma., Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6-18 x 10(6) IU/m2/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-alpha2a was administered subcutaneously at 3 X 10(6) IU three times each week until progression., Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 x 10(9) (range, 1-43 x 10(9)), and the median period of culture was 52 days (range, 45-60). rIL-2 was administered at doses ranging between 6 and 18 x 10(6) IU/m2/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2-35%)., Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-alpha2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.

The role of elective lymph node dissection (ELND) for treatment of cutaneous melanoma is still debated. Initially, lymphatic mapping technique was performed by an intradermic injection of vital blue dye; subsequently, it was improved by the use of radioguided surgery (RGS). Preliminary experience with this technique proved effective for detection of clinical occult lymph node metastasis; it may also enable the surgeon to perform a selective lymph node dissection (SLND) to concentrate on pathologic node-positive patients for the same potential benefits that have been provided by ELND. We performed sentinel node biopsy on 48 patients with stage pT3N0M0 melanoma. Vital blue dye mapping only was carried out on 39 patients; the remaining nine patients had a combined lymphatic mapping with both blue dye and RGS. The sentinel lymph node (SLN) was identified in 46 of 48 patients (95.8%). Ten patients (20.8%) were found to have metastatic melanoma cells in their SLN(s); all these patients underwent SLND of the affected basin. Our findings confirm that the intraoperative lymphatic mapping of the SLN using both blue dye and radiodetection is an appropriate and simple technique for selecting patients who are more likely to benefit from lymph node dissection.

Purpose: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL)., Patients and Methods: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B)., Results: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed., Conclusion: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.

Purpose: Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy., Patients and Methods: Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11., Results: Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001)., Conclusion: EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

Purpose: To determine whether perioperative polychemotherapy (PeCT) can significantly prolong the overall survival of women with early-stage breast cancer., Methods: A meta-analysis that used updated individual patient data from all available randomized trials of PeCT, both published and unpublished, was conducted. Data on 6,093 patients (1,124 deaths and 1,912 recurrences) from five clinical trials were available (median follow-up duration, 5.3 years; maximum, 11.3 years)., Results: No significant effect of PeCT on overall survival was observed. However, patients who received PeCT had a significantly longer disease-free survival (hazards ratio [HR], 0.89; 95% confidence interval [CI], 0.82 to 0.98; P = .02). Time to local recurrence was significantly prolonged in the PeCT arm (HR, 0.68; 95% CI, 0.58 to 0.80; P < .0001). Likewise, there was a borderline significant difference in favor of PeCT in terms of time to distant metastases (HR, 0.90; 95% CI, 0.81 to 1.00; P = .05). Subgroup analyses suggest that node-negative women benefited the most from treatment., Conclusion: At present, there is no evidence that PeCT is able to prolong overall survival in patients with early-stage breast cancer; however, further follow-up evaluation is required. PeCT significantly prolongs disease-free survival, especially in node-negative women, which emphasizes once more the need for clinical trials in this subgroup.

Background: The role of amenorrhea induced by chemotherapy in premenopausal women with early breast cancer is very controversial. Analyses by various authors of the effect of drug-induced amenorrhea (DIA) on treatment outcome have yielded conflicting results. In order to gain insight into the role of DIA, we reviewed all published data addressing the issue of DIA as a prognostic factor., Methods: Computerised and manual searches were conducted of relevant studies published from 1966 to 1995., Results: Thirteen studies involving 3929 patients were selected. In two papers, the prognostic role of DIA was analysed in three and two different groups of patients, respectively. Overall, 16 groups of patients were evaluated. With 12 groups, a higher disease free survival was observed in patients developing DIA compared to those who did not. This difference was statistically significant in eight groups. Data on overall survival, reported in only five studies, indicated that it was always improved in patients who became amenorrheic., Conclusions: Available data on the role of DIA support its importance as a favorable prognostic factor for early breast cancer patients. However, due to the possible biases of this type of evaluation, this result should be interpreted with caution.

From May 1985 to June 1992, 375 patients were enrolled in a prospective controlled randomized clinical trial of peri-operative adjuvant chemotherapy (PAC) associated with long-term adjuvant chemo-endocrinotherapy in order to test the effectiveness of reducing the time interval between surgery and chemotherapy. The short-term surgical complications related to PAC are reported in order to verify whether such treatment might negatively affect the results of breast cancer surgery. One hundred and eighty-nine patients were randomly assigned to the peri-operative treatment, and 186 to the control group. Patients undergoing PAC received one course of cyclophosphamide (600 mg/sqm), epidoxorubicin (60 mg/ sqm), and 5-fluorouracil (600 mg/sqm) (CEF) within 48-72 h following surgery. Pathologically node-positive (N+) patients, who were given peri-operative CEF, had five further cycles of CEF alternated with six cycles of CMF (cyclophosphamide 600 mg/sqm, methotrexate 40 mg/sqm, and 5-fluorouracil 600 mg/sqm). All the other N+ patients received six cycles of CEF alternated with six cycles of CMF, starting within 30 days of surgery. No significant difference in post-operative morbidity was observed as regards median hospital stay (8 days), number of outpatient dressings (3.5 vs 3), seroma (51 (26.9%) vs 45 (24.2%)), lymphatic drainage (400 ml vs 409 ml), and post-operative infections, both local (10 vs 9) and in extraoperative foci (6 vs 7), in the study and control group, respectively. The toxicity of the peri-operative CEF was mainly gastrointestinal (nausea and vomiting, 55%; stomatitis, 3%), with only a small percentage (9%) reaching grades III-IV. Hair loss was the other main side effect (55%) with baldness in only 3%. Post-operative complications following radical breast cancer surgery seem to be primarily related to operative details (type of incision, accurate nerve-sparing technique, bleeding control, closure of subcutaneous and skin, drainage, aseptic technique) rather than to the one course of PAC.

Background: Angiosarcoma (AS) accounts for 1 to 2% of all soft tissue sarcoma. Both primary and secondary AS may occur, the latter being reported in the upper extremity with lymphedema after extended radical mastectomy for breast cancer (postmastectomy AS) or following radiotherapy of the breast, the thoracic wall, or other sites (radiation-associated AS). The authors report two cases of cutaneous radiation-associated AS and review literature regarding treatment planning and follow-up data to define the most appropriate therapy for cutaneous and noncutaneous radiation-associated AS., Methods: The clinical records of two patients with radiation-associated AS were analyzed and previously reported cases were reviewed., Results: Case 1: a female age 67 years developed cutaneous AS in the residual breast 27 months after breast-conserving therapy and conventional external beam radiotherapy (EBR). She underwent chemotherapy followed by simple mastectomy and chemotherapy with the same regimen but developed early recurrence that was treated with hyperthermia and EBR, wide excision, and second-line chemotherapy. She died 30 months after primary diagnosis of AS with multiple metastases. Case 2: a male age 59 years developed cutaneous AS in the left groin, 10 years after conservative surgery and EBR for a penile carcinoma. Early recurrence following wide excision was treated with chemotherapy, re-excision, and immunochemotherapy but the patient died 24 months after the primary diagnosis of cutaneous AS with local progression and distant metastases., Conclusions: The prognosis of radiation-associated AS is dismal, due mostly to its poor differentiation and frequent diagnostic delay. Simple mastectomy is advised for patients with cutaneous AS after breast-conserving surgery with wide tumor-free margins. If primary surgery fails, survival is seriously compromised because adjuvant or palliative treatments are not effective.

Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect peripheral blood progenitor cells (PBPC). Fourteen patients were in partial remission, 16 patients were in relapse ('sensitive', 12; 'resistant', 4) and five patients were refractory to conventional treatment. A good yield of PBPC was obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen in two cases. Two patients entered progression and one patient died. Thirty patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients entered complete remission (CR). Two patients died in CR of infection following marrow aplasia 3 and 6 months after autografting. At 3 years the probability of survival and disease-free survival (DFS) are 62 and 51%, respectively.

Purpose: To evaluate the effect of previous adjuvant chemotherapy with or without anthracyclines on overall survival (OS), progression-free survival (PFS), and objective response (OR) rates of metastatic breast cancer patients treated with cyclophosphamide, epidoxorubicin, and fluorouracil (CEF) as first-line chemotherapy., Patients and Methods: Three-hundred twenty-six assessable metastatic breast cancer patients entered onto four consecutive randomized trials performed in our Institution and North-West Oncology Group (GONO) cooperative centers from 1983 to 1994. Patients received CEF-based chemotherapy as first-line therapy and were then evaluated. One hundred forty-four patients (44%) did not receive previous adjuvant chemotherapy, and 143 (44%) and 39 (12%) patients received cyclophosphamide, methotrexate, and fluorouracil (CMF)-based and anthracycline-based adjuvant chemotherapy, respectively., Results: ORs to CEF chemotherapy were observed in 161 patients (49.4%). On univariate analysis, patients who had received prior adjuvant chemotherapy had a significantly lower probability of response than patients who did not: 43% versus 58% (P=.02). No difference between CMF-based (OR rate, 43%) and anthracycline-based (OR rate, 44%) adjuvant chemotherapy was observed. Stepwise logistic regression analysis indicated that adjuvant chemotherapy (P=.005), bone as dominant metastatic site (P=.02), and previous hormonotherapy for metastatic disease (P=.005) were the most important factors in predicting a poor OR rate. The median PFS and OS times of the whole group were 9.8 and 17.9 months, respectively. Patients who did not receive adjuvant chemotherapy had a longer survival time (21.1 months) compared with patients previously treated with CMF-based (15.3 months) or anthracycline-based (15.8 months) adjuvant chemotherapy. Multivariate analysis confirmed adjuvant chemotherapy to be among the strongest prognostic factors associated with both a poor PFS and OS., Conclusion: Previous adjuvant chemotherapy adversely affects OR, PFS, and OS in metastatic breast cancer patients treated with the CEF regimen as first-line chemotherapy. No difference was observed between patients previously treated with CMF-based or anthracycline-based adjuvant chemotherapy.

To verify whether the association of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) would allow both the acceleration and the dose escalation of the cyclophosphamide/epidoxorubicin/5-fluorouracil (CEF) regimen as first-line therapy in advanced breast cancer patients, we conducted a dose-finding study. Cohorts of three consecutive patients received cyclophosphamide (Ctx, dose range 800-1400 mg/m2), epidoxorubicin (Epidx, dose range 70-100 mg/m2), and 5-fluorouracil (5-Fu, 600 mg/m2, fixed dose) given as an intravenous bolus on day 1 every 14 days; GM-CSF at 5 micrograms/kg given as a subcutaneous injection from day 4 to day 11; and EPO at 150 IU/kg given as a subcutaneous injection three times a week. In no single patient was any dose escalation allowed. A total of 14 patients entered the study. At the 4th dose level (Ctx 1400 mg/m2, Epidx 100 mg/m2, 5-Fu 600 mg/m2), two patients had dose-limiting mucositis and one patient developed dose-limiting neutropenia. Therefore, the 3rd cohort received the maximum tolerated dose, i.e. Ctx at 1200 mg/m2, Epidx at 90 mg/m2, and 5-Fu at 600 mg/m2, given every 18.5 (+/-2.5) days. Toxicity was moderate and manageable in an outpatient setting. Only 1 admission at the 4th dose level was required. Throughout the 4 dose levels there was no toxicity-related death; grade IV leukopenia ranged from 24% to 75% of cycles and grade IV thrombocytopenia ranged from 6% to 8%. No grade IV anemia was recorded. Increasing the doses of Ctx and Epidx while maintaining a fixed dose of 5-Fu with the support of both EPO and GM-CSF allows safe acceleration and dose escalation of CEF chemotherapy. Further controlled studies will evaluate the activity and efficacy of this strategy.

Purpose: The aim of this multicentric randomized trial was to determine whether reducing the interval between surgery and chemotherapy improves the outcome of breast cancer patients., Patients and Methods: Between June 1985 and July 1992, 600 breast cancer patients, clinical stages T1-3A,N0-2,M0 were randomly assigned to a perioperative cycle (PC) of cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF). Node-negative (N-) patients did not receive any further treatment. Node positive (N+) patients received 11 cycles if previously given PC, or 12 cycles of CEF alternated with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF). In addition, N+ patients received concomitant or sequential 5-year tamoxifen therapy., Results: At a median follow-up duration of 5.7 years, no significant difference in survival (88% v 84%, P = .3) between the two treatment arms was seen. However, a difference of borderline significance in relapse-free survival (RFS; 76% v 70%, P = .053) was evident. A significant survival advantage for the PC arm was detected only in the estrogen receptor-negative (ER-) patients (P = .003). RFS was significantly improved in N- patients, postmenopausal patients, and ER- patients. Multivariate analyses show that pathologic tumor size, nodal status, receptor status, and treatment (only in ER- patients) are significantly correlated with survival and RFS. PC toxicity did not influence wound healing., Conclusion: This study provides preliminary evidence that PC positively affects relapse rate and survival in some subgroups, namely, ER- patients.

Aims and Background: In patients undergoing potentially curative surgery for colorectal adenocarcinoma, the presence of occult disease is thought to be responsible for distant metastases, particularly of the liver. During the 1980's preoperative intra-arterial chemotherapy was used in patients with adenocarcinoma of the sigmoid colon since it was thought that the biological effects induced by radiation in rectal lesions could be induced by cytotoxic agents in sigmoid cancer which was found to be less sensitive to radiation. The aim of the present paper is to report long-term results of an early pilot study on 20 patients with sigmoid colon adenocarcinoma treated with a 6 preoperative intra-arterial infusion of mitomycin-C followed by curative surgery., Methods: From January 1980 to December 1986, 20 patients with adenocarcinoma of the sigmoid colon were treated with a 6 hours preoperative intra-arterial infusion of mitomycin-C followed by potentially curative surgery (Group A). Eighteen hours prior to surgery the patients underwent selective arteriography of the inferior mesenteric artery through puncture of the femoral artery at the inguinal fold. The Seldinger technique was applied and Cook BP6 catheter was used. At the end of the examination, the catheter was positioned in the inferior mesenteric artery and mitomycin-C, 10 mg/m2, was infused in 500 ml of normal saline over a 6 hours period after which the catheter was definitively removed. Within 18 hours following intra-arterial mitomycin-C infusion all 20 patients underwent potentially curative surgery of their sigmoid adenocarcinoma. During the same period, 48 comparable sigmoid colon cancer patients underwent potentially curative resection alone (Group B)., Results: At 5 years overall recurrence rate was 30% and 39.6% in Group A and B patients, respectively (P = n.s.). In patients with Stage C disease, recurrence was less frequently observed in Group A (44.4%) than in Group B (77.7%) (P = n.s.). Overall survival at 5 years was comparable in the two groups of patients (70% and 64% for Group A and B, respectively) and median survival was > 60 months in both groups. In patients with Stage C lesions, there was a trend for improved survival at 5 years in Group A patients (55%; median > 60 months) compared to Group B (22%; median 27 months) patients (P = n.s.)., Conclusions: Although the difference indicating decreased recurrences and improved survival for Stage C patients treated with preoperative intra-arterial mitomycin-C were not statistically significant, the long term results of this small pilot study are encouraging.

Many clinical trials have tested the combination of 5-fluorouracil and recombinant alpha-interferons in metastatic colorectal carcinoma. The efficacy of 5-fluorouracil and lymphoblastoid interferon was evaluated in a phase II study in which 31 patients with advanced colorectal carcinoma were enrolled. 5-Fluorouracil was administered at the dose of 600 mg/sqm bolus weekly and lymphoblastoid interferon was given intramuscularly at 3 million units every two days. All patients were evaluable for toxicity. Thirty patients were available for response: no complete response was recorded, three patients reached a partial response (10%), three a minor response (10%) and 18 progressed (59.4%). Overall median survival was 8 months. No grade IV toxicity was observed: in 2 patients grade III occurred and in 8 patients grade III fever and fatigue attributable to interferon developed. It appears that this combination does not yield better results than 5-fluorouracil alone.

Purpose: The aim of our study was to compare in a multicentric randomized trial two regimens widely used in the treatment of advanced-stage intermediate- to high-grade non-Hodgkin's lymphoma and to assess whether a third-generation regimen (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) was superior to a second-generation regimen (procarbazine, methotrexate with leucovorin, doxorubicin, cyclophosphamide, and etoposide [ProMACE-MOPP])., Patients and Methods: Between January 1987 and August 1991, 221 patients with diffuse intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation groups F, G, H, and K), stage II bulky (> 10 cm), III, or IV, were randomized by the Non-Hodgkin's Lymphoma Cooperative Study Group (NHLCSG) to receive ProMACE-MOPP for six cycles or MACOP-B for 12 weeks. Survival, progression-free survival, and disease-free survival were determined, and multivariate analysis of prognostic factors was performed., Results: In the two groups of patients, there was no significant difference in terms of complete remission (CR) rate (49.1% with ProMACE-MOPP and 52.3% with MACOP-B), 3-year overall survival rate (45.2% with PROMACE-MOPP and 52.3% with MACOP-B), and 3-year progression-free survival rate (36.4% with ProMACE-MOPP and 36.1% with MACOP-B). In terms of toxicity, no significantly greater toxicity occurred in either arm. Overall toxicity was acceptable. The most frequent side effects were grade II through IV leukopenia, infection, mucositis, and anemia. Treatment-related deaths were equally distributed., Conclusion: No significant differences in terms of efficacy and/or toxicity between ProMACE-MOPP and MACOP-B are evident. These results are consistent with recent randomized trials showing that the new-generation aggressive regimens are no better than previous ones.

Tumour-infiltrating lymphocytes (TIL) derived from several histotypes, including melanoma, can be expanded in vitro in the presence of recombinant interleukin-2 (rIL-2) and infused as part of experimental adoptive immunotherapy protocols. Several authors have described the isolation and the expansion of TIL, but little is known about the actual proportion of unselected melanoma biopsies that give rise to 'positive' TIL cultures. We evaluated the proliferative, phenotypic, functional and molecular characteristics of cultured TIL obtained from 26 patients with metastatic melanomas, eligible for inclusion in a protocol of adoptive immunotherapy. Sixteen proliferating cultures were obtained. All TIL belonged to the T cell lineage and were characterized by a wide range of cytolytic activity against autologous and, to a lesser extent, allogeneic melanoma cells. Molecular analysis of the constant region of T cell receptor-beta (TCR-beta) showed an oligoclonal population of TIL in the majority of expanded samples, indicating that a selected subset of lymphocytes present in the tumour site could be expanded in vitro. These features, together with the high number of proliferating samples, make these populations of TIL suitable for infusion into patients with advanced disease.

Purpose: Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone. In an attempt to confirm this hypothesis, a randomized study was performed with the further intent of observing whether low doses of recombinant interferon alfa-2a (rIFN alpha 2a) could be as effective as intermediate doses., Patients and Methods: Two hundred sixty-six patients were randomized onto three different treatment arms: DTIC 800 mg/m2 intravenously (IV) days 1 and 21; DTIC plus rIFN alpha 2a 9 mIU intramuscularly (IM) daily; and DTIC plus rIFN alpha 2a 3 mIU IM three times per week. Major prognostic factors were well balanced among the three arms. Chemotherapy was administered for a maximum of eight cycles. After 6 months of therapy, rIFN alpha 2a was continued until disease progression at 3 mIU three times per week in responding patients who had received the combined treatment., Results: The percentage of objective responses did not differ among the three groups (20%, 28%, and 23%, respectively), although a significant prolongation of response duration was observed when rIFN alpha 2a was added to DTIC (2.6 v 8.4 v 5.5 months, respectively). However, this improvement in response duration did not translate into an amelioration of overall survival. The addition of rIFN alpha 2a led to the onset of flu-like syndrome, but in no case was it necessary to withdraw the treatment program and no toxic deaths or life-threatening toxicities were reported., Conclusion: In this study, rIFN alpha 2a significantly prolonged response duration, whereas no effects on response rate and survival were observed; rIFN alpha 2a 3 mIU appeared to be equally effective and better tolerated than 9 mIU.

32 consecutive early breast cancer patients were treated to evaluate the feasibility of an accelerated CEF regimen (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2) given intravenously every 2 weeks for six cycles together with granulocyte colony stimulating factor, 5 micrograms/kg/day subcutaneously from day 4 to day 11. One hundred and eighty two out of 192 planned cycles (95%) were administered. Toxicity was mild: no cases of grade IV non-haematological toxicity and only one episode of grade IV granulocytopenia were observed. Delays or dose reductions of anti-neoplastic drugs occurred in 14 cycles (7.7%). The mean duration of six cycles of treatment was 71 days (planned 70) and 93% of average planned dose intensity was actually administered. The short course CEF therapy is a feasible, well tolerated outpatient chemotherapy regimen, allowing a 46% increase in dose intensity compared with a standard CEF regimen given every 3 weeks. A randomised study comparing this regimen to a standard CEF regimen is now in progress in early breast cancer patients.

The hypothesis that the results of second line hormonotherapy for breast cancer may be ameliorated with continuation of the first line has been explored in a randomized trial. Patients progressing under tamoxifen were randomly allocated to aminoglutethimide and hydrocortisone acetate with or without tamoxifen continuation. No difference has been observed between the two arms in terms of response rate and progression-free overall survival.

The chemotherapy dose intensity for breast cancer has been recently considered to be an important factor in determining clinical outcome. Many trials have shown routine postoperative irradiation to have a detrimental effect on the delivered dose of adjuvant chemotherapy. In this paper the impact of radiotherapy on the dose intensity of adjuvant chemo- or hormonotherapy was evaluated in 237 breast cancer patients. 177 patients had radical mastectomy and 60 quadrantectomy followed by radiotherapy. Chemotherapy comprised 6 cycles of FEC (5-fluorouracil, epidoxorubicin, cyclophosphamide) alternated to 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil)+tamoxifen for 5 years. There were no significant differences in the adjuvant chemotherapy dose intensity in the mastectomy group compared to the radiotherapy group.

15 patients with small-cell lung cancer were treated with an "accelerated" chemotherapy consisting of standard-dose cyclophosphamide-doxorubicin-etoposide administered every 15 days (as opposed to the usual 21-day intervals) along with granulocyte-macrophage colony stimulating factor (10 micrograms/kg/day) administered prophylactically subcutaneously from day 4 to 13. The primary objective of this study was to examine the possibility of achieving a 50% dose-intensity increase by a shortening of chemotherapy intervals. 9 patients were not able to complete the planned six courses of chemotherapy owing to cumulative haematological toxicity. In fact, while leukopenia was acceptable and constant during treatment, both thrombocytopenia and anaemia progressively worsened with subsequent courses, becoming particularly severe after the 4th cycle when interruption of the treatment was often required. 13 patients who completed four courses of chemotherapy received a median of 96% of the planned dose-intensity. This corresponded with an average relative dose-intensity actually delivered of 1.44 compared with the planned dose-intensity of a standard cyclophosphamide-doxorubicin-etoposide every 21 days. In conclusion, acceleration of cyclophosphamide-doxorubicin-etoposide chemotherapy combined with granulocyte-macrophage colony stimulating factor can lead to a significant increase of dose-intensity but it is feasible only for a limited number of courses.

The clinical features of 7 cases of primary neuroendocrine carcinoma of the skin (Merkel cell tumor) are reported. This cancer arises in the dermis and subcutaneous tissues of elderly individuals. Natural history is characterized by local recurrences (30%), regional lymph node metastases (65%) and distant metastases (40%). Surgery is the elective treatment, chemotherapy and radiotherapy resulted in only short-term palliative response.

The influence of various patient and disease-related parameters on survival (S) and disease-free survival (DFS) in 217 node positive primary breast cancer patients treated with surgery followed by adjuvant i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was evaluated by univariate and multivariate analyses. Five year actuarial S and DFS were 73.3% and 54.8%, respectively. Univariate analysis revealed that patient age, number of involved axillary nodes and ER status had a significant impact on both S and DFS. PgR positive tumors had improved DFS but no S difference was observed. Menopausal status predicted S but not DFS. Primary tumor size and CMF-induced amenorrhea did not predict disease outcome. Multivariate analysis demonstrated that only degree of nodal involvement and PgR status had independent significant impact on prognosis. Both S and DFS are significantly influenced by the number of involved nodes, whereas improved DFS but not S was evident in patients with PgR positive tumors.

The aim of this phase I study was to exploit the potential efficacy of an alpha-2a-interferon (alpha-2a-IFN)-subcutaneous interleukin-2 (IL-2) combination, bypassing the toxicity usually associated with bolus or continuous infusion of IL-2. Therefore, nineteen patients with metastatic malignancies (7 melanomas, 6 renal cell carcinomas and 6 soft tissue sarcomas) were treated according to a dose escalating schedule of subcutaneous IL-2 combined with intramuscular alpha-2a-IFN for 5 days/week for 3 consecutive weeks. Cycles were repeated every 2-4 weeks unless disease progressed. Alpha-2a-IFN (3 MU/die) was given continuously, including during the rest weeks. IL-2 doses were started at 2 MIU/day/sqm and the MTD of 6 MIU/day/sqm was progressively reached. The dose of IL-2 was given twice daily every 12 hours. Both of the cytokines were administered in an outpatient setting. The main side effects were fever, chills, fatigue, hypotension, nausea and vomiting. Toxicity was correlated with IL-2 dose level. It was found to be mild at 2 and 4 MIU/day/sqm, while, in contrast, grade III toxicity was observed only at the highest dose of 6 MIU/day/sqm. However, this grade III toxicity was manageable and did not prevent continuation of the treatment as long as the dose was not increased above 6 MIU/day/sqm. Three patients, one with melanoma and two with renal cell carcinomas, obtained clinical partial responses. In eight patients, stable disease, and in the remaining eight, progression, were observed. The data suggest that the combined use of the two BRMs has manageable side effects and would seem to be efficacious. A phase II study at the recommended dose of 6 MIU/day is now necessary.

148 patients with advanced untreated colorectal cancer were randomised to receive a weekly bolus of 5-fluorouracil (5-FU) 600 mg/m2 alone, with or without leucovorin (LV) 500 mg/m2. 5-FU plus LV produced a higher response rate than 5-FU alone: 23% (5 complete response, 11 partial response) vs. 8% (2 complete response, 4 partial response) (P = 0.03) out of 70 and 72 evaluable patients, respectively. Median survival was 11 months in both groups and median time to progression was not significantly different (P = 0.08). The combined regimen was more toxic than 5-FU alone, as evidenced by (a) a higher percentage of grade 3-4 diarrhoea, 19.5% vs. 8.5% (P = 0.045) and conjunctivitis, 26.5% vs. 5.6% (P = 0.0025); (b) the recording of one toxic death in the combined arm; and (c) the reduction of the median dose intensity of 5-FU actually delivered during the first 2 months of treatment. We conclude that 5-FU plus LV at a price of a higher toxicity is more active than 5-FU alone without improving survival and progression-free survival.

A phase I study to evaluate the use of i.p. infusion of recombinant interleukin-2 (rIL-2) was planned. The following dose levels were calculated: 0.1, 0.3, 1.0, 3.0 and 10 mg/m2/day for 14 days, but only the second levels were reached. In this trial the acute toxic effects at this dosage included cardiac ischemia, transient liver impairment and septic peritonitis. The maximum tolerated dose (MTD) was 0.3 mg/m2/day for 14 days. In addition, two patients developed peritoneal fibrosis. No objective responses were observed. Therefore, in order to explore the biological activity of low (nontoxic) doses, three patients (one untreated and two previously treated with rIL-2) were infused with 0.01 and 0.03 mg/m2/day for 7 days. Potentiation of cytolytic activities in peritoneal lymphocytes and activation of a lymphokine cascade in the ascitic fluid were observed at doses ranging from 0.03 mg/m2/day to 0.3 mg/m2/day. These findings in association with the toxic effects observed at the MTD suggest the use of the minimum effective dose for future locoregional immunotherapeutic protocols.

Primary and metastatic gastrointestinal tumours in the liver have been treated by intrahepatic artery infusion of chemotherapeutic drugs in an attempt to increase the efficacy of the administered agents. Among the several active agents, 4' epidoxorubicin, an anthracycline analogue, was selected for this study because of the therapeutic level reached in the liver by this drug. Seven patients with primary hepatic carcinoma and twenty with metastatic adenocarcinoma of the colon to the liver received intraarterial hepatic infusion of epidoxorubicin at the dosage of 30 mg weekly. No haematological or gastrointestinal grade 3-4 toxicity was recorded, only one patient experienced transient cardiac toxicity. No objective response was observed in primary hepatic carcinoma and six objective responses, 1 complete and 5 partial (30%), were achieved in metastatic colorectal cancer patients. This results is not far from those reported with FUDR, but does not justify epidoxorubicin in colorectal cancer patients as first line intraarterial treatment.

Between 1983 and 1986, the National Institute for Cancer Research in Genoa and affiliated institutions conducted a randomized study to compare two different ways of combining chemotherapy (CT) and radiation therapy (RT). One hundred sixteen patients were randomized to receive neoadjuvant CT followed by definitive RT (treatment arm A) or alternating CT and RT. In treatment arm A, RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction, five fractions per week. In treatment arm B, RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each, 2 Gy/fraction, ten fractions/2 weeks alternated with four courses of CT. CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly, day 1; methotrexate 200 mg intravenously, day 2; leucovorin rescue, day 3. CT was repeated every 2 weeks up to four courses. The same CT was used in both treatment arms of the study. Fifty-five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B, respectively (P less than 0.03). Four-year progression-free survival was 4% in treatment arm A and 12% in treatment arm B (P less than 0.02), and four-year survival was 10% in A and 22% in B (P less than 0.02). Mucosal tolerance was significantly worse in treatment arm B (P less than 0.00004). The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics.

87 patients with high risk of recurrence FIGO stage I and II ovarian carcinoma were treated with adjuvant chemotherapy consisting of cisplatin 50 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 28 days for 6 courses. Toxicity and efficacy of the regimen was evaluated after a median follow-up of 45 months. Treatment-related toxicity was mild and reversible, consisting chiefly of acute WHO grade 2 myelosuppression (10% of patients) and controllable grade 3 emesis (55%). No late toxicity was observed. Actuarial 7-year survival and relapse-free survival (RFS) were 76% and 61%, respectively; a statistically significant difference in outcome was observed for undifferentiated grade tumour (G1 vs. G2 vs. G3: P less than 0.01) but not for FIGO stage disease (stage I vs. stage II). In our opinion, short-term chemotherapy including the most active single agent, i.e. cisplatin, appears a tolerable and effective treatment which deserves further evaluation in large randomised trials.

In 19 patients with advanced pretreated breast cancer, vinblastine was administered by continuous venous infusion (2 mg/m2/24 h for 120 h every 3 weeks), using a totally implanted venous access and a portable pump. A total of 55 courses were given. Five objective responses were observed. Drug-related toxicity consisted mainly of leukopenia (4 patients), fever (4 patients) and nausea and vomiting (3 patients). Catheter-related toxicity was observed in 4 patients (21%) and consisted of infection of the skin pocket in 1 patient and dislodging of the needle with drug extravasation in 3 patients.

Since most patients with breast cancer are treated with CMF as first line chemotherapy (usually in the adjuvant setting), schedules with alternative drugs are needed for the metastatic disease. In this study a new combination of Mitomycin, Epidoxorubicin and Vinblastine was employed in a group of 24 patients with metastatic breast cancer. A response rate of 37.5% was observed with a mild to moderate toxicity.

Based on the report of some activity of combination therapy with dacarbazine (DTIC) and interferon alpha-2a (rIFN alpha-2a) in disseminated melanoma, we conducted a phase II study to determine the feasibility and efficacy in a large series of patients. DTIC was administered in 79 patients at the dose of 800 mg/m2 every 3 weeks and rIFN alpha-2a was given daily at the dose of 9 X 10(6) IU for the first 10 weeks and three times a week thereafter. Among the 75 evaluable patients, 25% achieved an objective response, with 8% complete and 17% partial remissions. The regression occurred within a mean time of 1.9 +/- 1.03 months from starting therapy and the mean duration of response was 8.2 +/- 4.2 months. The major side effects were vomiting, anorexia, fever, fatigue, and myalgia. There was one death related to sepsis after myelosuppression. In the other patients bone marrow and liver toxicities were not remarkable. Our data reveal that a combination regimen of rIFN alpha-2a with a cytotoxic agent has some therapeutic activity in the management of advanced malignant melanoma.

Fifty-three breast cancer patients receiving adjuvant chemotherapy entered a double-blind randomized trial of lorazepam 2.5 mg orally prior to chemotherapy and repeated after 12 hours (Arm A) versus placebo (Arm B) with methylprednisolone (MPN) 375 mg in 3 equal doses: 125 mg i.v. prior to chemotherapy and repeated i.m. 6 and 12 hours later. Adjuvant therapy with 5-fluorouracil 600 mg/m2, 4'-epi-doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 (FEC) day 1 was alternated every 21 days with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 (CMF) day 1 for a total of 12 courses. The majority of patients experienced greater than or equal to 5 emetic episodes with FEC therapy (Arm A = 52%; Arm B = 55%). Mild and moderate nausea were reported by 60% and 68% of patients in Arms A and B, respectively. With CMF therapy complete control of emesis was observed in 33% (Arm A) and 35% (Arm B) of patients. The addition of lorazepam did not improve results either with FEC or CMF. Sedation was experienced by 86 to 92% of patients treated with lorazepam and amnesia was observed in 48-50% of cases. FEC therapy must be considered a highly emetic regimen and antiemetic therapy planned accordingly.

Between August 1983 and December 1986, 116 previously untreated patients with squamous cell carcinoma of the head and neck were randomized to receive induction chemotherapy followed by radiotherapy given in conventional fractions (55 patients, arm A) or an alternating chemotherapy and radiotherapy (3 courses of 20 Gy, 10 daily fractions each; 61 patients, arm B). The same chemotherapy was used in both arms: 6 mg/m2 vinblastine sulfate, hour 0; 30 mg bleomycin, hour 6; 200 mg methotrexate, hours 24 to 26; 45 mg leucovorin, hour 48. Forty-five patients had stage III disease and 71 had stage IV disease. All patients were evaluated for survival, 112 for toxicity, and 105 for analyses of response and time from the start of treatment until progression of disease. At the end of the combined treatment, we observed an overall response rate of 52% in arm A and an overall response rate of 64.9% in arm B. The incidence of mucositis was more relevant in arm B compared to arm A (P less than .00004). The difference in complete response, progression-free survival, and survival was statistically significant, with an advantage for arm B (P less than .03, P less than .02, and P less than .03, respectively). The analysis at a median follow-up of 36 months (range = 19 to 59) demonstrates a higher effectiveness for the alternating program.

Two series of five consecutive patients with small cell lung cancer were treated with an "accelerated" chemotherapy regimen of cyclophosphamide-doxorubicin-vincristine (CAV) and cisplatin-etoposide (PE) alternated possibly every week. In the first group of patients (median age 49 years, range 46-52) recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) was given as soon as grade IV leukopenia occurred, while in the second group (median age 59 years, 55-68) no growth factor was administered. The mean interval between chemotherapy courses and the mean duration of chemotherapy were 10 and 57 days, respectively, in the patients supported with GM-CSF compared with 13 and 72 days in the control group. One GM-CSF treated patient was withdrawn after the third cycle because of severe toxicity. The mean white blood cell and platelet nadirs were 600 and 46,000/microliters in the first group vs. 840 and 105,000/microliters in the controls. Overall chemotherapy dose-intensity was increased by two fold in the patients given GM-CSF compared with a 1.5 fold increase in the control patients. In all cases, irrespective of their treatment, there was an impaired colony forming capacity of circulating and marrow haemopoietic progenitor cells when grade IV leukopenia occurred, with recovery after the end of leukopenia. This pilot study suggests that accelerated CAV/PE chemotherapy is feasible both with and without GM-CSF. Different GM-CSF schedules as well as combinations of different haemopoietic growth factors may further improve dose-intensity.

131 patients with resectable, node-positive breast cancer were treated at the National Institute for Cancer Research of Genoa, Italy with a systemic adjuvant regimen based on 14 cycles of chemotherapy, immunostimulation with levamisole, and--for postmenopausal patients--hormone therapy with tamoxifen. The present evaluation is performed eleven years after the admission of the first patient: so far, 75 patients (57.3%) have relapsed and 52 (39.7%) have died. An analysis of prognostic factors for relapse and death shows that the number of positive axillary lymph nodes and the dimension of the primary tumor are significantly associated with survival and relapse-free survival, while age and menopausal status are not.

Twenty consecutive metastatic renal cell carcinoma patients were treated with a combination of recombinant alpha-2a interferon (18 X 10(6) U three times weekly) and vinblastine (0.1 mg/kg every 3 weeks). Two patients (10% response rate; 95% confidence limits 1.23-31.7%) achieved partial response and 11 (55%) stable disease. Toxicity was significant but always acceptable: most frequently, patients complained of fever and flu-like symptoms (18 of 19 patients), fatigue (18 of 19 patients), worsening in performance status (15 of 19 patients), and anorexia (15 of 19). The combination of recombinant alpha-2a interferon and vinblastine is active in renal cell carcinoma.

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).

Human fibroblast interferon was given intranodularly to 14 patients with cutaneous metastases from breast cancer and malignant melanoma; 1,000,000 units/cm3 of tumor tissue was administered daily for 8-10 days. 13 patients were evaluated. Complete response was achieved in 1 of 7 breast carcinoma nodules and in 2 of 6 melanoma nodules; partial response was achieved in 1 of 7 breast carcinoma and in 3 of 6 melanoma nodules. The overall objective response was therefore 7 of 13 (53.8%) metastatic nodules. Pathological complete response was confirmed in 2 of 3 complete clinical responses. Necrosis, lymphocytic infiltration and fibrosis were observed in all the specimens pathologically examined. In spite of a clear antitumoral activity, this approach does not appear to have clinical significance due to its extremely localized effect.

Thirty-three patients with stage III-IV squamous cell carcinoma of the head and neck previously untreated with chemotherapy or radiotherapy were given a multidrug cytotoxic regimen, VBM (vincristine, bleomycin, and methotrexate), in combination with radical radiotherapy. Of the 32 evaluable patients, 11 (34.4%) achieved clinical complete response with negative biopsy, 15 (46.8%) achieved partial response, three (9.4%) had no change, and three (9.4%) had disease progression. At 30 months, the actuarial survival rate for complete responders with negative biopsy was 62.2% and the overall survival rate was 30.8%. Hematologic and gastrointestinal toxicity was moderate, but one patient developed life-threatening mucositis and one patient died due to acute renal failure. Our data do not confirm prior more favorable results obtained with the same treatment.

The survival of 229 patients treated with adjuvant i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) after surgery for primary breast cancer was analyzed according to three administration-related factors: total number of cycles received, time elapsed between surgery and start of chemotherapy, and dose intensity of treatment. All parameters were found to be significantly associated with survival of patients in a univariate analysis. Multivariate analysis confirmed the independent prognostic importance of dose intensity and time between surgery and chemotherapy. Although prospective studies are needed to confirm such results, clinicians should be aware that unnecessary treatment delays or dose reductions in adjuvant chemotherapy for breast cancer are probably detrimental to patient survival.

A controlled study was mounted to assess the possible benefit of a single phlebo administration of 600 mg lincomycin 1 hr prior to colon surgery, in addition to the erythromycin + neomycin combination proposed by Nichols, as a means of constituting a further pharmacological barrier to the spread of anaerobic bacteria. The study currently comprises two groups of 15 patients fully comparable with regard to pathology distribution and randomly assigned to the E.N. and the E.N.L. protocol respectively. Six instances of septic complication have been observed, five in the group prepared with E.N. and 1 prepared with E.N.L. No significance can be attached to the different incidence of complications in the two arms of the study, owing to the small number of cases examined.