Bonadonna G

Phase II evaluation of adriamycin in human neoplasia

Four hundred and seventy‐two patients with disseminated neoplasia were treated with two or more doses of adriamycin. The initial dose for “good risk” patients was 75 mg/m2 every 3 weeks, and for “poor risk” patients was 60 mg/m2 every 3 weeks. Objective remissions were seen in 118/472 patients, with best results noted in lymphomas (21/48), sarcomas (21/64), and carcinoma of the breast (16/50). Eighty‐nine per cent of remissions occurred within three courses. Hematopoietic toxic effects were seen in 73% of patients; nausea, vomiting, and/or stomatitis were observed in 43%. Changes in electrocardiograms were seen in 42/472 patients after cumulative doses of adriamycin ranging from 45 mg/m2 to 600+mg/m2. Irreversible congestive heart failure occurred in two patients after cumulative doses of 555 mg/m2 and 825 mg/m2, respectively. It is concluded that adriamycin is an active agent, most remissions occur promptly, and significant cardiotoxic reactions appear to be cumulative.

Second malignancies in Hodgkin's disease: A complication of certain forms of treatment

A total of 764 patients with Hodgkins disease treated with radiotherapy (RT) or chemotherapy or both were reviewed 3-186 months (median 43 months) after initial treatment to assess the incidence of second malignancies. Incidence of solid tumours and acute non-lymphoblastic leukaemia (ANLL) were calculated by a life-table method and percentages of patients affected derived from life-table plots. Within 10 years after initial treatment the overall incidence of second solid tumours was 7.3%, and over a comparable period 2.4% of patients developed ANLL. Solid tumours occurred only in patients given RT with or without adjuvant chemotherapy, and ANLL occurred only after treatment with MOPP (mustine, vincristine, procarbazine, and prednisolone) or modified MOPP regimens. Neither solid tumours nor ANLL occurred in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The highest incidence of leukaemia (5.4%) occurred after treatment with extensive RT plus (5.4%) occurred after treatment with extensive RT plus MOPP; hence the benefits of this approach in Hodgkins disease must be weighed against its carcinogenic potential.

Response and survival in advanced breast cancer after two non-cross-resistant combinations.

A prospective study with two cytotoxic combinations (cyclophosphamide, methotrexate, and fluorouracil (CMF), and adriamycin plus vincristine (AV)) was carried out in 110 patients with advanced breast cancer. There was no significant difference between the treatment groups in the response rate after primary treatment, the median duration of response, and the median survival. In both groups responders survived for longer than non-responders. Secondary treatment after crossover for progression or relapse resulted in response rates of 35% for AV and 20% for CMF. Toxicity was mainly represented by reversible haemosuppression. These results are comparable with those obtained with other multiple-drug regimens, and combination chemotherapy alone seems to have reached a plateau in its capacity to control disseminated breast cancer.

Multimodal treatment in operable breast cancer: Five-year results of the CMF programme

The five-year results of a prospective randomised trial of radical mastectomy (179 patients) versus radical mastectomy followed by adjuvant chemotherapy (207 patients) were analysed. Chemotherapy consisted of 12 monthly cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Both relapse-free survival (controls 44.6%, CMF group 59.5%) and total survival (controls 66.2%, CMF group 78.4%) were significantly improved. The findings were related to the number of diseased axillary nodes and amount of drug administered, and were independent of CMF-induced amenorrhoea. Menopausal state alone appeared to affect the five-year results only when the amount of drug administered was not taken into account. Salvage treatment at first relapse failed to improve total survival in the controls compared with the CMF group. Acute toxic manifestations were moderate and reversible. Chronic organ damage and increased incidence of second neoplasms (controls 1.7%, CMF group 1.4%) were not observed. The multimodality approach to treatment of primary breast cancer is a new and important advance. This and other studies are continuing.

Clinical trials with bleomycin in lymphomas and in solid tumors

Abstract The authors report the results of Phase I and Phase II evaluation of intravenous bleomycin (BLM) in 176 patients. During the trial different doses and schedules were employed. The less toxic regimen was that of 15 mg/m2 × 2/week per 4 weeks. Irrespective of the schedules, the side effects are represented by sclerotic changes of the skin of hands (88%), skin hyperpigmentation (78%), fever (70%), loss of hair (68%), stomatitis (47%) pulmonary toxicity (42%), gastro-intestinal symptoms (20%). No significant myelo-suppression was observed. Pulmonary toxicity occurred after 4–10 weeks from starting therapy and was detected on clinical bases (fine crepitations at the base), radiologically (reticulonodularity mostly at the lower lung zones) and histologically (edema of alveoli, hyaline membranes formation, collagen deposition). Upon prompt discontinuation of BLM, the signs of pulmonary damage remained unchanged or regressed in the majority of cases. Lower total doses of BLM produced a lesser incidence of lung toxicity. However, in about 5% of cases the presumptive cause of death could be related to extensive pulmonary drug-induced lesions. The incidence of lung toxicity was not found to be significantly related to the age of patients, to the total dose of BLM or to the presence of chronic pulmonary disease. BLM produced significant regression in all types of malignant lymphomas (40%), in epidermoid carcinomas of the head and neck (57%) and of the esophagus (60%). No significant responses were observed in epidermoid carcinomas of the lung. Regressions were prompt but usually short-lived with or without maintenance therapy. Because of its toxic and therapeutic properties BLM appears suitable for therapeutic trials either in short courses alone in or in combination with myelosuppressive agents.

T3b-T4 breast cancer: factors affecting results in combined modality treatments

Two hundred and seventy-seven consecutive patients with T3b-T4 breast cancer referred to the Milan Cancer Institute between 1973 and 1980 were treated with a combined modality approach. Chemotherapy (CT) consisted of AV, i.e. adriamycin (60–75 mg/m2 day 1) and vincristine (1·2 mg/m2 days 1 and 8) and was given for three to four cycles prior to local regional modality. Local-regional treatment consisted of either radiotherapy (RT) in 198 patients or surgery (S) in 79 women. Additional chemotherapy was then administered to a total of 205 patients.In the absence of distant metastases, frequency of good local control was significantly inferior in patients given CT + RT (63·9 per cent) compared to those treated with CT + RT + CT (75·4 per cent) and CT + S + CT (82·3 per cent, P=0·033). Also freedom from progression (FFP) and overall survival (SURV) were significantly superior in the groups receiving more prolonged chemotherapy treatment compared to patients treated with CT + RT (FFP: P·0001; SURV: P=0·002). None of the variables examined was able to affect the response rate, while axillary nodal status and tumor size played a major role in the duration of FFP and SURV.Our findings indicate that a more aggressive treatment is needed to improve current results in this stage of disease. To overcome the problem of local-regional recurrence, treatment should probably begin with cytoreductive surgery followed by postoperative radiotherapy in all patients with the exception of those having inflammatory carcinoma. Systemic treatment should then be delivered to control distant micrometastases.

LYMPHORETICULAR SARCOMAS WITH PRIMARY INVOLVEMENT OF WALDEYER'S RING. CLINICAL EVALUATION OF 225 CASES.

A total of 225 consecutive untreated patients with lymphoreticular sarcomas with primary involvement of Waldeyers ring was evaluated (151 without lymphography and 74 with lymphography). On admission, the anatomical distribution of the primary growth within Waldeyers ring was as follows: tonsil, 40%; nasopharynx, 27.5%; base of tongue, 2.7%; soft palate, 2.7%; oropharynx, 0.9%; other sites, 26.2%. In the group studied without lymphography, the disease was confined to Waldeyers ring in 22.5% of cases and had spread to the cervical nodes in 62.3% and to distant nodes in 15.2%. In the group studied more recently with lymphography, these figures were 13.5%, 41.9%, and 44.6%, respectively. At the time of initial evaluation, the lymphoma involved extranodal sites in only 24 of 225. In the 74 cases evaluated with lymphography, the mode of spread was studied by observing the first site of recurrence after radiotherapy. New manifestations occurred in most patients within 2 years from the end of treatment and preferentially in extranodal sites. The involvement of the gastointestinal tract, either at the time of admission or early in the follow‐up, was 20% in the group studied with lymphography. The possibility that a certain number of lymphoreticular sarcomas could arise concomitantly in Waldeyers ring and in the gastrointestinal tract is discussed.

Sequential pathologic staging of untreated non‐Hodgkin's lymphomas by laparoscopy and laparotomy combined with marrow biopsy

In a selected series of 119 patients with non‐Hodgkins lymphoma apparently limited to lymph nodes or to primary extranodal sites, two sequential combined surgical diagnostic procedures (laparoscopy plus needle marrow biopsy and laparotomy plus open marrow biopsy) were performed to compare their relative merits in the detection of occult extranodal disease. The final anatomic extent of disease was also correlated with two histopathologic classifications (Rappaport and Kiel). After the first combined procedure, which also included one or more splenic biopsies, 22% of patients showed liver infiltration, 29% splenic infiltration and 17% bone marrow involvement. After the second combined procedure, which was performed in 80 patients with negative histologic findings in the liver on laparoscopy and in the bone marrow on needle biopsy, liver involvement was documented in five patients (6%) while splenic infiltration was detected in eight additional cases. The open iliac crest biopsy revealed an infiltrated marrow in only two patients (3%). Laparotomy also detected other occult sites of lymphoma in abdominal nodes and in the small intestine (total 38%). Thus, most patients with stage IV disease were documented through laparoscopy plus needle marrow biopsy (89%) while laparotomy was mainly useful for a more complete definition of nodal and splenic involvement. The difference of extranodal infiltration between nodular and diffuse pattern already evident in the Rappaport classification (21% vs 41%) becomes even more pronounced in the Kiel classification in which follicular lymphomas belong to only one cytologic type, the centroblastic‐centrocytic subgroup. The diffuse histiocytic subtype of the Rappaport classification as well as the immunoblastic lymphoma of the Kiel classification revealed both a remarkably low incidence of extranodal invasion (17% vs. 23%) despite their high biological malignancy.

Clinical Trials with Adriamycin in Leukemia and Solid Tumors

Adriamycin is a new antitumor antibiotic of the anthracycline group. Its chemical structure is very close to that of daunorubicin. Pharmacological studies demonstrated that adriamycin has a higher therapeutic index (1.21) than daunorubicin (0.67). Adriamycin was given intravenously to 53 patients with different types of leukemia and cancer (13 children and 40 adults). Three doses were used: 0.4 mg/kg (pretreated patients), 0.65 mg/kg (untreated adults), 0.8 mg/kg (children). Three different schedules were also employed regardless of the single dose/kg (table 1): A) Loading-dose schedule: treatment for 4 consecutive days followed by a 3 day interval: the drug was then restarted 1–2 times a week; B) Alternate day-dose schedule: treatment every other day for 4–6 doses followed by a 3 day interval; the drug was then restarted 1–2 times a week; C) Intermittent-dose schedule: two treatments for 3 consecutive days separated by two intervals of 4 days; the drug was then restarted 1–2 times a week. The chief evidence of toxicity was a triad of symptoms: stomatitis, bone marrow depression and alopecia (table 2). The oral ulcerations where the first sign of toxicity in more than 50 % of cases. The first sign of toxicity usually precedes the other side effects by 1–3 days. Fever, gastroenteritis and phlebitis at the site of injection were toxic signs of minor importance. However, to avoid phlebitis the drug should be injected through a tube of a free-running intravenous infusion. Adriamycin seems from the present series to be devoid of significant cardiac toxicity. As expected, children tolerated higher doses than adults and all pretreated patients became rapidly intoxicated with small doses. The less toxic schedule appears to be the intermittent one (C). Prompt and consistent responses were observed in many cases (table 4), but they were usually short lived. The drug appears therefore to be a potent growth-inhibiting compound more useful for inducing the first remission than for mantaining it. Acute lymphoblastic and chronic myelogenous leukemias as well as malignant lymphomas, neuroblastomas and soft tissue sarcomas were the diseases most sensitive to adriamycin.

Malignant histiocytosis: a clinicopathologic study of 18 consecutive cases.

The clinical records and histologic material of 18 consecutive patients with malignant histiocytosis were reviewed. The age of the patients ranged from 20 months to 72 years (median 35 years). There were 14 males and 4 females (3.5:1). Lymph node and liver enlargement, fever, and skin nodules were the most common physical findings; and leukocytosis was frequently the most abnormal laboratory test. Seven of 18 patients died, and their survival ranged from 1 to 15 months (median 8 months) after histopathologic diagnosis. The histologic findings on lymph nodes, spleen, liver, bone marrow, and skin were investigated with special reference to both the cellular composition and the pattern of lymph node involvement. Vascular invasion of small perinodal vessels was observed in 4 fatal cases. The absence of capsular invasion and the lack of cohesiveness among atypical proliferating histiocytes of malignant histiocytosis appeared to be inconstant. Sequential lymph node biopsies revealed in later stages the extension of the histiocytic proliferation from the sinuses into the cords and the complete obliteration of the nodal structures. The radiologic investigations yielded numerous pathologic findings that were consistent with the dissemination of the disease. Complete response to initial treatment was achieved in patients that were treated with radiotherapy and/or chemotherapy. Complete response with chemotherapy was achieved only when the treatment included adriamycin. The histologic and clinical features of the present series provide further evidence for the recognition of malignant histiocytosis as a distinct clinical and pathologic entity.