Sergio Orefice

Metastatic Spread of Stage I Melanoma of the Skin

1164 patients with stage I melanoma of the skin who were submitted to wide excision only of the primary tumor were studied to evaluate the rates of regional lymph node and distant metastases. Of these, 516 (44.3%) had a recurrence of the disease which was at regional lymph nodes in 264 (22.7%), at distant sites in 91 (7.8%), and simultaneously at regional lymph nodes and distant sites in 161 (13.8%). Most of the patients had a relapse within 5 years: regional node metastases were most frequently observed during the first 3 years, and distant metastases appeared later. The ratio regional:distant metastases was not different (P > 0.05) when subgroups of patients were considered according to prognostic criteria (sex, site of origin, levels, thickness, ulceration). Sex, levels, thickness and ulceration were found to be significantly related with the frequency of recurrences (regional and distant). It is concluded that the prognostic criteria considered do not predict whether the tumor will metastasize to regional nodes or to distant sites.

Delayed cutaneous hypersensitivity reaction to carcinoembryonic antigen in cancer patients.

The delayed cutaneous hypersensitivity reaction to carcinoembryonic antigen (CEA) was tested in 84 patients with different diseases including large bowel adenocarcinoma and breast carcinoma, with or without metastasis, liver cirrhosis and inflammatory or degenerative diseases. Positive skin test to CEA was observed in a small proportion (11 %) of the patients tested. No difference in positive skin test reactions was observed in the 6 different groups of patients. Similar delayed cutaneous hypersensitivity reactions were found to various amount of CEA ranging from 0.5 to 25 μg. No correlation was seen between the results of skin test and blood CEA levels.

Intrahepatic doxorubicin in unresectable hepatocellular carcinoma. The unfavorable role of cirrhosis

To investigate the relationship between the presence of cirrhosis and the antitumor effects of locoregional chemotherapy with doxorubicin, 16 patients with nonresectable hepatocellular carcinoma (HCC) and satisfactory baseline clinical conditions (Child class A or B, Karnofsky index > 70%) were studied. Eight patients had post-necrotic cirrhosis, five had serum HBsAg. The dose of doxorubicin was 0.3 mg/kg body weight/day, given by continuous intracoeliac infusion for 8 consecutive days. Eight patients (six with cirrhosis) died prematurely after the first course of chemotherapy. Six (2 with cirrhosis) responded to therapy; they survived 3–33 months (median: 10). In these patients, the type and severity of drug-related side effects were comparable to those reported for patients treated by intravenous chemotherapy. The implication that in many patients with cirrhosis intrahepatic chemotherapy with doxorubicin may hasten death, lessens our interest in its use for nonresectable HCC. In fact, in Italy these cancers frequently occur in association with cirrhosis.

Long term results of surgical treatment of melanoma of the limbs.

The outcome of surgical treatment of malignant melanoma has been evaluated on the basis of 157 limbs patients observed at the National Cancer Institute of Milan from January 1950 to December 1973. It was found that sex, site of origin and excisional biopsy do not affect the prognosis. The presence of regional nodes metastases is the factor that weight most heavily on long term results: 57.6% of patients without regional node metastases and only 15.2% of patients with positive bodes are free of disease 10 years after treatment. The depth of invasion and histological type of melanoma were found to be useful because they reveal the potential aggressiveness of the tumor: 2 out of 11 cases of lentigo maligna, 4 out of 55 cases of superficial spreading melanoma, 23 out of 91 cases of nodular melanoma and 12 out of 79 cases of Clarks level III, 8 out of 44 level IV and 8 out of 14 level V had regional nodes metastases. These two parameters were found to be correlated: lentigo maligna and superficial spreading melanoma infiltrate little as a rule whereas about half of nodular melanoma were classified as levels IV or V. Since there is not at present a definite evidence that an « elective » node dissection achieves better risults than excision only of primary melanoma followed by a possible « curative » dissection the so called « prophilactic » node dissection is considered mainly as a « staging » procedure and indicated only for level V melanoma where the incidence of nodes metastases is higher than 50%.

Intravenous administration of BCG in advanced melanoma patients.

From June 1975 to August 1977, 19 patients with distant metastases of malignant melanoma of the skin that were no longer responsive to chemotherapy were treated with BCG given intravenously. A single dose of lyophilized Pasteur BCG ranging from 2×107 to to 3×108 viable units was given in 500 ml of saline infused in 5 to 6 h. Seven of the 16 evaluable patients benefited from treatment; 3 showed an objective regression of more than 50% of the original tumor volume, and 4 an arrest of tumor growth. The objective regressions lasted from 2 to 5 months, and 1 case had an arrest of tumor growth for 29 months. The regression rate was related to the BCG dosage: 2×108 viable units appears to be the dosage that gives severe but reversible toxicity and is able to induce objective regression. The most responsive lesions were skin and subcutaneous deposits (5 of 7) and lung metastases (1 of 4). Toxic effects seem to be related to the number of bacilli injected. In the group of 10 cases treated with less than 108 units, toxicity was modest: 4 patients had fever (up to 38.5 °C) that lasted a few days, and in 3 cases it was associated with shivering during the infusion period and weakness. One case only had vomiting and jaundice. Toxicity was severe in the 9 patients that were treated with a dosage higher than 108: patients had fever and weakness for at least 4 days and shivering during the infusion. Two had adrenal insufficiency and 7 had liver enlargement and jaundice with return to normality by day 21. In the whole series 8 patients had leucopenia and 5 thrombocytopenia for 2 to 3 days: only 1 patient required blood and platelet transfusion. No significant variations in immunoglobulin levels were observed. No variations of PPD or BCG skin tests were observed after treatment. Three patients expired; the first, treated with 6×107 units, had an intercurrent disease (autopsy showed a heart infarction); the second, treated with 1.8×108, showed a rapid growth of lung metastases and died 15 days after treatment; the death of the third patient was probably due to anaphylactic shock. All 3 patients had been previously treated with BCG, given by scarification or intranodular injection.

Preliminary Phase I Evaluation of Bleomycin, a New Antitumor Antibiotic

Bleomycin (BLM), a new antitumor antibiotic isolated in Japan from cultures of Streptomyces Verticillus, was administered by single intravenous injections to patients with different types of lymphomas and miscellaneous solid tumors for phase I evaluation. 85 out of the 110 patients included in the study were suitable for the evaluation of acute and delayed toxicity, while 93 patients were evaluable to detect the therapeutic effects of the drug. The average age of the patients was 54 years (range 7–83). 16 patients were untreated and 77 had received one or more courses of radiotherapy and/or chemotherapy. During this trial different doses and schedules were employed (table 2): A) 30 mg/m2 × 2/week × 4 weeks; B) 30 mg/m2/day × 8 days; C) 15 mg/m2/day × 8 days. After a month interval all 3 courses were repeated; D) 15 mg/m2/day × 5 days to be repeated twice after 3 weeks interval. Maintenance therapy consisted of 15–30 mg/m2/week. To diminish the febrile reaction, a suppository of indometacin (100 mg) was given 30–60 minutes prior to drug administration. The incidence of toxic manifestations, irrespective of dose and schedule, was as follows (fig. 4): sclerotic changes of the skin of hands (80%), fever (67%), alopecia (61 %), skin hyperpigmentation (60 %), stomatitis (48 %), gastrointestinal disturbances (20%) and pulmonary symptoms (19%). No definite signs of marrow toxicity nor significant changes in the blood chemistry attributable to the drug were observed. Symptoms and signs of pulmonary toxicity, appearing 1–4 weeks after the last dose were: rhonchi, rales and pleural friction rubs, in some cases associated with fever and dyspnea. The chest X-ray showed evidence of interstitial lesions (in early phases most marked at the costophrenic angle) which may become widespread with a bronchopneumonia-like appearance (fig. 5 and 6). No clearcut radiological signs of pulmonary fibrosis were observed (patients were not followed for a period longer than 5 months). If BLM is stopped in time and carticosteroids are given in association to antibiotics, both clinical and radiological findings may disappear completely (fig. 7). Of the 7 patients studied post mortem, 6 revealed lesions attributable to drug toxicity (alveolar collapse with edema, histiocytic proliferation, hyaline membranes, alveolar and interstitial fibrosis (fig. 8–11). In 7 patients pulmonary toxicity was suspected only on clinical grounds, in 2 cases the radiological aspect of the lungs was suggestive of interstitial lesions without concomitant physical findings, in 9 cases a good correlation between clinical and radiological diagnosis was observed and, finally, in 6 patients the pulmonary fibrosis was detected on histological examination (table 3). In the 17 patients in whom the diagnosis of pulmonary toxicity was documented either radiologically or histologically, the average age was 56,5 years (7–78 years) and the mean total dose, producing toxicity was 230 mg/m2 (range 60–480). Practically, all these patients prior to the treatment had different grades of chronic pulmonary lesions (emphysema, fibrosis post RT or tuberculosis, silicosis in 1 case). It is difficult to estimate in what proportion BLM could have contributed to the cause of death, since most patients dying during treatment had also lung metastases. However, at least in 1 case in whom postmortem examination did not disclose lymphosarcoma cells (complete remission), the cause of death could be related to drug administration (total 225 mg/m2) since extensive pulmonary fibrosis was seen on histological examination (table 4). Table 5 shows the incidence of side-effects after the first course of BLM. No significant differences were observed among cases treated with 4 different schedules, and the first sign of toxicity appeared in all groups after the 4th–6th dose irrespective of the dose and schedule. Regressions in different types of tumors were observed during this phase I study (table 6). The overall regression rate was 69 % (24 % greater than 50 % and 5% complete). The therapeutic response was prompt but usually short-lived (average 4–6 weeks). No cross-resistance with radiotherapy nor with some of the conventional agents was observed. The most responsive tumors were carcinomas of head and neck, carcinomas of esophagus (fig. 17) and malignant lymphomas (fig. 16). One 7-year-old boy with acute lymphosarcoma cell leukemia had a complete remission and autopsy revealed no signs of neoplastic disease. In 2/3 patients with CLL a moderate decrease in the volume of hepato-splenomegaly was observed without significant fall in the WBC. The minimal toxic dose was 45–60 mg/m2 in malignant lymphomas and 60–120 mg/m2 in the other solid tumors. BLM appears to be a potent new growth-inhibiting compound specific for epidermoid carcinomas and devoid of bone marrow toxicity. The optimal dose schedule as well as the real incidence and course of pulmonary toxicity should be more clearly defined in future studies.

[Polychemotherapy with 5-(3,3 dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC; NSC-45388), 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU, NSC-409962) and vincristine (NSC-67574) in the metastatic phase of melanoma].

The toxic and therapeutic effects obtained with a triple drug combination (BCNU, DTIC and VCR) administered in a cyclic fashion to 41 unselected evaluable patients with metastatic malignant melanoma are reported. Side effects were moderate and reversible. The overall regression rate was 44% without difference between males and females. Partial remission (> 50%) plus complete remission was 19.5% with an average duration of 5.1 months (1–20+). With the exclusion of bone lesions, all types of metastases showed regression especially those located in the soft tissues (lymph nodes and skin). The actuarial analysis of survival shows that responders live twice as long as non responders (median survival 12 months versus 6 months). However, the superior therapeutic efficacy of BCNU + DTIC + VCR over DTIC alone in metastatic melanoma remains to be demonstrated. A controlled study with different triple combinations is now in progress.

The value of the CEA test in the diagnosis of metastases of adenocarcinoma of the gastroenteric tract.

Of 174 patients previously resected for gastric, colon or rectal adenocarcinoma, 75 had distant metastases at the time of the first examination and provided information on the specific characters of different types of tumors as regards CEA sensitivity. The remaining 99 cases, all without clinical evidence of disease, showed positive CEA levels in 26 and negative CEA levels in 73. Of the 26 CEA-positive cases, 24 showed clinical signs of metastases in a period of time varying from 1 to 11 months. The remaining 2 cases, although CEA positive at subsequent tests, did not develop clinical metastases and have been disease-free for 5 years after the first test. Of 73 CEA-negative patients, 30 developed metastases: in 17 the clinical appearance of recurrences was preceded by a positive CEA test, while in 13 the CEA test remained negative even with the presence of disease. The remaining 43 cases are still CEA negative and without metastases from 44 to 51 months from the first examination. Altoghether, in 22 cases CEA was negative, but the clinical evidence of recurrences was positive, and in these cases 63.6 % were undifferentiated carcinomas; 2 patients were CEA positive but without signs of evident metastases.

[Immediate and long-term results of anterior resection in tumors of the rectum and sigmoid (author's transl)].

127 anterior resections for adenocarcinoma of the rectum and sigmoid were performed at the Istituto Nazionale Tumori from 1950 to 1972. In 48% of cases the site of tumor was upper rectum and recto-sigmoid. The surgical mortality rate was 4,7%. Complications were observed in about 40%, fecal fistula being the most frequent. It seems correlable with the anastomotic technique and is significantly reduced by colostomy. Local failure occurred in 8,3% of patients with maximum rate (28,5%) for tumors located under 12 cm from the anus. The 5-year over-all survival rate was 73,3% with substantial differences according to the extent of initial disease.

Clinical and radiological study of metastatic localizations of malignant melanoma of the breast

Six cases of metastasis of malignant melanoma in the breast are described. Mammography did not differentiate these lesions from primary breast lesions.