Guzzon A

Long-term tolerability of fenretinide (4-HPR) in breast cancer patients

A group of 53 patients initially participating in a phase I trial with the synthetic retinoid fenretinide was assessed for the long-term tolerability of this compound. The patients were evaluated after 42 months of drug intake at a dose of 200 mg/day, including a 3-day drug interruption at the end of each month, by the following examinations: a dermatological visit; an ophthalmological evaluation including an ophthalmological questionnaire and an electroretinogram (ERG); a study on blood chemistry and plasma retinol levels; a study on bone densities and on skeletal X-rays; and finally a psychological evaluation including various tests for anxiety, depression and overall mood. The results show that prolonged administration of fenretinide is well tolerated. No acute nor severe toxicity was observed and thus this compound can be considered a good candidate for chemoprevention trials in a variety of patient populations.

Accuracy of breast cancer diagnosis by physical, radiologic and cytologic combined examinations.

Physical examination, mammography and fine-needle aspiration cytology were performed in 1498 consecutive cases with a solitary solid lump of the female breast. The intent was to verify the validity of this diagnostic triplet in the accuracy of the preoperative diagnosis of breast cancer. Clinically sure cancers were excluded from the study. The collected data were evaluated in terms of sensitivity, specificity and predictivity of any procedure alone or in combination. In 1138 cases confirmed by histology (514 carcinomas and 669 benign or non-neoplastic lesions), the physical examination and mammography were very sensitive (respectively 96% and 84%) but with a high rate of false-positive reports (respectively 20% and 18%). The cytologic diagnosis was less sensitive (65%), mostly due to many inadequate smears, but highly specific (93%) and predictive for malignancy (99%) when the cytologic report was frankly positive. Any single procedure improved the overall sensitivity, and taken together this triplet appears to be the most effective noninvasive diagnostic combination that provides in a short time with minimal cost and discomfort, a diagnosis of certain malignancy in about 50% of carcinomas with a predictivity close to 100%, when cytology detected malignancy.

Problems in Fine-Needle Aspiration Biopsy Cytology of Clinically or Mammographically Uncertain Breast Tumors

From June 1978 to December 1980 at the Istituto Nazionale Tumori of Milano, a fine-needle aspiration biopsy was performed on each of 4834 cases of palpable mammary nodules, the large majority of which were clinically and mammographically suspicious for cancer and only a small part clinically definitely positive. Of these, 1173 underwent surgery at this institution, and 534 (45.5%) had a histologically proven carcinoma. The aspirations were performed by individuals different from those who read the cytologic smears. The aspirations were never repeated, and methods for the retrieval of cells were never applied. Under the circumstances, sensitivity was 0.67, specificity 0.98, and the predictive value for positive results 0.97. The high percentage of inadequate samples (25.5%) influenced the low sensitivity. The few false-positive results occurred exclusively during the first year. Frozen sections can be avoided in those cases (about 50%) with definitely positive cytologic diagnosis by the application of strict criteria. The intrinsc incapability of cytology to yield any information on the extent and the invasiveness of a malignant lesion does not seem to effect its pre-operatory conclusiveness.

Growth rate of primary breast cancer and prognosis: Observations on a 3- to 7-year follow-up in 180 breast cancers

The disease-free probabilities after 3 to 7 years of follow-up of 180 breast cancers of known doubling times were studied to assess the prognostic significance and clinical implications of the growth characteristics of primary breast cancer. Fast-growing tumours, N+ greater than 3, showed a prognosis significantly worse (P less than 0.01) than that of slow-growing tumours of the same class; no significant differences were found among N- or N+ (1-3) fast-, intermediate- and slow-growing tumours. Highly significant differences were found among fast- and intermediate-growing tumours with different degrees of lymph node involvement (respectively P less than 0.0001 and P less than 0.001), with the worst prognosis for N+ greater than 3 tumours. In contrast, no significant differences were found among slow-growing tumours of the different N classes. When the Cox model was applied, the relationship between lymph node involvement and doubling time was significant, as was the interaction term. It is suggested that growth rate and metastatic potential are not the same in primary breast cancers, and their relation should be investigated.

Systematic Use of the Clinical-Mammographic-Cytologic Triplet for the Early Diagnosis of Mammary Carcinoma

Of about 8500 women with a minimum age of 30 years who had a breast examination at our Ouptatient Clinic from April 1982 to March 1983, we found in 286 cases a clinically evident carcinoma, and in 534 cases an apparently benign or suspect solid lump. All 534 of these cases were subjected to the triplet clinical, mammographic and cytologic diagnostic investigation by needle aspiration within 1 to 4 days. The clinical judgment was based on a method of scoring of the characters of 9 physical features (Clinical Diagnostic Index) in use at our Institute. The results of the examinations were grouped into 5 categories: 1) certain benignancy or negativity of the examination; 2) probable benignancy (excluding the cytologic examination); 3) probable malignancy; 4) certain malignancy; 5) nonevaluability of the examination (excluding the clinical examination). Except for 80 cases with collectively negative examinations which were clearly or completely regressed at the control within 2 months, all the others were subjected to surgery. On the basis of the histologic examination (or if regression occurred), 284 of the 534 lumps examined were found to be benign or nontumoral, whereas the other 250 (47%) were carcinomas. Of the latter, 57% were not more than 20 mm in size, whereas in 67.6% there was no microscopic evidence of axillary metastases. Sensitivity of the clinical, mammographic and cytologic examinations was 0.79, 0.76 and 0.72, respectively; specificity 0.71, 0.75 and 0.94, respectively, and the predictive value for malignancy of the positive response of the three examinations 0.71, 0.75 and 0.93, respectively. The use of the diagnostic triplet demonstrated an overall sensitivity of 0.95, specificity of 0.59, and a predictive value for malignancy of 0.98 and 0.93 for benignancy. These results confirm the usefulness of the systematic use of the diagnostic triplet in solid breast lumps of over thirty aged women for the early detection of cancer.

Prognostic significance of the growth rate of breast cancer: Preliminary evaluation on the follow-up of 196 breast cancers

The doubling time (DT) of 196 consecutive breast cancers was studied by means of a double mammographic examination (average time between the 2 mammographies, 30 days) and calculated with the formula of exponential growth. On the basis of DT values the case series was divided into 3 groups of growth: fast (DT from 1 to 30 days), 31 cases (15.8 %), intermediate (DT from 31 to 90 days), 84 cases (42.9 %), slow (DT more than 90 days), 81 cases (41.3 %). No relationship was found between growth rate and size of tumor, or menopausal status of the patient. After mastectomy fast and slow cases were equally distributed in the N− and N+ groups, whereas for the intermediate cases the N−: N+ ratio was 1: 2. One hundred and thirty-four cases were followed for a period of 12 to 52 months. Evaluation was done on the basis of the subdivision into N− and N+, and the latter group into N+ (1–3) and N+ (> 3). For N− tumors the course of the disease was apparently not affected by the growth rate. However, the case of fast growing tumors showed a higher proportion of recurrences with respect to N+ slow growing tumors. This difference was even more noticeable the higher the number of involved lymph nodes, but not statistically significant. The course of slow growing tumors was identical in the N− and N+ groups, but all the N+ tumors were subjected to adjuvant chemotherapy.

ADRENAL GLAND METASTASIS IN OSTEOGENIC OSTEOSARCOMA. A RADIOLOGICAL CASE REPORT

Adrenal gland metastases from osteogenic sarcoma are rare and an unusual pattern of relapse. The recognition of solitary metastases, particularly when located in uncommon sites is very important for subsequent treatment. The authors describe the radiological features of an adrenal metastases from osteogenic sarcoma.

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.

The Growth Rate in the Interpretation of the Natural History of Lung Cancer

The relationship between growth rate, expressed as doubling time (DT), of 110 lung cancers from randomly collected patients and patient age, sex, histological type, symptoms, smoking habits, size and lymph node involvement was studied. Median DT values of epidermoid carcinomas and adenocarcinomas were superimposable (98 and 99 days, respectively), but 15 % of adenocarcinomas had a DT of more than one year. Significant correlations were found with sex (slower growth rate in females) and symptoms (faster growth in symptomatic patients), but only for adenocarcinomas. The number of cigarettes smoked did not seem to affect the growth rate of lung cancers. There was no correlation between growth rate and tumor size or lymph node involvement.

Clinical evaluation of procarbazine and fluorouracil in advanced lung cancer

Procarbazine and 5-fluorouracil were given to 69 untreated patients with inoperable or metastatic lung cancer. 62 were adequately evaluable. The patients were divided into 3 groups: A) 26 cases received procarbazine (250 mg/day i.v. for 4 weeks); B) 24 cases received procarbazine in association with 5-fluorouracil given by rapid single i.v. injection (10 mg/kg on alternate days for 4 weeks); C) 12 cases received procarbazine in association with 5-fluorouracil which was given by 2 hour i.v. infusion on alternate days for 4 weeks. No maintenance treatment was given. The objective responses were evaluated following the categories of Karnofsky. Considering only the category 1 responses, 15 % of patients of group A showed objective improvement, in comparison to 43 % and 16 % of patients of group B and C respectively. Therefore, it seems that the combination of procarbazine and 5-fluorouracil (rapid i.v. injection) is better than procarbazine alone, and that the combined treatment is more successful when 5-fluorouracil is given by single i.v. injection rather than through slow i.v. infusion. Regressions were observed in all histologic types. However, in the group of cases with adenocarcinoma none (0/5) responded to procarbazine alone but 5/6 to procarbazine plus 5-fluorouracil. It is likely that procarbazine is more effective in the oat-cell type and 5-fluorouracil in adenocarcinomas. Toxicity consisted in nausea and vomiting during the first 7–10 days in the group treated with procarbazine alone (15/26 cases), while only 2/26 patients had transient leukopenia. In group B the side-effects were diarrhea (13 cases) and leukopenia (9 cases), both possibly due to 5-fluorouracil. Only 2/12 patients of group C showed side-effects (1 vomiting and 1 diarrhea). The fact that no patients of this group showed signs of bone marrow depression confirms what is already known, i.e. that when 5-fluorouracil is given by slow i.v. infusion toxicity rarely occurs. The conclusion is that the association of procarbazine with 5-fluorouracil can produce consistent regressions in patients with advanced carcinoma of the lung, although unmaintained remissions are almost always short lived.