Carlo Nervi

Effectiveness of microwave hyperthermia combined with ionizing radiation: Clinical results on neck node metastasest☆

Abstract Patients with superficial malignant lesions have been treated with local hypertbermia in association with radiation. Heat was applied by means of a newly assembled apparatus with a variable frequency microwave generator (200–3000 MHz). The apparatus was operated at a frequency of 500 MHz; heat was delivered with non-contact applicators designed for different surface curvature. Adequate heating for depths up to about 3 cm was demonstrated by isothermal maps in chopped meat phantoms. A group of 15 patients with N2–N3 multiple cervical nodes from bead and neck cancer were treated with a multiple daily fractionation (MDF) radiotherapy, according to our previous clinical experience, and with MDF combined with local hypertbermia. A direct comparison of the two treatments on different nodes was possible for each patient: 17/20 nodes (95%) achieved a complete response with this combined schedule, 6 13 (46%) with MDF alone, and 14/46 (30%) with conventional fractionation (historical series). The same combined treatment also was delivered to a group of 4 patients with other kinds of tumors. Complete or satisfactory responses were also obtained in these patients. The results suggest that MDF can be advantageously combined with local hyperthermia.

Combined radiation and drugs: The effect of intra-arterial chemotherapy followed by radiotherapy in head and neck cancer

This study was designed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation. 142 patients with head and neck cancer (oropharynx, maxillary antrum and intra-oral) were randomized for the study. In 72 cases, irradiation was preceded by a continuous intra-arterial infusion of 3-5 mg/day methotrexate to a total dose of 90-120 mg; the other 70 patients were treated with radiotherapy alone. Chemotherapy, given prior to radiotherapy, caused a shift in the tumor stage (i.e. a reduction in tumor size) in more than one third of the cases. The overall 5-year survival was 43% in the combined treatment group and 25% in the group treated with radiation alone (statistical difference: p less than .05). However, when analysed separately the difference was statistically significant only in oral cavity tumors (5-year survival of 54% in the combined modality group vs. 27% in the control group), although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors. In these last lesions, however, the dissemination of disease was more frequent; therefore, the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases. Mild and transient local and systemic toxicities were observed during chemotherapy infusion, but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy.

Enhanced effectiveness of adriamycin and bleomycin combined with local hyperthermia in neck node metastases from head and neck cancers.

The results of this study concern the comparison of the clinical effects of adriamycin (ADM) or bleomycin (BLM) alone and combined with local hyperthermia on 15 patients with multiple (29) neck node metastases from head and neck cancers. With repeated low fractional daily doses of drug a significant though transient tumor regression was obtained in 2/8 and in 3/6 of the lesions treated with ADM or BLM alone, respectively. When the drugs were combined with 42-43°C hyperthermia, an overall response, either complete or partial, was seen in all the lesions. Complete regression was observed in 38% (3/8) and 43% (3/7) of the lesions treated with ADM or BLM, respectively, combined with heat. At a 4-month follow-up, 33% (2/6) and 40% (2/5) of the same groups of lesions remained still undetectable. These results suggest that the combined treatment of drugs and local hyperthermia can be advantageously employed in clinical practice for treating local tumors, especially recurrences in previously irradiated areas.

The relevance of tumor size and cell kinetics as predictors of radiation response in head and neck cancer. A randomized study on the effect of intraarterial chemotherapy followed by radiotherapy

Size and extent of a primary tumor strongly influences its response to irradiation. In order to investigate the relevance of this statement a randomized study was carried out in which irradiation of advanced carcinoma of head and neck was compared with a combined treatment where preirradiation intraarterial chemotherapy was administered in order to reduce the extent of the tumor. Intra‐arterial chemotherapy (MTX 3–5 mg/day for 25–35 days) was given to 72 cases with lesions in the oral cavity, the oropharynx and maxillary antrum. Depending on response the patients were restaged and submitted to radiotherapy. In 68 other cases randomly allocated, radiotherapy only was given with the same modality and technique. After chemotherapy 21 cases with intraoral and 14 cases with maxillary antrum and oropharynx cancers were classified Stage I and II (0 and 23, respectively, before treatment). Results after 4 years follow up showed both local control and survival statistically better in the combined treatment in intraoral cancer where irradiation was delivered by a combination of external and interstitial technique. In the other cases no statistically significant difference was found. Amelioration of the results in the oral cavity could be ascribed to the greater use of interstitial irradiation due to the tumor shrinkage obtained with preirradiation chemotherapy more than to some synergistic effect between drug and irradiation. In 8 cases tumor cell kinetics were performed and the nuclear DNA content measured, but none of the kinetic parameters could be correlated with the response to treatment, even when the cancers were grouped according to their clinical growth characteristics. Late results in the irradiation of head and neck cancer probably depends on the presence of some resistant component which cannot be predicted by the cell kinetic or nuclear DNA content. Surgical excision or a second course of chemotherapy must be considered as a part of the multimodality treatment.

Significance of growth rates, cell kinetics, and histology in the irradiation and chemotherapy of squamous cell carcinoma of the mouth

In eight cases of extended tumors of oral cavity, we have studied the growth rate, the cell kinetics parameters, and the histology before and during treatment. We have found that growth rate and cell kinetics are not useful for clinical purposes because the first is not related to the response to treatment, while the second is unable to give relevant parameters in solid human tumors. New information was obtained from examination of serial biopsies before and throughout the treatment. These data suggest that multiple subpopulation groups of cancer cells with different intrinsic sensitivity to chemotherapy and/or radiotherapy may exist in the same tumor. Resistance of the tumor is related to some groups of cells scarcely sensitive to treatment.

Multiple daily fractionation (MDF) radiotherapy in association with hyperthermia and/or misonidazole: experimental and clinical results.

Several modalities involving a Multiple Daily Fractionation (MDF) course in combination with hyperthermia and/or the hypoxic sensitizer misonidazole have been tested on a mouse tumor system and then applied, with the proper sequencing, to a group of patients with multiple (N2–N3) neck node metastases from H&N cancers. Different lesions of the same patients underwent different modalities. The clinical results indicate the effectiveness, in respect to a historical series of patients treated with conventional fractionation (200 rads/day, five days/week), of either MDF alone (200 + 150 + 150 rads/day, five days/week) or MDF + hyperthermia (500 MHz, 42–43 C, 45 min., after 2nd daily fraction, on day 1, 3, and 5 of each week) or MDF + misonidazole (1.2 g/m2 daily, 2 hours before 1st fraction, up to a maximum dose of 12 g/m2), or MDF + hyperthermia + misonidazole. The latter modality appears to be possibly the most effective at inducing a complete local tumor response lasting longer in time (follow‐up to a minimum of four months). The pharmacology of misonidazole has been monitored in the patients to avoid undesired excessive drug plasma level. No neurological symptoms have been observed. Oropharyngeal mucositis has been observed only in patients treated with misonidazole and radiation through two cross‐firing portals. The problem of selecting individual patients for a particular modality is discussed.

Cytokinetic evaluation in human head and neck cancer by autoradiography and DNA cytofluorometry

As part of a comprehensive research program on cell proliferation characteristics of squamous cell carcinoma in humans and the relation of these characteristics to treatment, 4 untreated cases of head and neck cancer and 2 recurrences were studied. Previously, cell kinetics following the percent labelled mitoses method were done and the same carcinomas now studied by measuring microfluorometrically the time distribution of the nuclear DNA content. Two cases were characterized by a homogeneous cell population, whereas in 2 other cases, two cycling subpopulations distinguished by their DNA content were encountered. The clinical response was not related to the occurrence of single‐ or multiple‐cell populations. In all cases, a great variability in the mitotic index (MI) and in the proportion of cells in the different cycle phases was found. The heterogeneity in the proliferative structure of these tumors stresses the need for a greater accuracy in performing cell kinetics studies in vivo and could account for the difficulties in devising a therapeutic regimen based on cycle or phase‐specific agents.

Dose-survival relationship for epithelial cells of human skin after multifraction irradiation: evaluation by a quantitative method in vivo

Abstract The dose-survival relationship for normal epithelial cells after single and fractionated radiation exposures has been established by Withers for the mouse, 11 but it is not available for humans according to a strict criterion for survival of single cell reproductive integrity. In an attempt to obtain such a quantitative estimation, 2 patients requiring radical radiation therapy to the chest wall were treated according to particular Multiple Daily Fractionation (MDF protocols i) 250 + 150 + 150 rad/day, 4 hr interval, 5 days/week; and ii) 150 + 150 + 150 + 150 rad/day, 3.5 hr interval, 5 days/week. In both cases, different strips of skin received different total doses: 6300, 6850, and 7150 rad, and 6300, 6750, and 7200 rad, respectively. In case (i), moist desquamation appeared and thereafter repopulating colonies of epithelium could be recognized and counted. Using these counts a survival curve having a D 0 value of 490 ± 150 rad was estimated according to the formula proposed by Withers. 11 In case (ii), no moist desquamation was reached at the doses delivered. The difference observed may imply that the initial region of the survival curve deviates appreciably from exponential between doses of 150 and 250 rad. If such is the case, a 1 D 0 value of 490 rad may represent an underestimate. These results are discussed from the point of view of both the shape of the survival curve and the effectiveness of nonconventional fractionation courses.

PROTRACTED INTRA-ARTERIAL CHEMOTHERAPY WITH SEQUENTIAL COURSES OF ANTIMITOTICS AND RADIOTHERAPY IN THE TREATMENT OF EXTENDED HEAD AND NECK CANCER.

51 patients with extensive inoperable head and neck cancer were treated with sequential continuous arterial infusion of anticancer agents. Mtx, 5 FUDR and Mitomycin C were administered in that order. At the end of the chemotherapy the patients were subjected to a full dose of external radiotherapy with the aim of destroying the residual cancer cells. Objective tumor regression was achieved in 27 patients lasting twice as long as in the same number of patients treated with external radiotherapy only. The study suggests that the idea of treating an extensive cancer with different drugs and therapeutic methods used sequentially with the aim of destroying the greatest number of cancer cells, is valid.

Combination of Low Doses of Vincristine with High Doses of Methotrexate in the Therapy of Solid Tumors

58 patients with advanced carcinoma were treated with a low dose of vincristine followed by 24-hour intravenous infusion of methotrexate. Vincristine enhanced the antineoplastic effect but not the toxicity of methotrexate. In 31 of the 58 patients there was objective regression of the disease. The best results were obtained in head and neck and uterus carcinomas whilst in lung tumors regression was less marked. The method, which was well tolerated by all the patients, is indicated for palliation in advanced tumors or before irradiation in combined chemoradiotherapy.