Clifton D. Howe

Vinblastine in the management of testicular cancer

The activity of vinblastine alone and in combination with melphalan was studied in 32 patients with metastatic testicular neoplasia of germinal origin. There was a total of 16 objective responses. Twenty‐one patients received 0.4 to 0.8 mg/kg of vinblastine intravenously in 2 or 3 equal daily fractions, which was repeated at 3‐ to 4‐week intervals. There were 4 complete and 7 partial responses, the longest being 42+ months. The combination of vinblastine, 3.5 to 4.0 mg/kg intravenously in one dose, followed in 24 to 48 hours with melphalan, 0.5 to 1.0 mg/kg in 500 ml of 5% glucose in water, was given to 11 patients. Treatment was repeated at 4‐ to 6‐week intervals. There were 2 complete and 3 partial responses, the longest being 66+ months. There was no significant difference in the number of responses or the median duration of response between the 2 treatment groups. Partial responses were seen in all histologic groups. Complete responses were limited to embryonal carcinoma, pure or mixed with seminoma, and teratoma, pure or mixed with embryonal carcinoma, seminoma or choriocarcinoma (Groups II and IV of Dixon and Moore). Statistical analysis of survival data shows a highly significant difference (P < 0.001) between responding and nonresponding patients.

Enlargement of the supraclavicular lymph nodes as the initial sign of prostatic carcinoma.

During the past 12 years, 19 patients have presented themselves with enlargement of the supraclavicular lymph nodes as the initial manifestation of previously unrecognized prostatic carcinoma. Of the 19 patients, 18 had enlargement of the left supraclavicular lymph nodes, and one had enlargement of those on the right side. This study group was compared with a control group of 100 consecutive previously untreated patients exhibiting the typical signs and symptoms of prostatic carcinoma. The histologic picture in both the lymph nodes and prostate gland of the study group was that of a less well‐differentiated carcinoma than was usually observed in the control group. The disease should, therefore, be considered when metastatic adenocarcinoma is discovered in the supraclavicular lymph nodes, usually those on the left, of men over 45 years of age. Prostatic carcinoma appearing initially as metastases in supraclavicular lymph nodes does not differ significantly in its response to therapy or survival from prostatic carcinoma manifested by the typical clinical features.

Cyclophosphamide in the management of Ewing's sarcoma

The activity of alkylating agents, cyclophosphamide and melphalan, was studied in 13 patients with metastatic Ewings sarcoma. A total of 15 courses of melphalan was administered to five patients at a dose of 1.0 to 1.5 mg/kg per course. There were no responses. Cyclophosphamide was administered to 11 patients, including three melphalan failures. Five partial and two complete responses were obtained, two of whom were melphalan failures. An intermittent intravenous schedule of 15 mg/kg once weekly was convenient and effective, resulting in five of the seven responses. The direct intrapleural instillation of two doses of 15 mg/kg produced total control of pleural effusion in one patient. Only one of four patients on a daily oral schedule of 5.0 mg/kg demonstrated a partial response. The mean dose to response was 45 mg/kg, and the mean duration of response was 5+ months. Factors adversely affecting responsiveness are short‐duration of disease prior to initiation of chemotherapy and a “symptom status” indicating marked disability from disease. Severe vomiting, noted in four of the seven patients receiving parenteral therapy and one of the four on oral therapy, was the most disabling side reaction. Ewings sarcoma should be considered a cyclophosphamide‐responsive neoplasm in the same category as neuroblastoma and malignant lymphoma.

Clinical method of testing radiation‐sensitizing agents in squamous cell carcinoma

Squamous cell carcinomas of the oral cavity and oropharynx provide suitable material for the evaluation of combined chemotherapy and radiotherapy because the therapeutic results in the primary lesions and in the metastatic lesions to the neck nodes can be assayed by palpation and inspection. From 1948 through 1960, approximately 400 cases of squainous cell carcinoma of the oropharyax, 500 of the oral cavity, and 250 of the supraglottic region of the larynx and of the piriform sinus and lateral hypopharynx were treated by a flexible program that included surgical resection, radiotherapy with x rays and Co60 gamma rays, preoperative irradiation, and the use of radiation- sensitizing agents. Data on the treatment and outcome are tabulated. Results are presented from a clinical study on selected cases of the potentiation of radiation effects by 5-fluorouracil or 5-bromodeoxyuridine. It is pointed out that these chemical agents have different mechanisms of action and different modes of administration were used for each. Experimental procedures are described and results are discussed. (C.H.)

Clinical trials with N‐isopropyl‐α‐(2‐methylhydrazino)‐p‐toluamide hydrochloride in malignant lymphoma and other disseminated neoplasia

The antitumor agent, N‐isopropyl‐α‐(2‐methylhydrazino)‐p‐toluamide hydrochloride (Procarbazine) was administered to 66 patients with disseminated neoplastic disease, 48 of whom could be evaluated. Eight of 11 patients with Hodgkins disease had partial or complete tumor regression for a median of 4 months. Since most of them were considered refractory to x‐irradiation, alkylating agents and periwinkle alkaloids, the agent is not cross‐resistant with conventional treatment and may be used effectively in sequence in the treatment of patients with Hodgkins disease. For patients having lymphoma or “solid tumor” there was a positive correlation between response and symptomatic and performance status. Response occurred more frequently in patients with a better performance status and few symptoms. Bone marrow depression and neurotoxicity were the major toxic and dose‐limiting effects. The myelosuppression involved all three formed elements produced by the marrow and was dose related. Neurotoxicity consisted of nausea and vomiting (38%), sensorium changes (12%), hypotension (12%) and peripheral neuritis (20%). The authors establish the efficacy of the drug in Hodgkins disease and indicate the need for more extensive exploration of epithelial neoplasms.

Murine Lymphoma: Augmented Growth in Mice with Pertussis Vaccine-Induced Lymphocytosis

Injection of Bordetella pertussis vaccine caused an excessive lymphocytosis, associated with an augmented growth of a lymphoma cell homotransplant in mice. A markedly impaired reactive cell proliferation was revealed in the spleens of the vaccine-pretreated mice after stimulation with phytohemagglutinin or Freunds complete adjuvant.

Regional pulmonary function in metastatic carcinoma to the lung studied with xenon‐133

Lung function was studied in 21 patients with nodular pulmonary metastases. Routine pulmonary function studies demonstrated that reduction in vital capacity and arterial PO2, related to the degree of tumor involvement, are characteristic features of metastatic lung disease. The reduced arterial PO2 is largely explained by increased right to left shunt. Regional pulmonary function studied with xenon‐133 and 8 scintillation detectors revealed frequent ventilatory defects in the vicinity of single metastases. In patients with multiple bilateral metastases, defects in pulmonary blood flow and ventilation were commonly observed in the vicinity of the tumor masses.

Chemotherapy as an Adjuvant to Radiotherapy

The rationale of combining a chemotherapeutic agent with radiation therapy can be on one of two hypotheses: 1. Agents like 5-fluorouracil (5-FU) or 5-bromodeoxyuridine (5-BUdR) have been shown to be radiation sensitizers (Bagshaw, 1961; Berry and Andrews, 1962; Bosch et al., 1958; Djordjevic and Szybalski, 1960, Kaplan et al., 1961, 1962; Vermund, 1961). The limiting factor in the effectiveness of such a sensitizing agent is the fraction of cells which can be affected by the agent. Furthermore, as the agent also sensitizes normal cells, clinical usefulness depends on the fraction of tumor cells which are sensitized versus the fraction of normal cells sensitized in the volume of tissue irradiated. 2. Alkylating agents or antimetabolites like methotrexate are cytotoxic agents producing shrinkage of tumors but are not radiation sensitizers. The rationale of the combination of chemotherapy with such an agent prior to irradiation is based on the following radiobiological facts.

Leukemogenic effect of human leukemic materials. Attempts to enhance effect in mice by combination of materials with inactivated mouse leukemia virus

Human leukemic bone marrow cells or fluids from cultures of such cells were mixed with heat‐inactivated (56°C for one hour) Rauscher mouse leukemia virus and the mixtures were inoculated into two to three‐day‐old Swiss mice of a low‐leukemia line. Control mice were inoculated with (1) the human material mixed with heat‐inactivated normal mouse spleen extract and (2) the heatinactivated Rauscher virus mixed with fluids from normal human cell cultures. Sixteen human leukemic materials were tested with equivocal results except in one instance. When mixed with heat‐inactivated Rauscher virus, tissue culture fluids from lymph node and bone marrow cells of a 15‐year‐old girl with acute leukemia repeatedly caused leukemia with significantly higher incidence than the corresponding controls. Theoretically, an increased leukemogenic potency of human leukemic materials and inactivated murine leukemia virus can be explained by recombination of human and murine leukemia viruses (“genome rescue”) but other mechanisms, such as phenotypic mixing, multiplicity reactivation of the murine leukemia virus or increased activity of virus‐decoating enzymes, are also possible.

Mouse leukaemia, a dichotomy of virus neutralizing and cytotoxic antibodies

Mice exposed to subliminal doses of live, or to large doses of properly inactivated mouse leukaemia viruses, or cells, will develop antibodies. These antibodies can be detected by virus neutralization (1, 2, 3, 4) and cytotoxic tests (5, 6, 7), among other techniques. I t is not known how these serologic faculties are correlated. Studies in progress suggest tha t the virusneutralizing and cytotoxic antibodies are not identical. The following is a preliminary report on these studies. An immune serum was obtained from mice with adoptive immunity. The cell donors were low leukaemia Timco (Texas Inbred Mouse Company, Houston) S~dss mice vaccinated with photodynamieally inactivated Rauseher mouse leukaemia virus. The technique of photodynamic inactivation of this virus has recently been reported (4, 8). A cell-free spleen extract of leukaemic mice is mixed with high dilution of methylene blue and the mixture is transill~minated with visible light for 25 minutes a t 37 ~ C. Due to photooxidation, the virus loses its infectivity. In the experiment described here, 3 doses of such inactivated virus were injected intraperitoneally into young adult mice a t 3-week intervals. The second dose of the vaccine was given together with Freunds complete adjuvant. These mice produced both virus neutralizing and cytotoxic antibodies. The pooled and inactivated (56 ~ C for 20 minutes) serum neutralized more than 102 LDs0 of the Rauscher virus (8). In the cytotoxic test, 15 per cent of Rauscher leukaemic spleen cells responded with swelling and pinkish