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In a period of a little over 20 years, chemotherapy of cancer has evolved from a period of empiricism with little impact on the cancer problem to become part of a sound medical discipline with firm scientific underpinning playing an increasingly important role in the control of cancer. This progress has come from an increasing knowledge of cancer biology and pharmacology and the application of this knowledge to improved design of clinical trials, with due consideration to the intricacies of the natural history of each disease in question. Now that the chemotherapeutic tools are sharpened, their use in combinations with other modalities in the previously unfamiliar setting of the patient with early stages of the disease promises to lead to an even more exciting chapter in clinical cancer research in the next decade.

The malignant germinal tumors found in the testis (seminoma, teratocarcinoma, embryonal carcinoma, choriocarcinoma, and mixtures of these) can originate in the anterior mediastinum. An occult testicular tumor must be sought, but primary mediastinal germinal tumors constitute a true entity. The details of 24 such patients treated at Walter Reed General Hospital are presented. Of 19 patients who died, 2 were women; postmortem examination of the testes of 13 men failed to reveal a primary tumor. Five patients are alive and well with no testicular abnormality. It is important to distinguish the histopathologic types. Seminomas are readily controlled with modest doses of irradiation. Embryonal carcinomas are also radiocurable with somewhat higher doses; 2 long-term disease-free survivors are reported. Teratocarcinomas are highly malignant and require higher doses for control. Choriocarcinomas progress so rapidly that chemotherapy is necessary.

Eight patients with choriocarcinoma of the ovary treated at the Choriocarcinoma Research and Treatment Center are presented and the previously reported cases reviewed. A more optimistic prognosis can be offered for these tumors than previously. Four of the 8 patients are in remission and 4 have died. Triple therapy should be used for these tumors despite the increase in toxicity.

Choriocarcinoma with a primary site in the chest is rarely found. Characteristically, it is seen in young men presenting with cough, gynecomastia and chest pain. The disease is invariably fatal. The presently accepted therapy (triple therapy), consisting of methotrexate, actinomycin D and chlorambucil, has been unsuccessful to date.

Despite the rapid advances in carcinochemotherapy, the possibilities for the treatment of solid tumors are rather limited, so that the advantages and disadvantages of chemotherapy must be very carefullly considered in each case of incurable cancer. It should also be emphasized that there are several tumor types in which skillfull application of chemotherapy does not only lead to an objective improvement in the clinical findings but also prolongs the patient's life.

Despite recent advances in the systemic chemotherapy of patients with malignant trophoblastic disease, there remains a small group of patients who fail to achieve remission with this type of treatment. The present study presents 19 patients with malignant trophoblastic disease who underwent a total of 25 arteriographic studies for localization of persistent malignant lesions and 8 patients who underwent arterial infusional chemotherapy after they had failed to achieve remission by standard administration of systemic methotrexate or actinomycin D. Patients underwent pelvic, pulmonary, carotid, and multiple abdominal selective arteriograms with a high correlation of positive findings and the later documented presence of persistent malignant disease. Findings include prominent uterine arteries, arteriovenous shunts, hypervascularity, irregular vessels, and tumor staining within the tumor. Arterially infused chemotherapy with methotrexate or actinomycin D was used in 8 patients whose disease was resistant to systemic chemotherapy. Technics of arterial infusion are discussed.

Thirty-one patients with nonmetastatic trophoblastic disease (NMTD) and 39 patients with metastatic trophoblastic disease (MTD) of gestational origin were treated primarily with actinomycin D. Complete and sustained remission was achieved with actinomycin D alone in 94% of patients with NMTD and 67% with MTD. In the nonmetastatic group, 93% of patients without choriocarcinoma (non-CCA) achieved remission with actinomycin D, as compared to 100% (only 3 patients) with CCA. in the metastatic group, 76% of patients without CCA achieved remission with actinomycin D, as compared to 56% where CCA was present. Fourteen of the 15 patients who failed to respond completely to actinomycin D alone subsequently responded to methotrexate (10 patients), triple therapy (3 patients), methotrexate plus triple therapy (1 patient), and methotrexate plus vinblastine (1 patient). One patient died with widespread metastases despite intensive chemotherapy with actinomycin D and triple therapy. No serious toxic side effects were encountered even in treated patients with pre-existing laboratory evidence of impaired hepatic function.

The department of Gynecology and Obstetrics of Florence University reports the following findings for the chemotherapy of gestational choriocarcinoma during the period 1962-74. Sixteen cases, 11 of which were rated high risk cases, were given chemotherapy with MTX alone or in association with other cytotoxic agents. In the 12 surviving cases that may be considered the incidence of complete remission (from 4 to 13 years) is 67%. Of the 8 cases rated as cured 3 were high risk cases at the beginning of treatment. Intermittent chemotherapy with MTX only was given by slow intravenous injection at doses of 3 to 4 mg/kg for 24-48 h followed from the 48th h by folinic acid treatment for 1-2 days. This schedule is recommended because of its negligible toxicity as a replacemen for intramuscular MTX in 5-day courses, which carries a fairly high risk of toxicity.

Bleomycin and its combinations have a definite place in the treatment of metastatic testicular carcinomas other than seminomas and may also prove to be effective, when given as adjuvant postoperative therapy in state II disease. A study, using the combination of Bleomycin and CCNU in 17 patients with metastatic testicular teratoma, is reported. A remission rate of 59% has been observed. Only patients with a complete remission had a satisfactory remission duration. Sequential combinations, using all drugs effective in this disease, may be the most promising way to further improve therapeutic results in terms of remission rate and survival.

2 cases of malignant chorionepithelioma are reported on account of their interesting symptomatology and the procedure by which a correct diagnosis was made. Chemotherapy must now be considered superior to surgical treatment and the most important chemotherapeutic drug is methotrexate. The therapeutic efficacy of this preparation is offset by severe side effects, which may even have a lethal outcome.

The paper retrospectively reviews the modalities and the long-term results of treatment of 200 consecutive patients with pure seminoma and of 125 patients with testicular carcinomas admitted to the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan from 1929 to Jan 1973. Radical orchiectomy with high ligation of the spermatic cord at the internal inguinal ring was performed in all previously untreated patients. Those who had had a scrotal operation performed elsewhere were radically reoperated upon. Lymphography and cobalt 60 telecurietherapy were introduced in 1960 and new treatment plans were employed for the irradiation of the deep lymphnodes. Since 1968 all operable carcinomas have undergone bilateral retroperitoneal lymphadenectomy and since 1964 all patients with advanced disease have been treated with chemotherapy (single agent or combination). Survival rates were calculated by the actuarial method. The new treatment modalities proved to be significantly superior to the old ones. In pure seminoma a 92% cure rate was obtained in NO patients after prophylactic irradiation of retroperitoneal nodes (2,500-3,000 rad in 3 weeks). In NI-3 patients the cure rate was as high as 75% after radical irradiation of retroperitoneal nodes (3,500-4,000 rad in 4 weeks) as well as prophylactic irradiation of mediastinum and both supraclavicular fossae. Extended radical radiotherapy (combined with chemotherapy in some patients) cured 2/6 N4 and 3/8 M1 patients. According to the old modalities of treatment, figures were respectively 72% in NO cases, 40% in N1-3 and 0% in N4 and M1 patients. In carcinomas, the cure rate after retroperitoneal lymphadenectomy was 91% in N--patients and 47% in N+ cases. In N+ patients post-operative radiation was also performed (4,000-5,000 rad in 5 weeks). After radiotherapy alone (without lymphadenectomy) the rates were 62% in NO and 28% in N1-2 patients. In primary inoperable patients (N3-4 and M1) chemotherapy, with or without radiation, significantly prolonged the survival rate. It is concluded that radiotherapy is the treatment of choice for pure seminoma and in N4 and M1 cases a full course of chemotherapy must be combined with extensive irradiation. Retroperitoneal lymphadenectomy is mandatory in all operable cases of testicular carcinoma while adjuvant chemotherapy may further improve the prognosis in N+ cases. For inoperable carcinomas chemotherapy (plus radiotherapy) is the treatment of choice. The new multiple drug regimens are providing encouraging results.

In three patients with malignant disease HBsAg was detected in the serum at least 6 months before the development of acute hepatitis type B, which in each case followed a fulminant course to death. It is suggested that suppression of the normal immunological responses to hepatitis-B viral antigens by cytotoxic drug therapy permitted widespread infection of hepatocytes. Subsequently, upon withdrawal of these drugs, recovery of immunocompetence resulted in rapid destruction of all infected hepatocytes and massive liver damage. Screening for HBsAg before cytotoxic drug therapy, careful monitoring of liver function during its withdrawal, and prompt treatment with corticosteroids should abnormalities occur may prevent this unfortunate sequence of events.

Radioimmunoassays and bioassays based on the reactions of the native molecule of human chorionic gonadotropin (HCG) fail to differentiate HCG from pituitary luteinizing hormone (LH). An assay based on the beta-subunit of HCG which detects HCG exclusively has been used in our laboratory to monitor patients undergoing chemotherapy for gestational trophoblastic disease (GTD). We have been able to differentiate minimal, persisting tumor activity from normal levels of pituitary gonadotropins and have based therapy on these findings. Alternatively, treatment has been terminated when HCG is no longer detectable in the serum. Tumor activity has been detected in the beta-subunit assay at a time when biologic activity in the urine indicated remission.