Treatment Of Disseminated Disease Research Articles

Evaluation of cis-platinum and DTIC combination chemotherapy in disseminated melanoma. A Southwest Oncology Group Study.

The development of disseminated melanoma is associated with an extremely poor prognosis. Use of a variety of chemotherapy agents alone and in combination has yielded response rates of only 10-30%. Surgery and radiation therapy play a useful role in palliative treatment, but have little or no value in the treatment of disseminated disease. In order to evaluate the response of disseminated malignant melanoma to combination chemotherapy with cis-platinum and 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC), a phase II pilot study was developed and conducted at Oregon Health Sciences University. Thirty patients were treated from January 1983 to October 1986 and evaluated. There were two complete responses (7%) and nine partial responses (30%) for a total response rate of 37%. The median duration of response was 31 weeks. This response rate is higher than has been previously achieved with DTIC and cis-platinum, or with other drugs alone or in combination. Severe (grade 3) renal, neurologic, and hematologic toxicity was seen in four of 30, three of 30, and ten of 30 patients, respectively.

Embryonal carcinoma of the testis.

Long-term survival rates were correlated with selected clinical features in 479 patients with embryonal carcinoma of the testis and 33 patients with endodermal sinus tumor (infantile embryonal carcinoma, yolk sac tumor). In the period 1977 to 1982 embryonal carcinoma accounted for 26.8% of newly diagnosed germ cell tumors and 43% of nonseminomatous germ cell tumors entered in the Centralized Cancer Patient Data System. Among patients with embryonal carcinoma, over 80% were diagnosed in the 15-to-34 year age group. Seventy-four percent of the patients had metastatic disease at the time of diagnosis, and 50% of these had distant metastases, attesting to the aggressiveness of embryonal carcinoma and its tendency to early hematogenous spread. Despite the highly malignant nature of the tumor, the overall 5-year survival rate with treatments used was an excellent, 88%. Survival was correlated with the extent of disease at the time of diagnosis; the 5-year actuarial survival rates for patients with localized, regional, and distant disease were 98%, 96%, and 74%, respectively. Endodermal sinus tumor was uncommon (1.8% of all testicular germ cell tumors), occurred predominantly in the younger age group (0-24 years), and in 50% of the cases was localized to the testis. The survival rate for the 33 patients with this form of tumor was slightly worse than for the "adult form" of embryonal carcinoma. The authors conclude that survival of patients with embryonal carcinoma has greatly improved over the last decade as a result of improved methods for early detection of metastatic deposits and the effectiveness of newer chemotherapies in the treatment of disseminated disease.

Combination chemotherapy for metastatic or recurrent adenocarcinoma of the cervix.

Twenty-four patients with recurrent or widespread adenocarcinoma of the cervix were treated with combination chemotherapy. The drugs used were 5-fluorouracil (5-FU) (500 to 800 mg/m2), doxorubicin (40 to 50 mg/m2), and cisplatin (50 to 60 mg/m2). The chemotherapy was administered as a 76-hour continuous infusion via a silastic central venous catheter and repeated every 28 days. The total response rate was 42% (25% complete and 17% partial). Median duration of response was 7 months. Areas of response were usually lung and lymph node metastases. Toxicity, mainly neutropenia, was acceptable. All patients relapsed. This combination chemotherapy results in a modest response rate for a malignancy about which there is little information regarding the treatment of disseminated disease. Future studies should determine the activity of this combination administered in a bolus fashion.

Current status of the treatment of disseminated disease

The treatment of disseminated cancer began in the mid40’s, less than 40 years ago, with the observations of the regression of advanced lymphomas when nitrogen-mustard was administered.” These important observations, however, promised only palliative control of disseminated cancer. In 1948, Farber et al. described the first complete remissions of advanced disseminated cancer when he observed the complete disappearance of all signs and symptoms of acute leukemia in children treated with anti-folic acid compounds.4 The conversion of a patient with disseminated cancer to a patient without evidence of disease was a truly unique and provocative clinical observation. However, Dr. Farber was also conservative and noted that virtually all, but not all, of the children in complete remission had their disease recur promptly. So even these observations only stimulated the therapeutic scientist to think in terms of palliation for disseminated cancer. It was Dr. M. C. Li who first conceived of curative therapy for advanced disseminated cancer.15 Li and coworkers reported the first complete remissions in patients with advanced metastatic choriocarcinoma and they made the enormously important observation that the women in remission had persistently elevated levels of chorionicgonadotrophin, which they recognized as due to residual metastatic choriocarcinoma which could not be demonstrated by clinical means. With the aid of this first “tumor marker” Dr. Li applied intensive therapy with methotrexate to patients early in remission and reported the first cures of metastatic choriocarcinoma. Subsequently the observations of multiple agent combination chemotherapy in childhood leukemia by Freireich and Frei demonstrated that intensification of remission even in the absence of a tumor marker could be associated with a detectable fraction of patients who had prolonged disease and treatment-free survivorship which represented the equivalent of cure.’ Subsequently the studies by Frei et al. and DeVita et al., applying the same principles of multiple agent combination chemotherapy to the treatment of Hodgkin’s disease, added yet another diagnosis to the growing list of diseases which had a detectable cured fraction.3.7 At the present time, in addition to the previously mentioned diagnoses, adults with acute myeloblastic leukemia, patients with diffuse histiocytic lymphoma, and paiticularly striking, males with embryonal tumors of testis add to a growing list of diagnoses where at least some of the patients can be cured with chemo

In vitro cytotoxicity to various human tumor cell lines of a tumor cytotoxic factor(s) produced by human alveolar macrophages.

When human alveolar macrophages (AM) obtained by lavage of the lungs of healthy donors were incubated in medium with or without lipopolysaccharide (LPS) they released a factor(s) with tumor cell killing activity. This tumor cytolytic and/or cytotoxic factor(s) (TCF) was assayed by measuring its effect in inhibiting target cell growth. TCF activity was not observed in the supernatant from cultures of LPS-treated hematopoietic malignant cell lines (monocytic leukemia, B-cell leukemia and T-cell leukemia cell lines). Human TCF was significantly cytotoxic to 13 of 15 solid-tumor cell lines tested and to 7 of 9 hematopoietic malignant cell lines, but not to two different normal, nontumorigenic cell lines. TCF-rich supernatants contained low levels of interferon (IFN) activity that were not significantly cytotoxic to A-375 melanoma cells. Human TCF and IFN-alpha or IFN-beta had additive cytotoxic effects. These data suggest that human TCF released by activated human AM may be of potential use in the treatment of malignant disseminated diseases.

Adjuvant chemotherapy for testicular teratoma with Bleomycin and Vinblastine.

Introduction Adjuvant chemotherapy is now being employed in the management of several solid tumour malignancies in an attempt to improve prognosis. It is based on the concept that chemotherapy has the greatest chance of eliminating the disease when the tumour cell mass is minimal, and therefore, it is argued that if chemotherapy be employed at a stage when metastases are likely to be present, but as yet have not become apparent (micro-metastases), they may be eliminated completely in a proportion of cases. Many centres report work based on this hypothesis, notably Bonnadonna et al and Fischer with breast cancers, and currently trials are in progress with other solid neoplasms such as bone tumours with encouraging results. We are endeavouring to extend this work to Stage I and Stage II Testicular Teratoma and we publish a preliminary report on nine such cases. Testicular teratoma is a disease mainly of males in their third and fourth decades, and not surprisingly is one of the commoner maligancies seen in service personnel, especially during years of conscription. Some of the larger series in this disease have come from military sources both in the United States and Great Britain. The British Army experience has been extensively reviewed in the past, notably, by Stephen' on clinical aspects and Field 2 on pathology. The chemosensitivity of these tumours has been shown by the high remission rates achieved in many centres in the treatment of disseminated disease, the most recent being a rate of 80% of complete remission using vinblastine, Bleomycin and Cisplatin reported by Einhorn • Encouraged by the results of Samuels we selected an adjuvant regime of Bleomycin and vinblastine, but one patient received vincristine alone. The prognosis of these neoplasms depends upon the extent of the disease at presentation, histological type, and time between presentation and treatment (Field).

Back to the drawing board--the need for more realistic model systems for immunotherapy.

In experimental animals the growth of tumors which display strong immunogenicity can be slowed by immunological maneuvers that increase the magnitude of the host response to the specific tumor antigens. Such immunogeneic tumors do not, in general, cause distant metastases and may, therefore, not be relevant to the treatment of disseminated disease in man. This may explain why the current experience with immunotherapy based on such animal models has, with very few exceptions, been disappointing. Animal tumors which are not immunogenic by standard transplantation tests frequently disseminate and it seems likely that clinically useful immunotherapy has to be based on procedures which are effective against such tumors. The lack of immunogenicity detectable by transplantation may be due to the absence of tumor-specific transplantation antigens (TSTAs), in which case if there is to be any immunotherapy it will have to be direct at boosting some innate type of host resistance. Alternatively, the lack of immunogenicity may be attributable to the intervention of "escape mechanisms" which pervert the immunologically specific host response to TSTAs. In this case, the immunological maneuvre should be directed at overcoming the escape problem and not at boosting the magnitude of the specific host reaction to the TSTAs.