Sarcoma: etiology and advances in therapy with immunotherapy, limb salvage surgery, and hyperthermia.
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Biomedical subjects
Publications and source records attributed to D L Morton.
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Hyperthermia greater than or equal to 42 C is tumoricidal, apparently a function of absolute temperature and duration of heating. However, because the technology for producing safe and effective deep hyperthermia did not exist, there was virtually no data on the thermal death times of human cancers. The development of a fundamentally new radio frequency device that produces uniform hyperthermia to any depth without surface tissue injury has allowed preliminary testing of this hypothesis in 38 patients with advanced cancer. Temperature measurements were taken in tumors and normal adjacent tissues. Tumors were heated from 40 C to greater than or equal to 50 C, one to ten times (13-600 minutes). Serial tumor biopsies compared percent necrosis (total absence of nuclei) by type of therapy. Of 44 tumors evaluated (21 superficial, 23 visceral), 31 (70%) were heated greater than or equal to 42 C, 23 (52%) greater than or equal to 45 C, and 14 (32%) greater than or equal to 50 C, with virtually no normal tissue injury. Single, short duration hyperthermia at greater than or equal to 50 C resulted in 20-100% tumor necrosis, while lower temperatures had no effect. Two or three treatments at 45-50 C produced 70-100% necrosis, while lower temperatures produced less necrosis at more than twice the duration of heating. Multiple treatments produced increased necrosis at lower temperatures; however, at the same temperature duration, higher temperatures were most effective. These clinical results support the hypothesis that the observed necrosis is related to both temperature and treatment time and suggest that higher temperatures and longer durations of therapy are most beneficial.
Radionucleotide scanning with colloidal 198Au and 99Tc sulfur colloid was used to evaluate preoperative and postoperative lymphatic drainage in 10 patients with primary malignant melanoma of the trunk. After an intradermal injection of radionucleotide aroung the primary melanoma site, tomographic scanning was performed to identify the regional lymph nodes to which the radionucleotide drained. Approximately one year following lymphadenectomy, each patient was rescanned to see if the lymphatic drainage had changed. Of the 10 patients tested, 8 had postoperative drainage patterns that differed from the preoperative scans. Three patients had no drainage to the lymphadenectomy site, which two patients retained some drainage to the lymphadenectomy sites but also showed drainage to a new site. One patient retained drainage to only one of two preoperative sites, and 2 patients had no identifiable lymphatic drainage postoperatively. Thus, interruption of lymphatic channels is temporary, and new routes that may differ from preoperative ones generally develop within one to two years.
Case histories of 10 patients with neurofibrosarcoma, including 14 (70%) with neurofibromatosis, evaluated over 10 years were reviewed to determine the incidence of local and systemic recurrence and the most effective means of therapy for this rare neoplasm. Initial therapy resulted in complete local disease control in only 11 (55%) patients. Local excision, or local excision plus radiation or chemotherapy resulted in local recurrence in 8 of 12 patients. Radical surgery alone, or radical surgery combined with radiation and chemotherapy resulted in local recurrence in 1 of 6. Even with complete local disease control, 7 of 16 (44%) patients died of metastases. Both A.J.C. Clinical Stage II and III patients had a similar poor prognosis. Associated neurofibromatosis did not worsen prognosis. These data suggest that both moderate and high-grade primary neurofibrosarcoma are highly malignant neoplasms and should be treated by radical resection. Preoperative intraarterial Adriamycin and radiation--found to be successful for other highly malignant sarcomas--may be of benefit. Since distant disease occurs despite local control, postoperative adjuvant chemotherapy trials are warranted.
Urine samples from patients with solid tumors and from donors without malignant disease were concentrated and tested for the presence of tumor-associated antigens. In the complement-fixation assay using serum from a source autologous with the source of the urine, 87.4% of cancer patients were positive, while only 6.9% of control donors were positive. When serum from an allogenic source was used, 94.7% of cancer patients and 35.1% of control donors were positive. Absorption of a cancer patient's serum with autologous tumor cells removed antibody activity to autologous and allogeneic urine samples. Normal lymphocytes, skin, or muscle-cell suspensions were ineffective as absorbents. The excretion of antigen into urine is dependent upon the presence of tumor. Surgical removal of tumor resulted in cessation of antigen excretion. The urine remained antigen-negative as long as the patient remained disease-free. The antigenic activity was heat-stable and comprised molecules of greater than 1,000,000 daltons which could be dissociated into smaller molecular weight active fractions by treatment with 6 M urea.
The human colon carcinoma cell line HT-29 was adapted to grow in chemically defined medium (CDM). The spent CDM (S-CDM) was concentrated by Amicon filtration and the crude HT-29 S-CDM purified by 40% saturated (NH4)2 SO4 precipitation. The purified antigen was tested by a microcomplement fixation (MCF) assay against the sera of cancer patients of various histologic types and against the sera of normal donors. Fifteen of 20 (75%) colon cancer, 16/20 (80%) breast cancer sera, 14/19 (74%) lung cancer sera, and 13/20 (65%) miscellaneous carcinoma sera were positive in the MCF. By contrast, 2/21 (10%) melanoma sera, 7/20 (35%) sarcoma sera, and 2/19 (11%) normal sera were positive. These data suggest the presence of a carcinoma-associated antigen in the spent CDM of the HT-29 colon carcinoma cell line adapted to grow in CDM.
Tumor-associated antigen(s) from a specimen of human malignant melanoma and from spent culture medium of a melanoma cell line were extracted and purified. The incidence of antibody activity to these antigens, in sera from cancer patients with neoplasms of various histologic types, was higher (65--83%) than normal donors' (19--25%) by the complement fixation assay. These purified antigens were then used to raise antisera in rabbits and sheep. After absorption with various human normal tissues, these antisera reacted against melanoma, sarcoma, and carcinoma extracts, but not against human normal liver, skin, or muscle extracts. However, the antisera showed reactivity against a human fetal homogenate. Results indicate that the xenogeneic antisera contained antibodies to fetal antigens and to tumor-associated antigen(s). Xenogeneic antisera could be used to purify tumor-associated antigens and oncofetal antigen(s) from crude extracts by affinity chromatography.
Human malignant melanoma was transplanted to the cheek pouch of immunosuppressed (corticosteroid-treated) hamsters. Significant differences were observed in tumor growth constants for animals treated with methotrexate, DTIC, BCNU, and vincristine (P < 0.05) compared to controls. However, no appreciable effect was demonstrated for Adriamycin, 5-FU, and cytoxan. In addition, single doses as high as 400 mg/kg body weight of methotrexate were no more effective than other agents now used against this neoplasm.
Surgical resection plays an important role in the treatment of sarcoma that is metastatic to the lung. Multiple bilateral metastases are not contraindications to surgery. The rapidity of growth and the response to chemotherapy can be accurately determined by the tumor doubling time. Preoperative chemotherapy provides an in vivo measurement of tumor sensitivity, and the response to chemotherapy correlates with prognosis. Since residual microscopic pulmonary disease appears to be responsible for most failures after thoracotomy, attention should be directed toward delivering more effective adjuvant therapy to the lungs.
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Of 980 patients with malignant melanoma treated during the past seven years, 55 (5.6%) were found to have metastatic disease and no detectable primary tumor. Thirty-six of these patients with "unknown primary melanoma" had disease limited to lymph nodes (Stage II), whereas 19 had disseminated melanoma (Stage III). The sex and age distribution of these 55 patients were similar to those of a control group of 86 patients with palpable lymph node metastases from a known primary. The site of lymph node metastases for Stage II patients in each group was similar although unknown primary patients seemed to have slightly more involved lymph nodes. By studying patients with the same stage and similar extent of disease, the prognosis of unknown primary melanoma could be determined and compared to known primary melanoma. The overall recurrence rate of patients with unknown primary was no higher than that of patients with known primary. This observation appeared to be true even when patients were compared with respect to adjuvant immunotherapy. The use of adjuvant immunotherapy appeared to favorably affect recurrence rates among the unknown primary patients. Since the recurrence rate for patients with unknown primary melanoma was no higher than that of patients with known primary melanoma, we advocate aggressive surgical management. The occasional long-term survivor with Stage III unknown primary suggests that judicious surgical intervention may benefit these patients as well.
The rationale for amputation for local tumor control of skeletal and soft tissue sarcomas was based on results obtained from surgical therapy alone. However, our previous results from a pilot trial of multimodality therapy of preoperative chemotherapy and radiation therapy followed by surgical resection indicated that limb salvage (without amputation) could be accomplished in most patients with little morbidity and low recurrence rate. This report summarizes our experience in a prospective trial from January 1972 to December 1979. A total of 105 consecutive patients with soft tissue sarcomas (65 patients) or bone sarcomas (40 patients) were treated with preoperative intraarterial adriamycin, 3500 rads of rapid-fraction radiation and radical en bloc resection of primary tumor. Diseased bones were replaced with cadaver allografts (22 patients), metallic endoprostheses (10 patients) autologous bone (2 patients), or no replacement (ilium or fibula-4 patients). Salvage of a viable, neurologically intact, functional extremity was achieved in 98/105 patients (98%); 97% of limb salvage patients were free of local recurrence after a median follow-up period of 28 months. Major complication rate that required amputation was 3/105 patients (2%). Postoperative adjuvant chemotherapy with cyclical adriamycin and high-dose methotrexate was employed for all patients with osteosarcoma and 35 patients with grade III soft tissue sarcomas. The overall disease-free rate is 50% (18/35) for osteosarcomas and 65% (42/65) for soft tissue sarcomas. These results indicate that local tumor control can be achieved in 91% of patients without amputation. Their functional capabilities are excellent with a low complication rate. Since the advent of adriamycin and methotrexate has significantly improved the overall survival for patients with skeletal and soft tissue sarcomas, the quality of this survival has become even more important. Preoperative multimodality therapy is a major advance in this direction and since results of limb salvage procedures appear to be equal or superior to those achieved by amputation we believe these alternatives should be offered to all patients.
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In order to assess the association of enhancement or suppression of humoral immune responses with cancer histology, sera from age and sex matched patients with sarcoma, melanoma and breast cancer and from normal donors were tested for natural antibodies in six serologic assays. Patients with melanoma were found to have a significantly higher level of antibody than the other groups tested. Antibody levels in patients with breast cancer were lowest.
Immune responses of 36 patients with stage II unknown primary melanoma were compared to those of 83 stage II patients with known primary melanoma. The two groups of patients were similar in age, sex, and extent of disease. Delayed cutaneous hypersensitivity to dinitrochlorobenzene (DNCB) was nearly identical in both groups. Patients with unknown primary melanoma had a mean level of reactivity of 4.7 +/- 0.37 and the patients with known primary had a mean level of 5.0 +/- 0.17. Of unknown primary patients 4.2% were unreactive to DNCB and 4.8% of known primary patients were unreactive. Antibodies to cultured melanoma cells were slightly more prevalent in serum from the unknown primary patients (67%) than from known primary patients (45%), but mean titer of positive sera did not differ significantly. Lymphoproliferative assays did not demonstrate differences in lymphocyte reactivity among the two groups when tested with Concanavalin A, mixed leukocyte culture, or unstimulated lymphocyte blastogenesis. No differences could be detected in these assays of humoral and cellular immune responses when patients with unknown primary melanoma were compared to those with known primary melanoma and similar clinical characteristics.
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