Prognostic variables in osteosarcoma: a multi-institutional study.

This is a report of a multi-institutional study of all patients with osteosarcoma who were seen at 13 comprehensive cancer centers from July 1, 1977, to December 31, 1982. Follow-up extended to 9 years; a minimum of 3 years was obtained for greater than 90% of the patients. All patients with osteosarcoma were considered, but only those with tissue confirmation who had had at least part of their first course of treatment at one of the 13 institutions were included. There were 543 patients. In a search for prognostic indicators, 38 patient characteristics, three treatment categories, and an institutional variable were studied. A combination of nine of these constituted the best indicator of survival. They were morphology (two parts), site of primary cancer (two parts), spread of tumor, grade and size of tumor, duration of symptoms, weight loss of greater than 4.5 kg (10 lb), swelling at primary site, and lytic appearance. Unexpectedly, treatment was not one of the indicators of survival. A prognostic score was developed in which the coefficients were obtained from the Cox regression (step-down) method. Each patient had a score (S) and an observed survival time that together provided the expected risk of death for that patient. Although this was not a randomized study, treatments were compared before and after adjusting for characteristics identified as prognostic. Three treatments differed little: surgery alone, surgery plus chemotherapy and/or radiotherapy, and chemotherapy and/or radiotherapy followed in 1-4 months by surgery. Patients with amputations and those with resections had similar death rates, but the observed progression rates differed widely. However, when the rates were adjusted for prognostic characteristics, the difference disappeared. Complete surgery (if osteosarcoma existed within surgical margins) was no better than incomplete surgery (if osteosarcoma existed beyond surgical margins) with respect to death but, as would be expected, complete surgery was much better with respect to disease progression.

A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma.

Thirty-eight patients whose primary extremity or limb girdle osteosarcomas had been completely excised (37 amputations, one limb sparing procedure) were allocated at random to two treatment groups receiving respectively regular follow-up examinations plus a high-dose methotrexate (HDMTX) regimen or regular follow-up without primary adjuvant chemotherapy. Although the vincristine, HDMTX, leucovorin regimen was generally quite tolerable when given at three-week intervals for one year and most of the chemotherapy patients followed the planned HDMTX dose escalations from 3 to 6 to 7.5 g/m2, delayed methotrexate excretion limited dosage escalations in 25%. An estimated 52% of the 38 patients were surviving five years after randomization and an estimated 42% remained continuously relapse-free after five years. No significant differences between the outcomes of the 20 treated and the 18 untreated patients were apparent; however, power to detect differences was low. Furthermore, no significant differences in postmetastasis survival were apparent between the 12 treated and 10 untreated patients who relapsed. Approximately 20% of these failing patients appear to have been salvaged for long-term survival. This pilot study of HDMTX confirms the continuing need for controlled clinical trials in determining the therapeutic value of adjuvant chemotherapy programs for patients with primary osteosarcoma.

Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas.

Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy.

Hemangioendothelial sarcoma of bone.

Hemangioendothelial sarcoma of bone is a rare tumor. A series of 112 cases was studied to define the clinical and pathologic features of this disease. Of the various histologic features evaluated to define the ones most significant prognostically, the histologic grade of the lesions was the single feature that correlated best with disease-free survival. In this series, patients with multi-focal tumors did not have a better prognosis than patients with unicentric disease. Surgery remains the primary treatment for these patients. Radiotherapy may be useful for surgically inaccessible lesions of the axial skeleton. Too few patients have received adjuvant chemotherapy to evaluate its usefulness in this setting.

Postradiation sarcoma of bone: review of 78 Mayo Clinic cases.

Postradiation sarcoma of bone is an uncommon but serious sequela of radiation therapy. Seventy-eight Mayo Clinic patients have been treated for sarcomas arising in irradiated bones. They received their initial radiotherapy for a wide variety of nonneoplastic and neoplastic conditions, both benign and malignant. Thirty-five sarcomas arose in bone that was normal at the time of radiotherapy, and 43 arose in irradiated preexisting osseous lesions. The latent period between radiotherapy and diagnosis of sarcoma averaged 14.3 years. Ninety percent of the postradiation sarcomas were either osteosarcomas or fibrosarcomas; chondrosarcoma, malignant (fibrous) histiocytoma, malignant lymphoma, Ewing's tumor, and metastasizing chondroblastoma also occurred. Prompt radical surgery, when feasible, is usually the treatment of choice for the sarcoma. About 30% of patients with sarcomas of the extremities or craniofacial bones survived 5 years without recurrence; there were no disease-free survivors among patients with tumors of the vertebral column, pelvis, or shoulder girdle. The low risk of sarcoma following radiotherapy for the treatment of cancer should not be a contraindication to its use in these patients; however, radiation therapy for benign bone tumors should be reserved for lesions that are not amenable to surgical treatment. An unusual case is also reported herein in which a fibrosarcoma was discovered in the humerus of a patient who had received radiotherapy 55 years previously for a verified osteosarcoma in the same site.

Total joint arthroplasty. Applications in the management of bone tumors.

Limb-saving resection has become a valid alternative to amputation in carefully selected patients with bone tumors. As interest grows in this technique, efforts continue to improve our methods of bone and joint reconstruction to restore a functional extremity. Previously there was little interest in this form of treatment despite a limb-saving potential, because of inadequate methods of skeletal reconstruction. The purpose of this paper is to review these previous methods and to outline our present approach to the problem.

Trends and variability in survival from osteosarcoma.

Survival of patients with primary osteosarcoma who received traditional surgical management has been very poor. Several studies have reported the percentage of patients alive 3 years after first treatment to be between 20 and 25%. In a study of such patients first treated at the Mayo Clinic between Jan. 1, 1963, and July 1, 1974, the survival noted in the first few years was typical of that of other reports, about 25%. However, by 1972 through mid-1974, the 3-year survival had become 50%. This improvement was not the result of adjuvant treatment or any basic change in type of patient treated, yet it is similar to that reported in connection with some of the new adjuvant therapies used in trials depending on historical controls. Our results cast doubt on findings made in the absence of concurrent, randomly selected controls.

Trends and variability in survival among patients with osteosarcoma: a 7-year update.

This report is an update of a 1978 article on osteosarcoma in Mayo Clinic patients. It includes additional follow-up on previously reported cases and incorporates new cases treated since the time of that original study. From 1963 through 1981, 336 patients with classic, previously untreated osteosarcoma received their first definitive treatment at our institution. Survival of these patients was studied in detail. The most significant result was that survival in the 1960s was much worse than that in the 1970s. The first evidence of improvement in survival was noted in 1969; subsequently, further improvement occurred but was not consistent. This finding prevailed with respect to duration of survival to death, survival to detection of metastasis, and survival from occurrence of metastasis to death. On the basis of detailed regression analysis, several variables had independent prognostic value. From these findings, a prognostic score was developed, which was based on the number of the following unfavorable characteristics: age younger than 10 years, male sex, tumor diameter more than 15 cm, cell type osteoblastic or chondroblastic, duration of symptoms 2 months or less, and involvement of the femur or humerus. Patients with five or six of these unfavorable characteristics had a very poor survival; in contrast, patients with only one or two characteristics had a good outcome. Even when these scores were fairly constant, however, the calendar period had a strong influence on survival. Likewise, when treatment was considered and adjustments by score were made, no significant differences could be found between those patients treated by amputation only and those treated by amputation supplemented with chemotherapy or radiotherapy.

Transfer factor versus combination chemotherapy: a preliminary report of a randomized postsurgical adjuvant treatment study in osteogenic sarcoma.

Twenty-six patients with classic osteosarcoma were randomized to receive either transfer factor or combination chemotherapy. Eight of 14 patients who received transfer factor converted their skin test markers, evidence of activity of the transfer factor. Of these eight patients, all are alive; four are free of disease. Of the 18 patients who received combination chemotherapy, 14 are alive, 12 of whom are free of disease. The immunologic test procedures performed sequentially reveal that transfer factor appears to enhance cell-mediated immunity, but it is evident that in this study, a control (saline) arm in the protocol could not be included. It is of interest that the chemotherapy regimen used does not appear to suppress such activity permanently. The individual test results, however, are not very helpful for predicting response to treatment. The small numbers of patients and the short duration of this study, combined with the exclusion of parosteal osteogenic sarcomas and jaw tumors, do not permit a meaningful comparison with other published studies.

Management of osteogenic sarcoma at the Mayo Clinic.

In a Mayo Clinic prospective study of metastasis from osteogenic sarcoma, so-called prophylactic whole-lung irradiation (a 1,500-rad tumor dose to the whole of both lungs, in divided doses, with oxygen and actinomycin) proved ineffective. 14 patients underwnet an operation for metastatic pulmonary disease. The earlier the excision of a metastatic lesion, the greater the chance of an effective cure. Preoperative irradiation of the bone tumor had no positive effect. The primary lesion should also be excised as soon as possible. Surgical removal of a tumor should be followed by immunotherapy or chemotherapy or both. The rate of reliably "cured" cases could be improved by extensive studies of immunologic reaction before and after surgical intervention.

Immunologic aspects of human sarcomas.

Forty-seven patients with mesenchymal sarcoma seen at the Mayo Clinic were tested for humoral and cellular immunologic responsiveness by means of a humoral cytotoxicity test, skin tests for delayed-type hypersensitivity, and lymphocyte transformation with concanavalin A, phytohemagglutinin, and pokeweed. Prospective follow-up of the clinical and laboratory results revealed that patients with low humoral cytotoxic indices, anergic skin test responses, or low lymphocyte transformation responsiveness tended to have the worst short-term clinical outlook.

Is the BANS concept for malignant melanoma valid?

In this study of 427 patients with stage I malignant melanoma seen at the Mayo Clinic between 1973 and 1981, only those patients with complete data with respect to thickness and level of penetration of lesion, morphologic type, and anatomic site were included. Although supporting the widely accepted concept of the prognostic importance of thickness of the lesion, the level of penetration was of much lesser significance in our series, and prophylactic node dissection could not be shown to be of significant benefit. Likewise, the BANS concept proposed by Day et al [1] was not corroborated. The reasons for these discrepancies are not fully apparent, although a preponderance of thin and intermediate thickness lesions in our patients may have had some influence on our results.

Extra-articular synovial chondromatosis.

Four patients with extra-articular synovial chondromatosis and one patient with combined intra-articular and extra-articular involvement are described. In all five patients the lesion was anomalously located (knee, shoulder, hip, and ankle). The lesion usually occurs in the hands and feet. Accurate diagnosis is important, because if the synovial origin of the cartilaginous proliferations is ignored, the evidence of cellular activity may lead to an erroneous diagnosis of chondrosarcoma. All five patients had a benign clinical course.

Pulmonary resection for metastatic osteogenic sarcoma.

A retrospective analysis of thirty patients who underwent pulmonary resection for metastatic osteosarcoma over a twenty-eight-year period revealed that most were young males with previous amputations for primary lesions of the lower extremity. In each, one to four thoracotomies had been performed, for a total of fifty-two chest operations with resection of 124 pulmonary metastatic lesions. At last follow-up, eleven of the thirty patients were alive and free of disease. At five years 28 per cent had survived: three of them were alive at more than nine years, and one was alive at nearly twenty years. Adverse survival factors identified were short tumor-free interval and multicentricity of pulmonary metastases. Long-term survival was associated with a tumor-free interval of more than two years and one to four thoracotomies at which few foci were present. As a group, patients selected for lung resection had significantly longer suvival than did patients whose pulmonary metastasis was untreated.