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.

Elective whole-lung irradiation in osteosarcoma treatment: appearance of bilateral breast cancer in two long-term survivors.

The effect of "prophylactic" lung radiation in preventing pulmonary metastasis was studied in a subset of patients with osteosarcoma. Benefit was not noted. Thirteen of the irradiated patients in the treatment group were females; in 2 of the 13, bilateral breast cancer developed approximately 15 years later. Radiation administered to the breast of an adolescent female carries a considerable risk of causing breast cancer.

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.

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.

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.

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.

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.

Osteosarcoma arising in heterotopic ossification of dermatomyositis: case report and review of the literature.

A patient with dermatomyositis developed malignant transformation of the benign interfascial heterotopic bone. This patient had classic childhood dermatomyositis at the age of 3 years, and the disease was arrested after a one-year course of corticosteroid therapy. Extensive subcutaneous calcinosis cutis and deep interfascial calcinosis were the residua of the disease. Twenty-eight years later, the patient developed a high-grade osteosarcoma within the benign intermuscular heterotopic calcification and ossification that had been previously documented at the age of 8 years by a roentgenogram and at the age of 16 years by biopsy. This case represents the first report of the association of osteosarcoma and dermatomyositis, and possibly the first well-documented case of malignant transformation of benign heterotopic bone.

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.

Management of osteogenic sarcoma: a perspective based on the Mayo Clinic experience.

We reviewed pertinent aspects of the Mayo Clinic experience with osteogenic sarcoma to place into perspective some of the recent advances in the management of patients with this tumor. Various histopathologic subtypes have been recognized and can be differentiated from the conventional or classic osteogenic sarcoma. Our experience indicated that, when appropriate, crossbone amputation provided adequate and effective surgical treatment. A controlled study in which pulmonary micrometastases were evaluated failed to demonstrate that prophylactic pulmonary irradiation after amputation conferred any therapeutic advantage. The use of combination chemotherapy or transfer factor did not improve disease-free survival when the results were compared with our recent experience with surgical treatment alone. Progressive improvement in disease-free and total survival was observed between 1963 and 1974, although we have been unable to relate this to the effects of adjuvant chemotherapy. Aggressive surgical excision of pulmonary metastatic lesions had a positive effect on total survival. These observations led us to conclude that carefully controlled studies are still needed to define more clearly the role of adjuvant chemotherapy in nonmetastatic osteogenic sarcoma. Although such a study is in progress at the Mayo Clinic, it is too early for any evaluation of the results.

Malignant transformation of extra-articular synovial chondromatosis: report of a case.

A 47-year-old woman had a chondrosarcoma arise in extra-articular synovial chondromatosis near the ankle. A review of the literature suggests that this lesion is rare and that proper interpretation of histopathologic preparation of cartilage lesions can be difficult.

Malignant fibrous histiocytoma: a retrospective study of 167 cases.

A retrospective study of 167 patients with soft-tissue malignant fibrous histiocytoma of the trunk, extremities, and retroperitoneal region revealed twice as many deeply situated tumors as superficial tumors. Malignant fibrous histiocytoma may be subclassified into fibrous, giant-cell, myxoid, and inflammatory variants. The fibrous variant accounted for two-thirds of the lesions. The prognosis is no different among the histologic subtypes. The depth of the tumor significantly affects survival, and three important groups were identified: superficial tumors, superficial tumors that recur in deep locations, and deeply situated tumors. The group with superficial tumors that subsequently did not recur in deep locations had a significantly better 4-year survival rate than did the other two groups (65% versus 34% and 40%, respectively). Patients with distally located tumors had a better 5-year survival rate than did patients with proximally located tumors (73% versus 28%). Local recurrence was found in 51% of patients who had a "complete" excision. Patients with superficial tumors had a higher local recurrence rate (71%) than did those with deep tumors (41%). Few patients with retroperitoneal tumors were long-term survivors; the 5-year survival rate was 14%.

Atlanto-occipital instability as a result of pituitary adenoma: case report with successful management by cervico-occipital fusion.

A 48-year-old woman with an extensive pituitary adenoma developed atlanto-occipital instability secondary to erosion of the base of the skull by the tumor. The pathophysiology, diagnosis and surgical treatment are described.

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.

Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study.

After nodal metastasis from malignant melanoma, approximately 80% of patients die from disseminated disease. To clarify the role of radiation therapy (XRT) following node dissection. 56 patients with biopsy-proven nodal metastasis participated in a randomized, prospective clinical trial which compares radiation therapy to the regional lymph node area following lymphadenectomy (27 patients) with lymphadenectomy alone (29 patients). Interesting differences in the survival curves (p = 0.09) and in the disease-free interval curves (p = 0.08) for the two treatment groups proved to be attributable to imbalances in the age and nodal distributions in the treatment groups. Covariate analysis identified age and sex as the factors having the most significant (p less than 0.04) effect on survival and identified the number of positive nodes as the covariate having the most significant (p less than 0.02) effect on disease-free interval. Treatment did not have a significant effect upon survival or disease-free interval.

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.

A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results.

To determine whether immediate or delayed lymphadenectomy is more beneficial than none in cases of localized (stage I) melanoma, we undertook in 1972 a prospective randomized study. Patients with midline trunk lesions were excluded as well as patients with lesions situated directly over the node-bearing area. In addition, because of the low risk of metastasis, the protocol was changed to exclude level 2 lesions. Of the 173 patients studied, 63 were randomized to no lymphadenectomy, 56 to delayed (3 months) lymphadenectomy, and 54 to immediate lymphadenectomy. None of these regimens differed significantly from the others in its effect on length of survival or interval to metastasis. And of the 110 patients who underwent elective lymphadenectomy, 103 were without nodal involvement. Our preliminary conclusion is that elective node dissection is not beneficial in management of melanoma. However, disease progression was advanced significantly by age of the patient (greater than 60 years) and by invasiveness (level 4 or 5) and thickness (greater than 1.5 mm) of the melanoma.

Adjuvant therapy for nonmetastatic osteogenic sarcoma: an evaluation of transfer factor versus combination chemotherapy.

A randomized study compared the effects of combination chemotherapy (high-dose methotrexate, adriamycin, and vincristine) with immunotherapy in the form of transfer factor in the adjuvant treatment of patients with nonmetastatic osteogenic sarcoma after apparent complete surgical ablation of the primary tumor. Thirty-two patients were evaluated. Of 22 patients who received chemotherapy, three died of drug-related complications and six were alive without disease recurrence between 260 and 673 days after operation. Ten patients in the transfer factor group converted their markers, and of these, five were alive without recurrence 420--753 days after operation. Neither treatment program was considered superior with respect to disease-free survival.