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THE CLASSIC: Amputation and Adriamycin in Primary Osteosarcoma

2005; Lippincott Williams & Wilkins; Volume: &NA;; Issue: 438 Linguagem: Inglês

10.1097/01.blo.0000180428.42894.b3

1528-1132

Engracio P. Cortes, James F. Holland, Jaw J. Wang, Lucius F. Sinks, Johannes Blom, H. J. Senn, Arthur Bank, Oliver Glidewell, Henry H Sherk,

Cancer Treatment and Pharmacology

This month’s Classic Article, republished from the New England Journal of Medicine in CORR for the first time this month, was published in the early 1970s and its authors described their results of treatment of the tumors with a single new agent (Adriamycin). They reported that after using the prescribed course of Adriamycin, 71% of their patients were free of pulmonary metastasis. The effect of this course of treatment therefore was “chemotherapeutic eradication of micro metastases.” This month’s Classic Article was actually produced by a committee, the Cancer and Leukemia Group B (CALGB), one of several national cooperative groups. Although a number of individuals collaborated in this study reported in this Classic Article, Dr. Lucius F. Sinks (Fig 1) figured prominently in this and a number of other comparable projects. When this paper was being developed, Dr. Sinks was the chief cancer research pediatrician at the Roswell Park Memorial Institute in Buffalo, New York. Before that time he was educated at Yale University, Jefferson Medical College in Philadelphia, Ohio State University, and he spent two additional years working as a research fellow at Cambridge University in England. He has published more than 125 papers on sarcoma, leukemia, and related subjects in children. He recently retired from active practice.Fig 1.: Lucius F. Sinks is shown.Abstract Adriamycin has been found effective in metastatic osteogenic sarcoma. To determine its efficacy in osteosarcoma without detectable metastases, 21 patients were given adjuvant adriamycin therapy two weeks (median) after surgical amputation of the primary lesion. Six courses of adrianmycin (30 mg per square meter daily for three days, repeated every four to six weeks) were administered. Nineteen of the 21 patients survived from more than one to more than 32 months (median, more than nine months) after operation. Five of the 21 relapsed (two with local and three with pulmonary metastases). At 18 months, 71 per cent of treated patients may be expected to be free of pulmonary metastases as determined by life-table analyses (95 per cent confidence limits, 100 to 43 per cent), in contrast to 30 per cent of the series of 145 patients analyzed by Marcove et al. The data demonstrate an effect of adriamycin in delaying gross metastases from osteosarcoma and are consistent with chemotherapeutic eradication of micrometastases. (N Engl J Med 291:998-1000, 1974) The five-year survival of patients with osteogenic sarcoma (osteosarcoma), regardless of primary therapy (operation or radiotherapy, or a combination of the two) ranges from 5 to 23 percent.1 Radiologic evidence of pulmonary metastases occurs at a median of 8.5 months after potentially curative surgical amputation.2 The patient usually dies within six months from the onset of detectable pulmonary metastases.3 These data indicate that pulmonary involvement must either have been present at the time of operation or have arisen from osteosarcoma cells that circulated in the blood during the amputation.4 The effectiveness of chemotherapy in metastatic osteosarcoma is limited.1,5 Adriamycin (doxorubicin), a cytotoxic antibiotic derived from Streptomyces peucetius var. caesius has been found to be active in a wide spectrum of neoplastic diseases.6 We observed that adriamycin produced tumor regression in seven of 17 (41 per cent) patients with pulmonary metastases from osteosarcoma.7 Encouraged by this result in metastatic osteosarcoma treated with adriamycin, the Acute Leukemia Group B undertook a study of intermittent adriamycin treatment shortly after radical surgical amputation of primary osteosarcoma in an effort to apply chemotherapy when the body burden of tumor cells was lowest. METHODS AND MATERIALS The criteria for entry to study included histologically proved osteosarcoma, characterized by osteoid or bone apposed to tumor cell. No effort was made to subclassify osteosarcoma further into chondroblastic, fibroblastic, and osteoblastic subtypes. None of the patients had parosteal osteosarcoma, chondrosarcoma, fibrosarcoma, radiation-induced osteosarcoma, or osteosarcoma after Paget’s disease, all of which have different clinical courses.8 A second requirement was that the primary tumor be completely operable without roentgenologic evidence of metastases. Other criteria were a minimum leukocyte count of 4000 and platelet count of 100,000 per cubic millimeter, and blood urea nitrogen less than 25 and creatinine less than 1.5 mg per 100 ml. Drug Dosage and Schedule Adriamycin was supplied by Farmitalia, Milan, Italy, though the National Cancer Institute, USA. Each vial was diluted with 5 ml of sterile saline, and the calculated dose was injected as an intravenous bolus. Adriamycin was scheduled to be given when wound healing was complete. The dose was 30 mg per square meter of body-surface area daily for three successive days repeated every four to six weeks for six courses. In come cases the first course was given in the hospital, but other treatments were administered on an ambulatory basis. All but four patients were treated within eight weeks after operation and the median onset of adriamycin treatment for the entire group was two weeks. The total cumulative dose of adriamycin was 540 mg per square meter over a period of five to seven months. Thereafter, patients remained untreated. From November, 1971, to December, 1973, 30 patients from 10 institutions were entered into the study. Nine patients were disqualified: three had no records; three had gross metastases at entry; one was never started on adriamycin; and in two the treatment was stopped after two courses because the patients refused further treatment. Neither had metastases at the time of discontinuation. The remaining 21 patients form the basis of this investigation. Hematologic, biochemical, and electrocardiographic examinations, chest x-ray study and tomography, and bone survey were conducted before, during, and after therapy as measures to check for possible tumor recurrence and toxicity to the drug. The response to therapy was measured by the disease-free interval after surgical amputation. Treatment failure was defined an unequivocal roentgenologic evidence of recurrence. A leukocyte count of less than 1000 per cubic millimeter required the adjustment of succeeding doses of adriamycin to 20 mg per square meter daily for three days. No dose adjustment was to be made if the leukocyte nadir was over 1000 per cubic millimeter unless an accompanying complication such as septicemia occurred. RESULTS Of the 21 patients, 11 were male and 10 female. Their ages ranged from nine to 60, with a mean and median age of 16 and 14 years, respectively. Table 1 shows the primary sites of osteosarcoma and the type of surgical amputation done. In 15 of the 21 (71 percent) the lesion was localized around the knee joint.Table 1: Sites of Primary Osteosarcoma and Types of Operation Performed.Pulmonary metastasis is usually the first evidence of recurrent osteosarcoma.2,3,8 The data of Marcove et al2 of 145 patients less than 21 years of age with operable osteosarcomas of the extremities were used as a historical comparison group. Only 30 per cent were free of pulmonary metastases 18 months after operation (Fig. 1). In the adriamycin-treated group, five of 21 relapsed (two of local recurrences and three of pulmonary metastases). At 18 months, 45 per cent of treated patients may be expected to be free of any evidence of disease, as determined by life-table method (95 per cent confidence limits, 60 to 15 percent) (Figure not shown). Freedom from pulmonary metastases at 18 months is estimated to be 71 per cent by life-table analyses (95 per cent confidence limits, 100 to 43 per cent) (Figure not shown). With observation periods ranging between more than one and more than 32 months (median, more than nine months). 19 of 21 patients in the present study remain alive (Figure not shown). Table 2 shows the relation of protocol deviation and recurrence of disease. For reasons unrelated to leukopenia (counts between 1000 per cubic millimeter) or to delayed recovery of leukocyte counts, six patients had their adriamycin dosage decreased or the interval between courses increased beyond the prescribed six weeks. Four of these six have relapsed.Table 2: Relation of Protocol Deviation and Recurrence of Disease.Table 3 presents the relation between type of operation and recurrence of disease. Relapses were seen in four of six patients who had subradical amputation of the primary lesion. In contrast, pulmonary metastases developed in only one of 15 patients who had radical amputation.Table 3: Relation between Type of Surgery and Prognosis.In 13 patients in the present series, no protocol violation in terms of dose, interval, or extent of amputation occurred. In these patients, disease-free intervals were seen in 89 per cent at 18 months (95 per cent confidence limits, 100 to 73 per cent) (Figure not shown). Adriamycin toxicity consisted of transient capital alopecia in all patients. A nadir of leukopenia (count below 3000 per cubic millimeter) occurred in 62 per cent, nausea and vomiting in 50 per cent, and stomatitis in 43 per cent. No cases of septicemia or pneumonia occurred. The hemoglobin dropped over 2 g per 100 ml in 30 per cent, platelet counts were less than 100,000 per cubic millimeter in 10 per cent, but none below 75,000 per cubic millimeter, and transient electrocardiographic ST-segment and T-wave changes appeared in 10 per cent without other detectable cardiac changes. DISCUSSION The concept that chemotherapeutic agents are most effective when the body burden of tumor cells is lowest is strongly supported by data from laboratory-animal systems.9–11 That this is also true for human cancer is evident in Wilms’s tumor, in which a combination of operation and chemotherapy increases the cure rate.12 The type of surgical amputation alone has never influenced the survival of osteosarcoma.2,13 Local recurrence, however, was reported by Sweetnam et al14 in nine of 42 patients (21 per cent) when mid-thigh amputation rather than disarticulation was the surgical procedure for distal-femur osteosarcoma. In contrast, they also reported that no stump recurrence was noted either in osteosarcoma of the tibia treated by amputation through the thigh or in femoral osteosarcoma treated by disarticulation of the hip. In the present study, it appears that subradical amputation shows a higher risk of local recurrence and pulmonary metastases than radical amputation. It is possible that the remaining unresected involved bone contains microfoci of tumor cells not completely eradicated by adriamycin. These tumor cells may be responsible for future local recurrence or pulmonary metastases (or both) upon termination of therapy. Lowering the dose of adriamycin to avoid leukopenia was also associated with recurrence of disease. This dose-dependent antitumor activity of adrianmycin in osteosarcoma is consistent with our earlier report.7 In that study objective response of established pulmonary metastases was seen in zero of one, one of five, three of seven, and three of four patients when adriamycin was given in a daily dose of 17.5 mg per square meter for four days, 20 mg per square meter for four days, 30 mg per square meter for three days and 35 mg per square meter for three days, respectively, repeated every four weeks. Radical amputation, therefore, coupled with the administration of adriamycin at 30 mg per square meter per day for three days repeated every four to six weeks, is the recommended therapy of this study. The toxicity from adriamycin has been well tolerated. The great frequency of serious cardiomyopathy in patients receiving a total cumulative dose of adriamycin over 550 mg per square meter15,16 was not seen in any patient in this study; the total cumulative dose of adriamycin was limited to 540 mg per square meter. The present data indicate that adriamycin therapy after radical amputation of primary osteogenic sarcoma is effective in delaying the clinical appearance of pulmonary metastases and death. Whether this form of therapy will result in an augmented cure rate remains to be proved. Application of this treatment in practice should be conducted in association with research centers where data can be accumulated to define the eventual optimal treatment for osteogenic sarcoma. The simultaneous construction of other effective approachs to adjuvant chemotherapy of osteogenic sarcoma detailed in the companion paper17 and in multi-combination regimens18–21 suggests a basis for guarded optimism concerning the hitherto bleak prognosis for osteogenic sarcoma. Note added in proof: In an additional three patients on study pulmonary metastases developed. One patient relapsed 12 months after operation. He received a lower dose of adriamycin. The second and third patients who were appropriately treated with adriamycin and surgery relapsed in the seventh and 12th months, respectively. The follow-up observation period of the 13 patients who remain free of disease ranges from more than nine months to more than 40 months (median, more than 19 months), after operation. We are indebted to Dr. Lowell E. Irwin, of the University of Southern California School of Medicine, and Drs. Ruth Heyn and Roxiel Holland, of the University of Michigan, for joining with Acute Leukemia Group B investigators conducting this study.