Ralph C. Marcove

Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy

Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high‐dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4–16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. All patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, HDMTX with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin in addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%) have remained continuously free of recurrent or metastatic disease from 6–34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6–35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival in responding patients and in helping identify patients whose disease‐free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease‐free survival rate reported to date for osteogenic sarcoma.

Primary osteogenic sarcoma. The rationale for preoperative chemotherapy and delayed surgery

From 1973–1975, 31 patients with biopsied primary osteogenic sarcoma were treated with preoperative chemotherapy followed by surgical ablation of the primary tumor. Surgery was delayed in order to obtain a custom‐fitted prosthetic bone implant in an attempt to avoid amputation. Preoperative chemotherapy included high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (T‐5 protocol) and was administered for 3 months preoperatively and continued with the inclusion of cyclophosphamide for approximately 5 months postoperatively. At a follow‐up period of 30–52 months, 23 of 31 patients (75%) are surviving (21 of 23 with no evidence of disease). Histologic examination of primary tumor removed at surgery revealed varying degrees of tumor destruction (from very little effect to no evidence of viable tumor) attributable to the effect of chemotherapy. The 21 patients that are disease‐free survivors had a more complete effect of preoperative chemotherapy on the primary tumor. Some patients achieving favorable effects upon the primary tumor did so only after the dose of HDMTX was escalated to greater than the starting dose of 8 g/m2. Preoperative chemotherapy for all patients with osteogenic sarcoma would seem to offer the following advantages: 1) Evaluation of the effect of HDMTX with CFR on the primary tumor with escalation of the dose of HDMTX until a clinical response is observed, thus defining the dose of HDMTX effective in that patient, to be continued postoperatively as adjuvant therapy; 2) The early use of systemic therapy to eradicate distant microfoci of disease that will eventually kill the patient if not adequately treated by effective chemotherapy; 3) Allow more time for postoperative healing without the need to start adjuvant chemotherapy immediately; and 4) Provide the surgeon time to plan resection surgery. To date, 20 additional patients with biopsy proven osteogenic sarcoma have been treated with more aggressive preoperative chemotherapy (T‐7) for approximately 2 1/2 months prior to definitive surgery (resection or amputation). Doses of HDMTX were escalated where necessary and good clinical responses were obtained in 19 of 20 patients. In the majority of patients, no evidence of viable tumor was found on histologic examination of the surgically removed primary tumor. All 20 patients are surviving free of active disease at this brief follow‐up period of 4–20 months.

Radiation-induced sarcoma of bone

During the period 1931 to 1970, 50 cases of radiation‐induced osteogenic sarcoma were seen at the Memorial and James Ewing Hospitals. Twenty‐two of these cases had previously been described; the present paper adds an additional 28 cases to the existing series and reviews those factors related to the development of neoplastic changes. In 35 patients, there was evidence of preexisting bone pathology in the form of benign osseous growths. Fifteen patients had soft‐part and visceral neoplasms, such as retinoblastoma, seminoma, and breast carcinoma, the involved bone lying in the pathway of the radiation beam. Symptoms ranged from a palpable tender mass in the involved bone to intestinal obstruction secondary to metastatic radiation‐induced osteogenic sarcoma. Essentially all bones in the skeletal system appear to have been vulnerable. The radiation dosages ranged from 1,200 rads given in a few weeks to 24,000 rads given in 2 years. Induction time covered a period of 4 through 30 years with a mean of 9 years. Thirty‐two of the patients developing this neoplasm have since died of their disease.

Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma

In an attempt to shrink primary osteogenic sarcoma and allow complete surgical removal of the primary tumor, without amputating the involved limb, intensive preoperative chemotherapy with high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (ADR) was initiated in 20 patients with biopsy‐proven primary osteogenic sarcoma of the distal femur (15 patients) and proximal tibia (five patients). Following intensive chemotherapy, en bloc resection of the primary tumor with prosthetic replacement of the involved bone was planned. After surgery, adjuvant chemotherapy, consisting of HDMTX with CFR, ADR, and high dose cyclophosphamide was given sequentially for 1 year. Of 20 patients with primary osteogenic sarcoma (two with evidence of pulmonary metastases), 18 had primary tumors that could be clinically measured. Of these 18, 17 demonstrated a decrease in the size of primary tumor prior to surgery, while on chemotherapy. To date, 12 of these patients with osteogenic sarcoma of the distal femur have had total femur and knee joint replacement, and three patients with osteogenic sarcoma of the proximal tibia have had total knee replacement. In all 15 patients, surgical margins were grossly and microscopically free of tumor. There has been no evidence of soft tissue recurrence in any of the 15 patients who have undergone surgery for from 2 to 15 months postoperatively. These preliminary results indicate that with the use of aggressive chemotherapy, it is possible to demonstrate objective tumor regression in primary osteogenic sarcoma, allowing the surgeon to perform en bloc resection of tumor and prosthetic replacement of the involved bone. Although the limb is preserved, it is important to stress that extensive surgery yielding tumor‐free margins is performed. The ultimate evaluation of this approach to the treatment of primary osteogenic sarcoma awaits longer observation, to determine limb function and the continued disease‐free status, once adjuvant chemotherapy is discontinued.

Ewing's sarcoma: ten-year experience with adjuvant chemotherapy.

Since May 1970, 67 consecutive patients with primary (nonmetastatic) Ewings sarcoma were treated with adjuvant chemotherapy (CT) in addition to radiation therapy (RT) or surgery for the primary tumor. The first 19 patients were treated with four‐drug sequential CT (T‐2). The second protocol was a seven‐drug induction combination CT (T‐6) followed by T‐2 maintenance CT; in both protocols CT was continued for 18 months. The current protocol (T‐9) consists of combination CT given continuously for a period of 9 months. Of the entire group of 67 patients, 47 (70%) had axial and proximal lesions (pelvis, spine, rib, humerus, and femur) and 20 (30%) had distal lesions (forearm, leg, and foot); 53/67 (79%) are surviving free of disease 12–118 months (median 41 months) from the start of treatment. Fifteen of 23 (65%) patients with axial lesions, 19/24 (79%) patients with proximal lesions, and 19/20 (95%) patients with distal lesions are free of disease. Disease‐free survivors include 28/39 (72%) male patients and 25/28 (89%) female patients. Thirty‐four patients had RT, and 33 had surgery or surgery and RT, in addition to chemotherapy, for local treatment. The disease‐free survival rate was 76% in the RT group and 82% in the surgery group; failure in the RT group was attributable to local recurrence in 7/34 (21%) patients. Recent experience with T‐9 CT has demonstrated that CT given prior to RT or surgery can cause a great reduction in the size of the primary tumor while allowing the pathologicallyeroded bone to heal prior to the initiation of RT; this also allows the high‐risk patient with an axial primary (pelvis or spine) to tolerate the aggressive CT needed to prevent distant metastases. In addition to dramatically increasing survival in patients with Ewings sarcoma, combination CT has helped achieve permanent local control. The superior survival rates for all sites of primary tumor are attributable to the early use of aggressive combination CT.

Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases.

A consecutive series of 145 central-type osteogenic sarcomas in the long bones of patients under the age of twenty-one years was studied by analysis of the interval from surgery to onset of pulmonary metastasis and the interval from the onset of pulmonary metastasis to death. The effects of the time of surgery, age, sex, race, preoperative duration of symptoms, location of tumor, and preoperative radiation on the course of the disease were analyzed. One hundred and twenty-one patients had pulmonary metastasis prior to the end of the study and died of their disease. Twenty-four patients were free of metastasis at the end of the study. The five-year survival rate was 17.4 per cent. Age and location of the tumor were found to affect the time of onset of pulmonary metastasis but not the five-year survival figure. The first two years after definitive surgery were shown to be the critical period for studying the course of the disease. The data analyzed in this study may offer a valuable control series against which future methods of treatment can be evaluated.

Survival, prognosis, and therapeutic response in osteogenic sarcoma. The memorial hospital experience

Two hundred seventy‐nine consecutive patients with Stage II osteogenic sarcoma of the appendicular skeleton treated between 1976 and 1986 were studied to identify predictors of long‐term survival. Survival was 77% and 73% at 5 and 10 years, respectively, with continuously disease‐free survival being 70% and 69%. On univariate analysis, the most significant predictors of survival were the location of the primary lesion, local control of the tumor, and the degree of necrosis in the primary tumor after intravenous neoadjuvant chemotherapy (histologic response). On initial multivariate analysis, similarly, only location and histologic response to chemotherapy predicted disease‐free outcome. After statistical control for local recurrence, only histologic response to chemotherapy was retained as an independent predictor, suggesting that in this data set, the location of primary lesion exerted its effect only secondarily through its association with the ability to provide local control. The risk of local recurrence was almost fivefold higher in tumors of the femur than in tumors of other locations (relative risk, 4.6) and, within the femur, was more than threefold higher in the proximal femur than in the distal femur (relative risk, 3.4). None of the other primary tumor or patient characteristics studied yielded independent predictive significance for survival. The rate of failure was almost fivefold as high in those with an incomplete response to chemotherapy compared with those with a complete response to chemotherapy (relative risk, 4.9; 95% confidence interval, 2.2 to 11). Even in those patients with minimal or no necrosis in the primary tumor, ultimately 62% and 54% were disease‐free at 5 and 10 years, respectively.

Multiple Pulmonary Resections in the Treatment of Osteogenic Sarcoma

Abstract More than 80% of patients with osteogenic sarcoma develop pulmonary metastases within two years and, if untreated, die from their disease within a few months. With surgical resection of pulmonary metastases, solitary or multiple, nearly half the patients we treated were alive and free of disease two years after resection. Radiotherapy and chemotherapy have been of limited value in treating metastatic osteogenic sarcoma. Early detection of pulmonary metastases by roentgenographic follow-up examination at frequent intervals and surgical excision of all metastases, by repeated thoracotomies if necessary, appear to be the treatment of choice.

Primary osteogenic sarcoma: Eight-year experience with adjuvant chemotherapy

SummarySince October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.

Treatment of Unicameral Bone Cyst: A Follow-up Study Of One Hundred Seventy-five Cases

A series of 175 unicameral bone cysts is presented. The pathogenesis of the lesion and the results of treatment differed depending upon the specific bone involved. It is our opinion that prompt surgical treatment to establish an accurate histological diagnosis and to reinforce the involved segment of bone against fracture by thoroughly evacuating the cavity and filling it with bone grafts is a more satisfactory treatment than watchful waiting. A persistent and static roentgenographic defect after surgery should not be considered a clinical failure if adequate bone strength is present. A second operation is indicated only for an enlarging cyst with the threat of fracture. In this series of 129 primary operations, the incidence of re-operation was 30 per cent in the proximal end of the humerus, 17 per cent in the proximal end of the femur, 1 1 per cent in the proximal end of the tibia, and nil in most of the other less frequent locations. In retrospect, a number of second procedures were considered unnecessary since they were performed for asymptomatic and static roentgenographic defects associated with sufficient bone strength to prevent fracture. True recurrence followimug surgical treatment is significantly more frequent in patients under ten years of age. Age is a more reliable prognostic criterion than the proximity of the cyst to the epiphyseal plate when assessing the likelihood of recurrence after surgical treatment.