Brenda Caparros

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.

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.

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.

Curability of ewing's sarcoma and considerations for future therapeutic trials

Twenty previously untreated children with primary Ewings sarcoma and 8 children with primary tumor and metastatic disease were treated with surgery or radiation therapy (6,000–7,000 rads) for their primary tumor and T‐2 chemotherapy. Of the 20 children with primary Ewings sarcoma treated with T‐2“adjuvant” chemotherapy, 15 had no evidence of recurrent disease for from 31+−82+ months (median 46+ months) from the start of treatment. The actuarial 5‐year disease‐free survival rate for this group of patients was 75%. Eight patients presenting with metastatic disease had complete responses to T‐2 chemotherapy, but 7/8 with metastatic disease eventually had tumor recurrence. Examination of the treatment failures, both those patients relapsing after adjuvant chemotherapy for primary Ewings sarcoma (5), and those relapsing after having a complete response of metastatic disease (7) to T‐2 chemotherapy, revealed that all relapses occurred at the end of the second year of T‐2 chemotherapy or after chemotherapy was stopped. In addition, of 23 patients receiving “curative” radiation therapy to their primary tumor, 5 had local recurrence (22%) and 6 (26%) had severe functional debility secondary to combined radiation therapy and T‐2 chemotherapy. The conclusions drawn from this experience have led us to consider a new approach to the treatment of Ewings sarcoma, namely: 1) more aggressive initial or “induction” chemotherapy with subsequent T‐2“maintenance” chemotherapy to eradicate more completely all metastatic microfoci of disease presumed to be present in patients with primary tumor at the time of diagnosis, and ostensively present in patients with metastatic disease; 2) the use of surgery alone or in combination with moderate doses of radiation therapy in those patients in whom we can predict a high frequency of local recurrence (pelvic lesions) or a high percentage of “functional failures”(young children with lower extremity lesions). Preliminary results with this latter approach are encouraging with 11/13 patients with primary Ewings sarcoma free of disease at 12+−26+ months. A longer follow‐up of this more aggressive treatment is needed to determine the superiority of this approach for both increased survival and improved late physical rehabilitation.

Combination chemotherapy with bleomycin, cyclophosphamide and dactinomycin for the treatment of osteogenic sarcoma

Thirteen patients with osteogenic sarcoma were treated with multiple drug chemotherapy consisting of bleomycin, cyclophosphamide and dactinomycin. The dosage schedule used was: bleomycin 12 mg/m2/day, cyclophosphamide 600 mg/m2/day, and dactinomycin 450 μg/m2/day. All drugs were given intravenously for two consecutive days. Treatment was repeated every 2 weeks. Toxicity included severe nausea and vomiting (managed with antiemetics and intravenous hydration) and manifestations of bone marrow depression. Of 13 patients, eight were previously treated with high dose methotrexate with citrovorum factor rescue, cyclophosphamide and Adriamycin. Of these eight, three patients had objective evidence of tumor regression (37.5%). Five of five previously untreated patients had objective evidence of tumor regression. The overall response rate in osteogenic sarcoma patients to BCD was 61.5%. The combination of BCD appears to be more active against osteogenic sarcoma than cyclophosphamide alone or Adriamycin alone. The relative safety with which BCD can be administered makes this combination a valuable adjunct to high dose methotrexate with citrovorum factor rescue and Adriamycin in the treatment of osteogenic sarcoma. Cancer 40:2779‐2786, 1977.

Chemotherapy of malignant fibrous histiocytoma of bone: A report of five cases

Five Patients with evaluable malignant fibrous histiocytoma (MFH) of bone (three with primary tumor and two with primary tumor and metastatic disease) were treated with preoperative chemotherapy including high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) as is used for patients with osteogenic sarcoma. All five patients demonstrated a clinical response to chemotherapy. Three of four patients who underwent surgery had complete responses and one patient had greater than 90% tumor necrosis as documented by histologic examination of the resected primary tumor. All four patients who underwent surgery following preoperative chemotherapy are surviving free of disease from one to six years from the start of treatment; chemotherapy was discontinued after six to 11 months in these patients. The median disease‐free survival time is 31.5 months. This study demonstrates the effectiveness of chemotherapy in MFH of bone, and in particular the effectiveness of HDMTX with CFR which caused measurable responses in all patients while receiving this therapy as a single agent.

Chemical pleuritis as the cause of acute chest pain following high-dose methotrexate treatment

This report describes the clinical and roentgenographic features of a pleuritis seen following the administration of high‐dose methotrexate (HDMTX). Among 210 patients who received 3130 courses of HDMTX from 1977 through 1980, the incidence of this clinical entity was 8.5% (n = 18). The sudden onset of chest pain occurred only after the third or fourth HDMTX treatment and usually lasted between three and five days; the pain was often quite severe and led to extensive clinical examination before recognition of the benign transient nature of this syndrome. Roentgenographic examination of the chest revealed thickening of the intra lobar pleura, most prominent on the right side. Our observations support the hypothesis that this adverse drug reaction occurs more frequently than assumed, but is often ignored or misinterpreted.

Semiquantitative gallium scintigraphy in patients with osteogenic sarcoma

Sequential gallium scans were performed in 37 patients with newly diagnosed osteogenic sarcoma. High gallium uptake was found more often in males in the 10 to 19 age group and in femoral lesions. High uptake was also seen in patients who had predominantly osteoblastic or mixed changes on radiographs and in those who had a soft tissue mass. Following chemotherapy, significant decrease of tumor to nontumor ratio occurred in the patients who responded to treatment as shown by a Grade III or IV response on histologic examinations at the time of en bloc resection. It is concluded that semiquantitative gallium scintigraphy is useful in monitoring therapeutic response in patients with osteogenic sarcoma.

CISPLATIN IN METASTATIC OSTEOGENIC SARCOMA

Publisher Summary This chapter describes the potential antitumor activity of cis -diamminedichloroplatinum (II) (DDP or cisplatin). The compound has alkylating activity and is active in the treatment of a variety of human neoplasms, both as a single agent and in combination. DDP has been clinically useful in the treatment of a variety of head and neck tumors, epidermoid carcinoma of the lung, and germ cell tumors of the testes. The chapter discusses the efficacy of DDP in advanced osteogenic sarcoma. One complete response and 4 partial responses in 8 patients with advanced metastatic disease have been reported. Due to this, a phase II study of DDP is undertaken in a larger series of patients with evaluable osteogenic sarcoma at the Memorial Sloan–Kettering Cancer Center (MSKCC). High-dose DDP with mannitol diuresis does not show overlapping toxicity with many other agents, such as cyclophosphamide and adriamycin, that are effective in the treatment of osteogenic sarcoma and other solid tumors. This latter finding and the efficacy of high-dose DDP with mannitol diuresis in the treatment of osteogenic sarcoma and other solid tumors makes this agent an ideal candidate for future phase II trials of combination chemotherapy in the management of these tumors.