M. Lois Murphy

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.

The cardiotoxicity of adriamycin and daunomycin in children.

Eight (16%) of 50 children receiving adriamycin and 2 (3%) of 60 receiving daunomycin had severe cardiomyopathy with congestive heart failure. All 110 patients received cumulative doses of over 500 mg/m2. The incidence was significantly higher in those who also had incidental cardiac radiation. The electrocardiogram, with few exceptions, provided the first indication of cardiac abnormality. There were no deaths from heart failure. Two had thromboembolic episodes. Recommendations are discussed.

The rationale for multiple drug chemotherapy in the treatment of osteogenic sarcoma

Based on our prior experience in treating children with metastatic osteogenic sarcoma, a multidrug regimen was developed. Nine children with evaluable osteogenic sarcoma were treated with vincristine 1.5 mg/m2 on day 1, high‐dose methotrexate 200‐300 mg/kg i.v. on day 2, with p.o. citrovorum factor “rescue” 9 mg every 6 hours × 12, followed in 2 weeks by cyclophosphamide 40 mg/kg i.v., then 2 weeks later Adriamycin 1.5 mg/kg/day × 2; in 2 weeks cyclophosphamide was repeated. After a 2‐week rest, the 56‐day cycle was repeated for a total period of 1 year. Oropharyngeal mucositis was the most frequent severe manifestation of gastrointestinal toxicity. Hematologic depression was mild to severe. Nine patients with clinically evaluable osteogenic sarcoma and no previous chemotherapeutic treatment were treated with this regimen. One patient had only a transient shrinkage in tumor mass, and one patient had no progression of multiple pulmonary and bone metastases for 16 months while on therapy. Of the remaining seven patients, all had clinically significant responses with tumor regression demonstrated for from 5 to 20+ months. Four of these patients (three presenting with primary tumor and pulmonary metastases) demonstrated regression of their primary tumor. In an attempt to increase the cure rate in osteogenic sarcoma, chemotherapy that has proven to be effective against metastatic osteogenic sarcoma should now be employed as prophylactic therapy, after amputation, at cancer treatment centers where it can be safely and effectively administered.

A long-term clinical follow-up of children with acute lymphoblastic leukemia treated with intensive chemotherapy regimens

One hundred and thirty‐three children 15 years old and younger with acute lymphoblastic leukemia were treated with two different protocols. Both regimens consist of a multi‐drug program, without CNS irradiation, administered for three years. Seventy‐five children were enrolled on the first protocol, L‐2; and 58 were treated on the subsequent regimen, L‐10. Of the 70 evaluable patients on the L‐2 program, 40 continue in complete remission from 72–111 months. Seventy‐four percent of the children qualified for treatment cessation, and 59% have remained in continuous remission for six years. The estimated seven year disease‐free survival for the 70 evaluable children on the L‐2 protocol is 57% and for all entries is 53%. Of the 57 evaluable patients on the L‐10 program, 35 are in complete remission from 15–67 months. The combined frequency of primary CNS leukemia for the two regimens is 7%. The off‐therapy results of the L‐2 protocol cannot be compared to the L‐10 at present, but the on‐therapy outcomes, despite the modifications that were designed to improve the L‐10 regimen, are comparable.

Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma

Fourteen patients with 16 metastatic osteogenic sarcoma lesions were treated with high‐dose methotrexate (HDMTX) with citrovorum factor rescue (CFR), Adriamycin, and pulse high‐dose cyclophosphamide combined with radiation therapy. Thirteen of 16 lesions responded. Responses consisted of relief of pain (6/6 patients) in bone lesions, roentgenographic and clinical evidence of decrease in the size of the bone lesions (6/7 patients), and a decrease in the size of pulmonary metastases (2/4 patients). The 2 patients whose pulmonary metastases responded to combined therapy developed pulmonary fibrosis and pneumonitis in the treated areas 3 months after radiation therapy (RT) (1400 and 1600 rads respectively). Of two bulky primary tumors that appeared to respond, both were ultimately found to contain viable tumor; a third less bulky primary tumor appeared to respond more completely. Three smaller metastatic bone lesions that were ultimately biopsied showed no evidence of active tumor. It is concluded that: 1) combination therapy (particularly HDMTX and RT) has an additive effect in controlling osteogenic sarcoma bone lesions, but bulky primary tumors cannot be completely eradicated; 2) although synergistic in treating osteogenic sarcoma, combination therapy can produce enhanced toxicity in surrounding normal lung tissue; and 3) combination therapy is of value in the palliative treatment of metastatic lesions other than that of lung, and in the treatment of small primary bone lesions. However, experience to date does not justify the delay in surgical ablation of a primary lesion in a child who presents without metastatic disease.

Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. A review of 17 cases

Seventeen patients treated for acute lymphoblastic leukemia by combination chemotherapy before their reaching 10 years of age were studied for altered dental root development of their premolar teeth. Five of the 17 patients showed subjective radiographic evidence of marked shortening of the premolar dental roots; 13 had thinning of the roots. A quantitative analysis was developed and verified, which disclosed a 63.33% to 84.38% reduction of premolar root length when compared with the mean of the historical controls. With recent significant increases in long‐term survival rates of children with malignancies, altered dental development becomes an important factor to follow years after chemotherapy is discontinued. The findings of these chemotherapy‐associated dental development changes impacts on the patients quality of life and also can serve as a research tool to assess permanent effects of chemotherapy on normal tissue growth and development.

Predinsome therapy of acute childhood leukemia: Prognosis and duration of response in 330 treated patients

Induction of remission with prednisone in 330 children with acute leukemia resulted in improvement to complete remission in 40 per cent and in good partial remission in another 34 per cent of patients. Complete bone marrow remission occurred in 63 per cent. Remission was maintained without treatment for a median duration of 58 days. Infants under 1 year of age, patients with initially high white blood cell counts, and those with a morphologic diagnosis of acute granulocytic leukemia responded less favorably than the other children.

Long-Term Survivors in Acute Leukemia

It is obvious from the many publications on the subject that long-term survivors, defined as those patients who survive either with or without evidence of the disease for more than 5 years from the diagnosis, do occur in acute leukemia [1–5]. Previous studies have shown that those patients surviving for 5 years have a 50% chance of surviving indefinitely [6]. Most of those who relapse will do so between the 5th and 8th years, and only a very few after the 9th year. For instance, of the 101 patients reported as 5-year survivors in 1964, 64 were living and well at that time with no evidence of the disease. In the ensuing 4 years, 6 of these had relapsed so that there were 58 out of 101 surviving with no evidence of the disease, or an annual drop-off of approximately 2.5% [7].

Malignant ovarian tumors in childhood. Prognosis in relation to initial therapy

Twenty‐two children with malignant ovarian tumors (12 malignant teratomas, six endodermal sinus tumors, and four embryonal carcinomas) were studied from 1960 through March 1975. Comparison is made between different modalities of therapy, such as surgery alone or surgery in combination with either radiation or chemotherapy. Because of the poor results obtained with the aforementioned treatment methods, a new approach, consisting of more aggressive initial surgery followed immediately by radiation therapy and an intensive chemotherapeutic regimen called the T2 protocol, was begun in 1971 with encouraging results. To date six of ten patients are alive and free of disease with a median observation period of 22+ months. A new grouping defining the extent of disease is also provided. Of the ten patients on the T2 protocol, only one was a Group I; eight were Group III and one was Group IV at the time treatment was initiated. An analysis of the mode of spread, as well as a discussion of the results obtained with previous modalities of therapy in relation to initial grouping and pathology, constitute the background for the proposed treatment.