Alan R. Baker

Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.

PURPOSE This randomized, prospective study assesses the impact of postoperative external-beam radiation therapy on local recurrence (LR), overall survival (OS), and quality of life after limb-sparing resection of extremity sarcomas. PATIENTS AND METHODS Patients with extremity tumors and a limb-sparing surgical option were randomized to receive or not receive postoperative adjuvant external-beam radiotherapy. Patients with high-grade sarcomas received postoperative adjuvant chemotherapy whereas patients with low-grade sarcomas or locally aggressive nonmalignant tumors were randomized after surgery alone. RESULTS Ninety-one patients with high-grade lesions were randomized; 47 to receive radiotherapy (XRT) and 44 to not receive XRT. With a median follow-up of 9.6 years, a highly significant decrease (P2 = .0028) in the probability of LR was seen with radiation, but no difference in OS was shown. Of 50 patients with low-grade lesions (24 randomized to resection alone and 26 to resection and postoperative XRT), there was also a lower probability of LR (P2 = .016) in patients receiving XRT, again, without a difference in OS. A concurrent quality-of-life study showed that extremity radiotherapy resulted in significantly worse limb strength, edema, and range of motion, but these deficits were often transient and had few measurable effects on activities of daily life or global quality of life. CONCLUSION This study indicates that although postoperative external-beam radiotherapy is highly effective in preventing LRs, selected patients with extremity soft tissue sarcoma who have a low risk of LR may not require adjuvant XRT after limb-sparing surgery (LSS).

The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.

Between May 1975 and April 1981, 43 adult patients with high-grade soft tissue sarcomas of the extremities were prospectively randomized to receive either amputation at or above the joint proximal to the tumor, including all involved muscle groups, or to receive a limb-sparing resection plus adjuvant radiation therapy. The limb-sparing resection group received wide local excision followed by 5000 rads to the entire anatomic area at risk for local spread and 6000 to 7000 rads to the tumor bed. Both randomization groups received postoperative chemotherapy with doxorubicin (maximum cumulative dose 550 mg/m2), cyclophosphamide, and high-dose methotrexate. Twenty-seven patients randomized to receive limb-sparing resection and radiotherapy, and 16 received amputation (randomization was 2:1). There were four local recurrences in the limb-sparing group and none in the amputation group (p1 = 0.06 generalized Wilcoxon test). However, there were no differences in disease-free survival rates (71% and 78% at five years; p2 = 0.75) or overall survival rates (83% and 88% at five years; p2 = 0.99) between the limb-sparing group and the amputation treatment groups. Multivariate analysis indicated that the only correlate of local recurrence was the final margin of resection. Patients with positive margins of resection had a higher likelihood of local recurrence compared with those with negative margins (p1 less than 0.0001) even when postoperative radiotherapy was used. A simultaneous prospective randomized study of postoperative chemotherapy in 65 patients with high-grade soft-tissue sarcomas of the extremities revealed a marked advantage in patients receiving chemotherapy compared with those without chemotherapy in three-year continuous disease-free (92% vs. 60%; p1 = 0.0008) and overall survival (95% vs. 74%; p1 = 0.04). Thus limb-sparing surgery, radiation therapy, and adjuvant chemotherapy appear capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremity.

The Effect of Adjuvant Chemotherapy on Relapse-Free Survival in Patients with Osteosarcoma of the Extremity

We conducted a randomized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high-grade osteosarcoma of the extremity, as compared with concurrent controls. After undergoing definitive surgery, 36 patients were randomly assigned to adjuvant chemotherapy or to observation without adjuvant treatment. At two years the actuarial relapse-free survival was 17 percent in the control group, similar to that found in studies before 1970, and 66 percent in the adjuvant-chemotherapy group (P less than 0.001). Similar results were observed among 77 additional patients who declined to undergo randomization but who elected observation or chemotherapy. We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades, that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high-grade osteosarcoma, and that it should be given to all such patients.

Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities

Sixty‐five patients with high‐grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high‐dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow‐up of 653 days revealed an advantage in continuous disease‐free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one‐sided Mantel‐Haenszel test). The continuous disease‐free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty‐eight percent of patients had limb‐sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease‐free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four‐year follow‐up, reveals an improvement in disease‐free and overall survival due to chemotherapy (P < 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment of adult patients with soft tissue sarcomas of the extremities.

Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study.

The multiinstitutional osteosarcoma study (MIOS), a randomized trial of adjuvant therapy for osteosarcoma with a concurrent control group, registered 113 patients from June 1982 to August 1984. Preliminary analysis of the study indicated a significant event-free survival advantage favoring immediate adjuvant chemotherapy, (P less than .001). For patients treated with surgery alone or with surgery and adjuvant chemotherapy, the lungs were involved in more than 80% of the relapses. Patients relapsing after surgery alone tended to relapse earlier (P less than .01), had more pulmonary nodules (P less than .01), and had more frequent bilateral pulmonary involvement (P less than .01) than those treated with immediate postsurgical adjuvant chemotherapy. However, patients relapsing after treatment with surgery alone experienced a significantly longer interval to further disease progression (P less than .01) and improved survival after relapse (P = .01) when compared with patients who relapsed after treatment with immediate adjuvant chemotherapy. The only factor predictive of survival after relapse was if the patient could be made surgically disease-free after initial relapse (P = .03).

A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk

Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high‐grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000–6300 rads over 7–8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (⩽550 mg/m2), cyclophosphamide (⩽5500 mg/m2), and methotrexate (⩽1000 mg/kg). Three‐year actuarial disease‐free survival in the chemotherapy arm was 77%, compared to 49% in the no‐chemotherapy arm (P = 0.075). Three‐year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3‐year actuarial disease‐free survival in the chemotherapy arm was 92%, compared to 47% in the no‐chemotherapy arm (P = 0.006). Actuarial 3‐year overall survival in the chemotherapy arm was 82%, compared to 61% in the no‐chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow‐up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3‐year actuarial disease‐free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease‐free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease‐free survival (P < 0.001). The most significant toxicity associated with chemotherapy was doxorubicin‐induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease‐free survival, but additional patients and longer follow‐up are necessary to determine if improved overall survival will result. Cancer 55:1206‐1214, 1985.

Management of symptomatic malignant melanoma of the gastrointestinal tract.

Background: Melanoma metastatic to the gastrointestinal (GI) tract is asymptomatic or presents with pain, bleeding, or obstruction. To determine whether surgery influences outcomes, we reviewed our experience with this patient population.Methods: Medical records of patients with metastatic melanoma to the GI tract were reviewed. Patients were divided into four groups, i.e., complete resection, partial debulking, unresectable, or unexplored. Analysis was performed using the Kaplan-Meier method.Results: Fifty patients with melanoma metastatic to the GI tract were identified (40 men and 10 women; mean age, 44 years). Presenting symptoms included pain (62%), bleeding (28%), and obstruction (18%). Diagnosis was confirmed using contrast studies (38%), endoscopy (20%), or computed tomography (30%). Thirty-six patients (61%) underwent a total of 39 operations. Seventeen patients underwent complete resection, whereas 14 underwent partial debulking. Five patients had unresectable lesions, and 14 patients did not undergo exploration because of medical contraindications. The operative mortality rate was 2.5% (1 of 39). The mean survival times for the unexplored and unresected groups were similar (4.1 months). Patients who underwent partial resection exhibited a longer mean survival time (8.9 months) than did patients in the unresected group (P < .001). The complete-resection group demonstrated a mean survival time of 23.5 months, which was significantly longer than that for patients who underwent less than complete resection (P < .0001).Conclusions: Metastatic melanoma to the GI tract can result in significant morbidity and death. Surgical resection can be performed safely. Patients for whom all sites of disease are completely resected experience significant improvements in survival times, compared with patients who undergo less than complete resection. For selected patients, surgical treatment of metastatic melanoma involving the GI tract is appropriate therapy.

Metastatic malignant melanoma of the oral cavity: A retrospective study

Metastatic malignant melanoma of the oral cavity is rarely reported in the dental literature. This retrospective study identified metastatic oral lesions in 3.0% of 809 patients with melanoma treated at the National Institutes of Health between 1953 and 1989. Fifteen cases met established rigorous criteria for metastatic tumors and were reviewed for disease course and outcome. Nine white men and six white women, with an average age of 40.6 years, had cutaneous primary tumors predominantly of the trunk and head and neck region that commonly presented as moles that were enlarging, bleeding, or showing both of these signs. A mean of 4.2 years elapsed between primary tumor and oral metastasis diagnosis. Tongue, buccal mucosa, and parotid gland were the predominant oral sites. Enlarging oral masses, pigmented lesions, and nonhealing extraction sites with masses were common oral presentations. Surgery, chemotherapy, radiation therapy, and immunotherapy were used in various combinations for treatment of the primary lesion and oral metastasis. Prognosis, although poor, was highly variable.

Surgical management of pulmonary infections in chronic granulomatous disease of childhood

Chronic granulomatous disease of childhood is an inheritable disorder of phagocytic cell respiratory burst resulting in recurrent, life-threatening, catalase-positive infections. The lung is the most common site of infection, and pulmonary disease is the primary cause of death in greater than 50% of children with chronic granulomatous disease. Still, the role of surgery in management of this disease remains undefined. Between 1974 and 1990, 19 patients with chronic granulomatous disease required 31 thoracic interventions at our institution. Patients ranged in age from 2.5 to 27 years (mean age, 15 years). Seventeen of 19 patients (89%) had had previous pulmonary infections. Patients presented as toxic (temperature > 38.5 degrees C, chest pain, and cough) in 22 instances before the 31 procedures. Aggressive surgical intervention for diagnosis and extirpation of localized infections was undertaken with lobectomy/pneumonectomy with or without other procedures (5), bisegmentectomy (2), segmentectomy with or without other procedures (5), or wedge with or without other procedures (13). In five instances, an empyema was drained; a chest tube for a sterile collection was placed in one instance. There was one intraoperative death, and 3 patients died 22 to 600 days postoperatively with overwhelming sepsis. The mean hospitalization was 101 days (range, 24 to 600 days). Wound complications occurred in 5 patients, requiring 17 separate anesthetic debridements. A change in therapy was dictated by the results of the procedure in 23 of 31 instances (74%). Thoracic surgeons must be aware of this rare cause of immunosuppression in these children and, due to the unusual nature of the pulmonary infections, should follow an aggressive approach in their diagnosis and management.

The Prognosis of Melanoma Patients with Metastases to Two or More Lymph Node Areas

The prognosis of melanoma patients who present with metastatic involvement of two or more noncontiguous lymph node regions before the detection of extranodal metastases has not been previously reported. We identified 21 patients with metastatic melanoma in at least two nodal basins in a review of 175 patients with melanoma undergoing lymphadenectomy at the National Cancer Institute. The median survival time of these patients was 46 months, with 55%, 27%, and 17% of the patients alive 2, 5, and 10 years, respectively, after the second lymphadenectomy. Because the prognosis of melanoma patients with metastases to two or more regional nodal areas appears equivalent to that of patients with metastatic involvement of only one regional node site, lymphadenectomy of the involved groups should be performed with therapeutically curative intent.