William F. Sindelar

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.

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.

Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas.

Between January 1980 and September 1985, 35 adult patients with resectable retroperitoneal soft tissue sarcomas were entered on a randomized trial comparing two forms of adjuvant radiation therapy. Fifteen patients received the experimental therapy consisting of intraoperative radiotherapy (IORT) to 20 Gy using high-energy electrons followed by low-dose (35 to 40 Gy) postoperative external beam irradiation. Twenty patients received standard therapy consisting of high-dose (50 to 55 Gy) postoperative external beam irradiation. With a minimum follow-up of 15 months, there is no significant difference in the actuarial disease-free survival (DFS) and overall survival (OS) comparing the two groups (median DFS, 34 months; median OS, 38 months). At 5 years follow-up, approximately 40% of patients are alive and 20% of patients remain disease-free. Although there is a trend towards an improvement in in-field local control in the experimental arm, the predominant pattern of failure in both groups was locoregional within the retroperitoneum and/or peritoneal cavity. Acute and late radiation enteritis were significantly reduced in the experimental group. However, four experimental patients developed late (greater than 6 months following treatment) peripheral neuropathy believed related to the use of IORT; all four recovered. We conclude that there is no difference in the therapeutic effectiveness of the combination of IORT and low-dose external beam radiation compared with conventional high-dose radiation as adjuvant treatment in retroperitoneal sarcomas, although the former appears to be less toxic. Newer combined modality treatment strategies are discussed to improve the prognosis in these patients.

Transdermal fentanyl for pain control in patients with cancer

&NA; Five cancer patients experienced satisfactory pain relief for periods of 3–156 days using continuous transdermal delivery of the narcotic fentanyl. The patients, aged 16–68 years, had all been experiencing pain and were either unable to take oral analgesic medications or these agents were ineffective in controlling pain. Doses were adjusted to individual patient needs and varied from 75 &mgr;g/h to 350 &mgr;/h (median = 225 &mgr;g/h). Plasma fentanyl levels reflected the administered dose and remained constant throughout the treatment. Transdermal delivery of narcotics provides a new option for the cancer patient unable to achieve satisfactory analgesia with oral medications.

Evaluation of the utility of a radioimmunoassay for serum CA 19-9 levels in patients before and after treatment of carcinoma of the pancreas.

By radioimmunoassay we determined circulating levels of a tumor-associated antigen, CA 19-9, in 47 patients with pancreatic adenocarcinoma, to learn if serial testing was useful in predicting prognosis or in detecting disease progression. Before treatment, 42 (89%) had an abnormal serum level, and 45 (96%) had an abnormal level at some time during the disease course. A pretreatment value of less than 1,000 U/mL (normal, less than or equal to 37 U/mL) was found in 38 patients; 20 (53%) had resectable disease. One of nine patients (11%) with a pretreatment value greater than 1,000 U/mL had resectable disease (P2 = .05). Among 14 patients who underwent pancreatectomy and were studied serially, the CA 19-9 level normalized in eight; seven (88%) survived greater than or equal to 18 months. Six patients whose levels did not normalize after pancreatectomy all died in less than 12 months (P2 less than .005). Greatly elevated levels occurred in 11 patients after pancreatectomy 1 to 7 months before clinically apparent recurrence. The other three patients without significant elevations remain clinically free of disease. The data suggest that serial determination of serum CA 19-9 levels are useful as a prognostic indicator and in detecting disease recurrence following pancreatectomy. Concurrent determinations of carcinoembryonic antigen (CEA) levels showed abnormal preoperative values in 28 of 46 patients tested (61%). Concurrent serial postoperative determinations of CEA were available in ten patients. Whereas CA 19-9 values clearly indicated eight recurrences, CEA was helpful in only four. In this small group of patients, CA 19-9 was a better predictor of recurrence.

TOLERANCE OF' PERIPHERAL NERVE TO INTRAOPERATIVE RADIOTHERAPY (IORT): CLINICAL AND EXPERIMENTAL STUDIES

In our clinical experience combining wide excision and intraoperative radiotherapy (IORT), five patients have developed clinical signs of lumbosacral or sciatic neuropathy within 9 months of receiving IORT to a dose of 20-25 Gy. Three patients showed recovery of nerve function over several months while two patients have shown no recovery and have near complete loss of extremity function. In an attempt to investigate this clinical observation further, the lumbosacral plexus and sciatic nerve of American foxhounds were surgically exposed and received a single dose of IORT ranging from 20-75 Gy. An approximate linear relationship between radiation dose and time to onset of hind limb paresis is found with 19 of 21 irradiated dogs showing clinical signs of nerve injury within an interval of 1-19 months. No recovery of nerve function is seen in these dogs. Histological study of the irradiated nerves demonstrates a loss of nerve fibers, particularly those of the large myelinated type without evidence of vascular occlusion or thrombosis. These studies suggest that peripheral nerve may be a dose-limiting normal tissue in clinical studies of IORT.

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.

Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors

PURPOSE Phase I study designed to determine the maximum tolerated dose of intraoperative photodynamic therapy (PDT) at laparotomy/debulking surgery in patients with refractory or recurrent, disseminated intraperitoneal tumors. METHODS AND MATERIALS Patients received dihematoporphyrin ethers (DHE) 1.5-2.5 mg/kg by i.v. injection prior to surgery. Patients resected to < or = 5 mm of residual disease underwent laser light delivery to all peritoneal surfaces. RESULTS Fifty-four patients entered the study. Thirty-nine underwent resection and light delivery/PDT. PDT dose was escalated by increasing DHE from 1.5 to 2.5 mg/kg, shortening the interval between DHE injection and surgery from 72 to 48 hr, and increasing the light dose. Initially, 630 nm red light alone was used. In this group, PDT of 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Further light dose escalation, however, was achieved by switching to less penetrating 514 nm green light to the bowel/mesentery. In later patients, whole peritoneal PDT was supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas. Small bowel complications were not seen after switching to less penetrating green light. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. These patients had pleural effusions that required thoracentesis and postoperative respiratory support for 7-9 days, while one had a gastric perforation. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease. CONCLUSION The maximum tolerated dose of intraoperative PDT following debulking surgery performed 48 hr after intravenous administration 2.5 mg/kg DHE is 3.75 J/cm2 of 514 nm green light to the entire peritoneal surface with boosts to 5.0-7.5 J/cm2 of 514 nm green light or 10-15 J/cm2 of 630 nm red light to sites of gross disease encountered at surgery.

Electron microscopic observations on formation of pulmonary metastases

The development of pulmonary metastases after local surgical control of malignant tumors has represented a major cause of treatment failure in a variety of neoplasms. The metastatic process has been a subject of considerable interest, investigation, and speculation for many years, but it remains as a poorly characterized and little understood phenomenon. The formation of blood-borne metastases is generally considered to involve several steps, including: (1) growth of a primary tumor with eventual shedding of viable malignant cells into the blood, either directly through vascular invasion or indirectly by lymphatic drainage; (2) transport of tumor cell emboli through the circulation to distant organs; (3) arrest of blood-borne malignant cells in distant vascular beds; (4) penetration of vascular walls by embolized tumor cells; and (5) growth of metastasized malignant cells in the parenchyma of target organs. Histologic investigations of the metastatic process were undertaken early [ 181. Various initial studies of experimental metastases in animal neoplasms indicated that once malignant cells shed from a primary tumor reach the venous circulation, they are carried to the capillary bed of target organs where the cells become arrested prior to invasion of the target organ parenchyma [ 11, 24,251. The initial attachment of circulating tumor cells to the capillary endothelium of distant organs has been regarded as a crucial step in metastasis [6, 131. Numerous investigations have suggested that circulating tumor cells embolize to target organs, where they arrest in vascular channels and attach to the endothelium prior to invading the surrounding tissue parenchyma [4, 5, 26, 271. Various workers have proposed that the attachment of embolized malignant cells to the vascular walls is largely dependent upon entrapment of the tumor embolus within a thrombus or fibrin meshwork [2, 8, 17, 28, 291. Such a thrombus might serve to stabilize the tumor emboli within the vessels until the cells are able to penetrate the endothehum and establish metastatic foci within the perivascular connective tissue. Despite active research efforts, there have been relatively small amounts of data concerning the mechanisms involved in the arrest of circulating tumor cells and their method of growth in metastatic sites [9, 16, 301. Recently, electron microscopic investigations have attempted to characterize events in metastasis formation through examination of embolic tumor cells arrested within vascular beds [12, 141. Jones and coworkers [12] investigated the sequence of events in experimental pulmonary metastases of the Walker 256 carcinosarcoma in rats, utilizing both electron microscopy and fibrin-specific immunofluorescence. These investigators demonstrated that after intravenous injection, tumor cells were arrested in pulmonary capillaries and were surrounded by a thrombus formed from ag-