Ephraim S. Casper

Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.

PURPOSE This trial was performed to evaluate the impact of adjuvant brachytherapy on local and systemic recurrence rates in patients with soft tissue sarcoma. PATIENTS AND METHODS In a single-institution prospective randomized trial, 164 patients were randomized intraoperatively to receive either adjuvant brachytherapy (BRT) or no further therapy (no BRT) after complete resection of soft tissue sarcomas of the extremity or superficial trunk. The adjuvant radiation was administered by iridium-192 implant, which delivered 42 to 45 Gy over 4 to 6 days. The two study groups had comparable distributions of patient and tumor factors, including age, sex, tumor site, tumor size, and histologic type and grade. RESULTS With a median follow-up time of 76 months, the 5-year actuarial local control rates were 82% and 69% in the BRT and no BRT groups (P = .04), respectively. Patients with high-grade lesions had local control rates of 89% (BRT) and 66% (no BRT) (P = .0025). BRT had no impact on local control in patients with low-grade lesions (P = .49). The 5-year freedom-from-distant-recurrence rates were 83% and 76% in the BRT and no BRT groups (P = .60), respectively. Analysis by histologic grade did not demonstrate an impact of BRT on the development of distant metastasis, despite the improvement in local control noted in patients with high-grade lesions. The 5-year disease-specific survival rates for the BRT and no BRT groups were 84% and 81% (P = .65), respectively, with no impact of BRT regardless of tumor grade. CONCLUSION Adjuvant brachytherapy improves local control after complete resection of soft tissue sarcomas. This improvement in local control is limited to patients with high-grade histopathology. The reduction in local recurrence in patients with high-grade lesions is not associated with a significant reduction in distant metastasis or improvement in disease-specific survival.

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management.

PURPOSE Retroperitoneal soft tissue sarcomas are rare tumors. Studies characterizing long-term follow-up and patterns of recurrence are limited. The purpose of this analysis is to identify patterns of recurrence and prognostic factors associated with long-term survival after resection of retroperitoneal soft tissue sarcomas. METHODS Between July 1, 1982, and June 30, 1990, 198 adult patients were identified from our prospective soft tissue sarcoma database carrying the diagnosis of retroperitoneal soft tissue sarcoma who were eligible for > or = 5 years of follow-up. Of these, 48 patients (25%) were documented to be alive > or = 5 years from the time of operation. Statistical analysis was by log-rank or Wilcoxon test for univariate analysis. Multivariate analysis was by the Cox model. RESULTS The recurrence rate during the follow-up period was approximately 5% per year from the time of initial operation. Of the patients who were disease-free for > or = 5 years from initial surgery, 40% recurred by 10 years. Radiation therapy was the only factor significant (P = .02) for a reduction in the risk of local recurrence. Age < or = 50 years and high-grade tumors were significant factors (P = .003 and .009, respectively) for an increased risk of distant metastasis. Incomplete gross resection was the only factor significant for an increased risk of tumor mortality (P = .003). CONCLUSION Complete surgical resection at the time of primary presentation is likely to afford the best chance for long-term survival. With long-term follow-up, it is clear that recurrence will continue to occur, and a 5-year disease-free interval is not a cure. Patients with an incomplete initial resection, age less than 50 years, and high-grade tumors are candidates for investigational adjuvant therapy.

Comparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremity.

The use of amputation in extremity soft tissue sarcoma has been decreasing at Memorial Sloan-Kettering Cancer Center (MSKCC) over the last 15 years. In an attempt to define the efficacy and future role of amputation in extremity soft tissue sarcoma, a prospective sarcoma database compiled at MSKCC from July 1982 to January 1990, consisting of 649 patients, was analyzed in a retrospective fashion. Ninety-two patients underwent amputation, and 557 had a limb-sparing procedure. Patients selected for amputation were those who had large (T ≥ 5 cm) high-grade tumors that invaded major vascular or nervous structures. The amputation group achieved significantly better local control than the limb-sparing group (p = 0.007). No survival benefit could be demonstrated, however, in the groups selected for amputation (i.e., large, high-grade tumors) when compared with patients undergoing a limb-sparing procedure with similar tumors. Prevention of local recurrence by amputation also did not improve survival in this group compared with similar patients undergoing limb-sparing surgery who did develop a local recurrence. The group of patients with high-grade tumors 10 cm or larger who received chemotherapy did have a significant improvement in survival (p = 0.01) compared with a similar group of patients who did not receive chemotherapy, regardless of the type of operation. The prognosis of patients most likely to undergo an amputation for extremity soft tissue sarcoma (those with high-grade, large tumors) is not related to their local disease, but rather to the risk of distant metastases. Therefore, amputation in this cohort of patients can be recommended only when a limb-sparing procedure cannot achieve gross resection of tumor while still preserving a useful extremity, because amputation improves only local control and does not address distant disease. Further improvement in survival in this group of patients will be dependent on better systemic treatment for extremity soft tissue sarcoma, and not on more radical surgery.

Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma.

ObjectiveThe authors reviewed a series of adult patients with extremily soft tissue sarcoma to determine the incidence of pulmonary metastases and outcome after treatment. MethodsOf 716 patients admitted between January 1983 and December 1990, 135 (19%) had isolated pulmonary metastases as the initial site of distant recurrence. Fifty-eight percent (78 of 135) of the patients were treated surgically, and 83% of them had their tumors completely resected. ResultsThe median survival after complete resection was 19 months; incomplete resection, 10 months; and no operation, 8 months (p = 0.005). The 3-year survival rate after complete resection was 23%, compared with a 2% rate (1 of 57) in those treated nonsurgically (p < 0.001). Factors associated with an increased risk of pulmonary metastases included high tumor grade, tumor size greater than 5 cm, lower extremity site, and histologic type (spindle cell, tendosynovial, and extraskeletal osteosarcoma). Factors associated with complete resectability were the histologic types of spinde cell and extraskeletal osteosarcoma. ConclusionsComplete surgical resection remains the only possibility for cure from pulmonary metastases in soft tissue sarcoma; however, only 11% of the 19% of patients with an extremity sarcoma whose first distant recurrence is in the lung will be alive at 3 years, despite therapy. Complete resection and the development of more effective adjuvant treatments are imperative to improve outcome for this group of patients.

The role of multimodality therapy in soft-tissue sarcoma.

Soft-tissue sarcomas are uncommon malignancies. The development during a period of 8 years, in one institution, of a prospective data base incorporating more than 1600 patients with these tumors is described. The most common sites for occurrence are the extremities, but they can occur in any of the soft tissues of the body. Liposarcoma and leiomyosarcoma are the most common histopathologic conditions identified. Prognostic factors for both recurrence and survival include site, histopathology, size, grade, and adequacy of resection. A prospective randomized trial of the use of adjuvant radiation by the brachytherapy technique in extremity lesions has shown a decrease in local recurrence, but no impact on survival. Eligible patients not randomized to the trial show no difference in local recurrence or survival, regardless of whether they received adjuvant radiation.

Gastrointestinal autonomic nerve tumors. A clinicopathological, immunohistochemical, and ultrastructural study of 12 cases.

The gastrointestinal autonomic nerve tumor (GAN tumor) is an uncommon stromal tumor of the intestinal tract and retroperitoneum first described by Herrera and associates in 1984. Distinction of GAN tumors from other gastrointestinal stromal tumors is based on electron microscopic findings. Thus far there have been 12 reported cases. We present an additional 12 GAN tumors, identified by us during 4 years. There were seven male and five female patients and they ranged in age from 10 to 85 years (mean: 58 years). Sites of the tumors were stomach (three), jejunum (two), ileum (four), mesentery (one), and retroperitoneum (two). Eight of the tumors measured > 10 cm in greatest dimension. Usually well circumscribed, the neoplasms were tan to light pink, sometimes hemorrhagic, and soft. There was a variety of histologic patterns including fascicles, palisades, and whorls. Mitotic activity varied from 0 to 23 mitosis per 10 high-power fields (HPF). Using a panel of 10 immunohistochemical stains, only vimentin was consistently positive. There was neuron-specific enolase reactivity in six and S-100 protein reactivity in two cases. All muscle markers were negative. Ultrastructural studies showed neuron-like cells with long axonic cytoplasmic processes ending in bulbous synapse-like structures containing dense-core neurosecretory granules and clear vesicles. Basement membrane was absent. These features are reminiscent of ganglia of the intestinal autonomic nervous system. The patients were followed for 5-125 months (mean of 26 months). Tumor recurred or metastasized to the liver in seven patients (58%) and four patients died with tumor. There were correlations between tumor size (> 10 cm), mitotic count (at least five per 10 HPF), and aggressive behavior.

Primary gastrointestinal sarcomas: Analysis of prognostic variables

AbstractBackground: Primary gastrointestinal sarcomas are uncommon, and the clinicopathological determinants of survival remain unclear. In order to correlate clinical presentation, pathological assessment, and treatment with outcome, we have analyzed our institutions recent experience with these tumors. Methods: Records of adult patients admitted to our institution between July 1982 and December 1991 were reviewed. Results: During this period, 38 adult patients (>16 years of age) were admitted to our institution with a primary gastrointestinal sarcoma. They accounted for 2% of all adult sarcoma admissions during that period. The study population was composed of 26 men and 12 women. Ages ranged from 29 to 82 years (mean 59). Disease was localized to the primary site in 30 patients (81%). The stomach was the most frequent site of disease (20 cases). The small bowel was affected in nine cases (five duodenum, four jejunum) and the large bowel in nine cases (two colon, seven rectum). Ninety-two percent of patients were symptomatic at presentation. A complete resection was performed in 27 cases, incomplete resection in seven cases, and biopsy only in the remaining three patients. Nine patients received doxorubicin-based chemotherapy. Leiomyosarcoma (n=35) was the predominant histological diagnosis. Twenty-six tumors were classified as high grade (68%) and 12 as low grade (32%). Overall actuarial 5-year survival was 28% (median follow-up 26 months). Weight loss (p=0.02) and pain at presentation (p=0.05) were adverse prognostic factors. Histological grade (p=0.0002), completeness/extent of surgical resection (p=0.005), or a small bowel primary site were significant determinants of overall survival. The resection of contiguous organs did not affect survival if the primary tumor was completely excised (p=0.422). Age, race, sex, presentation (prior surgery), tumor size, or adjuvant therapy were not significant prognostic factors. Recurrence was noted in 44% after complete resection, and mean time to recurrence was 9 months (median 7, range <1–37). Hepatic metastases (42%) and local recurrence (42%) were the predominant sites of initial failure. For patients with a complete resection, grade was the major prognostic determinant (5-year survival: high grade/complete resection 18% vs. low grade/complete resection 72%, p=0.002). Conclusion: The prognosis of gastrointestinal sarcomas is poor. Complete surgical excision is the optimal therapy. However, our results suggest that surgery alone is inadequate for high-grade tumors. We believe that these patients should be considered candidates for investigational adjuvant therapies.

A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high‐grade extremity soft tissue sarcoma and an analysis of prognostic factors

A prospective randomized trial was conducted to compare the cardiotoxic and therapeutic effects of doxorubicin (60 mg/m2 every 3 to 4 weeks) administered by bolus or 72‐hour continuous infusion as adjuvant chemotherapy in 82 eligible patients after resection of high‐grade soft tissue sarcoma of the extremity or superficial trunk. Cardiac toxicity, defined as a 10% or greater decrease in left ventricular ejection fraction as assessed by radionuclide cineangiography, was evaluated in 69 patients. Cardiotoxicity was seen in 61% of patients in the bolus treatment arm with the median doxorubicin dose of 420 mg/m2. Among patients who received continuous infusion, 42% had cardiotoxicity with a median dose of 540 mg/m2. The rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm (P = 0.0017). Two patients in each group had clinical congestive heart failure, with one cardiac death occurring in each. There was a trend toward a lower rate of metastasis (P = 0.19) and a significantly lower rate of death of disease (P = 0.036) for patients treated with the bolus dose. Cox model analysis identified three unfavorable characteristics for the rate of developing a distant metastasis: blood transfusion within 24 hours of operation (P < 0.00001), tumor deep to the fascia and 5 cm or more in size (P = 0.0043), and a histologic subtype other than liposarcoma (P = 0.0002). The unfavorable effect of continuous infusion was not selected in the model (P = 0.16). Adjuvant chemotherapy for patients with soft tissue sarcoma is investigational. Furthermore, the impact of perioperative blood transfusion merits further study.

Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma.

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.