Phase II trial of postoperative adjuvant intraperitoneal cisplatin and fluorouracil and systemic fluorouracil chemotherapy in patients with resected gastric cancer.

PURPOSE: This study was performed to assess the short- and long-term toxicities and the impact on relapse pattern and survival of postoperative intraperitoneal (IP) cisplatin and fluorouracil (FU) plus systemic intravenous (IV) FU as adjuvant therapy for gastric cancer patients who are at high risk for recurrence after potentially curative resection (T2N1-2M0 or T3-4N(any)M0). PATIENTS AND METHODS: Starting 14 to 28 days after potentially curative resection of primary gastric cancers, 35 patients were given IP cisplatin 25 mg/m2 and FU 750 mg daily for 4 days; FU 750 mg/m2 was concurrently given as a continuous 24-hour i.v. infusion. Five cycles of therapy delivered at 1-month intervals were used. RESULTS: After a median follow-up of 24 months, 51% of patients remain alive and free of disease. Sixteen patients have recurred; 13 of 16 had an intraabdominal component, whereas three had extraabdominal failure only. Two major treatment-related toxicities were noted: neutropenia and a late toxicity of peritoneal fibrosis (sclerosing encapsulating peritonitis [SEP]). There was one postoperative death. Eleven patients underwent second laparotomy: five patients had SEP, two patients had bowel obstruction from adhesions unrelated to SEP, and four patients had recurrent cancer. Potential causes of SEP included an alkaline pH of infused FU and cisplatin that possibly led to activation of cisplatin before infusion. CONCLUSION: IP cisplatin and FU and concurrent systemic FU is a tolerable adjuvant therapy in the postoperative setting for patients with resected gastric cancer. The recommended dosage schedule with this technique is cisplatin 25 mg/m2 and FU 750 mg total dose IP with FU 500 mg/m2 as a continuous 24-hour infusion daily for days 1 to 4. SEP as a late toxicity, which was observed in 15% of patients, is treatable by surgical lysis of adhesions.

Hypophosphatemia after major hepatic resection.

METHODS: We performed a retrospective study of 44 patients who underwent right or extended right hepatic lobectomy to determine the incidence and significance of hypophosphatemia after major hepatic resection. RESULTS: The postoperative serum phosphate level (measured as inorganic phosphorus) dropped in all 44 patients studied. Profound hypophosphatemia (less than 1.0 mg/dl) was significantly (p less than 0.001) associated with the frequent development of major postoperative complications (cardiorespiratory, five cases; infections, four cases; hemorrhage, one case; and liver failure, one case). Factors such as extent of liver resection, blood loss, blood or plasma transfusion, postoperative bilirubin level, and preexisting liver diseases showed no significant correlation with the nadir inorganic phosphorous level. Use of aluminum-containing antacids caused a further drop of the serum values (p less than 0.05). Early phosphorous replacement showed a significant protective effect (p less than 0.05), with higher serum levels and fewer major complications. CONCLUSIONS: These observations affirm the importance of frequent monitoring and replacement of phosphate after major hepatic resection.

Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma.

Recent studies suggest an improved survival in patients who undergo radical lymph node dissection for the curative treatment of gastric carcinoma. We have undertaken a retrospective review to compare morbidity and mortality between patients who underwent radical lymph node dissection and those who underwent resections of lesser scope. Of the surgically related events compared, only the amount of postoperative abdominal drainage was significantly different in the group that underwent radical lymph node dissection Forty-four percent of patients who underwent radical lymph node dissection and 35% of patients who underwent a procedure of lesser scope developed a major complication. There was also no significant difference in the postoperative death rate, with a total of two 30-day in-hospital deaths (1.1%). Our observations indicate that radical lymph node dissection can be performed as safely as lesser operations for gastric carcinoma, and should not be avoided because of the fear of complications.

Brachytherapy and function-saving resection of soft tissue sarcoma arising in the limb.

The treatment of soft tissue sarcoma of the limb by function-saving resection and brachytherapy (BRT) was systematically studied from 1975 to 1990 at the Memorial Sloan-Kettering Cancer Center, using iridium-192 temporary tumor-bed implants. Initial experiences showed an 88% local control rate in 33 patients who had locally advanced sarcomas, many of which would have required treatment by amputation. The technique also controlled 70% of tumors that abutted or invaded a major neurovascular bundle that was dissected out and preserved. A prospective randomized study (BRT vs no BRT) confirmed the highly significant efficacy of BRT in preventing local recurrence. This salutary effect is mainly seen in high-grade tumors. Major complications of wound healing occurred in the earlier years of this experience. Adoption of improved techniques of surgical wound repair, standardization of radiation dose planning, and in particular, postponing the loading of radiation sources until after the fifth postoperative day has reduced the rate of serious wound complications, to a level not significantly different from that seen after surgical resection alone. These results rival those currently achieved in centers experienced in external beam therapy of soft tissue sarcomas, and offer the advantage of completion of treatment in one relatively short hospital stay.

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.

Role of brachytherapy in recurrent extremity sarcoma in patients treated with prior surgery and irradiation.

The treatment options for recurrent extremity sarcoma following conservative surgery and irradiation are limited. Amputation is the treatment of choice offered for the majority of these patients. In a selected group of patients with recurrent sarcoma, we have investigated the role of brachytherapy along with function-preserving resection. From 1979 to 1988, 40 patients underwent resection and brachytherapy for recurrent extremity sarcoma. There were 23 males and 17 females. All of the patients received function-preserving resection and an afterloading temporary tumor bed implant. A median dose of 4500 cGy was delivered with a range from 3000 to 4800 cGy. The median follow-up was 36 months with a range of 12 to 120 months. The actuarial local control at 5 years is 68%. Five patients (12.5%) developed complications such as wound ulceration (4) and femoral fracture (1) requiring surgery. Five patients developed local failure and an additional two patients had both local and distant failure. All of the failures occurred in patients with more than two prior recurrences. This review suggests that brachytherapy can be used as an effective treatment option in selected patients with recurrent extremity sarcoma following prior surgery and irradiation with satisfactory limb preservation. The data also suggest that higher local control rates can be achieved with early brachytherapeutic intervention.

Early gastric cancer. Twenty-eight-year experience.

A retrospective study of early gastric cancer (60 patients) was performed to evaluate its diagnosis and treatment. Ninety-five per cent of patients presented with nonspecific gastrointestinal symptoms and 53.3% had been treated for presumed benign disease for up to 48 months before diagnosis. Fiberoptic endoscopy detected these lesions more accurately than radiologic examination. The disease-free 5-year survival rate after resection was 76.4%. Survival showed no significant correlation with sex, tumor site, macroscopic appearance, extent of gastric resection, or histopathologic type. Tumors larger than 1.5 cm in diameter, invasion of submucosa, or lymph node metastasis resulted in significantly lower survival rates. Three of eight patients with nodal metastasis survived 5 or more years, including one who had second-echelon deposits. A high index of suspicion may permit more frequent detection. Extended lymphadenectomy (R2) is recommended to achieve the highest possible cure rate.

Effect of splenectomy on morbidity and survival following curative gastrectomy for carcinoma.

We performed a retrospective analysis of 392 patients who underwent curative resection of gastric adenocarcinoma to evaluate the impact of splenectomy on survival from gastric cancer and postoperative morbidity. Twelve factors, including splenectomy, were associated with a poor prognosis by univariate analysis. Multivariate analysis identified six of these factors, but not splenectomy, as independently predictive of death due to gastric cancer. The apparent adverse effect of splenectomy was due to its association with other significant risk factors. Postoperative complications occurred more commonly in patients who underwent splenectomy than in those who did not (45% vs 21%); patients in the splenectomy group also had a higher percentage of infectious complications than those in the nonsplenectomy group (75% vs 47%). We conclude that splenectomy has no direct influence on survival, but that it increases the morbidity of curative gastrectomy and should be avoided unless the spleen is close to or invaded by the tumor.

Combined surgical resection and iridium 192 implantation for locally advanced and recurrent desmoid tumors.

Thirty-eight histologically confirmed desmoid tumors were treated with conservative surgical resection and interstitial iridium 192. Patients included in this series constituted a poor prognostic group. Seventy five percent (75%) had previous recurrences of their disease and 50% had tumors 8 cm or greater in size. In addition, 16% of the patients had gross residual disease after surgical excision and 79% had positive or close margins of resection. With a median follow-up of 5.5 years, the 5-year actuarial in-field local control rate was 75% and the overall local control rate was 66%. Four of the 12 local recurrences developed at the periphery of the implant volume and four patients failed at least 3 cm or more beyond the treated volume. After salvage therapy, the 5-year actuarial local control rate was 95%. Two patients required amputation for recurrent disease. Thirty of 34 patients remain free of disease with an excellent functional result achieved. The authors conclude that surgical resection and postoperative interstitial iridium 192 is effective therapy for patients with desmoid tumors. Despite the fact that most patients in this series had bulky, recurrent tumors, excellent long-term local control and limb function were achieved.

Limb salvage in soft tissue sarcomas involving neurovascular structures using combined surgical resection and brachytherapy.

While there is debate in the literature concerning the tolerance of neurovascular structures to external beam radiation, the tolerance of these tissues to interstitial radiation has never been established. To evaluate the dose of radiation and its effect on early and late toxicity of neurovascular structures, a retrospective review of our experience was undertaken. Between 1975 and 1987, 299 patients with extremity sarcomas underwent limb-sparing surgery and tumor bed Iridium-192 interstitial implantation at Memorial Sloan-Kettering Cancer Center. Forty-five patients (15%) of this group were found to have locally advanced tumors involving major neurovascular structures. Of these patients, 64% had high grade lesions. Eleven percent had evidence of gross residual disease on these structures, and an additional 58% had microscopic residual disease at or close to the margins of resection. After loading catheters were placed directly upon the neurovascular structures in the exposed tumor bed and a median dose of 4400 cGy was delivered to the target volume. Eight patients had previous radiation to the treated field and 13 patients received postoperative radiation. With a median follow-up of 4 years, the 5-year actuarial disease-free survival was 69% and the 5-year actuarial freedom from in-field failure was 79%. The 5-year actuarial incidence of distant metastases was 30%. Eighty-four percent of the patients maintained long-term preservation of limb function without the need for amputation. Four patients (9%) ultimately developed evidence of radiation neuritis 6-20 months post therapy. All four patients had received additional radiation with cumulative doses exceeding 9000 cGy to the neurovascular bundle. We conclude that combined surgical resection and interstitial radiation for locally advanced sarcomas with neurovascular involvement can provide excellent local control with preservation of limb and neurovascular function without significant toxicity.

Soft tissue sarcomas of the head and neck in adults.

We reviewed the clinical records and pathologic material of 176 adults with primary soft tissue sarcomas treated at Memorial Sloan-Kettering Cancer Center between 1950 and 1985. Seventy-two patients (41%) had low-grade sarcomas and 104 (59%) had high-grade sarcomas. All but 18 patients underwent some form of excision as initial therapy. Adjuvant radiotherapy and chemotherapy combined with surgical excision showed no significant effect. A significantly increased risk of treatment failure was associated with large tumor size, positive surgical margins, bone involvement, local recurrence, metastatic spread, and high histologic grade. Except for recurrence, the p value by univariate analysis in the log-rank test for comparison of survival according to these clinical and pathologic characteristics was p less than 0.0001. Although the overall survival was 75% at 2 years, 55% at 5 years, and 46% at 10 years, only 20% of the patients with high-grade sarcomas were alive 10 years after treatment. Most patients with rhabdomyosarcoma, high-grade peripheral nerve tumor, and high-grade fibrous histiocytoma and all patients with high-grade angiosarcoma died of disease less than 5 years after diagnosis. New therapeutic strategies are needed to improve the survival of adult patients with high-grade soft tissue sarcomas of the head and neck.

Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors.

The cellular schwannoma is a variety of schwannoma with a predominantly cellular growth but no Verocay bodies. Because doubt has been raised about the original assessment of this tumor as benign, the clinical and pathologic characteristics of 58 cellular schwannomas from 57 patients were reviewed. The patients were most often middle aged (63% were female), and their tumors most commonly were painless masses with a predilection for the paravertebral region of the retroperitoneum, pelvis, and mediastinum. Most tumors were solitary and encapsulated, and an associated nerve was identified for 43% of the cases. Electron microscopic and immunohistochemistry studies confirmed the tumor's Schwann cell nature. Worrisome features such as bone erosion, hypercellularity, foci of necrosis (four tumors), hyperchromasia, nuclear pleomorphism, and the presence of mitotic figures led to a malignant diagnosis for 28% of the cases. Treatment in all but one case was surgical excision. Two patients also received radiation therapy and chemotherapy. Follow-up of from 1 year to 24 years, 7 months (median of 6 years and mean of 7 years) for 61% (35 cases) of the cases reveals three patients with a local recurrence but no cases in which the tumor metastasized or the patient died of the tumor. Awareness of this tumor type is important so that the surgeon will avoid unnecessary sacrifice of functionally important nerves attached to these tumors and so that needless adjuvant radiation and chemotherapy will not be instituted.

Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases.

Using strict clinical and pathologic criteria for the inclusion of cases, the authors have reviewed the clinicopathologic features of 43 malignant peripheral nerve sheath tumors of the buttock and extremity seen over a 35-year period. Twenty-three (53%) of the patients had neurofibromatosis (VRN), whereas 20 (47%) did not. Fifty-one percent of the patients were women. The mean age at presentation was 36 years for patients with VRN and 44 years for patients without VRN. A nerve of origin was identified for 72% of the cases and an associated neurofibroma for 44% (65% with VRN and 20% without VRN). The mean greatest dimension of the tumors was 12.3 cm, and this did not differ significantly between the two groups. The predominant histologic pattern in 86% of the tumors was that of tightly packed spindle cells in an interlacing and woven pattern; heterologous sarcomatous elements were noticed in 12% of the cases. Surgical resection was the main modality of treatment for all patients; 65% also received adjuvant therapy. Follow-up evaluation was done in every case. An unexpected finding was the absence of a significant difference in survival rates between patients with and without VRN. Overall, 63% of the patients died of tumor: 65% of the patients with VRN and 60% of the patients without VRN. Large tumor size and high mitotic rate (greater than 20 per 10 high-power fields) portended a poor prognosis, as did the need for resection by amputation. Adjuvant radiation therapy and chemotherapy did not affect survival rates.

Role of brachytherapy in malignant melanoma: a preliminary report.

From August 1979 to May 1986, various brachytherapy techniques were applied at Memorial Sloan Kettering Cancer Center (MSKCC) in an adjuvant setting with/without surgery and external radiation therapy in the management of advanced malignant melanoma. Thirty-three patients underwent brachytherapy procedures. The patients' ages ranged from 35 to 82 years, with a median age of 56 years. Fourteen patients had disease localized to the implant site, whereas 19 patients also had disseminated disease elsewhere. The indications for implant were residual gross disease (21), microscopically positive margins (3), and histologically negative but clinically close margins of resection (9). Local control at the implant site was noted in 80% of patients at 6 months and 42% of patients at 1 year; two patients had reached 54 months and 72 months with no evidence of disease. Local control was 100% (9/9) in patients with histologically negative but clinically close margins of resection, and 48% (11/23) with microscopically positive margins and/or gross residual disease. Complications were seen as follows: delay in wound healing (1), wound infections (4), radiation enteritis (1), small bowel obstruction (1). The present study suggests that brachytherapy combined with surgery can achieve a good local control in patients with negative but clinically close margins of resection. In patients with gross residual disease who are at a high risk for local recurrence, approximately one-half can be locally controlled with this approach. These preliminary results should be tested in a prospective controlled study.

Malignant soft-tissue tumors of the anterior abdominal wall.

Malignant soft-tissue tumors of the abdominal wall consist of desmoid tumors and nondesmoid soft-tissue sarcomas. These neoplasms tend to invade adjacent musculoaponeurotic and bony structures. Transperitoneal organ invasion can also occur with devastating sequelae, especially after an incomplete excision. Extirpation with the full-thickness of the abdominal wall is required except for small, superficial lesions. A wide-margin resection, including any adherent viscus, segments of adjacent ribs, and iliac or pubic crest, offers the best assurance of local control. Adjunctive radiotherapy can be given when the margin of resection is unavoidably limited, but an effective radiation dose can be difficult to administer, due to the sensitivity of underlying intestines. Metastases develop frequently with high-grade sarcomas; adjuvant chemotherapy may be tried in these patients, but its value remains unproven.

Soft tissue sarcomas: current trends in diagnosis and management.

Sarcomas (fleshy tumors) were distinguished from carcinoma (crab leg tumors) at the time of Hippocrates. Sarcomas are related embryologically to leukemias and lymphomas because all are thought to be malignancies of mesodermal embryologic origin. Neurosarcomas, however, are an exception, since they arise from tissue of neuroepidermal origin. Malignant sarcomas of the soft tissue represent an unusual primary malignant tumor. These lesions are characterized by their diversity in the histologic appearance and in their biologic behavior, as well as in anatomical origin. Currently there are approximately 7,400 newly diagnosed bone and soft tissue sarcomas, and approximately 4,200 deaths per year in the United States.1 The incidence of sarcomas varies by histologic type in various age groups. Embryonal rhabdomyosarcoma in the orbit peaks in the 4-year-old, and in the urinary tract in adolescence.2 Osteosarcoma has peak incidence in the teenage years, and Ewing's sarcoma develops between the ages of 15 and 30. Other sarcomas such as malignant fibrous histiocytoma and chondrosarcoma generally occur in patients aged more than 55 years. The incidence of osteosarcoma in whites and nonwhites is equal; Ewing's sarcoma is predominantly a disease of Caucasians.3 The relatively infrequent occurrence of these tumors plus their diverse histology and diverse presentations have made it difficult for any one institution to have enough patients to directly compare, in a randomized prospective fashion, one treatment with another in order to determine the optimal primary therapy. The purpose of this monograph is to review recent concepts in terms of pathology, surgery, radiation therapy, chemotherapy, and multimodality therapy.

Pancreatic cystadenoma. A clinicopathologic study.

A retrospective study of 19 patients with pancreatic cystadenoma included 15 patients with microcystic and 4 with mucinous cystadenomas. The typical clinical presentation was that of an elderly woman with an upper abdominal mass. An association with diabetes mellitus and extrapancreatic malignant disease was noted. Total tumor resection provided the best chance of cure and removed the risk of compression of adjacent organs and, in mucinous cystadenomas, the risk of malignant transformation.

Adenocarcinoma of the stomach: a multivariate analysis of clinical, pathologic and treatment factors.

We performed a retrospective prognostic study of 246 patients treated for adenocarcinoma of the stomach with curative intent over the period 1960-1984. Lesions of the cardia and gastro-esophageal junction were excluded. The study examined the prognostic influence of nine clinicopathologic and six treatment variables by univariate and multivariate analysis. Five-year survival rates (Kaplan-Meier) for TNM stages, IA, IB, II, IIIA, and IIIB were 88%, 80%, 55%, 30% and 9%, respectively. The Cox models of proportional hazards identified five independent variables predictive of death from gastric cancer: high TNM stage, metastatic involvement of four or more regional lymph nodes, poor differentiation of tumor, splenectomy and insufficient scope of regional lymph-adenectomy relative to the nodal stage (R minus N less than 1.5).

The desmoid tumor. Not a benign disease.

The necessity of aggressive therapy for desmoid tumors has not been clearly established. To evaluate the therapeutic value of adequate resection and radiation therapy, we conducted a retrospective study of 138 patients treated from 1965 through 1984. Univariate analysis revealed five factors predictive of local failure: (1) age between 18 and 30 years, (2) presentation with recurrent disease, (3) partial or limited margin excision, (4) tumor at or close to the microscopic margin of resection, and (5) radiation therapy not administered for gross residual disease. Multivariate analysis identified two of these factors as having independent predictive value for recurrence: (1) presentation with recurrent disease and (2) less-than-adequate margins of resection. The five-year survival probability was 92%, but 11 of the 138 patients died as a consequence of locally uncontrolled tumor. These findings confirm that desmoid tumors are malignant soft-tissue neoplasms that warrant aggressive therapy.