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BACKGROUND New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte–colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia. METHODS Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m2 every 3 weeks plus GCSF at a dose of 5 μg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/μL. RESULTS All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0–0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6–6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0–1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2–5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients). CONCLUSIONS Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended. Cancer 2001;91:1543–8. © 2001 American Cancer Society.

BACKGROUND The carcinoid syndrome is a common sequela in patients with carcinoid tumor metastatic to the liver. Cardiac involvement occurs in 19-56% of patients with symptomatic carcinoid syndrome and, in some patients, leads to valvular surgery to relieve symptoms due to progressive right-sided heart failure. Reports of these patients have emphasized amelioration of cardiac symptoms, but postoperative tumor status rarely has been discussed. METHODS This report describes four patients who underwent valvular heart surgery for severe carcinoid heart disease and had regression of their metastatic carcinoid tumor postoperatively. RESULTS All four patients had definite clinical improvement in cardiac function and relief of symptoms related to congestive heart failure postoperatively. Unexpectedly, they also had regression of their metastatic disease, as reflected in decreased levels of urinary 5-hydroxyindoleacetic acid, and objective evidence of a reduction in the size of hepatic metastases. CONCLUSIONS To the authors' knowledge, these four patients represent the first reported cases of metastatic disease regression after valvular surgery for carcinoid heart disease. Further descriptions of tumor status in patients having undergone a heart operation for this disease would be valuable in determining the clinical significance of this finding. Cancer 1997; 79:605-11. © 1997 American Cancer Society.

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Sixteen patients with metastatic neuroendocrine tumors and the malignant carcinoid syndrome were treated with cyproheptadine (Periactin, Merck, Sharp & Dohme, West Point, PA) at maximum tolerable doses that ranged from 12 to 48 mg daily. Usual side effects were mild sedation and dry mouth, but three patients found it impossible to sustain treatment due to nausea and vomiting. Most patients had significant relief of diarrhea, frequently associated with weight gain. Relief of flushing was uncommon. The therapeutic benefit produced by cyproheptadine would appear to be a peripheral effect because 5-hydroxyindoleacetic acid (5-HIAA) excretion in these patients was not reduced. Although there have been case reports of objective tumor regression with cyproheptadine therapy, this was not observed in any of these 16 patients. Cyproheptadine would appear to be a useful therapeutic tool for the management of diarrhea associated with the malignant carcinoid syndrome. An appropriate initial total daily dose is 0.4 mg/kg divided in three fractions with prompt modification to produce minimal and tolerable side effects.

The results of a randomized, multicenter, cooperative group trial evaluating hormonal therapy with either megestrol acetate or dexamethasone in advanced, hormonally refractory prostate cancer are reported. Three of 29 patients (approximately 10%) on the megestrol acetate arm experienced an objective response lasting 41, 84, and 202 days, respectively, whereas two of 29 patients (approximately 7%) on the dexamethasone arm achieved an objective response lasting 359 and 512 days, respectively. Twenty of 29 patients (approximately 69%) on the megestrol acetate arm had stable disease lasting for a median duration of 117 days, whereas 21 of 29 patients (72%) on the dexamethasone arm had stable disease for a median duration of 86 days. Median survival of all patients was 9 months from initiation of treatment. The median survival of all patients on the megestrol acetate arm was 268 days compared to 246 days for patients on the dexamethasone arm (P = 0.2). Neither dexamethasone nor megestrol acetate would seem to be of substantive value in altering the progression of advanced, hormonally refractory prostate cancer.

The authors report a retrospective review of their experience with bilateral testicular cancers over two 10-year periods, one each from the prechemotherapy era (1935-1944) and the postchemotherapy era (1977-1986). Three of 295 patients (1.02%) evaluated at Mayo Clinic (Rochester, MN) for testicular germ cell malignancy between 1935 and 1944 had evidence of bilateral testicular malignancy. Two of these were synchronous and one metachronous occurring 3 years after the first diagnosis. In all three, the histology was pure seminoma. None of these three had a history of undescended testes. Both patients with synchronous tumours died within 2 years (6 months and 2 years, respectively) in spite of appropriate treatment at that time, and the one with metachronous tumor survived long-term (47 years). During the modern chemotherapy era, 16 of 500 (3.2%) patients evaluated at the Mayo Clinic Rochester between 1977 and 1986 for testicular germ cell malignancy had evidence of bilateral testicular cancers (four of these were synchronous and 12 metachronous [eight seminomas, four non-seminomas]) occurring between 1 to 15 years after the first diagnosis. Only two of 16 had a history of undescended testes surgically corrected while the patients were in their teens. All patients did well after appropriate treatment. This study reemphasizes the small but definite risk for development of a second testicular malignancy and suggests a recent increase in incidence of bilateral testicular tumors as possibly related to improved treatment modalities with a higher cure rate of the original tumor.

Primary ovarian carcinoid tumors are uncommon, and carcinoid heart disease is a rare complication. Although carcinoid syndrome and carcinoid heart disease typically occur in the setting of metastatic carcinoid tumor, particularly involving the liver, this is not necessarily the case in patients with primary ovarian carcinoid tumors. After surgical resection of an ovarian carcinoid tumor, the prognosis is excellent; however, carcinoid heart disease can continue to progress. The following is a case report of a patient who, despite having complete resection of a primary ovarian carcinoid tumor, went on to develop progressive, debilitating carcinoid heart disease. This is an important scenario to recognize, because proper management and surgical intervention in carcinoid heart disease can be lifesaving.

To determine the efficacy of recombinant human leukocyte alpha-interferon (IFL-RA) in advanced hormone-refractory prostate cancer, the authors treated 40 patients with IFL-RA administered intramuscularly at a dose of 10 x 10(6) U/m2 three times weekly. Toxicity was substantial and necessitated at least a 50% dose reduction in all but five patients during the first 1-2 months of therapy. No responses were observed in patients with bone metastases, but complete and partial regression of nodal disease were observed in two patients with extraosseous disease (overall response rate, 5%; 95% confidence interval, 0.64-17.75%). The authors conclude that IFL-RA cannot be recommended at this dose and schedule in patients with advanced prostate cancer, but additional study of its use in patients with nodal disease may be warranted.

One hundred fifty-nine patients with unresectable but localized pancreatic cancer, as defined at exploratory laparotomy, were treated at the Mayo Clinic between February 1974 to April 1985. Postoperative therapy consisted of 4000 to 6000 cGy external beam irradiation (XRT) alone in 122 patients or 4500 to 5500 cGy XRT in combination with an intraoperative electron boost in 37. In addition, 132 (both groups) received 5-fluorouracil (5-FU) chemotherapy. Local control (LC) at 1 year was 82% with XRT + intraoperative radiation therapy (IORT) versus 48% with XRT and 66% versus 20% at 2 years respectively (P less than 0.0005). Due to the high incidence of hematogenous and/or peritoneal spread in both groups (abdominal failure in 54 and 56% of patients at risk), the decreased frequency of local progression did not translate into an improved survival. Neither median nor long-term survival of the two treatment groups (XRT versus XRT + IORT) was statistically different (median 12.6 months versus 13.4 months, P = 0.25). With tumor arising in the head of the pancreas, survival at 2 years was 18% as opposed to 0% for other locations (P less than 0.01). On the basis of a Cox multivariate analysis, no other treatment or prognostic factor significantly altered survival. Until the problem with systemic failure (usually abdominal) can be resolved, the median and long-term survival of patients with pancreatic carcinoma is likely to remain unchanged. Since IORT appears to improve local control, we will continue to utilize IORT in phase 1, 2 studies which also attempt to decrease the incidence of abdominal failures. Even with IORT + XRT combinations, the incidence of local progression is excessive and radiation dose modifiers need to be evaluated.

Fifty patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in a 21-day cyclic regimen. Thirty-one patients (62%) achieved a pathologically documented complete remission (CR). Of the 23 previously untreated patients, 13 obtained CR. Twenty-seven patients had been previously treated and 15/19 (79%) of those with prior major radiation therapy and 3/8 (37.5%) of those who had received both irradiation and chemotherapy achieved CR. Sixteen of the patients who attained CR received maintenance therapy with monthly alternating CCNU and vinblastine but as of this report, neither remission duration nor survival is significantly prolonged when compared to the 14 patients followed in remission on no therapy. Patients who received more than six courses of induction therapy (median 9.5, range 8-12) have had significantly fewer relapses and longer remissions than have those patients who received only six courses of therapy. It is concluded that: 1) CVPP is an effective regimen at inducing CR in patients with advanced Hodgkin's disease and has less gastrointestinal and neurologic toxicity than MOPP; 2) maintenance therapy with CCNU and vinblastine to date has not been beneficial; and 3) greater than six courses of induction chemotherapy prolongs remission duration and is associated with fewer disease relapses.

A patient is presented in whom a lymphocele developed after a retroperitoneal lymph node dissection for Stage I1 embryonal carcinoma of the testicle. The benign nature of this lymphocele has been confirmed not only by the diagnostic procedures outlined, but by its stability over a 42-month follow-up period with no further antitumor therapy. We conclude from reviewing the literature that while aggressive measures are necessary to confirm the diagnosis of a lymphocele, its management should be expectant. If significant obstruction of neighboring structures occurs, an attempt at percutaneous drainage (and possibly sclerosis) seems appropriate despite potential risks of interventional treatment such as hemorrhge and introduction of infection. Open procedures for marsupialization and drainage should be reserved for cases in which more conservative measures fail. Cancer 57:871-874, 1986.

We performed a Phase I assessment of recombinant human tumor necrosis factor (rTNF-alpha) in 27 patients with advanced solid neoplasms. Therapy consisted of a 30-minute intravenous (IV) infusion on days 1 through 5, every 2 to 3 weeks. Daily doses ranged from 5 micrograms/m2 to 200 micrograms/m2. Dose-limiting sequelae were hypotension, rigors, and phlebitis. Transient fatigue and fever (median, 38 degrees C) were not clearly dose-related between 5 micrograms/m2/d and 150 micrograms/m2/d. Other reversible complications in three patients included transient leukopenia (leukocyte count, 1.3, 1.2 X 10(3)/microliters in two patients) at a dose of 5 micrograms/m2/d and 150 micrograms/m2/d, respectively; and thrombocytopenia (leukocyte count, 73 X 10(3)/microliters) at 10 micrograms/m2/d. Among 22 patients with initial and subsequent differential counts, the median number of eosinophils at the commencement of therapy was 182 cells/microliters compared with a subsequent median of 462 cells/microliters. We also detected hypertriglyceridemia in all patients. The median baseline increased from 93 mg/dl (range, 56 to 219 mg/dl) to 203 mg/dl (range, 94 to 454 mg/dl). From our experience, a clinically manageable outpatient regimen for Phase II trials consists of rTNF-alpha (150 micrograms/m2) followed by a 1-hour IV infusion of 500 ml of normal saline to abrogate hypotension daily for 5 days every 2 weeks for four cycles, then every 3 weeks thereafter to facilitate recovery from constitutional sequelae.