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Am J Clin Oncol

Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma.

Year 1998
Rivera E. Ajani JA.
Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Metastatic islet-cell carcinoma is considered to be a slow-growing tumor. Patients are considered for systemic chemotherapy only when they are symptomatic or have impending organ failure, and streptozocin has been the chemotherapeutic agent of choice for the treatment of this disease. Chemotherapy regimens that include streptozocin have shown a higher response rate and a longer duration of response when compared with streptozocin alone. This study evaluates the objective response, response duration, and survival in patients having metastatic islet-cell carcinoma treated with a combination of doxorubicin, streptozocin, and 5-fluorouracil (DSF). Between January 1993 and March 1996, 12 patients were treated with doxorubicin, 40 mg/m2 intravenous bolus on day 1; streptozocin, 400 mg/m2 intravenous bolus on days 1 through 5; and 5-FU, 400 mg/m2 intravenous bolus on days 1 through 5. Courses were repeated every 28 days. Patients were required to have measurable disease, a Zubrod performance status < or = 2, adequate renal and liver function, and a survival expectancy of at least 12 weeks. Six (54.5%) of 11 evaluable patients achieved a partial response (durations in months: 1+, 3.5+, 13+, 17, 22, 26+); one had a minor response, two had stable disease, and two had progressive disease. One patient was lost to follow-up. No complete responses were observed. The median response duration was 15+ months and the median survival 21+ months (range, 3 to 32.5 months). No grade 3 or 4 nonhematologic or hematologic effects were observed. The DSF regimen appears to have significant activity in patients who have metastatic pancreatic islet-cell carcinoma, and patient tolerance of the regimen is excellent, thus warranting further investigation.

Daily low-dose subcutaneous recombinant interleukin-2 by alternate weekly administration: antitumor activity and immunomodulatory effects.

Year 1998
Tagliaferri P. Barile C. Caraglia M. Guarrasi R. Morelli D. Ricciardi B. Martignetti A. Librera MT. Matano E. Della Vecchia A. Catalano G. Famiani M. Palmieri G. Correale P. Bianco AR.
Cattedra di Oncologia Medica, Facolta di Medicina, Universita, Federico II di Napoli, Italy.
A phase II clinical trial of subcutaneous recombinant Interleukin 2 (rIL-2) given by 5 days pulses followed by a 9 days rest has been performed in patients affected by renal cell carcinoma, malignant melanoma and colorectal cancer. A total of 25 patients entered the study, completed at least six courses of treatment, and were evaluable for toxicity and response to treatment. This schedule of subcutaneous rIL-2 was well tolerated and no World Health Organization grade 3 side effects were observed. A 33.3% response rate was recorded in patients affected by renal cell carcinoma, although no major responses were achieved in patients with malignant melanoma and colorectal cancer. A durable increase of natural killer activity retained by poeripheral blood mononuclear cells was demonstrated in these patients and was paralleled by increased serum levels of interferon gamma and tumor necrosis factor a without changes of circulating interleukin-1d. It is concluded that this schedule of pulse administration of subcutaneous rIL-2 has antitumor activity in renal cell carcinoma and produces durable biomodulatory effects.

Metastatic adenocarcinoma arising in a congenital foregut cyst of the esophagus: a case report with review of the literature.

Year 1998
Lee MY. Jensen E. Kwak S. Larson RA.
Department of Medicine, Pritzker School of Medicine, University of Chicago, Illinois, USA.
Benign tumors and cysts of the esophagus are rare, and malignant transformation of esophageal cysts is even more rare. In this article, we report on the first case to our knowledge of a patient presenting with metastatic adenocarcinoma arising in a congenital foregut cyst of the esophagus. A 37-year-old woman had multiple cysts along the aerodigestive tract and diffuse soft tissue metastases. Endoscopic biopsies of a mediastinal mass revealed an enteric cyst with a spectrum of columnar epithelium ranging from benign through adenomatous to frankly malignant. There was only transient response to radiotherapy and chemotherapy. Only three other cases of carcinoma arising from esophageal duplication foregut cysts have been reported, and none of these were metastatic. Given the rarity of malignant transformation within an esophageal cyst, prophylactic excision of known esophageal cysts is not warranted. However, biopsy of the cyst may be useful to exclude the possibility of malignancy, particularly if the onset of symptoms has been recent.

Metastatic small-cell carcinoma of rectum responding dramatically to combination chemotherapy.

Year 1998
Yalcin S. Ozsik Y. Tekuzman G.
Hacettepe University Institute of Oncology, Ankara, Turkey.
Small-cell carcinoma of the rectum, is very rare with a dismal prognosis that follows a more aggressive course than the pure exocrine counterparts. As a result, survival is usually very poor. A male patient with metastatic disease is presented in this report. After receiving six cycles of combination chemotherapy regimen consisting of cyclophosphamide, adriamycin, and etoposide, he is in complete remission for >3 years. Although it is a single case, it shows that combination chemotherapy may achieve an excellent result even in a metastatic case of small-cell carcinoma of the rectum.

Stridor as a manifestation of supraglottic carcinoma in a patient with AIDS.

Year 1998
Wong PW. Moghtader S. Mina BA. Di Fabrizio L. Seriff NS.
Department of Pulmonary Diseases, Lenox Hill Hospital, New York, New York 10022, USA.
As patients with human immunodeficiency virus (HIV) infection are living longer, the differential diagnosis of stridor in acquired immunodeficiency syndrome (AIDS) patients should be broadened to include malignancies in addition to the common causes of infections and functional airway abnormalities. Herein, we describe a 50-year-old woman with AIDS who presented with stridor secondary to supraglottic squamous cell carcinoma.

Double modulation of 5-fluorouracil by methotrexate and high-dose L-leucovorin in advanced colorectal cancer.

Year 1998
Romero AO. Perez JE. Cuevas MA. Lacava JA. Sabatini CL. Dominguez ME. Rodriguez R. Barbieri MR. Ortiz EH. Salvadori MA. Acuna LA. Acuna JM. Langhi MJ. Amato S. Machiavelli MR. Leone BA. Vallejo CT. Lorusso V. DeLena M.
Grupo Oncologico Cooperativo del Sur, Neuquen, Republica Argentina.
A phase II trial was performed to evaluate the efficacy and toxicity of a double modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and L-leucovorin (L-LV) in patients with advanced recurrent (inoperable) or metastatic colorectal carcinoma (ACC). Between July 1993 and October 1995, 41 patients with ACC received a regimen that consisted of MTX 150 mg/m2 i.v., infused over a 20-minute period at hour 0, followed 19 hours later by L-LV 250 mg/m2 in a 2-hour i.v. infusion. 5-FU, 900 mg/m2, was administered by i.v. push injection at hour 20. Beginning 24 hours after MTX administration, all patients received four doses of L-LV, 15 mg/m2 i.m., every 6 hours. Cycles were repeated every 15 days. Two patients were not assessable for response. Objective regression was observed in 11 of 39 (28%) patients, [95% confidence interval (CI), 14-42%]. One (2%) patient achieved complete response (CR) and 10 (26%) partial response (PR). No change was recorded in 15 (39%) patients and progressive disease was noted in 13 (33%) patients. The median time to treatment failure was 6 months and the median survival time was 10 months. Toxicity was within acceptable limits, but one therapy-related death due to severe leukopenia was observed. The dose-limiting toxicity was mucositis. Eight episodes of grade 3 or 4 stomatitis were observed, and were responsible for dosage modifications of MTX and 5-FU. In conclusion, further in experimental and clinical studies are clearly necessary in order to design the best modulatory strategy of 5-FU.

Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin.

Year 1998
Meropol NJ. Blumenson LE. Creaven PJ.
Division of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
The somatostatin analog, octreotide, is effective in treating diarrhea associated with cancer chemotherapy. This study was undertaken to determine whether octreotide could be used as prophylaxis against chemotherapy-induced diarrhea and, thereby, permit increased dose intensity. Adult cancer patients were treated with a standard regimen of intravenous 5-fluorouracil (5-FU) (600 mg/m2) plus leucovorin (LV) (500 mg/m2) weekly x 6 weeks. In addition, 150 microg of octreotide was administered subcutaneously twice daily, beginning on the first day of chemotherapy and continuing for 43 days. Escalation of 5-FU was planned for successive cohorts based upon toxicity. Eleven patients were treated at the initial 5-FU dose level. In 10 evaluable patients, dose-limiting toxicities were diarrhea (two patients), fatigue (one patient), and hyperbilirubinemia (one patient). Diarrhea was experienced by six of 10 patients, and only three patients were able to receive six weekly chemotherapy treatments without dose reduction or delay. At a dose of 150 microg twice daily, octreotide did not prevent diarrhea associated with 5-FU plus LV, and 5-FU dose escalation was not possible. While octreotide is successful in the treatment of 5-FU-induced diarrhea, we were unable to demonstrate a role in toxicity prophylaxis.

Continuous venous infusion 5-fluorouracil and interferon-alpha in pancreatic carcinoma.

Year 1998
John WJ. Flett MQ.
Lucille Parker Markey Cancer Center, Lexington, Kentucky 40536-0093, USA.
Chemotherapy treatment for advanced pancreatic cancer is universally disappointing. Evidence suggested the possibility of improved activity of 5-fluorouracil (5-FU) in this disease when administered by continuous infusion in combination with interferon-alpha. Thirteen patients who had histologically documented stage III and IV adenocarcinoma of the pancreas were treated with 5-FU, 250 mg/m2/day by continuous infusion, in combination with interferon-alpha, 3 million units subcutaneously 3 times per week. Treatment was adjusted for toxicity and was continued until disease progression, unacceptable toxicity, or 8 weeks after a complete response. Responses were documented on two separate occasions that were separated by 4 weeks. Eleven men and two women were treated an average of 48 days. There was one responder, for a response rate of 7.7% (95% confidence interval, 0.1%-36%). The duration of response was 90 days. The median survival of the entire group was 8.3 months. Toxicity was significant, with more than 50% of patients requiring treatment breaks and dosage reductions. The most common toxicities were mucositis, hand-foot syndrome, diarrhea, and nausea. There were no treatment-related deaths. Treatment of advanced adenocarcinoma of the pancreas with continuous-infusion 5-FU and interferon-alpha is associated with significant toxicity without significant evidence of response.

Seventy-two hour epirubicin infusion plus quinidine in unresectable and metastatic adenocarcinoma of the pancreas: a phase II trial.

Year 1998
Abad A. Massuti B. Blanco E. Carrato A. Maurel J. Cervantes A. Aranda E. Anton A. Vicent JM. Dorta J. Garcia de Paredes ML. Ariza A.
Department of Medical Oncology, Hospital German Trias i Pujol, Badalona, Barcelona, Spain.
Twenty-two previously untreated patients who had unresectable and metastatic pancreatic cancer were treated in a prospective phase II trial with high-dose continuous infusion epirubicin (45 mg/m2 once every 24 hours continuous infusion days 4 through 6) plus quinidine (495 mg once every 24 hours on days 1-6). There were no objective responses (0 of 18 evaluable patients). Subjective responses were achieved in 2 of 21 evaluable patients (9%), all of whom had good performance status (Eastern Cooperative Oncology Group: 0-1). Median survival was 5.7 months for the overall population. Two patients who exhibited symptomatic improvement achieved responses lasting 7 and 13 months, respectively. Toxicity was generally mild and tolerable. Little benefit regarding survival and quality of life was observed with the use of this regimen. The role in chemoresistance of mdrl, p53, and the mismatch repair system was examined.

Closure of tracheoesophageal fistulas with chemotherapy and radiotherapy.

Year 1998
Ahmed HF. Hussain MA. Grant CE. Wadleigh RG.
Division of Medical Oncology, Department of Veterans Affairs Medical Center, Washington, DC 20422, USA.
In patients who have esophageal cancer with a tracheoesophageal fistula, chemotherapy and radiotherapy are usually contraindicated because it is thought to enlarge the fistula. The records of 50 patients who had esophageal cancer and received simultaneous chemotherapy and radiotherapy from January 1992 to January 1997 were evaluated in the Medical Oncology Section of the Veterans Administration Medical Center, Washington, D.C. All patients were staged radiographically and endoscopically. Four patients developed a tracheoesophageal fistula while receiving treatment. One patient developed a fistula before treatment and another patient developed a fistula after treatment. Closure of the tracheoesophageal fistulas was achieved in 4 of 5 patients who responded to therapy and in those who developed fistulas before or during therapy. One of the patients whose fistula did not close died during therapy, whereas the other who developed a fistula after therapy underwent stenting. This finding indicates that development of a tracheoesophageal fistula is not a contraindication to chemotherapy and radiotherapy, and patients who are responsive to therapy may have closure of their fistulas.

Preoperative radiotherapy for cancer of the extrahepatic bile duct.

Year 1998
Hishinuma S. Ogata Y. Matsui J. Ozawa I. Imura J.
Department of Surgery, Tochigi Cancer Center, Utsunomiya, Japan.
From January 1988 through June 1996, 12 patients who had extrahepatic bile-duct cancer received preoperative radiotherapy at doses of 40.6 Gy to 58.4 Gy. At restaging, 1 patient was found to have liver metastases and the remaining 11 patients were taken to surgery. Nine patients underwent resection, and 8 of the 9 received intraoperative radiotherapy. Complications occurred in 4 patients, 3 of whom died postoperatively. The 2 patients who died of intraabdominal complications received both preoperative radiation doses of more than 55 Gy and intraoperative radiotherapy doses of 14 Gy or more. Histologic evidence of irradiation effects was present in all specimens. Irradiation effects on perineural invasion were observed in varying degrees. Two of the four patients who had marked irradiation effects on perineural invasion developed local recurrence, which was found at autopsy to have infiltrated the hepatic hilum without obstructing the hepatic ducts. One patient who had minimal irradiation effects on perineural invasion developed local recurrence with obstructing the hepatic ducts. Of the 2 patients who had positive margins, the patient with marked irradiation effects on perineural invasion survived 18 months, but the patient with slight irradiation effects on perineural invasion survived only 5 months. The high complication rate requires modification of this strategy. The propriety of combining preoperative radiotherapy with intraoperative radiotherapy as well as the radiation dose should be reinvestigated.

A prospective randomized study comparing high- and low-dose leucovorin combined with same-dose 5-fluorouracil in advanced colorectal cancer.

Year 1998
Ychou M. Fabbro-Peray P. Perney P. Marcais O. Gouze C. Ribard D. Bons-Rosset F. Heran B. Veyrac M. Blanc F.
Service d'Oncologie Digestive, CRLC Val d'Aurelle, CHU Montpellier, France.
Although the efficacy of 5-fluorouracil (5-FU) modulated by leucovorin is well established for advanced colorectal cancer, the question of the most effective regimen and optimal dose of leucovorin remains unanswered. This prospective randomized trial compares low-dose (group 1) and high-dose (group 2) leucovorin, combined with the same dose of 5-FU to determine whether high-dose leucovorin was more beneficial than low-dose on overall survival. Inclusion criteria were: unresectable metastatic colorectal carcinoma, with or without evaluable tumor response; a performance status of less than grade 3 (World Health Organization classification); and no previous chemotherapy for metastases. Forty-two patients were randomized in group 1 (leucovorin, 20 mg/m2/day, days 1 through 5) and 41 patients in group 2 (leucovorin, 200 mg/m2/day, days 1-5). All the patients in the two groups received a 1-hour infusion of 400 mg/m2/day 5-FU every 4 weeks. The two groups were matched with no statistically significant differences in gender ratio, site of primary tumor, performance status, and tumor extent. Toxicity in the two regimens was low and not significantly different between the two groups. Overall median survival was 346 days in group 1 and 323 days in group 2 and was not significantly different between the two groups. At 1 year, the test of equivalence was significant (p < 0.01), demonstrating an absence of more than 20% benefit in 1-year survival for the high-dose regimen. The use of high-dose leucovorin combined with 5-FU in the 5-day regimen does not significantly improve overall survival for patients who have metastatic colorectal cancer.

Carcinoid tumor regression with high-dose octreotide acetate: a patient report.

Year 1998
Lokich J.
The Cancer Center of Boston, Massachussetts 02120, USA.
A patient who had carcinoid tumor of the ileum and liver and intraabdominal lymph-node metastases sustained a substantial (more than 50%) reduction of metastatic tumor burden when treated with accelerated-dosage octreotide.

A rare event of 5-fluorouracil-associated peripheral neuropathy: a report of two patients.

Year 1998
Stein ME. Drumea K. Yarnitsky D. Benny A. Tzuk-Shina T.
Department of Oncology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
5-Fluorouracil (5-FU) is known to cause multifocal cerebral demyelination, which is pathologically related to a central inflammatory demyelinating process. To date, no case of peripheral neuropathy has been described after the administration of 5-FU alone. The authors describe two patients who had peripheral neuropathy that developed while they were receiving 5-FU-based chemotherapy.

Advanced carcinoma of the pancreas: phase II study of combined chemotherapy, beta-interferon, and retinoids.

Year 1998
Recchia F. Sica G. Casucci D. Rea S. Gulino A. Frati L.
ULLS 2 Civilian Hospital, Division of Medicine, Avezzano, C.R.O.F.I., Monterotondo, Rome, Italy.
Because of the poor response of pancreatic cancer to conventional therapy, the authors performed a phase II pilot study to evaluate whether beta-interferon and retinoids, added to active chemotherapeutic agents, could increase response rate and survival in a group of patients who had metastatic disease. Twenty-three chemotherapy-naive patients were treated as follows: epirubicin, 60 mg/m2, and mitomycin C, 10 mg/m2, intravenously on day 1; folinic acid, 200 mg/m2, and 5-fluorouracil (5-FU), 370 mg/m2, intravenously for 5 consecutive days. beta-Interferon, 1 x 10(6) IU/m2, subcutaneously three times a week, and retinol palmitate, 50,000 IU orally twice a day, were given between chemotherapy cycles. Patients having responses and disease stabilization were maintained with the same dose of beta-interferon and retinol palmitate. Treatment was given every 4 weeks for four courses or until onset of progression. A median of three courses of chemotherapy was delivered to each patient. All patients were evaluable. Eight patients responded (35%) and 8 (35%) had stable disease. Median time to progression and survival for all patients were, respectively, 6.1 months and 11 months. Toxicity was severe: 60% of patients had hematologic toxicity, 40% had gastrointestinal toxicity, 13% had cardiac toxicity, and 1 patient had a hemolitic-uremic syndrome. The combination of chemotherapy, beta-interferon, and retinoids shows activity in metastatic pancreatic carcinoma. Toxicity was high but patients who had responses and disease stabilization had prolonged symptom palliation.

Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil.

Year 1998
deBraud F. Munzone E. Nole F. De Pas T. Biffi R. Brienza S. Aapro MS.
Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.

Monoclonal antibodies in the treatment of metastatic carcinoma to the liver: updated report of a pilot study including leukapheresis.

Year 1998
Hill BS. Minard T. Brady LW.
Department of Radiation Oncology, Allegheny University of the Health Sciences, Hahnemann Division, Philadelphia, Pennsylvania 19102, USA.
Twenty-two patients who had failed conventional treatment for advanced colorectal carcinoma metastatic to the liver were entered in this study. Survival from the date the hepatic disease was documented and ranged from 3 to 62 months, with an average of 20 months. Notably, 8 of the 22, or 36%, lived 24 months or more. Four patients, or 18%, survived 3 to 5 years after diagnosis of hepatic metastasis.

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