Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer.

BACKGROUND: The purpose of the study was to evaluate the efficacy of weekly paclitaxel (Taxol) in advanced esophageal cancer. PATIENTS AND METHODS: One hundred and two patients with advanced esophageal cancer were treated with paclitaxel 80 mg/m2 weekly over a 1-h infusion. One cycle was defined as 4 weeks of therapy. Ninety-five patients were assessable for toxicity and 86 patients who completed at least two cycles of treatment were assessable for response. Sixty-six patients had adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy. RESULTS: A median of three cycles was delivered (range 1-11). Partial responses (PRs) were seen in 11 patients [13%, 95% confidence interval (CI) 6% to 20%]. In patients without prior chemotherapy, PRs were seen in 10 patients (15%, 95% CI 6% to 24%), with comparable response in adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was seen in patients with prior chemotherapy (1/21, 5%). The median duration of response was 172 days. The median survival was 274 days. Therapy was well tolerated with minimal hematologic or grade 3 or 4 toxicity. CONCLUSION: Weekly paclitaxel has limited activity in esophageal cancer. The median survival, modest activity, and tolerance of therapy indicate that weekly paclitaxel may be an option in patients unable to tolerate combination chemotherapy.

Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV.

PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course. RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups. CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

Evolving management and outcome of esophageal cancer with airway involvement.

BACKGROUND: Esophageal cancer with airway involvement, including patients with esophagorespiratory fistula (ERF), has been associated with a poor prognosis. Multimodality treatment, self-expanding metal stents, and improved supportive therapy may be impacting outcome in these patients. There is concern for the development of ERF during therapy. METHODS: We retrospectively studied 74 consecutive male patients at a single institution presenting between 1/85 to 12/98 with bronchoscopic, endoscopic or radiographic confirmation of airway involvement with esophageal cancer, including 35 patients with ERF. Comparison was made between the first 35 patients (group I) and the last 39 patients (group II) with regard to antineoplastic therapy, stent placement, and survival. RESULTS: Treatment in group I included supportive care in 17 of 35 patients, plastic stent in 7 of 35 patients, and radiation or chemotherapy in 9 of 35 patients. In group II, radiation or chemotherapy was offered to 33 patients, and self-expanding metal stents were placed in 10 of 39 patients. Surgical resection was possible after neoadjuvant therapy in 13 of 39 patients in group II, including 2 initially presenting with ERF. Median survival in group I was 16 weeks and in group II was 37 weeks. Comparison of Kaplan-Meier survival estimates using log rank testing demonstrated improved survival in group II (p = 0.0026). Long-term survival in 4 group II patients initially presenting with ERF and receiving multimodality treatment was observed. Development of ERF during treatment occurred in 3 group II patients. Treatment failure was predominantly local in group I and local and distant in group II. CONCLUSIONS: More aggressive treatment may favorably influence outcome in esophageal cancer with airway invasion. Long-term survival and the development of ERF during therapy occurred at similar rates.

Refinement of regions with allelic loss on chromosome 18p11.2 and 18q12.2 in esophageal squamous cell carcinoma.

Esophageal cancer ranks among the 10 most common cancers worldwide and is almost invariably fatal. The detailed genetic repertoire involved in esophageal carcinogenesis has not been defined. We have shown previously that the esophageal squamous cell carcinoma genome exhibits a frequent loss of heterozygosity (LOH) in the pericentromeric region of chromosome 18. To construct a fine deletion map, we screened 76 new samples composed of microdissected esophageal squamous cell carcinoma and matched morphologically normal epithelial cells using closely spaced markers. Maximal LOH frequency (54%) was displayed by D18S542 on 18p11.2. The pattern of LOH in selected patients indicated that the short region of overlap extends 3 cM on either side of D18S542. On the long arm of chromosome 18, the highest frequency of allelic loss (42%) was detected by D18S978 on 18q12.2-q21.1. This analysis revealed a short region of overlap of approximately 0.8 cM. These findings further implicate unreported tumor suppressor genes encoded by 18p11.2 and 18q12.2 in esophageal squamous cell carcinogenesis and they indicate a refinement of their map location.

Simultaneous chemotherapy and radiotherapy with escalating doses of chemotherapy in patients with advanced esophageal carcinoma.

From January 1992 to January 1995, 39 patients were diagnosed with esophageal carcinoma at the Department of Veterans Affairs Medical Center in Washington, D.C. All of the patients were men aged 44 to 78, and the median age was 66. Staging included a physical examination, serum chemistries, barium swallow, endoscopy with biopsy, and computed tomographic scans of the chest and abdomen. Seven patients were ineligible for the study because they had poor performance status, refused treatment, or received treatment at another medical center. All the patients treated had a performance status of 1 to 2. In 1992, 15 patients received 400 mg/m2/d 5-fluorouracil; in 1993, eight patients received 500 mg/m2/d 5-fluorouracil; and in 1994, nine patients received 600 mg/m2/d 5-fluorouracil as a continuous intravenous infusion during radiotherapy, which consisted of 60 Gy over 6 to 8 weeks. The complete response rates were 26%, 25%, and 22% for 1992, 1993, and 1994, respectively. The median survival was 11 months, 14 months and 9 months for those same years, respectively. The major toxicities were hematologic. Three patients died of pneumonia during treatment. Simultaneous chemotherapy and radiotherapy is an effective mode of therapy for localized esophageal carcinoma. However, escalating doses of chemotherapy did not increase the complete response rate.

Treatment of a malignant enterocutaneous fistula with octreotide acetate.

An enterocutaneous malignant fistula developed in a patient who had a retroperitoneal angiosarcoma. He was treated with octreotide acetate subcutaneously. Drainage decreased and ceased after 2 weeks of therapy. The closure of this malignant fistula suggests that palliative therapy with octreotide acetate merits further study in view of the grave prognosis of this complication.

Hypercalcemia in patients with esophageal cancer.

Hypercalcemia is a paraneoplastic syndrome that is associated with squamous cell cancers and which may be of life-threatening proportions. We investigated the incidence and prognostic importance of hypercalcemia in patients with esophageal cancer at the Department of Veterans Affairs Medical Center, Washington, DC, USA. The medical records of 170 patients with esophageal cancer from January 1988 to January 1998 were examined. Of the 170 patients with esophageal cancer, 47 (27.6%) had hypercalcemia during the course of their disease. Five (10.6%) of the 47 hypercalcemic patients were found to have hypercalcemia at the time of diagnosis. Forty-six of the 47 hypercalcemic patients had squamous cell carcinoma and 1 had adenosquamous cell carcinoma. Seven (14.8%) had bony metastasis. The median survival of patients with hypercalcemia and esophageal cancer was 12.4 months and 12.6 months for patients without hypercalcemia. Hypercalcemia is a common complication of squamous cell esophageal carcinoma. The survival of patients with or without this complication is similar; thus, it may not be a poor prognostic factor.

Molecular cytogenetic fingerprinting of esophageal squamous cell carcinoma by comparative genomic hybridization reveals a consistent pattern of chromosomal alterations.

Esophageal cancer is the third most prevalent gastrointestinal malignancy in the world. The tumor responds poorly to various therapeutic regimens and the genetic events underlying esophageal carcinogenesis are not well understood. To identify overall chromosomal aberrations in esophageal squamous cell carcinoma, we performed comparative genomic hybridization (CGH). All 17 tumor samples were found to exhibit multiple gains and losses involving different chromosomal regions. The frequency of chromosomal loss associated with this type of tumor was as follows: in 2q (100%), 3p (100%), 13q (100%), Xq (94%), 4 (82%), 5q (82%), 18q (76%), 9p (76%), 6q (70%), 12q (70%), 14q (65%), 11q (59%), and 1p (53%). Interstitial deletions on 1p, 3p, 5q, 6q, 11q, and 12q were detected also. Chromosomal gains were displayed by chromosomes and chromosome areas: 19 (100%), 20q (94%), 22 (94%), 16p (65%), 17 (59%), 12q (59%), 8q (53%), 9q (53%), and 3q (50%). Two sites showing apparent amplification were 11q (70%) and 5p15 (47%). To validate the CGH data, we isolated a BAC clone mapping to 18q12.1. This clone was used as a probe in interphase fluorescence in situ hybridization of tumor touch preparations and allelic loss was clearly revealed. This study represents the first whole-genome analysis in esophageal squamous cell carcinoma for associated chromosomal aberrations that may be involved in either the genesis or progression of this malignancy.

Systematic screening of chromosome 18 for loss of heterozygosity in esophageal squamous cell carcinoma.

Esophageal cancer ranks among the 10 most common cancers in the world, and is almost uniformly fatal. The genetic events leading to the development of esophageal carcinoma are not well established. To identify genomic regions involved in esophageal carcinogenesis, we performed a systematic screening for loss of heterozygosity (LOH) in 24 samples of squamous cell carcinomas, initially focusing the analysis on chromosome 18. Thirteen short tandem repeat markers spanning 18p and 18q were used. We found a broad peak of LOH spanning 18p11.2 and 18q21.1 with the most frequent LOH (72%) at D18S978 on 18q12.2, which coincides with a known fragile site FRA18A. This region is 4 cM proximal to known tumor suppressor genes and therefore suggests the possible existence of a yet undiscovered tumor suppressor gene.

Closure of tracheoesophageal fistulas with chemotherapy and radiotherapy.

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.

Deletion of a consensus oestrogen response element half-site in the glucocorticoid receptor of human multiple myeloma.

We have carried out molecular scanning of the glucocorticoid receptor (GR) of the glucocorticoid resistant multiple myeloma cell line U266. An amplified fragment from the 3' untranslated region displayed an aberrant migration by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis. The mutant allele had a deletion of an 8 base pair sequence containing a half-site of an oestrogen response element. This motif was found conserved in rat GR. This same allele lacked four As in an upstream region with 18 consecutive As in the normal allele. These mutations may affect mRNA stability or alter interactions with regulatory factors.

Sequential chemotherapy and radiotherapy for squamous cell esophageal carcinoma.

A Phase II study of sequential chemotherapy with 5-fluorouracil and cisplatin followed by radiotherapy was initiated to see whether the use of two therapies sequentially could have an effect on response rate. Thirteen patients with advanced squamous cell carcinoma of the esophagus were treated with 1,000 mg/m2/day 5-fluorouracil days 1-5 continuously and 100 mg/m2 cisplatin on day 1. An average of four cycles (range, one to nine) were given every 28 days; 11 patients received more than three cycles. The radiation consisted of 60 Gy over 6-8 weeks. There was only one (8%) complete response (CR) and 11 (85%) partial responses (PRs). Restaging after radiation revealed no conversion of PR to CR. Median survival was 39 weeks (range, 6-208+). Chemotherapy alone or its use sequentially with radiotherapy is inadequate, and newer approaches are needed to to improve survival.

Management of secretions in esophageal cancer patients with glycopyrrolate.

BACKGROUND: There has been little emphasis in the past upon management of excessive secretions in patients with esophageal cancer. We used the drug glycopyrrolate for controlling secretions in patients with esophageal cancer. PATIENTS AND METHODS: Between January 1991 and September 1995, 45 patients with esophagus cancer were referred for evaluation. Seven of these patients were treated with glycopyrrolate for increased secretions. Secretions were measured in suction canisters which were used by patients. RESULTS: All the patients showed a decrease in secretions within 24 48 hours of administration. The incidence of side effects was minimal. CONCLUSIONS: Glycopyrrolate is quite effective in palliating esophageal cancer patients with excessive secretions.

Nonsurgical closure of esophago-respiratory fistulas: role for the somatostatin analogue octreotide acetate?

Esophago-respiratory fistulas (ERF) do not close spontaneously and are uniformly fatal. A somatostatin analogue (octreotide acetate) was used in three consecutive patients to promote the closure of ERF. In 2 patients with esophageal cancer, treatment with octreotide acetate was associated with fistula closure in 30 and 46 days, respectively. In a third patient with virally-induced ERF, treatment was associated with improvement of the inflammation of the fistula before the patient's death from pulmonary aspiration after 40 days of treatment. These preliminary observations suggest that octreotide acetate treatment of ERF should receive further investigative scrutiny.

Closure of tracheoesophageal fistulas with primary chemotherapy in patients with esophageal cancer.

BACKGROUND: In patients with tracheoesophageal fistula, radiation is thought to be contraindicated because cytoreduction enlarges the size of the fistula. The same caveat should also apply to cytoreduction with chemotherapy, but there are few data addressing this issue. METHODS: The records of 16 patients with esophageal cancer who received chemotherapy in 1991 were evaluated in the Medical Oncology Section of the Veterans Administration Medical Center, Washington, DC. All patients were staged radiographically and endoscopically. Four of these 16 were seen initially with or developed tracheoesophageal fistulas during therapy. Two patients whose fistulas closed during chemotherapy are presented. RESULTS: All four patients with tracheoesophageal fistulas had midesophageal squamous cell carcinomas. Objective complete responses with closure of tracheoesophageal fistulas occurred in two of four patients after three and four cycles of chemotherapy, respectively. One of these fistulas first developed, then healed during treatment, whereas the other presented at the time of diagnosis with fistula. CONCLUSION: The findings indicated that patients with tracheoesophageal fistulas should not be excluded from chemotherapy solely on the basis of having this condition. The treatment of patients with tracheoesophageal fistulas with chemotherapy needs to be reexamined.

Nocardiosis after corticosteroid therapy for malignant thymoma.

BACKGROUND: Nocardia asteroides is an opportunistic infection caused by an aerobic actinomycete, which, in the immunocompromised host, can be associated with severe invasive disease with a predilection for the brain. METHODS AND RESULTS: The authors describe a 62-year-old man with a malignant thymoma that was clinically responsive to oral prednisone. N. asteroides sepsis subsequently developed, leading to his death. CONCLUSIONS: Nocardiosis should be considered a potential pathogen in this immunocompromised setting.

Vitamin E in the treatment of chemotherapy-induced mucositis.

PURPOSE: To determine the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis in patients with malignancy. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study was performed to evaluate the efficacy of topical vitamin E in the treatment of oral mucositis in patients receiving chemotherapy for various types of malignancy. A total of 18 patients, 17 of whom had solid tumors and one with acute leukemia, were included in this study. Lesions were observed daily prior to and 5 days after topical application of either vitamin E or placebo oil. RESULTS: Six of nine patients receiving vitamin E had complete resolution of their oral lesions. In eight of nine patients who received placebo, complete resolution of their oral lesions was not observed. This difference is statistically significant (p = 0.025 by Fisher's exact test). No toxicity was observed in this study. CONCLUSION: These results suggest that vitamin E may be an effective therapy in patients with chemotherapy-induced mucositis.