Esophageal Cancer

ROCHESTER, MINNESOTA-A phase II study from the NorthCentral Cancer Treatment Group(NCCTG) showed that oxaliplatin(Eloxatin) combined with lower-dosecapecitabine (Xeloda) is active as first

Esophageal cancer frequently expresses cyclooxygenase-2 (COX-2)enzyme. In preclinical studies, COX-2 inhibition results in decreasedcell proliferation and potentiation of chemotherapy and radiation. Wereport preliminary results of a phase II study conducted by the HoosierOncology Group in patients with potentially resectable esophageal cancer.All patients received cisplatin at 75 mg/m2 given on days 1 and 29and fluorouracil (5-FU) at 1,000 mg/m2 on days 1 to 4 and 29 to 32with radiation (50.4 Gy beginning on day 1). Celecoxib (Celebrex) wasadministered at 200 mg orally twice daily beginning on day 1 untilsurgery and then at 400 mg orally twice daily until disease progressionor unexpected toxicities, or for a maximum of 5 years. Esophagectomywas performed 4 to 6 weeks after completion of chemoradiation. Theprimary study end point was pathologic complete response (pCR). Secondaryend points included response rate, toxicity, overall survival, andcorrelation between COX-2 expression and pCR. Thirty-one patientswere enrolled from March 2001 to July 2002. Respective grade 3/4 toxicitieswere experienced by 58%/19% of patients, and consisted of granulocytopenia(16%), nausea/vomiting (16%), esophagitis (10%), dehydration(10%), stomatitis (6%), and diarrhea (3%). Seven patients (24%)required initiation of enteral feedings. There have been seven deathsso far, resulting from postoperative complications (2), pulmonary embolism(1), pneumonia (1), and progressive disease (3). Of the 22 patients(71%) who underwent surgery, 5 had pCR (22%). We concludethat the addition of celecoxib to chemoradiation is well tolerated. ThepCR rate of 22% in this study is similar to that reported with the use ofpreoperative chemoradiation in other trials. Further follow-up is necessaryto assess the impact of maintenance therapy with celecoxib onoverall survival.

Esophageal cancer is a rare but highly virulent malignancy in theUnited States, and adenocarcinoma of the esophagus has had the mostrapid rate of increase of any solid tumor malignancy. Systemic metastaticdisease is present in 50% of patients at diagnosis. In the remaining50% presenting with local regional disease, systemic metastatic diseasewill develop in the vast majority of these patients.

From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

NEW YORK-A retrospective review of 10 years of data on patients who underwent surgical resection for esophageal cancer has shown no survival advantage for patients who had a complete pathologic response to neoadjuvant chemoradiation followed by surgery vs those who had surgery alone. In light of this finding, the researchers suggest that other therapeutic avenues be explored for patients with locally advanced esophageal cancer.

Both irinotecan (CPT-11, Camptosar) and paclitaxel have beenshown to have single-agent activity in adenocarcinomas of the esophagusand gastric cardia. A phase I trial of the combination at UCLAestablished the dose as irinotecan at 225 mg/m2 and paclitaxel at100 mg/m2 every 3 weeks. Preliminary data from a phase II trial of thisregimen in adenocarcinomas of the gastroesophageal junction showgood tolerability and promising activity (response rate of 27%), even inA previously treated patients.

The outcomes for patients with metastatic or recurrent esophagealcancer are dismal, with 1-year survival rates of approximately 20%. Inthis phase II study, we studied the combination of docetaxel (Taxotere)and irinotecan (CPT-11, Camptosar) in patients with metastatic orrecurrent esophageal cancer. Eligible patients included those withhistologic or cytologic diagnosis of adenocarcinoma or squamouscancer of the esophagus or gastroesophageal junction who had receivedno previous chemotherapy for metastatic esophageal cancer. Previouschemotherapy in the neoadjuvant or adjuvant setting was allowed.Patients received irinotecan at 160 mg/m2 over 90 minutes followed bydocetaxel at 60 mg/m2 intravenously over 1 hour, with chemotherapycycles repeated every 21 days. Patients were reevaluated every twocycles. Of a planned 40 patients, 15 were enrolled, with 14 patientsevaluable for toxicity and 10 evaluable for response and survival. Thecombination of docetaxel and irinotecan resulted in a response rate of30%. An additional 40% achieved stable disease. The median survivalwas 130 days, with three patients still alive at the time of this analysis.The toxicities included 71% incidence of grade 4 hematologic toxicities,with 43% febrile neutropenia. One patient died of cecal perforationafter one cycle. There was no evidence of pharmacokinetic interaction,as systemic clearance of both drugs was similar to that seen after singleagentadministration. In conclusion, the regimen of docetaxel andirinotecan is active in metastatic or recurrent esophageal cancer.However, this combination chemotherapy regimen has an unacceptablerate of febrile neutropenia. This regimen needs to be modified toreduce the incidence of febrile neutropenia.

ROCKVILLE, Maryland-The Food and Drug Administration has approved Photofrin (porfimer sodium, Axcan Scandipharm) for the ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo an esophagectomy. The agency acted less than 2 months after its Gastrointestinal and Coagulation Drugs Advisory Committee recommended that the FDA approve this new indication for the photodynamic therapy (PDT) agent.

Local-regional carcinoma of the esophagus is often diagnosed inadvanced stages because the diagnosis is established when symptomsare severe. The prognosis of patients with local-regional carcinoma ofthe esophagus continues to be grim. While preoperative chemoradiotherapyincreases the fraction of patients who achieve pathologiccomplete response, that percentage is approximately 25%. In an attemptto increase the number of patients with either no cancer in the surgicalspecimen or only microscopic cancer, we adopted a three-step strategy.The current study utilized up to two 6-week cycles of induction chemotherapywith irinotecan (CPT-11, Camptosar) and cisplatin as step 1.This was followed by concurrent radiotherapy and chemotherapy withcontinuous infusion fluorouracil (5-FU) and paclitaxel as step 2. Oncethe patients recovered from chemoradiotherapy, a preoperative evaluationwas performed and surgery was attempted. All patients signed aninformed consent prior to their participation on the study. A total of 43patients were enrolled. The baseline endoscopic ultrasonography revealedthat 36 patients had a T3 tumor, five patients had a T2 tumor, andtwo had a T1 tumor. Twenty-seven patients had node-positive cancer(N1). Thirty-nine (91%) of the 43 patients underwent surgery; all hadan R0 (curative) resection. A pathologic complete response was noted in12 of the 39 patients. In addition, 17 patients had only microscopic(< 10%) viable cancer in the specimen. Therefore, a significant pathologicresponse was seen in 29 (74%) of 39 taken to surgery or 29 (67%)of all 43 patients enrolled on the study. With a median follow up beyond25 months, 20 patients remain alive and 12 patients remain free ofcancer. Our preliminary data suggest that the proportion of patientswith significant pathologic response can be increased by using thethree-step strategy.

The limited effectiveness of chemotherapy in esophageal cancerused to palliate metastatic disease or to combine with radiotherapy inlocally advanced disease has prompted the evaluation of new systemicagents. Irinotecan (CPT-11, Camptosar) has shown promising activityin a number of gastrointestinal cancers, including esophageal cancer.The phase II evaluation of the combination of weekly irinotecan andcisplatin has shown encouraging response rates exceeding 30% to 50%in esophageal and gastric cancer. Novel regimens include the combinationof irinotecan with mitomycin (Mutamycin), the taxanes docetaxel(Taxotere) and paclitaxel, and continuous infusion fluorouracil(5-FU). Irinotecan is an active radiosensitizer, and trials have evaluatedthe combination of irinotecan with concurrent radiotherapy. We completeda phase I trial combining weekly irinotecan, cisplatin, andconcurrent radiotherapy in locally advanced esophageal cancer. Minimaltoxicity has been observed, with no grade 3/4 esophagitis ordiarrhea, and hematologic toxicity was also surprisingly minimal. Fulldoses of weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2) could becombined safely with concurrent radiotherapy, with a significant rate ofpathologic complete response. Phase II evaluation of this chemoradiotherapyregimen as preoperative therapy is planned at single institutionsand at the cooperative group level in the United States. Furtherphase I and II investigation of combined irinotecan, cisplatin, andconcurrent radiation is ongoing with the addition of targeted agents,including celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab(Avastin). Alternative combinations of irinotecan with radiotherapy,including the addition of docetaxel and continuous infusion 5-FU, arealso undergoing phase I and II evaluation.

Docetaxel (Taxotere) has been successfully investigated in the therapy for advanced gastroesophageal tumors as both a single agent and in combination regimens. As a single agent, phase II study results demonstrate an overall response rate of 17% to 24%, with occasional complete responses in a disease in which complete responses are rare. These figures classify docetaxel among the most active agents for the disease.

Combined-modality approaches for the treatment of non-small-cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer offer survival benefits by improving locoregional control and treating micrometastatic disease. The taxanes are active, tolerable drugs in these solid tumors and have radiation-sensitizing activity.

The limited effectiveness of currently available chemotherapy in the treatment of advanced esophageal cancer, and the poor survival achieved in locally advanced disease with combined chemoradiotherapy with or without surgery, have prompted the evaluation of new agents. Irinotecan (CPT-11, Camptosar) has promising single-agent activity in gastrointestinal cancers.

We conducted a phase II study to assess the response rate and toxicity profile of the irinotecan (CPT-11, Camptosar) plus cisplatin combination administered weekly to patients with at least one previous chemotherapy for advanced adenocarcinoma of the stomach or gastroesophageal junction. Patients with histologic proof of adenocarcinoma of the stomach or gastroesophageal junction with adequate liver, kidney, and bone marrow functions were treated with 50 mg/m² of irinotecan plus 30 mg/m² of cisplatin, both administered intravenously 1 day a week for 4 consecutive weeks, followed by a 2-week recovery period.

SAN DIEGO-A new rapid technique for quantitative reverse transcription-polymerase chain reaction (QRT-PCR) detects nodal micrometastases in esophageal cancer patients intraoperatively and predicts disease recurrence. The technique is quicker and perhaps more accurate than intraoperative histology, making it useful in determining the need for neoadjuvant therapy in some types of cancer.

A 65-year-old man with a history of a "bleeding ulcer" 7 years earlier presents with complaints of progressive dysphagia for solids and liquids over the past 4 months. The patient states that he has had a 40-pound weight loss during this time, but denies any fevers, chills, abdominal pain, melena, or anorexia. He states that recently he cannot go to his favorite restaurant, as whenever he eats he experiences severe coughing fits. He also describes regurgitation of undigested materials soon after eating.

A 60-year-old attorney presents with chronic heartburn and regurgitation. His symptoms have steadily increased over the last 2 years, and he is currently using daily therapy with a proton pump inhibitor. There is no history of gastrointestinal bleeding, dysphagia, or weight loss.

WASHINGTON-Combining gene therapy with radiotherapy may provide a useful approach to combating human esophageal cancers, said Vinay Kumar Gupta, MD, of the University of Chicago Medical School, at the 54th Annual Cancer Symposium of the Society of Surgical Oncology.

WASHINGTON-Sufficient evidence exists to suggest that patients undergoing pancreatic and esophageal cancer surgery have lower mortality rates at high-volume hospitals and that physicians and patients should consider this fact in making treatment decisions, a report by the Institute of Medicine (IOM) said.

The Food and Drug Administration (FDA) and the National Cancer Institute (NCI) inaugurated a new program in July that

SAN FRANCISCO-Two cycles of preoperative cisplatin (Platinol) and fluorouracil (5-FU) may improve survival in patients with resectable esophageal cancer, compared with surgery alone, according to a large study from the United Kingdom presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 502).

NEW YORK-Esophageal cancer, though relatively rare in the United States, is deadly, with a 90% mortality for patients treated with conventional therapy. David H. Ilson, MD, PhD, assistant attending physician at Memorial Sloan-Kettering Cancer Center in New York City, described new multimodal attempts to improve these outcomes.

SAN ANTONIO, Texas-Although combined-modality therapy is considered the standard of care for patients with advanced esophageal cancer, the anatomical and physiological characteristics of the esophagus pose serious limitations on dose escalation. Cytoprotective strategies that might allow clinicians to circumvent these limitations were reviewed by Charles R. Thomas. Jr., MD.

WASHINGTON-Medicare will begin or expand coverage of positron emission tomography (PET) diagnostic scans for several cancers on July 1. For the first time, Medicare will cover PET for head and neck cancers, except for central nervous system and thyroid cancers, and esophageal cancer. Coverage will apply to diagnosis, staging, and restaging.

Irinotecan (Camptosar) has shown activity in several solid tumor malignancies, including gastric and pancreatic cancer. In vitro studies suggest antitumor activity in esophageal cancer cell lines. Sequence-dependent synergy

PHILADELPHIA-Physicians should approach the use of retinoids for chemoprevention of aerodigestive cancers very carefully, warns a research scientist who has been studying the use of natural and synthetic vitamin A in animal models with esophageal cancer. The studies have shown increased tumorigenicity among the animals treated with the synthetic vitamin.

HAMBURG, Germany-Barely one fifth of patients who undergo surgery for esophageal cancer are alive 2 years later, and studies exploring the possible benefits of preoperative chemotherapy and radiotherapy have yielded equivocal results at best.

Chemotherapy for advanced gastric and gastroesophageal junction carcinomas remains suboptimal. Both irinotecan (Camptosar) and cisplatin (Platinol) are active against this group of malignancies. This article focuses