ONCOLOGY Vol 18 No 14_Suppl_14

The 1-year survival for patients with metastatic non–small-cell lungcancer is only around 35%. We are evaluating the combination ofirinotecan (Camptosar) and carboplatin (Paraplatin) in patients withstage IIIB and IV non–small-cell lung cancer. The first five patientsreceived irinotecan, 250 mg/m2 over 90 minutes followed by carboplatinat an area under the concentration-time curve of 5 over 1 hour. Thedose of irinotecan was subsequently reduced to 200 mg/m2 in view offebrile neutropenia in one of five patients. Chemotherapy cycles arerepeated every 21 days. Patients are reevaluated every two cycles. Of aplanned 42 patients, 37 have been enrolled so far. Of the 37 enrolledpatients, 25 received at least two cycles, 20 received at least four cycles,and 12 received all six planned cycles. Grade 4 neutropenia (absoluteneutrophil count < 500) occurred in 10 patients and 19 treatment cycles.Two of these patients also had grade 4 diarrhea. Thirty-six cycles (30%)were delayed for neutropenia, six of which occurred among the firstfive patients who received irinotecan at 250 mg/m2. Best response totherapy included 7 partial responses (23%), 11 stable disease (37%),with 12 patients having progressive disease (40%). The regimen ofirinotecan and carboplatin administered once every 3 weeks is tolerableand convenient, with early evidence of activity. The main toxicityis hematologic. This study is ongoing and actively accruing patients.

This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastaticbreast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) incomparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those withmetastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapyfor metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, openlabel,phase II study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for sixcycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weeklyafter an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions inleft ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treatedwith EC60 + H and in 14 patients (56%) treated with EC90 + H vs 6 patients (26%) in the EC90 alone cohort.LVEF decreases to < 50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+Hcohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overallresponse rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this studysuggest the cardiac safety of the combination of H with EC may be greater than that of H with AC (doxorubicin[Adriamycin]/cyclophosphamide); however, studies in larger numbers of patients are warranted. The combinationregimen revealed promising efficacy.

There are two conventional treatments for clinically resectable rectalcancer. The first is surgery followed by postoperative combinedmodalitytherapy if the tumor is T3 and/or N1/2. The second, if thetumor is ultrasound T3 or clinical T4, is preoperative combined-modalitytherapy followed by surgery and postoperative chemotherapy. Thereare a number of new chemotherapeutic agents that have been developedfor the treatment of colorectal cancer. Phase I/II trials are examiningthe use of new chemotherapeutic agents in combination with pelvicradiation therapy, most commonly in the preoperative setting. Thereis considerable interest in integrating irinotecan (Camptosar) into preoperativecombined-modality therapy regimens for rectal cancer. Basedon these trials, the recommended regimen for patients who receiveirinotecan-based combined-modality therapy is continuous infusionfluorouracil (5-FU), irinotecan, and pelvic radiation. New trials examiningpreoperative combined-modality therapy regimens substitutingcapecitabine (Xeloda) for continuous infusion 5-FU are in progress.

Overexpression of cyclooxygenase-2 (COX-2) is frequently presentin lung cancer and may play a significant role in carcinogenesis, invasion,and metastasis. It has been associated with shortened survival inpatients with resected early-stage adenocarcinoma of the lung. COX-2inhibition decreases tumor cell proliferation in vivo and has been shownto enhance tumor radiosensitivity. Additionally, COX-2 inhibition mayprotect normal pulmonary tissue from radiation fibrosis. Clinical studiesare under way to assess the potential benefits and risks of COX-2inhibition in the treatment of lung cancer. The rationale for COX-2inhibitors in the treatment of lung cancer will be reviewed. The resultsof a phase II study assessing the acute toxicity of concurrent celecoxib(Celebrex) and thoracic irradiation in patients with non–small-cell lungcancer (NSCLC) are reported, and an ongoing Radiation TherapyOncology Group study using celecoxib and concurrent radiation therapyfor NSCLC in patients with intermediate prognostic factors is reviewed.

Unresectable pancreatic cancer has few therapeutic options and adismal prognosis. Cyclooxygenase-2 (COX-2) expression is increasedat the RNA and protein levels in most human pancreatic cancers. Thepurpose of this trial was to determine whether the addition of a COX-2inhibitor to chemotherapy was beneficial. To date, 11 patients with inoperablepancreatic cancer have been treated with the combination ofgemcitabine (Gemzar), irinotecan (Camptosar), and celecoxib(Celebrex) at 400 mg orally twice daily. Encouraging pain relief, improvementin performance status, and decreases in CA 19-9 andcarcinoembryonic antigen levels have been observed.

The combination of irinotecan (Camptosar), epirubicin, andcapecitabine (Xeloda) has shown an acceptable toxicity profile. In thisopen-label phase I study, irinotecan was administered IV at a fixeddose of 250 mg/m2 on day 1 in combination with capecitabine at a fixeddose of 1,500 mg/m2 for days 2 to 7 and epirubicin starting at a dose of40 mg/m2 and escalating by 10 mg/m2 in cohorts of three patients forthose with metastatic adenocarcinomas. With the addition of granulocytecolony-stimulating factor (G-CSF [Neupogen]) to the regimen,patients received epirubicin at clinically relevant doses after dose-escalation.Results of the topoisomerase activity will be reported with thefinal results of this phase I study. The dose-limiting toxicity has not yetbeen reached. This combination regimen in patients with upper gastrointestinalmalignancies and breast cancer will be investigated as partof phase II studies, once the dose-limiting toxicity is determined. Theappropriate sequencing of the regimen to maximize clinical efficacywill also be determined.

Variations of fluorouracil (5-FU) therapy have formed the backboneof chemotherapy for advanced colorectal cancer for many years.With the advent of newer agents that often work best with or even requirechemotherapy to optimize their activity, the issue of the optimalschedule and regimen of administration of 5-FU has taken on a renewedimportance. The combination of irinotecan with 5-FU/leucovorinhas consistently improved survival and response rates in comparisonto 5-FU/leucovorin alone. However, the combination also increasesthe toxicity of the treatment, thus resulting in continuing attemptsto improve on the toxicity profile of the combination, while retainingor improving upon the therapeutic outcomes. This article reviewsthe various combinations of irinotecan with 5-FU/leucovorin.

Adjuvant chemotherapy has been shown to be beneficial in patientswith breast cancer, and anthracycline-containing regimens are more effectivethan non–anthracycline-containing ones. The French AdjuvantStudy Group (FASG) compared FEC100 and FEC50 (fluorouracil[5-FU]/epirubicin [Ellence]/cyclophosphamide [Cytoxan, Neosar])in patients with node-positive breast cancer, with an end point of overallsurvival. After a median follow-up of 10 years, the benefit/risk ratio of theFEC100 regimen in patients with positive axillary nodes is strongly positive.Furthermore, a medicoeconomic study showed that the cost per yearof life saved was very low-approximately 1,000 euros.

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 epidermal growth factor receptor (EGFR) plays an importantrole in cell growth, differentiation, and survival. Targeting EGFR inpatients with colorectal cancer has become an important therapeutictool. Recently, a monoclonal antibody against the extracellular domainof the receptor (cetuximab [Erbitux]) has been approved for the treatmentof patients with EGFR-positive metastatic disease refractory toirinotecan (Camptosar)-based therapy. The role of other targeted agentsagainst EGFR, including other monoclonal antibodies as well as inhibitorsof the intracellular tyrosine kinase domain, will also be discussed.

The 6th University of Texas M. D. Anderson Cancer Center Investigators’Workshop was held on July 16–20, 2003, in Amelia Island, Florida.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular emphasis on the broadly used agent irinotecan(Camptosar), and also novel regimens or agents.