Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

The impact of COVID-19 on cancer care and oncology clinical research: an experts' perspective.

The coronavirus disease-19 (COVID-19) pandemic promises to have lasting impacts on cancer clinical trials that could lead to faster patient access to new treatments. In this article, an international panel of oncology experts discusses the lasting impacts of the pandemic on oncology clinical trials and proposes solutions for clinical trial stakeholders, with the support of recent data on worldwide clinical trials collected by IQVIA. These lasting impacts and proposed solutions encompass three topic areas. Firstly, acceleration and implementation of new operational approaches to oncology trials with patient-centric, fully decentralized virtual approaches that include remote assessments via telemedicine and remote devices. Geographical differences in the uptake of remote technology, including telemedicine, are discussed in the article, focusing on the impact of the local adoption of new operational approaches. Secondly, innovative clinical trials. The pandemic has highlighted the need for new trial designs that accelerate research and limit risks and burden for patients while driving optimization of clinical trial objectives and endpoints, while testing is being minimized. Areas of considerations for clinical trial stakeholders are discussed in detail. In addition, the COVID-19 pandemic has exposed the underrepresentation of minority groups in clinical trials; the approach for oncology clinical trials to improve generalizability of efficacy and outcomes data is discussed. Thirdly, a new problem-focused collaborative framework between oncology trial stakeholders, including decision makers, to leverage and further accelerate the innovative approaches in clinical research developed during the COVID-19 pandemic. This could shorten timelines for patient access to new treatments by addressing the cultural and technological barriers to adopting new operational approaches and innovative clinical trials. The role of the different stakeholders is described, with the aim of making COVID-19 a catalyst for positive change in oncology clinical research and eventually in cancer care.

Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study.

BACKGROUND: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. PATIENTS AND METHODS: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. RESULTS: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. CONCLUSIONS: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer.

BACKGROUND: PEP02, also known as MM-398, is a novel nanoliposomal irinotecan that has improved pharmacokinetics and tumour bio-distribution of the free drug. This phase 2 study evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer. METHODS: Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status ≥70, and had progressed following gemcitabine-based therapy were eligible. Intravenous injection of PEP02 120 mg m(-2) was given every 3 weeks. Simon 2-stage design was used. The primary objective was 3-month survival rate (OS(3-month)). RESULTS: A total of 40 patients were enrolled. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhoea. Three patients (7.5%) achieved an objective response, with an additional 17 (42.5%) demonstrating stable disease for a minimum of two cycles. Ten (31.3%) of 32 patients with an elevated baseline CA19-9 had a >50% biomarker decline. The study met its primary end point with an OS(3-month) of 75%, with median progression-free survival and overall survival of 2.4 and 5.2 months, respectively. CONCLUSION: PEP02 demonstrates moderate antitumour activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients. Given the limited treatment options available to this patient population, a phase 3 trial of PEP02 (MM-398), referred to as NAPOLI-1, is currently underway.

Pancreatic cancer treatment and research: an international expert panel discussion.

BACKGROUND: Pancreatic cancer has proven extremely challenging to treat. A collaborative effort is needed to advance research and improve treatment. An expert conference was conducted to elicit perspectives regarding the current treatment and future research of pancreatic cancer. METHODS: The conference comprised an international panel of experts representing five European countries and the United States. RESULTS: Adjuvant radiotherapy is used more frequently in the United States than in Europe. In locally advanced disease, there is now more emphasis on early chemotherapy in both Europe and the United States. In metastatic disease, combination chemotherapy is commonly used in Europe and the United States. This varies by country. Advancing pancreatic research will require improving biorepositories and developing a roadmap to prioritize therapeutic targets in different models. Small randomized phase II trials of both non-selected and enriched patient populations will help identify activity of new agents. Phase III trials should only be initiated in appropriate patients based on strong clinical and biological signals. Developing drugs in the adjuvant setting may be preferable to eliminate some of the challenges of drug development in the advanced disease setting. CONCLUSION: Progress in research combined with encouraging improvements from the past offer hope for the future of pancreatic cancer patients.

The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007.

Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.

The management of pancreatic cancer. Current expert opinion and recommendations derived from the 8th World Congress on Gastrointestinal Cancer, Barcelona, 2006.

This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

Outpatient treatment with (131)I-anti-B1 antibody: radiation exposure to family members.

UNLABELLED: The Nuclear Regulatory Commission (NRC) regulations that govern release of patients administered radioactive material have been revised to include dose-based criteria in addition to the conventional activity-based criteria. A licensee may now release a patient if the total effective dose equivalent to another individual from exposure to the released patient is not likely to exceed 5 mSv (500 mrem). The result of this dose-based release limit is that now many patients given therapeutic amounts of radioactive material no longer require hospitalization. This article presents measured dose data for 26 family members exposed to 22 patients treated for non-Hodgkin's lymphoma with (131)I-anti-B1 antibody after their release according to the new NRC dose-based regulations. METHODS: The patients received administered activities ranging from 0.94 to 4.77 GBq (25--129 mCi). Family members were provided with radiation monitoring devices (film badges, thermoluminescent or optically stimulated luminescent dosimeters, or electronic digital dosimeters). Radiation safety personnel instructed the family members on the proper wearing and use of the devices. Instruction was also provided on actions recommended to maintain doses to potentially exposed individuals as low as is reasonably achievable. RESULTS: Family members wore the dosimeters for 2--17 d, with the range of measured dose values extending from 0.17 to 4.09 mSv (17--409 mrem). The average dose for infinite time based on dosimeter readings was 32% of the predicted doses projected to be received by the family members using the NRC method provided in regulatory guide 8.39. CONCLUSION: Therapy with (131)I-anti-B1 antibody can be conducted on an outpatient basis using the established recommended protocol. The patients can be released immediately with confidence that doses to other individuals will be below the 5-mSv (500 mrem) limit.

Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access.

PURPOSE: To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L). PATIENTS AND METHODS: Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression. RESULTS: Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months. CONCLUSION: The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.

Single-Dose versus fractionated radioimmunotherapy of human colon carcinoma xenografts using 131I-labeled multivalent CC49 single-chain fvs.

The prospects of radiolabeled antibodies in cancer detection and therapy remain promising. However, efforts to achieve cures, especially of solid tumors, with the systemic administration of radiolabeled monoclonal antibodies (MAbs) have met with limited success. Using genetic engineering techniques, MAbs have been tailored to improve the therapeutic index (tumor:normal tissue ratio) in clinical radioimmunotherapy. In the present study, we investigated the potential of tetravalent ([sc(Fv)2]2) and divalent [sc(Fv)2] single chain Fvs of MAb CC49 for therapy in athymic mice bearing s.c. LS-174T human colon carcinoma xenografts. Mice received 1,000 microCi of 131I-labeled [sc(Fv)2]2 or 131I-labeled sc(Fv)2, either as a single injection on day 6 or as four injections (250 microCi each) on days 6, 7, 8, and 9; the day of tumor implantation was taken as day 0. The median survival for the control group was 26 days. Comparisons of single and fractionated therapeutic regimens showed median survival as 32 (P < 0.001) and 53 days (P < 0.0001), respectively for [sc(Fv)2]2 and 26 (P > 0.5) and 38 days (P < 0.0001), respectively for sc(Fv)2 when compared with the control groups. The time for the quadrupling of tumor volume for single and fractionated therapeutic treatments were: 9.0 +/- 0.8 and 21.1 +/- 2.9 days respectively for sc(Fv)2; 16.6 +/- 1.9 and 32.9 +/- 2.7 days respectively for [sc(Fv)2]2; and 8.3 +/- 0.7 and 8.4 +/- 0.6 days respectively for the control group. No 131I-labeled systemic toxicity was observed in any treatment groups. The results show that radioimmunotherapy delivery for sc(Fv)2 and [sc(Fv)2]2 in a fractionated schedule clearly presented a therapeutic advantage over single administration. The treatment group receiving tetravalent scFv showed a statistically significant prolonged survival with both single and fractionated administrations suggesting a promising prospect of this reagent for cancer therapy and diagnosis in MAb-based radiopharmaceuticals.

High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial.

A Phase I trial of increasing administered activities of 90yttrium (90Y)-labeled monoclonal antibody (MAb) CC49 was conducted to determine whether extrahematopoietic toxicity occurred with this radioimmunoconjugate. Twelve patients with various gastrointestinal tract cancers were administered a tracer dose of 111In-labeled MAb CC49 for biodistribution and pharmacokinetic studies. Patients then underwent a single treatment with increasing administered activities of 90Y-labeled MAb CC49 (0.3, 0.4, and 0.5 mCi/kg). Biodistribution studies, using 111In-labeled MAb CC49 as a surrogate, were determined using planar and single photon emission computed tomography imaging. Pharmacokinetic studies were performed by measuring radioactivity in blood samples taken at intervals after radioimmunoconjugate infusions. Tissue biopsies of tumor metastases and related normal tissues (liver and bone marrow) were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using these data. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria. No dose limiting extrahematopoietic toxicity was identified in the range of administered activities used in this study. Radioimmunolocalization based on planar and single photon emission computed tomography images 111In-labeled MAb CC49 showed heterogeneous (nonspecific) liver and splenic uptake. Liver metastases were usually photopenic, and extrahepatic metastases showed faint to moderate uptake. The alpha and beta half-lives of 111In-labeled MAb CC49 and 90Y-labeled MAb CC49 in the blood were similar. Absorbed radiation dose estimates in metastatic tumor sites ranged from 180 to 3000 cGy. The percentage of injected dose/kg of tumor ranged from 1.12 to 18.14; however, tumor:normal liver ratios were consistently <1. No objective responses were observed. Doses of up to 0.5 mCi/kg could be administered with reversible grade IV myelotoxicity. Absorbed radiation dose in tumor was suboptimal, even at the highest administered activity level. Deposition of 90Y in liver was high, and estimates of absorbed dose in liver equaled or exceeded that which could be achieved in metastatic tumor sites. Strategies to enhance access of radioimmunoconjugates in tumor and diminish deposition in the liver need to be developed for effective treatment using MAb CC49 with chelated radiometals.

Phase I/II trial of multiple dose 131Iodine-MAb LL2 (CD22) in patients with recurrent non-Hodgkin's lymphoma.

The purpose of this to evaluate in a phase I/II study the efficacy and toxicity of a multi-dose administration of 131I labeled CD22 monoclonal antibody (131I-MAb-LL2) in escalating dose cohorts administered to relapsed non-Hodgkin's lymphoma (NHL) patients. Twenty-one patients with relapsed NHL received one of four dose levels of 131-MAb-LL2 administered in a twice weekly pattern. Starting with dose level 2, the patients also received 20 mg of unlabeled LL2 prior to each radiolabeled dose administered. Previously stored autologous peripheral blood progenitors were reinfused in case of prolonged cytopenias. Patients could repeat the same treatment if they had stable disease or a response to the first therapy at 8 weeks, and had not received their peripheral blood progenitors with the first cycle. Combining all of the dose cohorts, there were 5 complete responses or complete responses (undetermined) and 2 partial responses for a total response rate of 7/21 (33%). There was no dose response effect with responses documented at all dose levels. Expected toxicities were hematopoietic, requiring stem cell re-infusion in 5 patients. Other toxicities included hypothyroidism in 3 patients, and human anti-mouse antibody formation (HAMA) in 4 patients. In conclusion, 131I-MAb-LL2, when administered in a multi-dose fashion with 20 mg unlabeled antibody pre-dosing, resulted in a response rate of 33% in heavily pre-treated NHL patients. Non-hematologic toxicities were mild and few in number. Further evaluation of this treatment is warranted and further dose escalation will be possible.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer.

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (90Y-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5 +/- 10.3 mCi/m2) of 90Y-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered approximately 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 90Y. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.

Pharmacokinetics of levamisole in cancer patients treated with 5-fluorouracil.

PURPOSE: To investigate the pharmacokinetics of levamisole and a metabolite, p-hydroxylevamisole in patients with colorectal cancer treated with 5-fluorouracil (5-FU). METHODS: Following an intravenous bolus dose of 5-FU, 20 patients with colorectal cancer received oral doses of 50 mg levamisole every 8 h for 3 days. Immediately after the last dose, blood and urine samples were collected over at least an 8-h period. Samples were assayed for levamisole and p-hydroxylevamisole by GC/MS. The levamisole plasma and urine data were subjected to pharmacokinetic analysis using NONMEM software. RESULTS: Substantial interpatient variability was observed in the levamisole plasma concentration-time curves. Patients with cardiovascular or gastrointestinal complications demonstrated altered absorption of levamisole. Pharmacokinetic parameter values for levamisole were similar to those obtained previously in healthy subjects and other cancer patients. CONCLUSIONS: There is no evidence that the pharmacokinetics of levamisole are altered by 5-FU administered immediately prior to levamisole administration. The relationship between the substantial intersubject variability in levamisole plasma concentration-time curves and clinical outcome following 5-FU/levamisole adjuvant chemotherapy should be examined.

AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological Association.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. The paper was approved by the Committee in March 1999 and by the AGA Governing Board in May 1999.

Pancreatic cancer.

Despite the many advances reported during the past year, pancreatic cancer remains a profound therapeutic challenge. Helical CT has become the preferred staging study at many institutions. The role of chemoradiation therapy in a preoperative and postoperative setting is being defined. Gemcitabine has become first-line therapy for patients with advanced pancreatic adenocarcinoma. It is hoped that the increasing knowledge of the molecular biology of pancreatic carcinoma will lead to improvements in diagnosing, staging, and treating pancreatic adenocarcinoma.