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Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors., (©2013 AACR.)

The epidermal growth factor receptors (EGFR)-inhibitors are frequently responsible for cutaneous adverse drug reactions that may alter the patients' quality of life and hamper the continuation of treatment. We present here the experience of a group of French multidisciplinary experts - the PROCUR group (PRise en charge de la tOxicité CUtanée des anti-EGFR) - created in order to establish a therapeutic algorithm. It was built in three steps under the responsibility of a steering committee: (1) a systematic literature review was performed by a group of three dermatologists and one oncologist; (2) regional meetings evaluated practical aspect of the treatments in France; (3) a final meeting confrontating the practices in France and the evidence-based medicine including the steering committee, the bibliographic group, and oncologists, radiotherapists, dermatologists and hepato-gastroenterologists involved in regional scientific committees, resulted in a therapeutic algorithm, resulting in the collegial writing of this algorithm. This multidisciplinary study should facilitate the standardised, optimised management of skin toxicity associated with EGFR-inhibitors.

The 1st St. Gallen EORTC Gastrointestinal Cancer Conference 2012 Expert Panel clearly differentiated treatment and staging recommendations for the various gastroesophageal cancers. For locally advanced gastric cancer (≥T3N+), the preferred treatment modality was pre- and postoperative chemotherapy. The majority of panel members would also treat T2N+ or even T2N0 tumours with a similar approach mainly because pretherapeutic staging was considered highly unreliable. It was agreed that adenocarcinoma of the gastroesophageal junction (AEG) is classified best according to Siewert et al. Preoperative radiochemotherapy (RCT) is the preferred treatment for AEG type I and II tumours. For AEG type III, i.e. tumours which may be considered as gastric cancer, perioperative chemotherapy is the majority approach. For resectable squamous cell cancer of the oesophagus a clear majority recommended radiochemotherapy followed by surgery as optimal approach, irrespective of tumour size. In contrast, definitive RCT was judged appropriate for advanced tumours with extended lymph node involvement (N2) or for cancers of the upper oesophagus. Additional recommendations are presented on the use of endosonography, PET-CT scan and laparoscopy for staging and on the preferred approach to surgery., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: To investigate second-line chemotherapy in gemcitabine-pretreated patients with advanced or metastatic pancreatic cancer [(frequency, response, outcome, course of carbohydrate antigen 19-9 (CA 19-9)]., Methods: This retrospective study included all patients with advanced or metastatic pancreatic cancer (adenocarcinoma or carcinoma) treated with second-line chemotherapy in our center between 2000 and 2008. All patients received first-line chemotherapy with gemcitabine, and prior surgery or radiotherapy was permitted. We analyzed each chemotherapy protocol for second-line treatment, the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity, dosage modifications and CA 19-9 course., Results: A total of eighty patients (38%) underwent a second-line therapy among 206 patients who had initially received first-line treatment with a gemcitabine-based regimen. Median number of cycles was 4 (range: 1-12) and the median duration of treatment was 2.6 mo (range: 0.3-7.4). The overall disease control rate was 40.0%. The median overall survival and progression-free survival from the start of second-line therapy were 5.8 (95% CI: 4.1-6.6) and 3.4 mo (95% CI: 2.4-4.2), respectively. Toxicity was generally acceptable. Median overall survival of patients with a CA 19-9 level declining by more than 20% was 10.3 mo (95% CI: 4.5-11.6) vs 5.2 mo (95% CI: 4.0-6.4) for others (P = 0.008)., Conclusion: A large proportion of patients could benefit from second-line therapy, and CA 19-9 allows efficient treatment monitoring both in first and second-line chemotherapy.

Background: This prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC)., Methods: Patients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety., Results: Fifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study., Conclusion: Bevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The management of colorectal liver metastases has been improved these last years. The efficacy of chemotherapy regimens and targeted therapies has led to a better prognosis. It has also allowed the resection of metastases initially unresectable. In this setting, the pathologist plays a major role. He is involved in the gross examination, in order to perform an adequate sampling of the lesions. He is also involved at the morphological level, for the assessment of the pathological response, which is now recognized as a prognostic factor and a marker of sensitivity or resistance to a given treatment. Moreover, the determination of predictive markers of response or resistance to induction treatments will constitute a supplementary and major challenge for the pathologist., (Copyright © 2011. Published by Elsevier Masson SAS.)

Purpose: Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted., Methods: Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0-2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%)., Results: 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0-1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018)., Conclusion: This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.

Purpose: The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy., Patients and Methods: We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry., Results: In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS., Conclusion: BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.

Most Barrett's oesophagus-associated cancers are adenocarcinomas which occur in a pure form. They are rarely combined with another type of malignancy, such as endocrine tumours. Within the endocrine spectrum, small cell carcinomas (SmCC) usually have a highly aggressive behaviour with a poor prognosis. We report a case of composite SmCC and adenocarcinoma in the setting of a Barrett's oesophagus, in a 54-year-old man. This tumour was identified on a surgical specimen after neoadjuvant treatment with radiotherapy and 5-FU-Cis-platin based chemotherapy. The SmCC component was positive for chromogranin A, synaptophysin, neural cell adhesion molecule and neuron-specific enolase and negative for high molecular weight cytokeratin. The adenocarcinoma component showed a converse phenotype. In our case, the origin of the SmCC component could be explained by the numerous chromogranin A-positive cells observed in the Barrett's oesophagus or by the potential progenitor cells that may be located in the submucosal oesophageal gland ducts and the Barrett's metaplasia. Our report is thus indicative of the high and totipotential risk of Barrett's oesophagus. Moreover, it is particular because of its favourable behaviour, with a 6-year disease-free survival, after neoadjuvant chemoradiation, surgery and postoperative chemotherapy.

Background: The objective of this phase III study was to compare the safety and efficacy of FLP (modulation of 5-FU (Fluorouracil) by folinic acid or leucovorin (LV) and cisplatin vs. FP (5-FU combined with Cisplatin) as a first line chemotherapy in advanced oesophageal, gastric and pancreatic cancer., Patients and Methods: 232 patients with measurable lesions were randomised to receive at the first cycle either FP (arm A: 5-FU 800 mg/m2/d in continuous infusion 5 days and cisplatin 100 mg/m2 on day 1 or 2), or FLP (arm B: LV, 100 mg/m2/d in bolus 5 days, followed by 5-FU 350 mg/m2/d in 1 h infusion 5 days and cisplatin 100 mg/m2 on day 1 or 2). In case of no grade 3-4 haematological and diarrhoea toxicity, the dose of 5-FU was increased to 1000 mg/m2/d and 400 mg/m2/d in the two arms respectively, for the subsequent cycles until disease progression., Results: The distribution of primary tumours was: 19 squamous cell carcinoma of the oesophagus, 19 oesophageal adenocarcinoma, 91 gastric and 97 pancreatic adenocarcinoma. Safety remained acceptable and comparable in the two arms except for the severe grade 3-4 mucositis, which was lower in arm B (4.5 vs. 16.4%, p < 0.009). Efficacy in terms of tumour response and survival was similar in the two arms, showing an objective response rate (after external review) of 18.6% (95% confidence interval (CI) 11.4-25.8%) in arm A vs. 15% (95% CI 8.5-21.6%) in arm B, an overall median survival of 24 weeks in arm A vs. 24.7 in arm B (p = 0.83) and a progression-free median survival of 12.4 weeks vs. 12.1 in arms A and B, respectively (p = 0.91)., Conclusion: The FLP regimen is substantially equivalent to FP in terms of safety and quality of life, as well as for antitumour efficacy in these carcinomas; the only slight advantage of FLP in this study concerns mucositis. Based on these results, FLP could be used as an alternative to FP when appropriate.

In a dozen years of development, irinotecan (CPT11) became one of major therapeutics in the taking care of the metastatic colorectal cancer (CCRM). First used in monotherapy every three weeks, irinotecan has been later developed in association with 5FU and folinic acid according to two modalities of administration (bolus schedule administred weekly or infused schedule every two weeks). This association is now validated both in first and second line. Infused schedule (Folfiri) seems to introduce the best ratio of efficacy/tolerance. The association with the anti VEGF antibody (Avastin), bevacizumab) is promising. Moreover the association of the irinotecan with the anti EGFR antibody (Erbitux)), cetixumab) has show a efficacy in third line after progression under an protocol with irinotecan. Combinations with oxaliplatine (Irox, Irinox) or (Folfoxiri, Folfirinox) still remain in the course of appreciation notably in neoadjuvant context. An increment of dose seems accomplishable in monotherapy or in combination with/AF (high Folfiri doses) with a notable increment of responses rates. Nevertheless this strategy must again show a true clinical interest. Finally they are at promising developments in the fields of the irinotecan pharmacogenetic and pharmacogenomic.

We report a case of a locally advanced cardial adenocarcinoma, occurring in a 48-year-old woman, who underwent concomitant radiotherapy and 5 FU-cis-platin based chemotherapy. Surgical tumor resection was then performed, which incidentally revealed an isolated liver nodule measuring 12 mm. This nodule was histologically characterized by an intense sinusoidal dilatation and a central venular occlusion, similar to that seen in veno-occlusive disease. This lesion was not correlated to any clinical or biological dysfunction and was finally considered as a vascular injury linked to the additive effect of the combined chemotherapy and radiotherapy. This observation illustrates some iatrogenic hepatic side effects, that have been rarely described in digestive cancers and mainly in the case of colo-rectal metastases. Vascular damage may remain histological, as in our case. But one should be aware that vascular injuries could influence hepatic function and regeneration after wide hepatectomy as well as extensive fibrosis.

Methods: We evaluated the Epitax combination (epirubicin 60 mg/m2 and docetaxel 75 mg/m2, every 3 weeks) in advanced gastric cancer (AGC) as second-line treatment after fluorouracil and platinum in 50 patients, then as first-line treatment in 36 patients. We report here the results of these two phase II studies., Results: In the second-line treatment, the response rate (RR) was 15.5%. Grade 3-4 neutropenia was observed in 68% (febrile neutropenia in 40%, one treatment-related death). Median time to progression (TTP) and overall survival (OS) were 2.4 and 5.0 months, respectively. In the first-line treatment, the RR was 19.4%. With prophylactic granulocyte colony-stimulating factor, grade 3-4 neutropenia was reported in 38.9%. Then 22 patients received a second-line and 11 patients a third-line treatment. Median TTP and OS were 4.5 and 12 months, respectively., Conclusion: Epitax showed moderate activity in AGC. RR in both trials suggests a non-cross resistance with fluorouracil/platinum combination. The 12-month OS in the first-line treatment could be partly explained by early evaluation and active non-cross resistant second-line therapy.

Aim: Hepatic metastases are often present at diagnosis of carcinoma of unknown primary site (CUP). The objective of this study was to describe the diagnostic and therapeutic strategies used., Methods: One hundred and eighteen patients were treated at the Cancer Center of Montpellier from 1993 to 2002 for CUP initially metastatic to the liver. Initial characteristics, diagnostic tests, chemotherapies and outcome were retrospectively recorded., Results: The most frequent histological types observed were adenocarcinoma, undifferentiated, neuroendocrine and squamous-cell carcinomas. Hepatic metastases revealed the cancer in 66 patients and were isolated in 32 patients. Other metastatic sites involved lymph nodes, lung and bone. Pretreatment computed tomography scans of the chest, abdomen and pelvis evaluation were available for more than 80% of patients. Colonoscopy, gastroscopy and bronchoscopy were performed in 58, 56 and 26% of patients respectively. One hundred and seven patients had received at least a front-line of chemotherapy. Seventy-four patients had received platin salt-based chemotherapy, 67 in front-line treatment and 10 in second line. In first-line chemotherapy, overall response rates with or without platin were 19.4 and 20% respectively. One hundred and two of 111 deaths were due to disease progress and seven toxic-related deaths occurred. The median survival was 6.6 months, and 7.8 and 4.6 months in the with or without platin groups respectively (P=0,35). The median survival for treated patients was 7 months. Multivariate analysis identified two prognostic factors: serum lacto-dehydrogenase level and performance status., Conclusions: According to this study, pretreatment evaluations, which were very extensive in some patients, were insufficient to identify the primary site of liver metastases. Because of the poor prognostic, chemotherapy, in absence of clinically demonstrated benefit, has to be reserved for patients with better prognosis. Prospective trials are needed to determine whether use or not of cisplatin should be proposed for standard protocols.

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French regional cancer centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objectives: To elaborate clinical practice guidelines for patients with stomach adenocarcinoma. These recommendations cover the diagnosis, treatment and follow-up of these tumors., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. The Standards, Options and Recommendations are thus based on the best available evidence and expert agreement., Results: This guidelines presents the synthesis of the data concerning the evaluation of the therapeutic ones. The main questions concern the type of gastrectomy to realize (Total Gastrectomy or gastrectomy subtotal), the extent of the lymphadenectomy (D2, D3 versus D1, D3, D2 versus D4) and the role of postoperative chemotherapy and adjuvant concomitant chemoradiotherapy.

This study is concerning 70 patients (57 female, 13 male) with an epidermoid carcinoma of the anal canal which were treated homogeneously with a combination of an external beam radiation therapy ((45 Gy in 25 fractions of 1.8 Gy for 5 weeks) and a brachytherapy with Iridium wires (15 to 20 Gy delivered to the gross residual disease). The N1 patients and the patients with tumors more than 4 cm in diameter received a chemotherapy also (5 FU and cisplatinum). The overall local control was obtained in 68 cases out of 70 (97.1%). 63 out of 70 patients (90%) are alive and locally controlled. 56 pts out of 70 (80%) did have a preserved anus, and a normal sphincterian function was preserved in 53 pts out of 70 (75.7%). 17 pts had a colostomy (3 without and 14 with an abdominoperineal resection). With the salvage perineal resection, 11 patients out of 12 local recurrences were definitely locally cured (91.7%). The 5-year overall survival is 91.4%. The 5-year disease-free survival is 90%. The 5-year survival with preserved anal sphincter is 80% and with preserved sphincterian function is 75.7%. Five patients died from cancer (3 deaths due to metastases, and only 2 due to a locoregional evolution). These results have been analysed regarding the literature data and demonstrated the curative role of external beam and brachytherapy, in localized tumors, the contribution of chemotherapy in advanced stages and the efficiency of secondary salvage surgery in local recurrences., (Copyright John Libbey Eurotext 2003.)

Recent studies have demonstrated that ionizing radiation activate existing cellular response pathways involving protein kinases. These pathways mediate the cytotoxic and cytoprotective responses of cell death and cell survival, respectively. Cytoprotective responses involve dominantly mitogen-activated protein kinase (MAPK) through radiation-induced activation of EGF receptors and may stimulate cell proliferation if radiation-induced damage is successfully repaired. Similarly, overexpression of EGF receptor family members or their activation by ligands expressed at normal levels may also confer radioresistance. Recent encouraging results indicate that EGF receptor inhibitors such as antibodies or small molecule tyrosine-kinase inhibitors may be effective radiosensitizers in tumors. Within the antibody class of EGF receptor inhibitors are monoclonal antibodies such as cetuximab and trastuzumab. These agents have a common target of the extracellular domain of the EGF receptor. Striking synergistic antitumor effects on human epidermoid and on adenocarcinoma cancer-cell xenografts have been observed when cetuximab treatment is combined with radiotherapy. Promising results have also been obtained from the first clinical trial with cetuximab and radiotherapy in squamous-cell carcinoma of the head and neck. Trastuzumab has been poorly studied in combination with radiotherapy but showed an increased radiosensitivity of HER2-overexpressing breast cancer cells as measured by in vitro colony-forming assays. The mechanism of radiosensitization appears to involve DNA repair. There are well over a dozen agents in the small molecule tyrosine-kinase inhibitor category but the preclinical studies in combination with radiotherapy exist only for ZD1839 and CI1033. Preliminary studies confirm the capacity of ZD1839 and radiotherapy to produce a highly significant increase in tumor growth inhibition when compared to treatment with either modality alone. Another member of the quinazoline class of small molecule tyrosine-kinase inhibitors (CI1033) has recently been examined for its impact in conjunction with radiation in a series of HER-overexpressing breast cancer cell lines. This molecule inhibits tyrosine-kinase activity in all four members of the HER family, and preclinical studies showed a synergistic interaction of CI1033 with ionizing radiation. Finally, EGF receptor family member inhibitors may themselves be effective radiosensitizers and their use in future clinical investigations are based on a solid radiobiological rational.

Background: The prognosis of patients with carcinoma of unknown primary remains poor with an expected median survival of 6 to 12 months. We evaluated the activity of a chemotherapy regimen combining gemcitabine and docetaxel in patients who primarily failed cisplatin-based chemotherapy., Patients and Methods: Fifteen patients received cycles of gemcitabine 1,000 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 every 3 weeks., Results: The median number of cycles per patient was 3. Overall toxicity was moderate. Four partial responses were observed among 14 patients with measurable disease. The median survival was 8 months from start of therapy and 23 months from diagnosis., Conclusion: These results were obtained in a small series of selected patients and require further confirmation in the front-line management of the disease.

The late diagnosis of pancreatic cancer, at a locally advanced and metastatic stage explains in part its poor prognosis. In this situation, three phase II trials with gemcitabine, a synthetic analogue of deoxycytidine, yielded some interesting results in terms of tolerance and efficiency. A new concept has also been depicted: the clinical benefit (defined by the level of pain, the consumption of analgesics and the general condition of the patient). These trials led to the realization of a randomized phase III study including 126 patients. The study compared the use of gemcitabine, in monotherapy, with fluoro-uracil (5FU), the standard form of treatment. There was evidence of clinical benefit in 23.8% of the patients treated with gemcitabine compared to only 4.8% of those receiving 5FU. The median and the overall survival at one year were significantly higher for the patients treated with gemcitabine (5.65 months and 18% respectively, versus 4.41 months and 2% for 5FU). The tolerance profile of gemcitabine was favourable. These have been confirmed by a large compassionate study undertaken in the United States, led by Storniolo, with more than 3,000 patients. Used in monotherapy, gemcitabine thus obtained authorization in 1996 to be released in the United States and in 1998 in Europe, to be used in the case of locally advanced or metastatic adenocarcinoma of the pancreas as first line chemotherapy. The administration regimen is 1,000 mg/m2 once a week (30 minutes i.v. infusion), for 7 weeks out of 8, then 3 weeks out of 4 in consecutive cycles. It is currently considered as the standard chemotherapy in this situation. Trials have been carried out to optimize the scheme for the administration of gemcitabine by lengthening its perfusion time. Current studies are now also being directed towards an association between gemcitabine and other cytotoxics, like cisplatinum or oxaliplatin.

Gemcitabine is a pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors including bladder, non-small cell lung and pancreatic cancers. Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes preclinical studies designed to elucidate the mechanism of action of gemcitabine with ionizing radiation. Phase I-II ongoing trials of combination of radiation therapy and gemcitabine are trying to determine the optimal dose and schedule which could be used in daily clinical activity. The mechanism of radiosensitization is thought to be simultaneously gemcitabine-induced dATP (deoxyadenosine triphosphate) depletion and cell cycle redistribution into the S phase. Although there are no real study which has proven supra-additive combination, the recent acute side effects in several clinical studies oblige physicists to determine with precision the maximum tolerated dose of gemcitabine in association with ionizing radiation. Radiosensitization conditions can be obtained either with a long exposition to a low concentration or a short exposition to a high concentration. Radiation sensitivity begin to be detected four hours after treatment for 48 hours. A dose about 100 mg/m2/week of gemcitabine could be used with radiation therapy according to recent phase I results. This limiting dose is approaching to a radiosensitization context where the effect of one agent is increased by another agent which is inactive or poorly active for the effect under consideration. In this type of regimen, the two modalities do interact with a frequent inhibition of recovery from potentially lethal damage and a probably increase of late side effects of radiation therapy. In contrast, radio-chemotherapy combination is used for a therapeutic advantage when the drug by itself is active against the tumor but does not enhance late side effects of radiation on the critical normal tissues within the irradiated volume. Gemcitabine surely is a strong radiosensitizer even at low doses with future extended combined modality therapeutic indications. The ultimate goal of combined treatments should be an increased therapeutic ratio.