Biomedical subjects

David Azria

Publications and source records attributed to David Azria.

34 records · Page 2Linked to original sources

PubMed2005

[Anemia in head and neck cancers].

Anemia is very common in head and neck cancer patients, and seems to be correlated with intratumoral hypoxia. Anemia is one of the main prognostic factors of locoregional recurrence and, in some studies, of poor survival. Blood transfusions and human recombinant erythropoietin (rHuEPO) are the two main methods used in clinical practice to correct hemoglobin level during curative treatment. Blood transfusions were rarely evaluated, and did not influence locoregional control of patients treated with radiotherapy with or without chemotherapy. Retrospective studies evaluating combined treatment of rHuEPO and radiotherapy reported positive impact on locoregional recurrence and actuarial survival. Since the end of 2003, this approach is a matter for debate after the negative results of a prospective randomized study on progression-free survival concerning head and neck cancer patients treated with definitive or postoperative external radiotherapy with or without rHuEPO. Although many biases were reported against this publication, several questions are to be answered in the near future. Among them, erythropoietin receptor expression and activation on tumour cell seem to be the more appropriate explanation of these negative results. In October 2004, preliminary results of the RTOG 99-03 study have been presented at the Astro annual meeting in Atlanta. This prospective randomized trial was designed to determine if concurrent rHuEPO administration (40,000 units) with radiotherapy (with or without chemotherapy) could improve locoregional control in non-operative head and neck cancers. In the rHuEPO arm, haemoglobin level was significantly increased compared with control arm. However, the addition of concurrent rHuEPO to definitive radiotherapy did not improve locoregional control or survival for mildly/moderately anemic patients with head and neck squamous cell carcinoma. Future clinical trials using biological markers are thus imperative to target which patients could benefit from these molecules.

Anemia↗

PubMed2005

External radiotherapy and anaemia treatment: state of the art.

Anaemia is considered a common problem in many cancers secondary to the disease itself or related to chemo- and/or radiotherapy. Several clinical trials have advocated the prognostic value of anaemia and hypoxia in the outcome of many cancers. Erythropoietin is recognised as an effective treatment for anaemia, which also improves the quality of life in patients with malignant disease. External radiotherapy plays an important role in the treatment of loco-regional cancer but its efficacy can be compromised by many factors. Tumor hypoxia is considered by many authors as an important factor contributing to radioresistance. We report in this article the radiobiological rationale in favour of combining radiotherapy and erythropoietin, and review relevant clinical papers published in this field.

Anemia↗

PubMed2005

Surgery for esophageal cancer after concomitant radiochemotherapy: oncologic and functional results.

The aim of this study was to evaluate the results of surgery after preoperative radiochemotherapy (PRCT) for esophageal cancer. This retrospective study included 88 patients scan between 1992 and 2000. The median follow-up was 55.7 months (3.3-104.1 months). Surgical mortality was 15.9%. Multivariate analysis found that the following were risk factors for surgical mortality: gamma-glutamyltransferase level > 75 UI/ml (p = 0.007), weight loss = 10% (p = 0.05), and digestive toxicity World Health Organization grade III or IV during PRCT (p = 0.019). The median overall survival was 24.9 months. The 5-year overall survival (OS) and disease-free survival (DFS) were, respectively, 33.1% and 33.2%. Complete responder patients had a 71.8% 5-year OS (p = 0.01) and a 71.8% 5-year DFS (p = 0.009). The rate of recurrence was 37.5%. Multivariate analysis found that female gender (p = 0.03), weight loss = 10% (p = 0.03), preoperative computed tomography scan bronchial contact (p = 0.01), and N+ status (pN+) at pathology examination (p = 0.0001) were predictors of poor oncologic results. Patients with high preoperative risk of surgical mortality need to be selected for intensive perioperative management. In association with surgery, PRCT improves the local control, DFS, and OS of responder patients. Morphologic evaluation for staging esophageal cancer in predicting the pathologic response after PRCT is poor or controversial. Only surgical resection can provide accurate prognostic information for staging esophageal cancer and improving local control.

Adenocarcinoma↗

PubMed2005

[Targeted therapies and radiotherapy in colorectal cancer].

Growing evidence suggests that intracellular signal pathways play a significant role in radiation response. Promising results have been obtained in experimental studies assessing the combined use of specific inhibitors and radiotherapy. Based on these data, a number of clinical trials were started to enhance tumor responses and thus to decrease the rate of locoregional recurrences. Several prognostic factors on tumoral radiosensitivity have been identified including intracellular signal pathways. Nevertheless, these factors do not correlate with responses to targeted therapies. Concerning rectal cancer, promising results have recently been obtained with concurrent radiotherapy and a monoclonal antibody against VEGF (bevacizumab). Studies combining cetuximab (anti-HER1) and radiotherapy will start soon in this setting. Other specific inhibitors combined with radiotherapy are still in preclinical evaluation.

Colorectal Neoplasms↗

PubMed2004

Letrozole sensitizes breast cancer cells to ionizing radiation.

INTRODUCTION: Radiotherapy (RT) is considered a standard treatment option after surgery for breast cancer. Letrozole, an aromatase inhibitor, is being evaluated in the adjuvant setting. We determined the effects of the combination of RT and letrozole in the aromatase-expressing breast tumour cell line MCF-7CA, stably transfected with the CYP19 gene. METHODS: Irradiations were performed using a cobalt-60 source with doses ranging from 0 to 4 Gy. Cells were incubated with androstenedione in the presence or absence of letrozole. Effects of treatment were evaluated using clonogenic assays, tetrazolium salt colorimetric (MTT) assays, and cell number determinations. Cell-cycle analyses were conducted using flow cytometry. RESULTS: The survival fraction at 2 Gy was 0.66 for RT alone and was 0.44 for RT plus letrozole (P = 0.02). Growth of MCF-7CA cells as measured by the cell number 6 days after radiotherapy (2 and 4 Gy) was decreased by 76% in those cells treated additionally with letrozole (0.7 microM) compared with those receiving radiotherapy alone (P = 0.009). Growth inhibition, assessed either by cell number (P = 0.009) or by the MTT assay (P = 0.02), was increased after 12 days of the combination treatment. Compared with radiation alone, the combination of radiation and letrozole produced a significant decrease in radiation-induced G2 phase arrest and a decrease of cells in the S phase, with cell redistribution in the G1 phase. CONCLUSIONS: These radiobiological results may form the basis for concurrent use of letrozole and radiation as postsurgical adjuvant therapy for breast cancer.

Antineoplastic Agents↗

PubMed2004

A bispecific antibody to enhance radiotherapy by tumor necrosis factor-alpha in human CEA-expressing digestive tumors.

Tumor necrosis factor-alpha (TNF-alpha) enhances X-ray killing of human tumor cells in vitro and enhances tumor control when combined with radiotherapy (RT) in animal tumor models. In multiple Phase I studies, intravenous injection of TNF-alpha appeared to have severe systemic side effects. To overcome these limitations, we used a bispecific antibody (BAb) directed against carcinoembryonic antigen and human TNF-alpha to target this cytokine in human digestive carcinoma treated with simultaneous RT. We used human digestive carcinoma cell lines (colon cancer, LS174T, and pancreatic cancer, BxPC-3) to determine the interaction of TNF-alpha and RT on clonogenic cytotoxicity. Isobolograms were established to confirm additive or supra-additive effects between both treatments. LS174T and BxPC-3 cells were grafted subcutaneously at Day 0 into female nude mice (7-8 weeks old). When the tumors reached a volume of about 80 mm(3), the mice were randomly assigned to treatment: Group 1, normal saline i.v. injection (control group); Group 2, TNF-alpha at 1 microg/i.v. injection; Group 3, BAb at 25 microg/i.v. injection; Group 4, BAb plus TNF-alpha (ratio 25 microg to 1 microg) i.v. injection; Group 5, local RT plus normal saline (0.5 Gy. min(-1)) at a total dose of 30 Gy delivered in five fractions; Group 6, local RT plus TNF-alpha injections 3 h before RT; Group 7, local RT plus BAb plus TNF-alpha co-injected 24 h before RT. Tumor growth delay was used as the end point for all groups. In the LS174T experiments, TNF-alpha added 12 h before RT showed a statistically significant decrease in the survival fraction at 2 Gy compared with RT alone (0.23 vs. 0.42 Gy, p = 0.0017). These results were largely confirmed with the BxPC-3 cell lines (0.29 vs. 0.72, p <0.00001). Isobolograms confirmed the additivity between TNF-alpha and RT in both cell lines. At 50% survival, the data points were within the envelope of additivity. In the LS174T and BxPC-3 xenografts, RT as a single agent (Group 5) slowed tumor progression compared with Group 1 (p <0.027 and p = 0.00001, respectively). TNF-alpha alone, BAb alone, or BAb plus TNF-alpha (Groups 2, 3, and 4) had no effect. In the LS174T model, TNF-alpha plus RT enhanced the delay to reach 2000 mm(3) compared with RT alone but without statistical significance. This delay was significantly longer when BAb was added (p = 0.0033, for Group 6 vs. Group 7). In the BxPC-3 experiments, the median delay to reach 2000 mm(3) was similar between the RT and TNF-alpha plus RT groups (93 days). The use of our BAb in combination with TNF-alpha and RT dramatically enhanced this median delay (177 days, p = 0.0013). No body weight loss was observed in any group. Our data could be used as a solid preclinical rationale on which to base a clinical study of locally advanced pancreatic or rectal cancers in the near future.

Animals↗

PubMed2004

Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension.

PURPOSE: To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx. PATIENTS AND METHODS: Between 1983-2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35-92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60-74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21-79 days). Median follow-up period was 85 months. RESULTS: The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5-58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control. CONCLUSION: For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.

Adult↗

PubMed2004

Positive interactive radiosensitisation in vitro with the combination of two nucleoside analogues, (E)-2'-deoxy-2'-(fluoromethylene) cytidine and iododeoxyuridine.

(E)-2'-Deoxy-2'-(fluoromethylene) cytidine (FMdC), an inhibitor of ribonucleotide diphosphate reductase (RR), is a potent radiation-sensitiser acting through alterations in the deoxyribonucleoside triphosphate (dNTP) pool in the de novo pathway to DNA synthesis. The activity of thymidine kinase (TK), a key enzyme in the 'salvage pathway', is known to increase in response to a lowering of dATP induced by FMdC. Nucleoside analogues such as iododeoxyuridine (IdUrd) are incorporated into DNA after phosphorylation by TK. Radiation sensitisation by IdUrd depends on IdUrd incorporation. Therefore, we have investigated the radiosensitising effect of the combination of FMdC and IdUrd on WiDr (a human colon cancer cell-line) and compared it to the effect of either drug alone. We analysed the effects of FMdC and IdUrd on the dNTP pools by high-performance liquid chromatography, and measured whether the incorporation of IdUrd was increased by FMdC using a [(125)I]-IdUrd incorporation assay. The combination in vitro yielded radiation-sensitiser enhancement ratios of >2, significantly higher than those observed with FMdC or IdUrd alone. Isobologram analysis of the combination indicated a supra-additive effect. This significant increase in radiation sensitivity with the combination of FMdC and IdUrd could not be explained by changes in the dNTP pattern since the addition of IdUrd to FMdC did not further reduce the dATP. However, the increase in the radiation sensitivity of WiDr cells might be due to increased incorporation of IdUrd after FMdC treatment. Indeed, a specific and significant incorporation of IdUrd into DNA could be observed with the [(125)I]-IdUrd incorporation assay in the presence of 1 microM unlabelled IdUrd when combined with FMdC treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Accelerated postoperative radiotherapy with weekly concomitant boost in patients with locally advanced head and neck cancer.

BACKGROUND AND PURPOSE: To assess the feasibility and efficacy of accelerated 66-Gy postoperative radiotherapy (PORT) using a single-fraction regimen from Mondays to Thursdays and a concomitant boost on Friday afternoon sessions in patients with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS: Between December 1997 and June 2002, 89 consecutive patients with pT1-pT4 and/or pN0-pN3 LAHNC were included. PORT was indicated in patients with positive surgical margins, T4 tumors, or extracapsular nodal infiltration. RT consisted of 66 Gy (2 Gy/fr) in 5 weeks and 3 days. Median follow-up was 21 months (range 2-59). RESULTS: Acute morbidity was acceptable: grade 3 mucositis in 20 (22%) patients, grade 3 dysphagia in 22 (25%) patients, and grade 3 skin erythema in 18 (20%) patients. Median weight loss was 2 kg (range 0-14.5). No grade 4 toxicity was observed. Late effects included grade 3 xerostomia in 6 (7%) patients, and grade 3 edema in 2 (2%) patients. Median time to locoregional relapse was 10 months (range 2-21). Two-year overall, cause-specific, and disease-free survival rates were 70% (95% confidence interval (CI) 59-81), 75% (95% CI 64-86), and 63% (95% CI 52-74), respectively. The 2-year actuarial locoregional control rate was 80% (95% CI 70-90). Distant metastasis probability at 4 years was 38% (95% CI 20-56). Multivariate analysis revealed that pT-classification (pT1-2 vs. pT3-4) and extranodal extension (0, 1 vs. 2 or more) were the two factors independently influencing the outcome. CONCLUSIONS: We conclude that reducing the overall treatment time using an accelerated PORT schedule including a once-weekly concomitant boost (six fractions per week) is easily feasible with excellent local control. Acute and late RT-related morbidity is acceptable. Given the disease progression pattern (distant metastases), adjuvant chemotherapy should be considered.

Aged↗

PubMed2004

Fetal dose reduction in head and neck radiotherapy of a pregnant woman.

BACKGROUND AND PURPOSE: A pregnant woman was referred for post-operative radiotherapy of a malignant schwannoma in the head and neck region. A best-treatment plan was devised in order to minimize the fetal dose. MATERIAL AND METHODS: The fetal dose resulting from radiological examinations was determined according to international protocols, that resulting from radiotherapy was calculated according to Recommendation 36 of the American Association of Physicists in Medicine (AAPM) Task Group. Pre-treatment dosimetry was performed with an anthropomorphic phantom. Several alternative treatment plans were evaluated. The use of a multileaf collimator (MLC) and a virtual wedge (VW) was compared to cerrobend blocks (CB) and physical wedge (PW). In-vivo dosimetry was performed using a vaginal probe containing thermoluminescent dosimeters (TLD). RESULTS: The total fetal dose resulting from diagnostic and radiotherapy procedures was estimated to be 36 mGy. The technique based on MLC and VW was elected for patient treatment. Measurements for this configuration resulted in afetal dose reduction of 82%. The shielding of the patient's abdomen further reduced the fetal dose by 42%. CONCLUSION: The use of VW and MLC for the treatment of a pregnant woman is highly recommended. Each case should be individually studied with pre-treatment and in-vivo dosimetry.

Adult↗

PubMed2003

Enhancement of radiation therapy by tumor necrosis factor alpha in human colon cancer using a bispecific antibody.

PURPOSE: To overcome the systemic side effects of tumor necrosis factor alpha (TNFalpha) injected i.v., we used a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and TNFalpha to target this cytokine in human CEA-expressing colorectal carcinoma treated simultaneously with radiation therapy (RT). METHODS, MATERIALS AND RESULTS: LS174T cell line was used to study the interaction of TNFalpha and radiation on clonogenic cytotoxicity. When TNFalpha (2500 U/mL) was added 12 h before RT, the surviving fraction at 2 Gy was 54% lower than that obtained with irradiation alone (0.23 vs. 0.42, respectively, p = 0.001). At 20%, 50%, or 70% survival, data points were within the envelope of additivity. Concerning in vivo experiments, RT as a single agent slowed tumor progression as compared with the control group (p = 0.027), whereas TNFalpha, BAb, or BAb + TNFalpha had no effect. BAb + TNFalpha + RT combination enhanced the delay for the tumor to reach 2000 mm(3) as compared with RT alone (p = 0.033, for BAb + TNFalpha + RT group vs. RT group). CONCLUSION: These results suggest that TNFalpha in combination with BAb and RT may be beneficial for the treatment of locally advanced colorectal cancer.

Adenocarcinoma↗

PubMed2003

[External beam radiation therapy and interstitial brachytherapy in the treatment of anal canal carcinomas: a series of 70 patients].

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.

Adult↗

PubMed2003

[Radiotherapy and inhibitors of epidermal growth factor receptor: preclinical findings and preliminary clinical trials].

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.

Animals↗

PubMed2002

Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil and cisplatin.

INTRODUCTION: Adenocarcinoma of the pancreas remains one of the most difficult malignancies to treat. Its incidence has steadily increased over the past four decades, and its prognosis is still dismal. AIM To assess tumor control and the palliative benefit of 5-fluorouracil (5-FU), cisplatin (CDDP), and radiotherapy in patients with advanced pancreatic cancer. METHODOLOGY: Systemic chemotherapy consisted of 5-FU (600 mg/m ), given as a 22-hour infusion on days 1 to 5, and CDDP (100 mg/m ), given as a 90-minute infusion on day 2. Treatment courses were repeated identically on day 21. Radiotherapy was delivered using megavolt irradiation of 25-MV photons with a two- or four-field isocentric technique. RESULTS: Twenty-seven patients were treated with this radiochemotherapy (RCT). Twenty-one patients (78%) completed initial treatment. The median dose of radiation therapy delivered was 42.5 Gy. At the time of evaluation (1 month after the end of the RCT), no grade 4 (WHO) toxicity was observed; 12 patients had improved or stable body weight; pain was improved for 20 patients, with 11 experiencing no pain; and analgesic consumption decreased for 18 patients, of whom 11 stopped intake. The clinical benefit response was 7/27 (26%). Median survival and time to progression were, respectively, 9 and 4.4 months. CONCLUSION: This RCT regimen had a good impact on clinical benefit in locally advanced pancreatic carcinoma, without severe side effects.

Adenocarcinoma↗

PubMed2002

[Gemcitabine and ionizing radiations: radiosensitization or radio-chemotherapy combination].

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.

Adenosine Triphosphate↗

PubMed2002

[Gemcitabine and pancreatic cancer].

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.

Adenocarcinoma↗