Search

Purpose of Review: We present an update on the dramatic changes that have occurred over the past year in the management of patients with metastatic renal cell carcinoma., Recent Findings: Although it was demonstrated that benefit from immunotherapy is restricted to a minority of patients, a better understanding of the molecular mechanisms involved in the pathogenesis of clear cell carcinoma has led to development of multiple targeted therapies, with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of vascular endothelial growth factor receptor have been demonstrated to improve the progression-free survival of patients as first-line (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, which inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor risk characteristics. Finally, bevacizumab combined with interferon is yielding substantial response rates and increased progression-free survival compared with interferon alone., Summary: Four major drugs or regimens with proven efficacy are now available for first-line and second-line therapy in metastatic renal cell carcinoma. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.

It is useful to dispose reliable prognostic factors in Renal Cell Carcinoma (RCC) for 3 major goals: providing patient information, designing rationale follow-up algorithms and selecting patients for adapted treatment schedules as well as new clinical trials. Prognostic factors in RCC include: anatomical (TNM classification), histological (Fuhrman grade and histological subtype), clinical (symptoms and performance status) and molecular factors. For improving predicative accuracy of prognostic systems such as the TNM classification, new prognostic algorithms or nomograms have been designed combining independent prognostic variables. UISS and SSIGN are the 2 most effective prognostic systems within localized RCC. In metastatic disease, the two main systems that have been used for predicting response to immunotherapy are the model of the French Group of Immunotherapy and the Motzer model. Finally, there is an increasing interest in combining molecular variables with previously established models. These new systems will require further validation as part of large prospective clinical trials.

Purpose: A link between neuroendocrine cell differentiation and resistance to androgen deprivation has been observed in prostate cancer, suggesting the possible efficacy of specific treatments. We assessed the efficacy and toxicity of a chemotherapy regimen combining docetaxel and cisplatin in men with androgen independent prostatic adenocarcinoma and circulating neuroendocrine markers., Materials and Methods: A total of 41 patients were treated with a combination of 75 mg/m(2) docetaxel and 75 mg/m(2) cisplatin every 3 weeks for a maximum of 6 cycles. The primary study end point was the neuroendocrine response rate, defined as a decrease in neuron specific enolase and/or chromogranin A to 50% or greater of the supranormal baseline serum value. Median followup was 40 months., Results: A median of 6 cycles per patient was delivered. A neuroendocrine response was observed in 13 patients (33%). The median response duration was 4 months (range 2 to 10). The prostate specific antigen response rate was 48%. A clinical benefit was observed in 45% of patients who required analgesics at study entry. The objective response rate was 41% in 29 patients with measurable metastases. Five patients had to stop therapy due to toxicity. The main side effects were cumulative asthenia and sensitive neuropathy. Median survival was 12 months (range 1 to 38)., Conclusions: Regarding the disappointing efficacy and significant toxicity observed in this study, the combination of docetaxel and cisplatin cannot be recommended in daily practice. Further studies are necessary to determine whether patients with circulating neuroendocrine markers require specific therapeutic approaches.

Purpose: Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma., Materials and Methods: A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point., Results: There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses., Conclusions: To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.

Objective: To assess the clinical characteristics and outcome of patients with liver metastases in prostate carcinoma., Patients and Methods: From January 1995 to December 2005, 345 patients with metastatic prostate cancer were prospectively recorded in the database of the Montpellier Cancer Centre, France. The clinical characteristics and outcome of 28 patients who developed liver metastases during the course of the disease were analysed., Results: Six patients had liver metastases as the first site of metastatic disease, and for one of them, liver was the only metastatic site. All but one patient had hormone-refractory disease. Serum measurement of neuroendocrine markers showed increased levels of chromogranin A and neurone-specific enolase in 84% and 44% of patients, respectively. Six patients had a pathological analysis; there were two different histological patterns in liver biopsies, i.e. four were adenocarcinomas with a moderate (one patient) or poor (three) differentiation and two were neuroendocrine carcinomas. Three patients had no treatment because of a poor performance status. One patient had hormone therapy for synchronous liver metastases at diagnosis as the first-line treatment; other patients were treated with chemotherapy. The median (range) overall survival was 6 (1-27) months; the median survival of patients for whom liver was part of the initial metastatic pattern was 14 months., Conclusion: Liver metastases are not very rare but appear to be a rather late event in the course of the disease. They are frequently associated with neuroendocrine characteristics.

Objectives: To assess the impact on survival of high-dose chemotherapy with haematopoietic support in patients with high-volume, metastatic nonseminomatous germ cell tumours., Methods: One hundred fifteen patients were randomised to receive either four cycles every 21 d of vinblastine (0.2 mg/kg on day 1), etoposide (100 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and bleomycin (30 mg on days 1, 8, and 15) (arm A), or a slightly modified regimen followed by a high-dose chemotherapy including etoposide (350 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and cyclophosphamide (1600 mg/m2/d on days 2 through 5) (arm B)., Results: In an intent-to-treat analysis, there were 32 (56%) and 24 (42%) complete responses in arms A and B, respectively (p=0.099). After a median follow-up of 9.7 yr, 31 and 27 patients have continuously shown no evidence of disease in arms A and B, respectively. There was no significant difference between the overall survival curves (p=0.167). According to the International Germ Cell Cancer Collaborative Group prognostic classification, the 5-yr survival rates were 88% and 82% in the intermediate group and 69% and 44% in the poor group (p=0.045) in arms A and B, respectively., Conclusions: This trial failed to demonstrate an impact on response and survival of high-dose chemotherapy with haematopoietic support in first-line treatment of patients with high-volume, metastatic nonseminomatous germ cell tumours.

The gold standard regimen for metastatic testicular germ cell tumours is a combination of bleomycin, etoposide and cisplatin. The number of cycles is defined by pathology (seminoma or non seminoma) and the prognostic criteria of the international classification (degree of elevation of serum tumour markers and presence or not of non pulmonary visceral metastases). The surgical resection of all residual metastatic masses is mandatory after the normalization of serum tumour markers in non seminoma patients. The cure rates after chemotherapy and surgery are about 90% and 50% in good-risk and poor-risk patients, respectively.

In several cases of prostate cancer, resistance to hormonal therapies is observed. Alternative therapeutic strategies for the treatment of prostate cancer are of great interest. Participation of the nuclear receptor PPARgamma in the physiopathology of the prostate, in particular in prostate cancer has been recently studied. PPARgamma is a member of the hormone nuclear receptor superfamily. As for most members of the family, its activity is regulated by ligands. PPARgamma has been shown to be over-expressed in several cancers, including prostate cancer. In vitro and in vivo studies have demonstrated anti-proliferative and pro-apoptotic actions of the PPARgamma agonists thiazolidinediones, suggesting that PPARgamma could be a promising therapeutical target for the treatment of cancer. No effects of PPARgamma agonists have been observed, however, in a large randomized clinical trial in the "rising PSA" group of prostate cancer patients. This suggests that PPARgamma activity is controled by other factors, in addition to its ligands, in prostate cancer. We have shown that PPARgamma activity is repressed by HDACs. Moreover, PPARgamma activity is enhanced in the presence of HDAC inhibitors. A combination treatment using HDAC inhibitors and PPARgamma agonists results in growth arrest of prostate tumors in mice. Furthermore, the combination therapy inhibits invasion of prostate cancer cells in vivo, through upregulation of the expression of the E-cadherin gene.

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-alpha or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.

Peroxisome proliferator-activated receptor gamma (PPARgamma) might not be permissive to ligand activation in prostate cancer cells. Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPARgamma agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPARgamma agonists, defining a new class of PPARgamma target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.

The impact of adjuvant chemotherapy in locally advanced bladder cancer is still not fully established. Between January 2000 and November 2001, 30 patients entered the trial to receive four cycles of a combination of gemcitabine 1,250 mg/m on day 1 and day 8 and cisplatin 70 mg/m on day 1, repeated every 3 weeks. Histologic diagnoses included pT2-pT3-pT4 tumors and/or pN1-pN2. Combination treatment with gemcitabine and cisplatin was considered feasible if 70% of the patients received a relative dose intensity of each drug of more than 90%. Twenty-seven patients received four cycles of combination treatment. The relative dose intensity of cisplatine and gemcitabine was 96 and 88%, respectively. No toxic death occurred. We conclude that giving four cycles of the gemcitabine-cisplatin regimen in the adjuvant setting after cystectomy is feasible with a manageable toxicity and a high relative dose intensity. Whether this approach may increase survival is currently assessed in a randomized trial.

Unlabelled: Chemotherapy occupies an increasingly important place in the management of hormone-resistant metastatic prostate cancer. For the first time in this disease, docetaxel increases the survival of patients, with a modest, but definite median gain of about 2 months. In everyday practice, the indication for second-line chemotherapy after immediate or delayed failure of first-line chemotherapy is sometimes considered, although objective data concerning its efficacy are limited. The objective of the present study was to retrospectively evaluate the results obtained with second-line chemotherapy in a patient cohort managed at the Montpellier Regional Cancer Centre., Patients and Methods: Clinical characteristics, treatments delivered and outcome of 43 patients who received two successive lines of chemotherapy were retrospectively collected by means of a standardized questionnaire. Three groups of patients were defined as a function of the chemotherapy protocols delivered: docetaxel alone or in combination, mitoxantrone and other protocols not comprising either docetaxel or mitoxantrone. Responses to chemotherapy were analysed according to three criteria: objective responses, laboratory responses and palliative responses., Results: At the time of second-line chemotherapy, the median age of the patients was 69 years (range: 46 to 83). The median interval between the end of first-line chemotherapy and the start of second-line chemotherapy was 3 months (range: 1 to 15). The protocols administered comprised docetaxel alone (12 patients) or in combination with cisplatin (4 patients), mitoxantrone in 13 patients, or other cytotoxic molecules such as vinblastine, doxorubicin or etoposide in combination with a platinum salt (14 patients). The median number of cycles delivered was 4 (range: 1 to 10). No objective response was observed. Six (14%) patients obtained a laboratory response. A palliative response was observed in 16 (37%) patients, 7 of whom were treated with a docetaxel-based protocol, 6 were treated with mitoxantrone and 3 were treated by other protocols. The median duration of palliative response was 3 months (range: 1 to 6). The median survival was 8 months (range: 1 to 24), with no significant difference between the various protocols., Conclusion: In 2006, the objective of second-line chemotherapy in patients with hormone-resistant prostate cancer appears to be purely palliative. No reference protocol has been defined among currently available cytotoxic molecules. The indication must therefore take into account the benefit/risk balance to avoid compromising the patients quality of life. Therapeutic trials are essential to develop effective new molecules.

The objective of this study was to determine the impact of single versus sequential exposure to melphalan on the proliferation of an androgen-independent prostate cell line, PC-3, and to report the results of a pilot phase II study. For exposure to a single bolus dose, the doses were added at the start of the study and cell culture was continued for 96 h. For sequential exposure, 1/9 of the dose was added every 1.5 h over 12 h, followed by cell culture for 84 h. Cell growth inhibition was determined by the MTT assay. The clinical study was carried out on 14 patients with advanced prostate cancer. Melphalan was infused over a 24-h period. The sequential-dose schedule was more effective than the single-dose exposure, IC50 values: 0.074 versus 0.77/microg/ml. Out of the 14 patients (42 courses) enrolled into the study, two patients were removed within the first 2 weeks because of rapid disease progression. The toxicity profile did not differ greatly from that reported after a 1-h infusion. Four PR and two SD were observed. The median survival of the twelve patients was 23 weeks. Melphalan administered over a 24-h period to patients with androgen-independent prostate cancer appeared to provide some clinical benefits with manageable toxicity.

Objectives: To assess the efficacy and toxicity of an immunotherapy regimen combining subcutaneous (SC) interleukin-2 (IL-2) and interferon-alpha (IFN) in patients with metastatic renal cell carcinoma (MRCC)., Methods: The present study included 86 patients with MRCC. Data on treatment toxicity and efficacy (responses rates and overall survival) were collected on a hospital database. Treatment consisted of 6-week cycles repeated every 2 months for a maximum of 3 cycles. Each cycle included SC IL-2 20 x 10 MIU/m2 3 times/wk on weeks 1 and 4; 5 x 10 MIU/m2 3 times/wk on weeks 2, 3, 5, and 6, in combination with IFN 6 x 10 MIU/m2 once weekly on weeks 1 and 4; and 3 times/wk on weeks 2, 3, 5, and 6., Results: Seventy (82%) and 71 (83%) patients received more than 80% of the planned doses of IL-2 and IFN during the first cycle, respectively. Ten patients had to stop therapy before the end of the first cycle because of excessive toxicity (7 patients) or rapidly progressive disease (3 patients). Only 17 (28%) proceeded to the second cycle. Main toxicities included fever and asthenia in 86 (100%) patients, nausea/emesis in 83 (96%) patients, skin disorders in 69 (80%) patients, hypotension in 56 (65%) patients, and diarrhea in 50 (58%) patients. Sixty-seven (78%) patients developed at least one episode of grade 3 toxicity. Objective responses were observed in 13 patients, including 4 complete and 9 partial responses (15%; 95% confidence interval, 9.5-20.5%). After a median follow-up of 45 months, the median time to progression was 4 months (range, 1-41) and the median survival was 14 months (range, 1-89)., Conclusions: Only a small subset of patients with MRCC is likely to benefit from treatment with IL-2 and IFN. As toxicity is significant, the refinement of predictive variables for sensitivity to immunotherapy is mandatory.

Background: Retroperitoneal sarcomas are characterized by a high local recurrence rate despite optimal surgical treatment. The definition of prognostic factors for recurrence could help offer high-risk patients a closer follow-up and a multidisciplinary therapeutic approach., Patients and Methods: A cohort of 40 patients treated for a primary retroperitoneal sarcoma was retrospectively analyzed. Median follow-up was 24 months. Patient (sex and age), tumor (maximal size, histologic type, tumor localization, and histologic grade), and treatment (complete vs. incomplete surgery) characteristics were included in univariate and multivariate prognostic factor analyses., Results: After a median follow-up of 24 months (range 3-121), the overall recurrence rate was 65%. Median time between initial surgery and recurrence was 15 months (range 11.5-29.5). In univariate analysis, surgical positive margins (P = 0.011), bilateral tumors (P = 0.0034), nonliposarcoma histologic subtypes (P = 0.043), and a high histologic grade (P = 0.0072) were associated with an increased recurrence rate. All these factors except the histologic subtypes retained an independent prognostic value in the multivariate analysis. Death was strongly related to recurrence (P = 0.0033)., Conclusion: The optimal treatment of patients with primary retroperitoneal sarcoma should be based on radical surgery, with en bloc organ resection if necessary, to minimize the risk of positive margins. In high-risk patients, close follow-up is mandatory to offer optimal subsequent surgical procedures. The impact of a multidisciplinary therapeutic approach remains to be proved.

Considering genito-urinary tumors, the use of oxaliplatin should be restricted to clinical trials since no marketing approval has been obtained. Results of prospective studies currently suggest that the development of oxaliplatin should be carried on with first-line management of poor prognosis metastatic germ cell tumors as well as metastatic bladder cancer patients not eligible for cisplatin 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.

Introduction: Radiation recall is an inflammatory skin reaction at a previously irradiated field subsequent to the administration of a variety of pharmacologic agents. Although skin has been the major site of radiation recall toxicity, instances involving other organ have been reported., Materials and Methods: Data for this review were identified by searches of Medline and Cancerlit. The search terms "radiation", "recall", and "toxicity" were used. References identified from within retrieved articles were also used. There was no limitation on year of publication and no abstract forms were included. Only articles published in English were taken into consideration., Results: Idiosyncratic drug hypersensitivity phenomenon is a recent hypothesis which correlates best with the available facts at this moment. The phenomenon may occur days to years after radiotherapy has been completed. The majority of the drugs commonly used in cancer therapy have been involved in the radiation recall phenomenon. A mixed non-specific inflammatory infiltrate seems to be the common histopathologic criteria in previous published reports. Universally, corticosteroids or the use of non-steroidal anti-inflammatory agents, in conjunction with withdrawal of the offending agent, produce prompt improvement., Conclusion: We propose to collect all future radiation recall phenomenon in a Rare Cancer Network database in order to augment our understanding of this rare reaction.

A transdermal therapeutic system (TTS) is recommended for use in chronic cancer pain, particularly in the advanced stages. The aim of this trial was to study intra- and interindividual variabilities in fentanyl transdermal absorption and investigate physiological and clinical parameters that can influence the absorption in patients treated using a TTS for moderate to severe cancer pain. The study group consisted of 108 patients (71 men and 37 women; mean age, 61.3 years) with chronic cancer pain. A total of 507 patches were analysed. The TTSs used to administer fentanyl were removed after a 72-h period. The amount of fentanyl remaining in the patches was determined using a high-performance liquid chromatography method with ultraviolet detection. Depending on the analgesic requirements of the patient, the dose of fentanyl administered by TTS ranged from 25 to 500 microg/h. The study period was 6 months. Large interindividual variability in the amount of remaining fentanyl in the patches occurred. For 58.1% of patches, absorption was 60 to 84%; for 33.2% of them, it was lower; and for 8.8%, it was higher than this range. The intra-individual variability ranged from 2.8 to 75.1%. The bioavailability of fentanyl was statistically different according to patient age. Patients >75 years of age absorbed 50% of the fentanyl during the selected 72-h period, whereas patients <65 years absorbed 66%. Moreover, there is a significant difference in the percentage of absorbed fentanyl according to the type of cancer. The absorption was higher in patients with breast or digestive cancer than in those with lung cancer. Hyperhidrosis, hypertrichosis and the localization of patches on the skin did not influence bioavailability. For the entire group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

The follow-up of testicular tumours must be rigorous in view of the high cure rate in the case of recurrence. This follow-up is based on clinical examination, thoracoabdominopelvic CT and the tumour marker assays. The frequency of these examinations depends on the tumour stage.

Perception of pain by the patient is frequently one of the early signs preceding a diagnosis of cancer and, later, a sinister sign of disease progression. Among opioid drugs, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The objective of this study was to investigate the intra- and interindividual variabilities in pharmacokinetics after fentanyl drug delivery by the transdermal fentanyl patch delivery system in patients with cancer pain. As a first step, a liquid chromatography-mass spectrometry method was developed for the determination of the analgesic fentanyl in human plasma. This method was validated over the concentration range 0.15-100 ng/mL. The study group consisted of 29 inpatients (18 men and 11 women; age range 29-80 years). The initial transdermal fentanyl delivery rate was chosen depending on the patient's analgesic requirements. For 20 patients, the initial TTS fentanyl delivery rate was 25 or 50 microg/h. For 6 patients, the initial delivery rate was 75-150 microg/h. Two patients received up to 300 microg/h fentanyl delivery rate, and 3 patients received up to 350 microg/h fentanyl delivery rate. Fifteen of the 29 patients received rescue doses of subcutaneous or oral morphine, and 26 patients received paracetamol with codeine (30 mg per os). Blood samples were collected at the following intervals: 2-5, 22-26, or 45-47 hours following fentanyl patch application. The severity of pain experienced by the patient was assessed thrice daily using a visual analogue scale. The study period was 46 days. Large patient-to-patient variations in pharmacokinetic parameters occurred, although intraindividual variability was limited. A mean bioavailability of 78% was estimated; the total clearance averaged 41 L/h. From 25 to 100 mug/h fentanyl delivery rate, the pharmacokinetics was linear. At the 2 highest doses, an increase of total clearance was observed (>60 L/h). For the whole group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

Background: Stage I nonseminomatous germ cell tumours are characterized by the absence of detectable metastatic extension at the time of diagnosis of the disease. The experience acquired with staging retroperitoneal lymphadenectomy or surveillance cohorts demonstrates that about 30% patients nevertheless present microscopic metastases. Should management after orchidectomy be based on watchful waiting or should complementary treatment be proposed immediately?, Methods: A review of the international literature was designed to: 1) evaluate the contribution to the decision-making process of histological variables able to predict the risk of micro-metastatic dissemination, 2) define the potential advantages and disadvantages of the three approaches usually adopted after orchidectomy (retroperitoneal lymphadenectomy, surveillance and adjuvant chemotherapy), 3) establish guidelines for daily practice., Results: Histological variables are especially reliable for prediction of the absence of micro-metastatic risk. The various approaches adopted after orchidectomy can achieve similar and excellent cure rates. The potential adverse effects are very different. Watchful waiting is preferable in low-risk patients (absence or small proportion of embryonic carcinoma and absence of vascular invasion in the primary tumour). Adjuvant chemotherapy must be strictly reserved to high-risk patients (predominant component of embryonic carcinoma and presence of vascular invasion). Retroperitoneal lymphadenectomy must be performed by specialized teams in patients at low or intermediate risk, especially when watchful waiting cannot be effectively ensured, when serum tumour markers are normal at diagnosis or when the primary tumour presents a predominant component of mature teratoma associated with vascular invasion., Conclusion: Histological data derived from the orchidectomy specimen, the urologist's learning curve in relation to retroperitoneal lymphadenectomy and the clinical context (patient's expected compliance with follow-up, expected adverse effects of the various treatment options) are the main decisional parameters to be taken into account by multidisciplinary teams. The optimal individual option can only be determined after discussion with the patient.

Purpose: The prognostic relevance of the rate of decline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors (NSGCT) was studied in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) classification., Patients and Methods: Data from 653 patients prospectively recruited in clinical trials were studied. Tumor markers were obtained before chemotherapy and 3 weeks later. Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization (TTN). A favorable TTN was defined when both AFP and HCG had a favorable decline rate, including cases with normal values., Results: The median follow-up was 50 months (range, 2 to 151 months). Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival (PFS; P <.0001) and overall survival (OS; P <.0001). The 4-year PFS rates were 64% and 38% in patients from the poor-prognosis group who had a favorable and an unfavorable TTN, respectively. The 4-year OS rates were 83% and 58%, respectively. This effect was independent from the initial tumor marker values, the primary tumor site, and the presence of nonpulmonary visceral metastases: tumor marker decline rate remained a strong predictor for both PFS (hazard ratio = 2.5; P =.01) and OS (hazard ratio = 4.6; P =.002) in patients from the IGCCCG poor-prognosis group in multivariate analysis., Conclusion: Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients.

In this article, we describe the case of 4 brothers, 2 of which had primary mediastinal nonseminomatous germ cell tumors (PMNSGCT), while the other 2 had benign mediastinal disease. We discuss the relationship between these diseases of the mediastinum and the thymic microenvironment. Additionally, we suggest that a genetic predisposition for germ-cell tumors (GCT) may be involved since the parents were relatives.

Background: As a single agent, 100 mg/m(2) of docetaxel every 3 weeks remains the standard schedule in the first-line treatment for metastatic disease. At this dose level, the major limiting toxicity is neutropenia. The current study was conducted to assess the feasibility of reducing time intervals between cycles while delivering standard doses of docetaxel with granulocyte-colony-stimulating factor (G-CSF; lenograstim)., Methods: In the first part of the study, 24 patients were randomized to receive 1 of 4 schedules: 100 mg/m(2) of docetaxel every 21 days without lenograstim; 100 mg/m(2) of docetaxel every 18 days with lenograstim; 100 mg/m(2) of docetaxel every 14 days with lenograstim; or 100 mg/m(2) of docetaxel every 10 days with lenograstim. In the second part of the study, 15 additional patients were included to confirm the feasibility of the recommended interval between cycles., Results: Of the 39 patients treated, 14 patients (36%) withdrew from therapy because of Grade 3 (according to standard World Health Organization criteria) nonhematologic limiting toxicities. Only 3 patients were treated in the 10-day interval arm and were withdrawn because of toxicity--1 patient had Grade 3 asthenia after the second cycle and 2 patients had Grade 3 dermatitis after 4 cycles. Of the 24 patients treated in the 14-day intervals, Grade 3 limiting toxicities occurred in 8 patients (33%), including dermatitis in 3 patients; diarrhea, myalgia/arthralgia, or asthenia in 4 patients; and ungual toxicity in 1 patient., Conclusions: Introduction of G-CSF (lenograstim) as primary prophylaxis allowed the administration of docetaxel every 14 days with manageable toxicities. Further studies are now required to assess the impact in terms of response rates and survival in patients with cancer., (Copyright 2004 American Cancer Society.)

Purpose: The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies., Methods: Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity., Results: Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels., Conclusion: The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.

Background: The current study was performed to evaluate the efficacy and toxicity of a noncisplatin-based chemotherapy regimen combining gemcitabine and docetaxel as front-line chemotherapy for patients with carcinoma of an unknown primary site., Methods: Patients were to receive intravenous gemcitabine at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 and docetaxel at a dose of 75 mg/m2 over 1 hour on Day 8 in an outpatient setting. The schedule was repeated every 3 weeks for a maximum of 6 cycles., Results: Thirty-five patients were assessable for response and survival. One complete and 13 partial responses were observed. The overall response rate was 40% (95% confidence interval, 28-52%). The median time to disease progression was 2 months (range, 1-4 months). The median overall survival time was 10 months (range, 0-32 months). Toxicity was reported to be manageable., Conclusions: The combination of gemcitabine and docetaxel was found to be active in patients with carcinomas of an unknown primary site. However, the overall outcome of these patients remains poor and novel treatment approaches are required., (Copyright 2004 American Cancer Society.)

Context: The "Standards, Options and Recommendations" (SOR) project, which 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 define Clinical Practice Guidelines (CPG) for the diagnosis of carcinomas of unknown primary site., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers., Results: The main recommendations for the diagnosis of carcinomas of unknown primary site are: 1) Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment. For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary. 2) An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies. This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. 3) A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later. 4) The clinician and pathologist should compare their opinions before and after the pathological diagnosis., (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: We developed gradient HPLC methods for quantification of the antimitotic drug irinotecan (CPT-11) and its four metabolites, SN-38, SN-38 G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4amino-1-piperidino]-carbonyloxycamptothecin (NPC), as the sum of the lactone and carboxylate forms, in human plasma and saliva. Camptothecin was used as internal standard., Methods: The sample pretreatment involved protein precipitation with methanol-acetonitrile (50:50 by volume) followed by acidification with hydrochloric acid to convert the lactone ring-opened form into its lactone form, quantitatively. HPLC separation was performed on a Xterra RP18 column. The excitation wavelength was 370 nm, and the emission wavelength was set at 470 nm for the first 24 min and then at 534 nm for the next 4 min. The stabilities of irinotecan and its four metabolites in plasma, saliva, and acidic extracts were also investigated under various conditions., Results: Assays were linear in the tested range of 0.5-1000 micro g/L. For the five analytes, limits of quantification were 0.5 micro g/L in both matrices. The interassay imprecision (as relative standard deviation) was 3.2-14% in plasma and 2.6-5.6% in saliva. Assay recoveries ranged from 92.8% to 111.2% for plasma and 100.1% to 104.1% for saliva. Mean extraction recovery from plasma or saliva was 90%., Conclusion: The developed assay can be used to determine pharmacokinetic parameters for CPT-11, SN-38, SN-38 G, APC, and NPC in plasma and saliva from patients with metastatic colorectal cancer.

Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site., Patients and Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done., Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively., Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Background: Patients with disseminated renal cell carcinoma (RCC) have a poor outcome, and the disease is considered highly resistant to chemotherapy. Irinotecan is an active drug in the treatment of a number of neoplastic diseases and is not concerned with the multidrug-resistance phenotype of tumor cells, a common mechanism of drug inactivation and resistance in patients with RCC. Therefore, the authors tested the antitumor activity of irinotecan in patients with RCC., Methods: Patients with disseminated RCC received irinotecan (350 mg/m(2)) every 3 weeks. The primary objective of the study was to determine the overall response rate. Two groups of patients were defined: previously treated patients (Group A) and nonpretreated patients (Group B)., Results: Forty-two eligible patients were recruited: Twenty-six patients (Group A) had received previous chemotherapy or immunotherapy, and 16 patients had received no previous systemic therapy (Group B). The median number of cycles received per patient was 3 cycles (range, 1-6 cycles). A dose reduction was required in only 8% of cycles. Two patients, one in each group, had minor responses. Eleven patients (42%) in Group A and 1 patient (12%) in Group B had disease stabilization. Overall, therapy was tolerated well. Grade 4 neutropenic fever occurred in 17% of patients. The 1-year overall survival rate was 61% (95% confidence interval, 42-80%) in Group A and 19% (95% confidence interval, 0-49%) in Group B., Conclusions: Irinotecan was tolerated well and had limited activity in patients with disseminated RCC at the dose and schedule used in the current study. A high percentage of disease stabilization was observed in cytokine-pretreated patients., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11474)

Acute DIC is a rare, but life-threatening complication of metastatic prostate cancer. The authors discuss the treatment modalities in the light of three cases and a review of the recent literature. The key to treatment of DIC is treatment anti of the tumour. Androgen blockade is indicated in hormone-dependent tumours. This treatment can sometimes be completed by low-dose oral anticoagulants. Chemotherapy is the treatment of choice of acute DIC during the hormone resistance phase.

Background: Despite the fact that new drugs have emerged from clinical research in urothelial cancer during the last decade, the prognosis of patients with advanced disease remains poor with a median survival of 12 to 14 months. We designed a feasibility study of gemcitabine and oxaliplatin (GO) in patients with advanced urothelial cancer., Patients and Methods: Twenty patients received bimonthly cycles of gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2. The cycles were given at 2-week intervals without G-CSF support. Thirteen patients were treated with the GO combination as first-line chemotherapy because of a poor performance status or a creatinine clearance < 1 ml/s., Results: The median number of cycles of GO was 5 (1-7). The median number of days between cycles was 14 throughout the treatment. Seven (8%) out of 87 cycles had to be delayed because of neutropenia or asthenia. A 25% dose reduction in the doses of cytotoxic drugs was necessary in 2 patients. Chemotherapy was stopped before the sixth cycle because of an early death related to a myocardial infarction in 1 patient, a grade 3 neuropathy in 1 patient and a progressive disease in 9 patients., Conclusion: Using these doses and schedules, the GO regimen appears a safe therapy for patients with advanced urothelial cancer. Phase II studies are required to assess the possible role of this combination in advanced urothelial cancer.

The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring.

Purpose: To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site and to develop a simple prognostic model for the selection of patients in prospective clinical trials., Patients and Methods: Univariate and multivariate prognostic factor analyses were conducted in a population of 150 unselected patients and led to the construction of two successive classification schemes. An external data set of 116 patients enrolled onto two prospective trials was used for validation., Results: When studying clinical variables only, poor performance status (2 or 3) and presence of liver metastases were retained in the multivariate analysis. The first classification scheme consisted of three subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse prognostic factors. With the introduction of serum lactate dehydrogenase (LDH) levels in a further step, liver metastases were no longer significant. The second classification scheme therefore included poor performance status (relative risk [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, respectively (P <.0001). The 1-year survival rates were 45% and 11%, respectively. This second classification scheme was validated in an external data set: the median survival rates of patients assigned to the good-risk group and the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1-year survival rates were 53% and 23%, respectively., Conclusion: A simple prognostic model using performance status and serum LDH levels was developed and validated. It allows the assignment of patients into two subgroups with divergent outcome. Further prospective trials will be designed using this prognostic model.

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 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. 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., Objectives: To develop clinical practice guidelines for carcinoma of unknown primary site (CUPS) patients according to the definitions of the Standards, Options and Recommendations project., Methods: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 81 independent reviewers., Results: The main recommendations for the management of patients CUPS are presented below: 1) An adapted immunochemistry test using a specific antibody battery should be performed for the anatomopathologic diagnosis. 2) The aim of the diagnosis is to identify specific anatomoclinical forms that can be treated by a specific treatment (standard, level of evidence B2). Except these forms, searching for the primary tumor site have no prognosis or therapeutic interest that can justify a systematic diagnosis assessment (standard, level of evidence B2). 3) The management of poorly differentiated neuroendocrine carcinoma consists of platin/etoposide based chemotherapy. There is no standard treatment for the differentiated forms. 4) Surgical node excision and adjuvant radiotherapy should be performed in case of epidermoid carcinoma with cervical node metastases. In the event of a non operable tumor, an irradiation should be performed. 5) The management of axillary node metastases in women with adenocarcinoma should be the same as the management of patients with lymph node metastases in breast cancer. If mammary MRI is negative, surgical treatment and mammary irradiation are not recommended and an axillary node excision should be performed. 6) The standard treatment for women with primary papillary serous carcinoma of the peritoneum is a surgical resection followed by chemotherapy, as recommended for ovarian cancer. 7) CUPS not belonging to any specific anatomoclinical forms can be treated by chemotherapy, symptomatic treatment alone or treatment based on biphosphonates in presence bone metastases.

Among genito-urinary tumors, gemcitabine has only got the marketing approval for advanced urothelial cancer. The combination of gemcitabine and cisplatin has been shown to be a new standard of treatment in this disease because of equal efficacy and lesser toxicity as compared to the classic M-VAC protocol which includes methotrexate, vinblastin, doxorubicin and cisplatin. However new trials are required with the aim of improving survival, especially in the adjuvant setting after cystectomy. The role of gemcitabine in other tumors of the genito-urinary tract has to be determined.

The aim of this study was to characterize the population pharmacokinetic of vinorelbine in elderly patients and to propose a limited-sampling strategy to estimate individual pharmacokinetic parameters. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2. The population parameters were computed, using a three-compartment model, from an initial group of 27 patients. Twelve additional courses were used for model validation and evaluation of eight different limited-sampling strategies. The inter-individual variability of CL was explained by a linear dependency with age. The population average parameters and the interindividual variabilities (CV%) were: CL=47.1 l/h (31.7%), V=16.6 l (64%), k21=0.776 h-1 (20%), k31=0.0346 h-1 (15.2%), alpha=0.431 h-1 (6.84%) and beta=0.0167 h-1 (25%). Bayesian estimation with three measured levels (end of infusion, and 6 and 48 h) can be selected, because it allows adequate estimation of CL, elimination half-life and vinorelbine concentrations with a non-significant bias. Moreover, the choice of these three sampling times presents practicality advantages for the patient's comfort. Vinorelbine clearance decreasing with age and AUC being a good predictor of several toxicity end points during vinorelbine treatment, the limited-sampling strategy developed in this paper may be clinically relevant.

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.

Background: Because carcinomas of unknown primary origin are highly malignant tumors with a bad prognosis (median survival, 6-12 months) and no current optimal therapy, the authors designed a prospective dose-dense chemotherapy regimen with the objective of improving the results observed in patients who receive conventional treatment., Methods: Eighty-two patients received alternative bimonthly cycles of doxorubicin 50 mg/m(2) with cyclophosphamide 1000 mg/m(2) (AC) and etoposide 300 mg/m(2) with cisplatin 100 mg/m(2) (EP). Cycles were given at 2-week intervals with granulocyte-macrophage-stimulating factor support (5 microg/kg per day) from Day 4 to Day 10. Patients without measurable lesions were included, because the major end point was survival., Results: The median number of alternative cycles of AC and EP was 4 cycles (range, 1-12 cycles). An objective response was observed in 24 of 62 patients (39%; 95% confidence interval, 30-48%) with measurable lesions, including 6 patients who achieved a complete response. Among 20 patients with nonmeasurable disease, 9 patients (45%) had no evidence of progressive disease at the end of chemotherapy. The overall median survival of 82 patients was 10 months, with 5 patients surviving clinically disease free at 17 months, 29 months, 45 months, 64 months, and 70 months after the end of treatment. Myelosuppression was the most common toxicity. Two toxic deaths occurred., Conclusions: Using these doses and schedules, a dose-dense chemotherapy regimen did not appear to improve the outcome of patients with carcinoma of unknown primary site. Alternative studies dealing with news drugs will be required., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10264)

Purpose: To take into account relationships between topotecan area under the plasma concentration (AUC) versus time curve and percentage decrease of neutrophil count previously shown when topotecan is administered on a 5-day, daily schedule. A multicentric clinical trial with individualized dosing of topotecan was performed in patients with platinum-refractory ovarian cancer. The primary goal of this study was to evaluate the toxicity of topotecan when the interindividual variability in plasma drug exposure is decreased., Experimental Design: A total of 39 patients were evaluable. In cycle 1, the daily dose for the last 2 days was dependent on the observed topotecan AUC at day 1; the general objective was to constrain the overall AUC (i.e., from day 1 to day 5) within 37,500-75,000 nM.min. A pharmacokinetic study was also performed on day 5 of cycle 1 and day 1 of cycle 2 to evaluate the intrapatient pharmacokinetic variability both within cycle 1 and between cycles., Results: The dose of topotecan was decreased for 20 patients and increased for only 1 patient within cycle 1. The total administered dose was correlated to the creatinine clearance. The dose adjustments allowed control of the topotecan exposure: mean (+/-SD) observed AUC of 70,697 (+/-12,364) nM.min. Fourteen cases of dose-limiting toxicity were observed, mainly in patients who previously received two different regimens of chemotherapy without a washout period before topotecan treatment. An overall response rate of 21% was observed in the 33 patients evaluable., Conclusion: Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60 ml/min (recommended starting dose is 1.2 mg/m(2)). By performing drug monitoring and taking into consideration the past treatment of each patient, better dose individualization can be obtained.

Purpose: As vinorelbine is 78% bound to platelets, it seems interesting to investigate the pharmacokinetic profile of this drug from blood and to compare it to that determined from plasma. Thus, in this study, the comparative blood/plasma pharmacokinetics of vinorelbine were investigated in 15 elderly patients with advanced metastatic cancer., Methods: The drug was given as a short (10 min) peripheral intravenous infusion; the administered dose ranged from 20 to 30 mg/m2 depending on the patient. Chemotherapy was repeated weekly. During the first and the fifth courses, each patient underwent pharmacokinetic evaluation. Toxicity evaluation was performed after each course of chemotherapy; a total of 109 courses was studied. Plasma and blood vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorimetric detection. Individual pharmacokinetic parameters were estimated with an empirical Bayes methodology. An open three-compartment pharmacokinetic model was used to describe the kinetics of vinorelbine., Results: The half-lives of the terminal part of the curves, determined from blood and plasma data, were of the same order of magnitude: 31-35 h. Mean total clearances were about 0.71 l/h/kg from plasma and 0.45 l/h/kg from blood. Except during the first 15-20 min following the end of infusion, vinorelbine concentrations were 1.9 times higher in blood than in plasma. The ratio AUC(B)/AUC(P) (AUC(B) and AUC(P) are the area under the concentration-time curve from blood and plasma data, respectively) averaged 1.7; it was comparable to the blood/plasma ratio of 1.6 that remained constant over the 72 h of the study. There was substantial intra- and interpatient variability in vinorelbine pharmacokinetic parameters. This variability is similar within and between patients, and between pharmacokinetic parameters computed from blood and plasma. The elimination half-life is the parameter with the lowest intra- and interindividual variability (10-14%), while the AUC is the parameter presenting the highest variability (20-65%). The main haematological toxicity was anaemia (12 patients) and neutropenia (10 patients). Thrombocytopenia occurred in only one patient. At the first cycle, significant correlations were found between AUC(B) and AUC(P) and the decrease in neutrophil count (P < 0.05). The highest haematological toxicities encountered in this study occurred in patients presenting the lowest platelet count. AUC computed from plasma data decreased significantly with the increase of platelet count (P = 0.03)., Conclusion: From the results of this study, blood did not appear to be a better predictor of haematological toxicity than plasma, but the decrease of platelet count seems to be a good predictor of this toxicity. Indeed, changes in platelet count are likely to produce strong variations in the unbound fraction of vinorelbine; this exposes the patient to a high risk of toxicity.