Search PubMed⌕ Search

Biomedical subjects

Karim Fizazi

Publications and source records attributed to Karim Fizazi.

At least 19 recordsLinked to original sources

Controversies in the management of clinical stage I testis cancer.

During the last two decades, definitive primary treatments and surveillance with definitive treatment deferred until relapse have demonstrated 98% to 99% cure rates in patients with stage I testis cancer, and these options have obtained firm positions in standard management. The development of optimal management strategies in various countries were at least partly guided by available surgical expertise in retroperitoneal lymph node dissection in the United States, and easy access to reference hospitals in densely populated countries in Western Europe that facilitated close surveillance programs; hence, treatment preferences differ on the two sides of the Atlantic. The success of both approaches is highly dependent on the skills of the practitioner, particularly of surgery and of scrutinized surveillance. As a result, local expertise and familiarity with a chosen modality has strengthened over the years, and investigators have been reluctant to embark on randomized trials designed to compare one modality with another. Such expertise with one particular technique, with the other approach being less familiar territory, has created controversy, because both physicians and patients seek evidence-based data coming from randomized clinical trials on which to make management decisions. Moreover, the reduced risk of relapse resulting from the use of radiotherapy or carboplatin in stage I seminoma and of cisplatin-based chemotherapy in stage I nonseminoma must be balanced against the potential long-term adverse effects in this population of patients with a normal life expectancy. The purpose of this review is to present the currently available data and discuss the merits and the disadvantages of the various approaches, yielding to the possible conclusion that all options appear to be equal in terms of efficacy, but that modality-associated adverse effects differ.

Humans↗

Chemotherapy in patients with teratoma with malignant transformation.

OBJECTIVE: Germ-cell tumours (GCTs) with a non-GCT malignant component are a unique and rare phenomenon called teratoma with malignant transformation (TMT). The only published series of patients with TMT treated with chemotherapy comprised 10 patients. We report here our experience in treating 14 patients with TMT. PATIENTS AND METHODS: Sarcoma was identified in 10 of 14 patients, with rhabdomyosarcoma ranking first (n=4). Other histological types included adenocarcinoma (n=3) and bronchoalveolar carcinoma (n=1). Immunohistochemistry was performed to help in identifying the malignant non-GCT component. RESULTS: Primary treatment consisted of surgery alone in 4 patients. The remaining 10 patients received first-line cisplatin-based chemotherapy with resection of residual masses (n=5): 4 patients had a complete response and 5 had a partial response. Overall, 9 patients developed a relapse with a median time of 84 mo (range: 6-168). At relapse, 8 patients received a chemotherapy regimen directed to the non-GCT component. Four of these patients achieved a partial response. With a median follow-up of 59 mo (range: 3-180), 4 of 14 patients are alive, including 3 who are disease-free. CONCLUSION: To our knowledge, this is by far the largest reported European series of chemotherapy in TMT. Although TMT has a poor prognosis compared to GCT, its management may be improved by adapted chemotherapy associated with surgical resection of residual masses.

Adenocarcinoma↗

STEAP, a prostate tumor antigen, is a target of human CD8+ T cells.

STEAP is a recently identified protein shown to be particularly overexpressed in prostate cancer and also present in numerous human cancer cell lines from prostate, pancreas, colon, breast, testicular, cervical, bladder and ovarian carcinoma, acute lymphocytic leukemia and Ewing sarcoma. This expression profile renders STEAP an appealing candidate for broad cancer immunotherapy. In order to investigate if STEAP is a tumor antigen that can be targeted by specific CD8(+) T cells, we identified two high affinity HLA-A*0201 restricted peptides (STEAP(86-94) and STEAP(262-270)). These peptides were immunogenic in vivo in HLA-A*0201 transgenic HHD mice. Peptide specific murine CD8 T cells recognized COS-7 cells co-transfected with HHD (HLA-A*0201) and STEAP cDNA constructs and also HLA-A*0201(+) STEAP(+) human tumor cells. Furthermore, STEAP(86-94) and STEAP(262-270) stimulated specific CD8(+) T cells from HLA-A*0201(+) healthy donors, and these peptide specific CD8(+) T cells recognized STEAP positive human tumor cells in an HLA-A*0201-restricted manner. Importantly, STEAP(86-94)-specific T cells were detected and reactive in the peripheral blood mononuclear cells in NSCLC and prostate cancer patients ex vivo. These results show that STEAP can be a target of anti-tumor CD8(+) T cells and that STEAP peptides can be used for a broad-spectrum-tumor immunotherapy.

Amino Acid Sequence↗

Gemcitabine and cisplatin after radical cystectomy for bladder cancer in an adjuvant setting: feasibility study from the Genito-Urinary Group of the French Federation of Cancer Centers.

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.

Adult↗

Cancer of unknown primary (CUP).

Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3-5% of all human malignancies. Patients with CUP present with metastases without an established primary site. CUP manifests as an heterogenous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Certain clinicopathological CUP entities are considered as favourable subsets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These subsets are: the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable subsets have a worse prognosis.

Female↗

Intra-abdominal desmoplastic small round cell tumors: CT findings and clinicopathological correlations in 13 cases.

PURPOSE: We report computed tomography (CT) findings in 13 patients with a primary abdominal desmoplastic small round cell tumor. MATERIALS AND METHODS: 13 cases (12 men, 1 woman, mean age=24.8 years) were found in our hospital database between 1991 and 2003. Clinical, CT and histopathological features were studied retrospectively. RESULTS: Peritoneal involvement was the most common feature. In 10 cases, several lobulated peritoneal soft tissue masses (with a mean of four masses per patient) were seen. Two patients had diffused irregular peritoneal carcinomatosis without any distinct peritoneal masses. One patient had a solitary mass in the pelvic space. The main sites of peritoneal involvement were the pelvic space (n=7), omentum (n=5), retroperitoneal space (n=4), small bowel mesentery (n=3), paracolic gutter (n=2 on the right and n=1 on the left), transverse colon mesentery (n=1), peri-splenic space (n=1), peri-hepatic space (n=1). The soft tissue masses were often bulky (mean 6cm, range 1-28cm), lobulated and heterogeneous with hypodense areas (in 73% of cases). In six cases, moderate ascites was seen. In one case of pelvic involvement, unilateral hydronephrosis was seen. Adenopathies were present in seven cases at the time of the diagnosis (at intraperitoneal, retroperitoneal and pelvic sites in six patients and in the groin in one patient). Five patients had liver metastases (four lesions per case excepted one patient with 30 metastases). Associated thoracic metastases were seen in three patients. The diagnosis was confirmed with four CT-guided percutaneous biopsies. CONCLUSION: Although CT features are nonspecific, the diagnosis of desmoplastic small round cell tumor may be suspected in young men with multiple bulky heterogeneous peritoneal soft tissue masses. Imaging is useful for staging and also to guide biopsies.

Abdominal Neoplasms↗

[Preclinical models of prostate cancer].

Although prostate cancer is a major cause of cancer death and morbidity in Western countries, one major hindrance in the study of the biology of prostate cancer has been the limited number of laboratory models, compared with the number of models available for other neoplasms. For a long time, only three cell lines, namely LNCaP, PC3, and DU145, were routinely used to study prostate cancer in the lab. The success rate to establish cell lines from human prostate cancer tissues is low, in the 1% range. Currently, only about 10 prostate cancer cell lines are available, and many of them do not reproduce typical features of the human disease, like androgen receptor expression or prostate specific antigen (PSA) secretion. Spontaneous models in animals (including rat and dog) are practically not convenient for research purposes. Several in vivo models were artificially established by transforming prostate cells by potent oncogenes. Other models were developed by injecting prostate cancer cell lines into the prostate (orthotopic model), the vessel, or the bones of immuno-deficient mice, to mimic localized and metastatic prostate cancer. This was successfully done with the MDA PCa2b cell line. This cell line was also used to generate an in vitro model of bone metastases by a co-culture system with osteoblasts. This model allows to study the paracrine cross-talk between the two cell compartments and the resulting molecular modifications. The objective of the present article is to review the currently available model systems of prostate cancer.

Animals↗

Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors.

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.

Biomarkers, Tumor↗

Patient preference for either the EORTC QLQ-C30 or the FACIT Quality Of Life (QOL) measures: a study performed in patients suffering from carcinoma of an unknown primary site (CUP).

The objective of this study was to examine and compare two core measures of Quality Of Life (QOL) used in cancer clinical trials: the European Organisation for Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) and the Functional Assessment of Chronic Illness Therapy (FACIT), in order to identify which one patients have the strongest preference for using. 68 patients suffering from Carcinomas of an Unknown Primary site (CUP) were recruited in a multicentric study; all of them completed both questionnaires, administered in a randomised manner. The criteria were the percentage of preferences, and four indicators of acceptability. The results indicated that an equal proportion of patients preferred the QLQ-C30 (19%) and FACIT (19%). 54% of patients felt both questionnaires were acceptable. All the indicators of acceptability favoured the QLQ-C30. Analysis of open-ended questions shed light on the difficulties encountered by the patients. As no significant preference was observed for one of the questionnaires, the QLQ-C30 was chosen on the basis of its significantly better acceptability criteria.

Adult↗

Bladder-conserving surgery and interstitial brachytherapy for lymph node negative transitional cell carcinoma of the urinary bladder: results of a 28-year single institution experience.

BACKGROUND AND PURPOSE: We retrospectively analyzed results for lymph node negative transitional cell carcinoma of the bladder treated with brachytherapy. PATIENTS AND METHODS: From 1975-2002, 58 patients received preoperative external irradiation, partial cystectomy (in 69%), iliac node dissection, and iridium-192. Pathologic stage was: 10 pT1, 41 pT2, and 7 pT3. A median total brachytherapy dose of 60 Gy was delivered to the tumor bed. RESULTS: Mean follow-up was 76 months (range, 0.5-296). Tumor stage significantly impacted cause-specific and disease-free survival (P=0.02). Eight pT1 patients were free of disease and 2 died of other cause. For pT2 patients, 5-year cause-specific and overall survival rates were, respectively, 70% (CI 95%: 53-87) and 60% (CI 95%: 43-77). Three pT3 patients died of cancer. For the pT2 patients, the probability of 5-year local control was 65% (CI 95%: 47-83) and being alive without disease with a functional bladder, 50% (CI 95%: 33-67). Previous transurethral resection (TUR) increased the bladder relapse risk among pT2 patients (P=0.03). Twelve patients had severe acute complications and 5 had severe late effects. A high dose of external irradiation increased risk of late complications (P=0.01). Most complications occurred in patients treated before 1985. CONCLUSIONS: Highly select patients presenting with pT2 tumors less than 5 cm with no history of previous TUR may be successfully treated with low-dose external irradiation, limited partial cystectomy, and interstitial brachytherapy. High-risk pT1 patients may also benefit. Postoperative complications and late side effects are minimized with modern management. We recommend lifelong cystoscopic surveillance, with prompt surgical salvage for recurrence.

Aged↗

Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01).

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.

Adult↗

Advanced seminoma--treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: a single-institution experience in 145 patients.

BACKGROUND: Advanced seminoma is a rare clinicopathologic entity. To the authors' knowledge, very few sizeable reports published to date have studied the outcome of patients with advanced seminoma after first-line and salvage therapy, and few have dealt with prognostic factors initially or in patients with recurrent disease. METHODS: The records of 145 men with advanced seminoma who were treated with cisplatin-based first-line chemotherapy regimens were reviewed. Six patient characteristics, including age, prior radiotherapy, primary tumor site, initial serum lactate dehydrogenase and human chorionic gonadotropin levels, and disease stage, were studied as initial prognostic factors. In patients with recurrent disease, outcome according to the site of recurrence and the salvage treatment was also reviewed. RESULTS: A complete response was obtained in 130 patients (90%) after cisplatin-based first-line chemotherapy, and the 5-year overall survival rate was 81% (95% confidence interval [95% CI], 73-87%). Nonpulmonary visceral metastasis at diagnosis was the only initial adverse prognostic factor. Thirty-one patients (21%) developed recurrent disease. Recurrence in the liver or the central nervous system was a major adverse prognostic factor, with a 5-year overall survival rate of 7% (95% CI, 1-32%), compared with 58% (95% CI, 33-79%) in patients who had lymph node, lung, or bone recurrences. The only durable complete remission after a liver recurrence was obtained with high-dose chemotherapy followed by autologous stem cell transplantation. All 12 patients who were treated for primary mediastinal seminoma with cisplatin-based chemotherapy alone were long-term disease free survivors. CONCLUSIONS: Overall, the prognosis of patients with advanced seminoma was good after cisplatin-based, first-line chemotherapy. Metastasis in the liver or the central nervous system, initially or at recurrence, is currently the only proven adverse prognostic factor.

Adult↗

A phase II study of irinotecan in patients with advanced renal cell carcinoma.

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.

Adult↗

A 10-year clinical experience with intermittent hormonal therapy for prostate cancer.

OBJECTIVES: To evaluate, over a 10-year period, the feasibility, efficacy, duration of action and adverse effects of intermittent hormonal therapy (IHT) in patients with advanced prostate cancer or biochemical recurrence after radical treatment. MATERIALS AND METHODS: Two hundred and thirty-three patients with prostate cancer have been included in an IHT protocol since 1992. Fifty-five patients had already been treated by radical prostatectomy (group A), 35 patients had received radiotherapy or a treatment with high-intensity focused ultrasound (HIFU) (group B) and 143 patients had not received any previous treatment (group C). Three-monthly injection of LHRH analogue combined with a non-steroidal antiandrogen was administered during the treatment phase ("on" phase). Treatment was stopped ("off" phase) when the PSA level fell below 4 ng/ml, regardless of the duration of the "on" phase. Criteria for resumption of hormonal therapy were PSA >20 ng/ml, PSA progression slope over the previous three months >5 ng/ml per month or recurrence of pain or urinary symptoms. RESULTS: The median follow-up was 34.9 months (range: 13-151) and the median initial PSA was 28 ng/ml (range: 1-433). Five cycles were performed in the patients with the longest follow-up. The mean duration of cycles was gradually decreased from 19.6 months to 11.8 months. The "on/off" ratio was close to 30% regardless of the cycle or patient group. Ten patients (4%) died from their cancer during the study, with a median survival of 42.2 months. Six patients (2.5%) developed painful symptoms during IHT. CONCLUSIONS: IHT ensures medium-term (three years) control of the disease, using a treatment resumption criteria of PSA >20 ng/ml and was not associated with major complications.

Aged↗

Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.

PURPOSE: Prostate cancer specifically metastasizes to bone where it leads to bone formation. We previously reported that coculturing MDA PCa 2b prostate cancer cells with primary mouse osteoblasts (PMOs) induced PMO proliferation and differentiation. An osteoblastic reaction was also observed in vivo after injection of MDA PCa 2b cells into the bones of severe combined immunodeficient disease mice. The aim of this study was to identify the sequence of events that leads to these osteoblastic lesions in vivo and, using this in vitro model, to define the contributions of various genes and cellular pathways in the pathophysiology of osteoblastic bone metastases of prostate cancer. EXPERIMENTAL DESIGN AND RESULTS: We show histological evidence of de novo bone formation as early as 2 weeks after injection of MDA PCa 2b cells in the bone of severe combined immunodeficient disease mice. In vitro, we show that PMOs induce MDA PCa 2b proliferation, suggesting a synergistic paracrine loop between these cells and PMOs. Endothelin (ET)-1, which is a mitogen for several cell types, is produced by all prostate cancer cell lines tested, and Atrasentan, an antagonist of ET-1 receptor A, partially reversed PMO proliferation induced by MDA PCa 2b cells. ET-1 is known to be comitogenic with a number of growth factors, including insulin-like growth factor (IGF)-I. In this study, we report that IGF-binding protein (IGFBP)-3 transcripts (that regulate levels of free IGF) are down-regulated in prostate cancer cells cocultured with PMO, whereas prostate-specific antigen (a protease known to cleave IGFBP-3) is detected in the 150-400 ng/ml range. Accordingly, IGFBP-3 has antiproliferative effects in PMOs, which were attenuated in our in vitro system. Taken together, our studies also implicate the IGF axis to play a role in this model of bone metastases. Secondly, the transcript level of mouse double minute 2 (a protein that regulate p53) was increased in prostate cancer cells grown with PMOs. The p53-dependent and -independent oncogenic activities of mouse double minute 2 suggest that osteoblasts induce a survival advantage in prostate cancer cells. Lastly, we show that expression of osteoprotegerin is decreased and of receptor activator of nuclear factor-kappaB ligand is increased in PMOs cultured in the presence of MDA PCa 2b cells, two events associated with osteoclast activation and bone resorption. CONCLUSIONS: Our results provide evidence that multiple and distinct molecular events affecting both bone formation and bone resorption concur to the increase bone mass in prostate cancer bone metastases. These data also provide a rationale for developing therapeutic strategies designed to target these molecular changes.

Alkaline Phosphatase↗

[Clinical practice guidelines: Standards, Options and Recommendations for the diagnosis of carcinomas of unknown primary site].

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.

Humans↗

Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site.

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.

Analysis of Variance↗

The emerging role of antifolates in the treatment of malignant pleural mesothelioma.

Clinicians have long regarded malignant pleural mesothelioma as a chemoresistant neoplasm and as a result no standard chemotherapy regimen has emerged. Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged: the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma. Indeed, responses were seen in cisplatin-refractory patients. Based on the promising results from these combination trials, two large phase III studies have begun. The first study was a multicenter, multinational trial sponsored by Eli Lilly and Company, which randomized more than 430 patients with malignant pleural mesothelioma to cisplatin with or without pemetrexed. That trial completed enrollment in February 2001 and is the largest trial ever conducted in mesothelioma. The second trial is being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and compares cisplatin with or without raltitrexed with planned accrual of 240 patients. In both trials, survival is the main endpoint. These trials will help to define the role of these new antifolates in malignant pleural mesothelioma.

Antimetabolites, Antineoplastic↗