Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients.

Background: Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer. Methods: Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided. Results: The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P = .01). These results were validated in an independent international cohort that included 241 patients from four hospitals. Conclusions: VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications.

Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer: intergroup study EORTC 30983.

PURPOSE: To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC). PATIENTS AND METHODS: Patients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m(2) in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual. RESULTS: Accrual was from November 1998 to April 2009. A total of 169 patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a good prognosis of GCC (eight patients administered BEP; six patients administered T-BEP) or a poor prognosis of GCC (one patient administered BEP; four patients administered T-BEP). PFS at 3 years (intent to treat) was 79.4% in the T-BEP group versus 71.1% in the BEP group (hazard ratio [HR], 0.73; CI, 0.47 to 1.13; P [log-rank test] = 0.153). PFS at 3 years in all eligible patients was 82.7% versus 70.1%, respectively (HR, 0.60; CI: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different. CONCLUSION: T-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

Molecular mechanisms behind the resistance of cisplatin in germ cell tumours.

Cisplatin has been one of the principal chemotherapy agents for the last 30 years and is still used widely in the treatment of testicular, ovarian, lung, head and neck, bladder and several other tumours. Resistance to chemotherapeutic agents is a major obstacle for successful treatment. Treatment effect on germ cell tumours (GCTs) is more successful than in adults suffering from almost any other solid tumour, but resistance still appears in 20% of patients with metastatic disease. However, because of the young age of patients and few data regarding the process of becoming resistant, this situation is still a challenge. In this review we are going to analyse the published literature on cisplatin resistance in GCTs and explain the initiatives that the Spanish Germ Cell Cancer Group (GG) is taking to try to elucidate the molecular mechanisms behind this process.

Imaging techniques contribute to increased surgical rescue of relapse in the follow-up of colorectal cancer.

PURPOSE: This study analyzes the results of a follow-up policy in colorectal cancer at our institution and evaluates the possible benefit provided by each test performed. PATIENTS AND METHODS: Six hundred nineteen patients who had radical surgery and adjuvant treatment for colorectal cancer were followed up with a protocol that included carcinoembryonic antigen testing and clinical examination every three months for the first two years, every four months in the third year, and every six months in the fourth and fifth years. Chest X-ray and colonoscopy were performed yearly for five years and abdominal ultrasound was done every six months for the first three years and yearly afterward. Abdominopelvic computerized tomography was performed yearly for the first two years in cases with rectal cancer. If relapse was detected, all operable cases underwent surgery if possible. RESULTS: Between 1993 and 1999, 619 patients were followed-up. Mean follow-up was 66.9 months. Two hundred eight relapses were detected, 83.6 percent in the first three years and 73 (35.1 percent) underwent surgical resection. Carcinoembryonic antigen testing detected 44.2 percent of recurrences and 31.9 percent of them were operated on. Imaging techniques detected a lower percentage of recurrences (18.7 percent) but were more often resectable: 52 percent and 60 percent of the recurrences detected by computerized tomography and chest X-ray, respectively, underwent surgery. Median overall survival of patients with resected relapse was 62 months, significantly higher than those who were not operable (12.4 months). CONCLUSION: Imaging techniques in the surveillance of resected colorectal cancer contribute to early detection of relapse with a high proportion of operable metastatic disease.

Expression of multidrug resistance proteins P-glycoprotein, multidrug resistance protein 1, breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications.

PURPOSE: Resistance to chemotherapy is a major obstacle to overcome in the conservative treatment of patients with locally advanced bladder cancer (LABC). We investigated the predictive value of the response to neoadjuvant chemotherapy (NACT) and prognosis of the expression of multidrug resistance (MDR) related proteins, P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance related protein/major vault protein (LRP/MVP) in LABC. MATERIALS AND METHODS: Using immunohistochemistry we studied the expression of MDR proteins in tumors from 83 patients with LABC treated with NACT using a bladder sparing approach. Expression was related to the response to NACT, bladder preservation and prognosis. RESULTS: P-gp, MRP1, BCRP and LRP/MVP were expressed at high levels in 53%, 59%, 28% and 70% of cases, respectively. P-gp expression correlated with shorter progression-free survival (p = 0.04) but not with overall survival. Surprisingly MRP1 expression correlated with a higher response (p = 0.005) and a higher probability of bladder preservation following NACT (p = 0.001). BCRP did not show any prognostic impact. High LRP/MVP expression was significantly associated with a worse response to NACT and a decreased probability of bladder preservation (p = 0.035). CONCLUSIONS: Our data suggest that MRP1 and LRP/MVP may be useful in combination with other clinicopathological prognostic factors for selecting patients with LABC to be candidates for bladder preservation after NACT. A large prospective study is warranted to confirm the prognostic value of these MDR proteins.

Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material.

Breast cancer resistance protein (BCRP/MXR/ABCP/ABCG2; hereafter ABCG2) is a member of the ATP-binding-cassette family of transporters that causes multi-drug resistance to various anticancer drugs. The expression of ABCG2 in human tumours and its potential involvement in clinical drug resistance are unknown. Recently, two monoclonal antibodies against human ABCG2 were produced, BXP-34 and BXP-21. This study describes an immunohistochemical method using BXP-21 to study ABCG2 expression in formalin-fixed, paraffin-embedded tissues. No staining was seen using BXP-34 with the same protocols. The expression of ABCG2 was then investigated in a panel of 150 untreated human solid tumours comprising 21 tumour types. Overall, ABCG2 expression was frequent. Specificity of immunohistochemistry was confirmed by the detection of a 72 kD band in western blotting. ABCG2 expression was seen in all tumour types, but it seemed more frequent in adenocarcinomas of the digestive tract, endometrium, and lung, and melanoma. Positive tumours showed membranous and cytoplasmic staining. In certain adenocarcinomas, prominent membranous staining was seen. Endothelial cells frequently displayed moderate to strong staining. ABCG2 is widely present in untreated human solid tumours and may represent a clinically relevant mechanism of drug resistance. Future studies in specific tumour types are needed to ascertain its clinical relevance. BXP-21 and the immunohistochemical protocol described here will be of value in these investigations.