Enrique Gonzalez-Billalabeitia

Assessment of procalcitonin as a diagnostic and prognostic marker in patients with solid tumors and febrile neutropenia.

Cancer patients with fever and neutropenia currently are assessed on clinical grounds only. The current study prospectively evaluated the efficacy of baseline procalcitonin (PCT) in the detection of bacteremia and in the prediction of outcome in patients with solid tumors and febrile neutropenia.

Strategies to design clinical studies to identify predictive biomarkers in cancer research

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.

Long-Term Follow-Up of an Anthracycline-Containing Metronomic Chemotherapy Schedule in Advanced Breast Cancer

To the Editor: Breast cancer is the most frequent neoplasm in women, and one of the leading causes of cancer death, accounting for 212,920 new cases per year and 40,970 deaths in the United States in 2006 (1). Continuous chemotherapy has been extensively used in breast cancer treatment during the past years. In the later sixties, Cooper (2) reported a highly effective five-drug weekly combination chemotherapy [cyclophosphamide, epirubicin, 5-fluorouracil, vincristine, and prednisone (CEFVP)]. Recent advances in tumor biology have demonstrated that many classical cytotoxic agents (cyclophosphamide, anthracyclines, fluorouracil, and vinca alkaloids) when administered in low continuous doses induce a tumor suppressive effect through an anti-angiogenic mechanism additive to the known cytotoxic activity (3). In February 1988, we began to treat metastatic breast cancer with an original Cooper-liker regimen in five drug weekly schedule with lower fixed doses of CEFVP we called ‘‘mini-Cooper.’’ Between February 1988 and February 1997, we treated 63 metastatic breast cancer patients (44 on first line and 19 on second line). Here, we report our long time results. All the evaluated patients had histologically confirmed metastatic breast cancer, adequate organ function, and bidimensional measurable disease. All patients firmed informed consent. The regimen consisted of continuous daily oral administration of cyclophosphamide 100 mg, weekly intravenous fixed doses of 4-epirubicin 30 mg, 5-fluorouracil 500 mg, and vincristine 25 mg and orally prednisone 20 mg every other day. Treatment was continued until disease progression, intolerable toxicity or death. After intolerable dose of 4-epirubicin (>950 mg ⁄ m), decrease greater than 10% or under 50% of left ventricular ejection fraction (LVEF) or cardiac toxicity, 4-epirubicin was substituted by weekly intravenous methotrexate 25 mg. Hematologic test was repeated every 2 weeks and a complete analysis with clinical examination and evaluation of toxicity was performed every 28 days. Treatment was delayed in case of neutrophil count <1,000 mm, platelet counts <100,000 mm, or severe non-hematologic toxicity. Tumor responses were evaluated on the basis of World Health Organization criteria every 3 months. Statistical analysis was performed with the SPSS version 14.0 (SPSS Inc., Chicago, IL, USA). Survival and time to progression were estimated using the Kaplan–Meier method. The median age was 54 years (range 33–94). Median Eastern Cooperative Oncology Group performance status was 2 (range 1–3), 46% were premenopausal and 35% were estrogen receptor and progestagen receptor negative. Seventy percent of patients had two or more organs involved. Bone, lung, and liver were the most frequent metastatic sites. More than one-half of patients (64%) had received prior chemotherapy, 34% in the adjuvant setting. One-fourth of patients (24%) had received prior anthracyclines with adequate baseline LVEF. A total of 2,120 cycles of chemotherapy were administered. The median number of cycles was 28 (range 9–93). The median cumulative dose of 4-epirubicin was 810 mg and methotrexate was used in 162 cycles. Dose intensity and median relative dose intensity of 4-epirubicin were 24 mg ⁄ week and 0.86, respectively. All 63 patients were evaluated for tolerability and toxicity. No toxic deaths were observed and the study treatment was well tolerated. The main toxicities were hematologic: grade 4 neutropenia was observed in 19% of patients, and febrile neutropenia in 6%. Severe thrombocytopenia was rarely observed, and only one patient developed grade IV anemia. No severe mucositis was observed. Forty-one patients were evaluated for LVEF. Eleven patients experienced Address correspondence and reprint requests to: Enrique GonzálezBillalabeitia, MD, PhD, Servicio de Hematologı́a y Oncologı́a Médica, Hospital General Universitario Morales Meseguer, Murcia, Spain, or e-mail: engonbil@um.es.

Recent advances in genitourinary tumors: A review focused on biology and systemic treatment

Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN)

Background Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. Patients and methods This is a multicenter, randomized, open-label, phase II/III study, following a Simons optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. Results Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. Conclusion This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. Trial number NCT01830231.

Consensus Recommendations from the Spanish Germ Cell Cancer Group on the Use of High-dose Chemotherapy in Germ Cell Cancer

BACKGROUND High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC). OBJECTIVE To establish a clinical practice guideline for HDCT use in the treatment of GCC patients. DESIGN, SETTING, AND PARTICIPANTS An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts. RESULTS AND LIMITATIONS The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended. CONCLUSIONS It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT. PATIENT SUMMARY This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.

A Risk-Adapted Approach to Patients with Stage I Seminoma according to the Status of Rete Testis: The Fourth Spanish Germ Cell Cancer Group Study

Objective: The aim of this study was to assess a risk-adapted strategy for stage I seminoma guided by the presence of rete testis invasion. Methods: Between January 2013 and December 2015, a total of 135 consecutive patients with stage I seminoma from 18 Spanish tertiary hospitals were included in a prospective multicenter study. Median patient age was 38 years (range 22–60). Preoperative beta-human chorionic gonadotropin was elevated in 9.6% of patients. Rete testis invasion was present in 47.4% of patients. After orchiectomy, subjects with rete testis invasion were treated with 2 courses of adjuvant carboplatin (area under the curve of 7, with 21-day interval). Those without this risk factor were managed by surveillance. Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Results: After a median follow-up time of 33 months, only 6 relapses were recorded (5 on surveillance, 1 after carboplatin). These cases were rescued with BEP or EP chemotherapy, and all 135 patients are currently disease free without sequelae. Three-year DFS was 92.0 and 98.2% for patients on surveillance and after carboplatin, respectively. Three-year OS was 100%. Conclusion: A risk-adapted approach based on rete testis invasion as a single risk factor is feasible and yielded an excellent outcome with a 3-year DFS of 94.9%.

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.

Should Anticoagulation Therapy Be Withheld in Patients With Active Cancer After 6 Months of Low-Molecular Weight Heparin?

TO THEEDITOR: Napolitano et al 1 recently published their work evaluating the role of residual vein thrombosis (RVT) to assess the optimal duration of anticoagulation therapy in patients with active cancer and deep vein thrombosis (DVT) of the lower extremities. We agree with the authors that the absence of RVT identified a group at low risk for DVT recurrence. However, we have some methodologic concerns that might hamper the applicability of this trial to our daily practice. Concerning the inferential extensibility, we deem it essential to report whether tumors were truly active at the time of random assignment (6 months from the index DVT), and whether the hypercoagulable states resolved throughout the study period. We base these recommendations on the following observations. Although, in the definition of the study population, the authors established active cancer as an inclusion criterion, 78% of patients did not have metastasis. Strikingly, 63% of the patients did undergo major surgery, and supposedly, many of them were thereafter free of disease. Notably, the low percentage of patients with metastatic or incurable tumors explains the low mortality rate that was reported in this study. Given that the persistence of tumor-related thrombophilia is a key determinant of venous thromboembolism (VTE) recurrence, this fact might limit the applicability of this study to patients with metastatic disease who are seen in daily practice, even in the absence of RVT. We would appreciate if the authors could clarify this point.

New advances in genitourinary cancer: evidence gathered in 2014

This review provides updated information published in 2014 regarding advances and major achievements in genitourinary cancer. Sections include the best in prostate cancer, renal cancer, bladder cancer, and germ cell tumors. In the field of prostate cancer, data related to treatment approach of hormone-sensitive disease, castrate-resistant prostate cancer, mechanisms of resistance, new drugs, and molecular research are presented. In relation to renal cancer, relevant aspects in the treatment of advanced renal cell carcinoma, immunotherapy, and molecular research, including angiogenesis and von Hippel-Lindau gene, molecular biology of non-clear cell histologies, and epigenetics of clear renal cell cancer are described. New strategies in the management of muscle-invasive localized bladder cancer and metastatic disease are reported as well as salient findings of biomolecular research in urothelial cancer. Some approaches intended to improve outcomes in poor prognosis patients with metastatic germ cell cancer are also reported. Results of clinical trials in these areas are discussed.