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Although androgen deprivation therapy is typically given long-term for men with metastatic prostate cancer, second-generation hormone therapies are generally discontinued before the subsequent line of treatment. We aimed to evaluate the efficacy of continuing enzalutamide after progression in controlling metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel and prednisolone.PRESIDE was a two-period, multinational, double-blind, randomised, placebo-controlled, phase 3b study done at 123 sites in Europe (in Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, Turkey, and the UK). Patients were eligible for period 1 (P1) of the study if they had histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, serum testosterone concentrations of 1·73 nmol/L or less, and had progressed during androgen deprivation therapy with a luteinising hormone-releasing hormone agonist or antagonist or after bilateral orchiectomy. In P1, patients received open-label enzalutamide 160 mg per day orally. At week 13, patients were assessed for either radiographic or prostate-specific antigen (PSA) progression (25% or more increase and 2 ng/mL or more above nadir). Patients who showed any decline in PSA at week 13 and subsequently progressed (radiographic progression, PSA progression, or both) were screened and enrolled in period 2 (P2), during which eligible patients were treated with up to ten cycles of intravenous docetaxel 75 mg/mBetween Dec 1, 2014, and Feb 15, 2016, 816 patients were screened for P1 of the study. 688 patients were enrolled in P1 and 687 received open-label enzalutamide. In P2, 271 patients were randomly assigned at 73 sites to receive enzalutamide (n=136) or placebo (n=135). The data cutoff for analysis was April 30, 2020. Median progression-free survival with enzalutamide was 9·5 months (95% CI 8·3-10·9) versus 8·3 months (6·3-8·7) with placebo (hazard ratio 0·72 [95% CI 0·53-0·96]; p=0·027). The most common grade 3 treatment-emergent adverse events were neutropenia (17 [13%] of 136 patients in the enzalutamide group vs 12 [9%] of 135 patients in the placebo group) and asthenia (ten [7%] vs six [4%]). The most common grade 4 treatment-emergent adverse event in P2 was neutropenia (23 [17%] of 136 patients in the enzalutamide group vs 28 [21%] of 135 patients in the placebo group). Serious treatment-emergent adverse events were reported in 67 (49%) of 136 patients in the enzalutamide group and 52 (39%) of 135 patients in the placebo group. Two (15%) of 13 deaths in the enzalutamide group (caused by septic shock and haematuria) and one (14%) of seven deaths in the placebo group (caused by actue kidney injury) were associated with docetaxel.PRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone.Astellas Pharma and Pfizer.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p &lt, 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

Objectives The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non‐small cell lung cancer (NSCLC) patients treated with first‐ or second‐generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods Stage IV NSCLC patients with locally confirmed EGFR‐TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first‐ or second‐generation EGFR‐TKI as first‐line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression‐free survival (PFS) event or until study completion (72‐week follow‐up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. Results A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty‐six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow‐up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48–2.54; p, The manuscript is a multicenter, prospective study conducted in the real‐world setting. The study reveals that the detection and quantification (MAF slope) of EGFR mutations in ctDNA using the highly sensitive BEAMing method may assist in optimizing treatment decisions for advanced NSCLC patients.

Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with ≥50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

This network meta-analysis (NMA) evaluates the safety of first-line programmed death-ligand 1 (PD-L1) inhibitor monotherapy in advanced NSCLC patients compared to platinum-based chemotherapy. We also compared the risk of adverse events (AEs) according to programmed cell death-1 receptor (PD-1) or PD-L1 inhibitors therapy. To that end, we conducted a series of metanalyses (MAs) using data from six phase III clinical trials, including 4053 patients. Our results show a reduced risk of any grade treatment-related AEs (risk ratio (RR) = 0.722 95% CI: 0.667–0.783, p = 0.002), and grade 3–5 AEs (RR = 0.406 95% CI: 0.340–0.485, p = 0.023) in immunotherapy as compared to chemotherapy. In contrast, a higher risk of immune-related AEs (irAEs) was estimated for immunotherapy versus chemotherapy. The subgroup MAs comparing PD-L1 to PD-1 inhibitors, determined a lower risk of AEs leading to treatment discontinuation in the anti-PD-L1 subgroup (RR = 0.47 95% CI: 0.29–0.75, p = 0.001); however, this statistically significant difference between anti-PD-L1 and anti-PD-1 subgroups was not reached for other safety outcomes analyzed. In conclusion, our findings show that PD-L1 inhibitor monotherapy improves safety outcomes in the 1L treatment of advanced NSCLC patients as compared to chemotherapy except for irAEs.

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.

Purpose The MAGE-A3 protein is expressed in approximately 35% of patients with resectable non–small-cell lung cancer (NSCLC). Several immunization approaches against the MAGE-A3 antigen have shown few, but often long-lasting, clinical responses in patients with metastatic melanoma. Patients and Methods A double-blind, randomized, placebo-controlled phase II study was performed assessing clinical activity, immunologic response, and safety following immunization with recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) in completely resected MAGE-A3–positive stage IB to II NSCLC. The primary end point was disease-free interval (DFI). Results Patients were randomly assigned to either MAGE-A3 immunotherapeutic (n = 122) or placebo (n = 60). After a median postresection period of 44 months, recurrence was observed in 35% of patients in the MAGE-A3 arm and 43% in the placebo arm. No statistically significant improvement in DFI (hazard ratio [HR], 0.75, 95% CI, 0.46 to 1.23; two-sided P = .254), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48 to 1.21; P = .248), or overall survival (HR, 0.81; 95% CI, 0.47 to 1.40; P = .454) was observed. Corresponding analysis after a median of 70 months of follow-up revealed a similar trend for DFI and DFS. All patients receiving the active treatment showed a humoral immune response to the MAGE-A3 antigen, although no correlation was observed with outcome. No significant toxicity was observed. Conclusion In this early development study with a limited number of patients, postoperative MAGE-A3 immunization proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.

Background: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. Methods: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. Results: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). Conclusions: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction., This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer. The authors gratefully say thanks to Ma Luz Samaniego for his help with the statistical analyses.

Sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, delays disease progression, with a median overall survival (OS) of more than 2 years, improves quality of life and is becoming the first-line standard of care for metastatic renal carcinoma (mRCC). To assess the economic value of sunitinib as first-line therapy in mRCC within the Spanish healthcare system. An adapted Markov model with a 10-year time horizon was used to analyse the cost effectiveness of sunitinib vs. sorafenib (SFN) and bevacizumab/interferon-alpha (BEV/IFN) as first-line mRCC therapy from the Spanish third-party payer perspective. Progression-free survival (PFS) and OS data from sunitinib, SFN and BEV/IFN pivotal trials were extrapolated to project survival and costs in 6-week cycles. Results, in progression-free life-years (PFLY), life years (LY) and quality-adjusted life-years (QALY) gained, expressed as incremental cost-effectiveness ratios (ICER) with costs and benefits discounted annually at 3%, were obtained using deterministic and probabilistic analyses. Sunitinib was more effective and less costly than both SFN (gains of 0.52 PFLY, 0.16 LY, 0.17 QALY) and BEV/IFN (gains of 0.19 PFLY, 0.23 LY, 0.16 QALY) with average cost savings/patients of a,not sign,124 and a,not sign23,218, respectively. Using a willingness-to-pay (WTP) threshold of a,not sign50,000/QALY, sunitinib achieved an incremental net benefit (INB) of a,not sign9,717 and a,not sign31,211 compared with SFN and BEV/IFN, respectively. At this WTP, the probability of sunitinib providing the highest INB was 75%. Our analysis suggests that sunitinib is a cost-effective alternative to other targeted therapies as first-line mRCC therapy in the Spanish healthcare setting.

Increase in the expression of epidermal growth factor receptors (EGFRs) has been observed in many tumours. EGFR overexpression usually correlates with a more advanced stage of the disease, a poorer prognosis and a worse chemotherapy response. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been extracellular domain receptor inhibition, using monoclonal antibodies. In this review, we summarize the current status as well as what is likely to be the future use of monoclonal antibodies directed against EGFR. We have focussed on cetuximab being the most developed one. It has been mainly studied in colorectal cancer, and the major portion of this review will focus on all the research that has been carried out on this tumour. Clinical development of cetuximab is also important in head and neck cancer and in lung cancer. Interesting studies have been carried out in pancreatic, gastric, oesophageal and ovarian tumours, as well as in malignant gliomas.

EGFR overexpression usually correlates with a more advanced disease stage, a poorer prognosis and a worse chemotherapy response. EGFR expression increase has been observed in many tumours. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been receptor inhibition of extracellular domain using monoclonal antibodies. Cetuximab is the most developed one and there is plenty information on the literature about its current status. In this review we focus on other EGFR monoclonal antibodies under clinical development. The more developed one is Panitumumab. Its clinical development is taking place very quickly and it has mainly been studied in colorectal cancer showing promising results. There are also other interesting drugs such as Matuzumab, Nimotuzumab and Zalutumumab.

Standard treatment of patients with T4b squamous cell head and neck cancer (T4b-SCHNC) is concomitant chemo-radiotherapy (CT-RT). Recent Phase III trials with Taxane containing induction chemotherapy (IC) suggest that IC could also play a role in this setting. The value of resecting the residual mass after IC and before RT is not yet clear in this context.We present the results of a retrospective analysis.Between 1984 and 2001, 113 patients (patients) with T4b-SCHNC were treated at our institution with IC. Four patients dead during IC and 57 patients achieved a complete or a90% partial response at primary and proceeded to definitive RT (or concomitant CT/RT). Surgical resection was reconsidered after IC and before RT in the other 52 patients. Surgery was performed in 13 of them: in 7 patients resection was R1, all of them had loco-regional progression (2 also developed systemic metastases) and median OS after surgery was 21 months, with no patient alive at 48 months. In the other 6 patients a R0 resection was performed: 3 of these patients had loco-regional relapses (1 also developed systemic metastases) and the other 3 patients remain alive and disease free 56, 62 and 72 months after surgery. Considering the 52 patients that achieved less than a 90% partial response at primary with IC, overall survival was equivalent when no Resection or an R1 resection was performed after IC (5 year OS 8 vs. 0%, lrk, p=0.74), but a statistically significant improvement in OS was observed when an R0 resection was obtained (5 years OS 50%, lrk, p=0.02).R0 resections after IC and before RT could indicate an improvement in OS in patients with T4b-SCHNC that obtain less than a 90% PR at primary after IC. We consider that this approach deserves further research in prospective clinical trials.

Gastric cancer is the second most frequent cancer in the world. Approximately 84% of patients with gastric cancer will have advanced disease and median survival of these patients without chemotherapy is only 3-4 months. "Classical" chemotherapy regimens, mainly CF (cisplatin plus infusional 5FU) and ECF (cisplatin plus infusional 5FU plus Epirubicin) obtain responses in 20-40% of the patients and improve quality of life. Nevertheless, duration of these responses is short with very few complete responses. Median time to tumor progression (TTP) with these regimens is only about 4-5 months and median survival does not exceed 7-10 months. Moreover, benefit seems to be limited to patients with good performance status and treatment toxicity and discomfort are not negligible, specially that of regimens with cisplatin or infusional 5FU. Trying to improve these results, the incorporation of new drugs has been explored. Among the new combinations, the more developed ones are those with Docetaxel (DCF), oxaliplatin (EOX, FLO), Capecitabine (EOX, cisplatin-Xeloda) and irinotecan (ILF). We have final results from Phase III trials that suggest that all these regimens could have a role in the treatment of these patients but survival is still very poor and toxicity remains important. It would be interesting to investigate other new combinations and the incorporation of drugs directed against new therapeutic targets in this setting. It would be of utmost interest that these clinical trials would also explore clinical and molecular prognostic and predictive factors.

Purpose To assess the efficacy of a risk-adapted treatment policy for patients with stage I seminoma by using universally accepted risk criteria. Patients and Methods Between 1999 and 2003, 314 patients with clinical stage I seminoma after orchiectomy were prospectively included. One hundred patients (31.8%) presented no risk factors and were managed with surveillance. In contrast, 131 patients (41.7%) had tumors larger than 4 cm, 33 patients (10.5%) had rete testis involvement, and 50 patients (15.9%) had both risk factors. All the latter received two courses of adjuvant carboplatin. Results Chemotherapy was well tolerated, as only 17 patients (7.9%) presented grade 3 to 4 toxicity. Relapses were observed in six patients (6.0%) on surveillance and in seven patients (3.3%) treated with carboplatin (0.8% of tumors larger than 4 cm, 9.1% of those involving the rete testis, and 6.0% of patients with both risk criteria). All were located at the retroperitoneum, except for one at the spermatic cord. Median tumor size was 25 mm (range, 11 to 70 mm), and median time to relapse was 9 months (range, 4 to 28 months). All patients were rendered disease-free with chemotherapy (etoposide plus cisplatin). Median follow-up was 34 months (range, 12 to 72 months). The actuarial 5-year disease-free survival rate was 93.4% for patients on surveillance and 96.2% for patients treated with adjuvant chemotherapy. Overall 5-year survival was 100%. Conclusion Adjuvant carboplatin is effective in reducing the relapse rate in patients with stage I seminoma and risk factors. A risk-adapted strategy is safe and feasible and should be considered an alternative to systematic approaches, such as irradiation, chemotherapy, or surveillance.

Background: Platinum-based doublets are the standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). Excision-repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) are essential to the repair of cisplatin DNA adducts. Multidrug resistance 1 (MDR1) has been related to antimicrotubule resistance. We assessed whether single nucleotide polymorphisms (SNPs) in ERCC1, XPD, RRM1 and MDR1, and ERCC1 mRNA expression, predicted survival in docetaxel–cisplatin-treated stage IV NSCLC patients. Patients and methods: Using the TaqMan 5′ nuclease assay, we examined ERCC1 118, XPD 751 and 312, RRM1 −37C/A, and MDR1 C3435T SNPs in peripheral blood lymphocytes (PBLs) obtained from 62 docetaxel–cisplatin-treated advanced NSCLC patients. ERCC1 expression was measured in RNA isolated from PBLs using real-time reverse transcriptase PCR. Results: Overall median survival was 10.26 months. Median survival was 9.67 months for 34 patients with ERCC1 118 C/T, 9.74 months for 17 patients with T/T, and not reached for 11 patients with C/C (P=0.04). Similar significant differences in time to progression were observed according to ERCC1 118 genotype (P=0.03). No other significant differences were observed. Conclusions: Patients homozygous for the ERCC1 118 C allele demonstrated a significantly better survival. ERCC1 SNP assessment could be an important component of tailored chemotherapy trials.

Objective: To describe the clinical characteristics and treatment results obtained with the application of a homogeneous treatment protocol in 1490 patients with germ-cell tumours (GCT) registered in the 55 hospitals belonging to the Spanish Germ-Cell Cancer Group (GG) during the period between January 1994 and April 2001. Methods: In general, surveillance was the common policy for stage I patients without local poor prognosis factors, whereas they received adjuvant chemotherapy in case those factor were present. Chemotherapy schedules used in advanced cases were cisplatin and etoposide (EP) for seminoma and BEP or BOMP-EPI in non-seminoma, according to whether the patient was in the good or poor prognosis IGCCCG (International Germ-Cell Cancer Collaborative Group) group. Excision of residual masses was mandatory in non-seminomatous germ-cell tumour (NSGCT). Results: Initial local symptomatology was increased testis size in 90% of cases. Sonography was an excellent diagnostic tool to suggest tumour. Non-seminoma (64.2%) was more frequent than seminoma (35.8%). Approximately 10% had the antecedent of cryptorchidism. Non-seminoma patients were 7 years younger than seminoma. Right testis was involved predominantly. Pre-orchidectomy tumour markers were elevated in 21% of seminoma (βHGC) and 79% in non-seminoma (αFP and/or βHGC). Scrotum violation occurred in only 1.8%. There were significant differences among stage I and the IGCCCG prognosis groups related to a longer interval between the first symptom and orchiectomy. Eighteen percent of non-seminomatous germ-cell tumour belonged to the poor prognosis IGCCCG group. With a median follow-up to 33 months, this series has achieved a 3 year overall survival of 98% for seminoma and 94% for non-seminoma. Only 10% of excised residual masses present after chemotherapy contained malignant cells. Conclusion: Spanish GCT have a similar clinical pattern to that described in the other occidental countries except for a slight increased proportion of non-seminoma upon seminoma. Co-operative groups as GG are unique structures to obtain quick and wide experience on the treatment of testis tumours, contributing to achieve a high cure rate.

A new nomogram was developed to predict disease-free survival in stage I seminoma. Rete testis invasion and tumor size resulted independent predictors of relapse in a series of 744 patients treated with a risk-adapted approach.We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

Summary From 1978 to 1992, 276 patients (pts) with MGCT were treated in our institution. Forty-three of the pts were female (15,5%). Median age at diagnosis was 20 years (newborn-70). Histology was dysgerminoma (D) in 14 pts (including 2 anaplastic D), endodermal sinus tumor (EST) in 9 pts, immature teratoma in 10 pts and mixed tumors in 10 pts. Primary locations were as follows: ovary (O) 33 pts and extragonadal (EG) 10 pts (pineal in 4 cases, mediastinum in 3, sacrum in 2 and pharynx in 1). Stage: I in 20 (16 0, 4 EG), U in 7 (5 O, 2 EG), IE in 12 (10 O, 2 EG) and IV in 4 (2 O, 2 EG). Serum AFP was elevated in 20/22 non-dysgerminoma pts, HCG in only 5 pts and LDH in 15/36 pts. Treatment results:Ovarian tumors all but one pt (biopsy only) underwent surgery: unilateral oophorectomy was performed in 15 pts and bilateral oophorectomy (+/− hysterectomy, + / − others) in 17 pts. Fourteen pts were rendered disease-free, 8 pts had residua] tumor (RT) ±2 cm and 11 RT >2 cm. Chemotherapy (PVB or BEP) was given to 28 pts, radiotherapy to 2 pts and no additional treatment to 3. Finally, 30 pts achieved complete response (CR) and none have relapsed at a median follow-up of 43 months. EG tumors: None of the pts underwent radical surgery. Radiotherapy was applied to 4 pineal tumors and BEP or PVB were given to all 10 pts. To date 6 pts are disease-free, 1 is alive with mature teratoma, 2 are alive with disease and 1 died of toxic effects. The projected overall survival of the series as a whole is 89% at 10 years, and it is significantly higher for pts without EST (p ± 0.02) and for pts with AFp ±1000 (p ± 0.01) and age ± 22 years at diagnosis (p ± 0.01). The projected event-free survival at 10 years is 80.4% (87.7% for ovarian rumors vs. 54% for extragonadal, p = 0.05). No events were recorded after 28 months. Conclusions The present results reflect the dramatic effectiveness of cisplatin-based chemotherapy for ovarian MGCT and confirm that unilateral oophorectomy can preserve fertility without compromising cure. Age >22 years, histology (EST) and serum AFP > 1000 ng/ml are possible prognostic factors (univariate analysis) to be tested in an independent body of data on cisplatin-treated patients.

Purpose To confirm the efficacy of a risk-adapted treatment approach for patients with clinical stage I seminoma. The aim was to reduce both the risk of relapse and the proportion of patients receiving adjuvant chemotherapy while maintaining a high cure rate. Patients and Methods From 2004 to 2008, 227 patients were included after orchiectomy in a multicenter study. Eighty-four patients (37%) presented no local risk factors, 44 patients (19%) had tumors larger than 4 cm, 25 patients (11%) had rete testis involvement, and 74 patients (33%) had both criteria. Only the latter group received two courses of adjuvant carboplatin, whereas the rest were managed by surveillance. Results After a median follow-up time of 34 months, 16 relapses (7%) have been documented (15 [9.8%] among patients on surveillance and one [1.4%] among those treated with carboplatin). All relapses occurred in retroperitoneal lymph nodes, except for one case in pelvic nodes. Median node size was 25 mm, and median time to recurrence was 14 months. All patients were rendered disease-free with chemotherapy. The actuarial 3-year disease-free survival rate was 88.1% (95% CI, 82.3% to 93.9%) for patients on surveillance and 98.0% (95% CI, 94.0% to 100%) for those treated with adjuvant chemotherapy. Overall 3-year survival was 100%. Conclusion With the limitations of the short follow-up duration, we confirm that a risk-adapted approach is effective for stage I seminoma. Adjuvant carboplatin seems adequate treatment for patients with 2 risk criteria, as is active surveillance for those with 0 to one risk factors. More reliable predictive factors are needed to improve the applicability of this model.

New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients. Material and methods Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0–1. Patients received intravenous doses of vinorelbine 25 mg/m 2 on day 1 and 8 and cisplatin 75 mg/m 2 on day 1, every 21 days, for a maximum of eight cycles. Results 94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0–12.9). Overall median time to progression was 5.89 months (95% CI 5.2–6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p = 0.036), MDR13435CC (HR CT vs. CC, 2.01; p = 0.017; HR TT vs. CC, 1.54; p = 0.22), and decreasing age (HR of age, 0.97; p = 0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p = 0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity. Conclusion In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.

Lung cancer is currently the most common malignancy and also the leading cause of mortality related to cancer in the world [1]. The crude incidence of lung cancer in the EU is 52.5/100,000/year, while the mortality 48.7/100,000/year. Among men the rates are 82.5 and 77.0/100,000/year, and among women 23.9 and 22.3/100,000/year, respectively. Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases. In Spain, there were 16,879 deaths in men, with a mean age of 68 years, and 2634 deaths in women, with a mean age of 66 years. The incidence of lung cancer in Spain was 68.3/100,000 among men and 13.8/100,000 among women, according to the latest data published in the year 2006 by the Instituto Nacional de Estadistica. About 90% of lung cancer mortality among men (and 80% among women) is attributable to smoking.

We conducted a multicentric randomized phase II trial comparing 5-FU continuous infusion (PF) and cisplatin, UFT and vinorelbine (UFTVP) as induction chemotherapy (IC) in locally advanced squamous cell head and neck cancer (LA-SCHNC). Primary objective was complete response (CR) to IC and overall survival (OS) was a secondary objective. PF: cisplatin 100 mg/m2 i.v. Day 1 (D1) and 5-FU 1,000 mg/m2 per day i.v. continous infusion D1–D5, every 21 days. UFTVP: cisplatin 100 mg/m2 i.v. D1; UFT 200 mg/m2 per day p.o. D1–D21 and vinorelbine 25 mg/m2 i.v. D1 and D8, every 21 days. Four IC courses were planned in both arms. A total of 206 patients (pts) were included (PF/UFTVP: 99/107): oral cavity: 8%/10%, oropharynx: 20%/25%, hypopharynx: 17%/14%, larynx: 54%/50%. Stage (TNM, 2002): III: 41%/35%, IVA: 23%/27%, IVB: 35%/38%. Complete response to IC: PF:36%/UFTVP:31% (P: no significative (NS)). G 3–4 toxicity (PF/UFTVP): neutropenia: 52%/72%; febrile neutropenia: 3%/20% (P

Patients with clinical stage I non-seminomatous germ cell tumour (NSGCT) with pathological high-risk features have a risk of recurrence on observation of approximately 40 per cent. This study evaluated the efficacy of adjuvant chemotherapy in a large series of patients treated in a multi-institutional setting.

Summary Background: Primary mediastinal non-seminomatous germ cell tumours (MNSGCT) constitute a rare malignancy. This study was performed to review our experience with cispatinbased chemotherapy in patients with MNSGCT. Patients and methods: Patients with MNSGCT treated with cisplatin-based combination chemotherapy between 1978-1995 in three university hospitals in Spain were retrospectively studied. Results: There were 25 males and two females with a median age of 26 years (range 4—71). Fifteen patients had disease confined to the mediastinum and 12 had metastatic disease. All patients were treated with cisplatin chemotherapy regimens (PVB: 7, BEP: 6, and other regimens 12) and considered for residual mass surgery (RMS) when indicated. Eleven patients (40.7%) were rendered disease-free with initial treatment: four with chemotherapy alone, one with surgery plus adjuvant chemotherapy and six with chemotherapy plus RMS. Three of these patients relapsed at two, six and seven months. The remaining 16 had unfavourable reponses (five partial response, three no change, seven progressive disease and one toxic death) . Eleven patients received salvage treatment but none of them achieved a durable response. After a median follow-up of 77 months (range 1-168), 10 patients remain alive. Actuarial survival at five years is 31.7%. No patients in this series developed a haematological malignancy. Chromosomal analysis showed that 2 out of 10 patients (20%) had a 47XXY karyotype. Conclusions' Only patients who achieved disease-free status are likely to be cured. Therefore, new up-front strategies are needed for the treatment of MNSGCT.

TPS4672 Background: Advanced transitional cell carcinoma of the urothelium (TCCU) on progression after previous cisplatin-based combination is generally an incurable disease. The appropriate management of these patients is still an unmet need. Many drugs have shown modest or no activity in previous phase 2 trials. Population heterogeneity in these studies emerges as one of the key determinants that could explain the variable outcomes. Recently, in a phase III study in this setting, prognostic factors (PF) for overall survival were identified (Bellmunt J et al, JCO 2010). Taxanes are active drugs in 2nd-line metastatic TCCU. Cabazitaxel (C) is a semi-synthetic taxane that is a poor substrate for the multidrug resistance system. C could be a valid alternative in this patient population. Methods: This is an open label phase II study of C in patients (pts) with advanced or metastatic TCCU who have progressed within 12 months after receiving a 1st-line platinum based chemotherapy. There are three treatment arms as patients will be assigned to one of three groups previously defined based on the presence of 0, 1 or 2-3 PFs as defined by Bellmunt et al. The activity of C will be assessed separately in each group and overall. The primary endpoint is response rate (RR) evaluated according to RECIST 1.1, a maximum of 35 pts are needed in each subgroup (maximum number of pts required: 105). Secondary objectives are RR in the whole population, toxicity, progression-free survival and overall survival. In addition, an external validation of the prognostic model proposed by Bellmunt will be conducted, as well as a pharmacogenomic study in order to better define the toxicity profile of the drug and the potential responders.

Background Malignant neoplasms of an unknown primary site (NUPS) remain a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have reviewed all autopsies performed in patients with NUPS in a single institution. Patients and methods By reviewing 1656 autopsies performed on adults in our Institution (1974-1990), 43 cases of NUPS were found. (NUPS was defined as histologically proven malignant tumor for which a primary site could not be found after anamnesis, complete physical examination, chest X-ray and routine chemistries.) Results There were 24 men (56 %) and 19 women. Mean age was 62 years (76 % of patients were aged 40-75). Clinical presentation included general deterioration (73 %), digestive symptoms (58 %), liver enlargement (58 %) abdominal pain (56 %), respiratory symptoms (45 %), ascites (26 %) and node enlargement (16 %). Abnormalities in analysis and image tests were frequent but nonspecific. Median time from admission to death was 42 days (range, 4-135). Pathologic diagnoses at autopsy were: 23 adenocarcinomas (53 %), arising from pancreas (6), biliary tree (6), lung (3), prostate (2), stomach (1), kidney (1) and unknown (4); 3 squamous carcinomas (5 %) (1 renal pelvis, 1 biliary tree, 1 stomach); 5 undifferentiated carcinomas (1 lung, 4 unknown); and 12 miscellaneous tumors (including 3 lymphomas, 3 neuroendocrine tumors, 3 hepatocarcinomas, 2 mesotheliomas and 1 melanoma). There was a tendency towards a metastatic pattern different from that expected from the primary tumor. Image tests were of little usefulness in the search for the primary tumor. Conclusions 1) Adenocarciomas were the most frequent tumor presenting as NUPS, especially from the pancreas and biliary tree. 2) In this series, at least 11 % of patients were amenable to standard systemic therapies (3 lymphomas and 2 prostatic adenocarcinomas) if a correct pathologic diagnosis could have been established when alive. 3) Presenting symptoms and metastatic pattern differed from those expected for the primary neoplasm eventually found. 4) Image tests were often misleading as regards the primary site, although they were useful to quantify the dissemination of the tumor.

16517 Background: Although standard treatment of patients with T4b Squamous Cell Head and Neck Cancer (T4b-SCHNC) for the last decade has been concomitant Chemo-Radiotherapy (CT-RT), recent Phase III trials with new Induction Chemotherapy (IC) regimens suggest that IC could also play a role in this setting. The value of adding surgery of the residual mass after IC and before RT if the resection is technically feasible is not clear in this context. Methods: We present the results of a retrospective analysis focused on this topic. Results: Between 1984 and 2001, 113 patients (pts) with T4b-SCHNC were treated at our institution with platin-based IC. Four pts dead during IC and 57 pts achieved a complete or a >90% partial response at primary and proceeded to definitive RT (or concomitant CT/RT). In the other 52 pts, surgical resection was reconsidered after IC and before RT and in 13 of them this surgery was performed: in 7 pts (6 had PR and 1 minor response after IC) the resection was R1, all these patients had loco-regional progression (2 of them also developed systemic metastases) and median OS after surgery was 21 months with no patient alive at 48 months; In the other 6 pts (3 had a PR and 3 had minor response after IC) an R0 resection was performed: 3 of these pts had loco-regional relapses (1 of them also developed systemic metastases) and the other 3 pts remain alive and disease free 56, 62 and 72 months after surgery. OS of the 52 pts that achieved less than a 90% partial response at primary with IC, was equivalent for those no resected after IC pts and for R1 resected pts (actuarial 5 year OS 8% vs 0%, lrk, p=0,74) but a statistically significant improvement in OS was observed when an R0 resection was obtained after IC (actuarial 5 years OS 50%, lrk, p=0,02).Conclusions: R0 resections after IC and before RT could improve OS in pts with T4b-SCHNC that obtain less than a 90%PR at primary after IC. R1 resection appears to have no value in this setting. This approach should be studied in properly designed prospective clinical trials. No significant financial relationships to disclose.

To evaluate the response of advanced squamous cell head and neck carcinoma to a combination of induction chemotherapy and radiotherapy. We present long-term results of a phase II trial of Induction Chemotherapy with UFT 200 mg/m 2 p.o. days 1 to 21, Vinorelbine 25 mg/m 2 i.v. days 1 and 8 and Cisplatin 100 mg/m 2 i.v. day 1 (UFTVP) each 21 days for 4 courses, followed by Radiotherapy concomitant with UFT 100 mg/m 2 p.o. daily and Carboplatin AUC = 0.5 i.v. weekly (RT/UFTJ) in patients (pts) with Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma (IV-B-SCHNC). Primary endpoint was Complete Response to induction UFTVP and secondary endpoints were Disease Free Status Rate after locoregional treatment and long-term Overall Survival. Between 1994 and 1997, 32 pts were included. Complete Response to Induction UFTVP was 59% (95% CI: 48%-70%). Main toxicity of UFTVP was G 3,4 neutropenia (94% of pts; 25% developed febrile neutropenia and 1 of this pts dead). After Induction Chemotherapy with UFTVP, 30 pts received radiotherapy and 25 of them received cocomitant Carboplatin and UFT (RT/UFTJ): main toxicity was mucositis (G3-4: 72%) and one patient died during RT/UFTJ because pneumonia. Twenty-five pts (78%) were alive and disease free at the end of the whole treatment. Actuarial 5 year Overall survival is 32%. Although toxicity is important, this approach has interesting activity and deserves further investigation.

7019 Background: About half of the patients with completely resected early-stage NSCLC will relapse. Adjuvant chemotherapy reduces the number of relapses at the expense of substantial toxicity. Activity of MAGE-A3 vaccination (i.e. recombinant MAGE-A3 protein and a potent GSK immunological adjuvant) has been proven in advanced melanoma. As about 35% of NSCLCs express the MAGE-A3 antigen, post-operative MAGE-A3 vaccination may be a targeted, well tolerated, and effective adjuvant therapy. Methods: Patients with completely resected, MAGE-A3 positive (assessed by quantitative RT-PCR), stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo. Vaccination was started ≥6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Randomization was stratified for stage (IB vs. II), histology (squamous vs. other), and lymph node procedure (sampling vs. dissection). Other anti-cancer adjuvant therapy was not allowed. Primary endpoint was time-to-recurrence, other endpoints were recurrence rates at different times, and survival. A sample size of 180 patients (120 active, 60 placebo) was chosen, to achieve 48% power (α=10%) to detect a 10% difference, assuming a 40% recurrence rate at month 30 in the placebo group (log rank test). A thorough interim efficacy analysis by an independent statistician (blinded to investigators and sponsor) is planned for 18 months after completion of recruitment. Results: 35% of 1,089 biopsies from 59 sites were MAGE-A3 positive. In two years, 182 patients were randomized (121 stage IB, 61 stage II). Overall, treatment was well tolerated, with high protocol compliance. Data collection for the interim efficacy analysis was initiated on December 19th, 2005. Median follow-up was 21 months, with 62 recurrences recorded. Conclusions: This study confirms expression of MAGE-A3 antigen in 35% of early NSCLC cases, and demonstrates good tolerability of postoperative MAGE-A3 vaccination. Efficacy results of the interim analysis will be available in February 2006. [Table: see text]

5547 Background: IC followed by RT if complete or nearly complete response at primary is an alternative to laryngectomy in patients (pts) with R-LA-SCC of Larynx and Hypopharynx. To avoid the added...

Presented in part at the 35th American Society of Clinical Oncology meeting. Atlanta (GA); 1999. Clinical Trial; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count

PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status ≤ 2 and creatinine clearance ≥ 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m2. Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles. RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m2 and gemcitabine 1,000 mg/m2 was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.