Adjuvant Cisplatin-based Chemotherapy Research Articles

Preoperative Hydronephrosis: Independent Predictor for Changes in Renal Function Following Nephroureterectomy

Partial or complete urinary obstruction caused by a tumor itself may affect renal function and the eligibility for perioperative cisplatin-based chemotherapy in patients with upper tract urothelial carcinoma. We investigated whether the status of preoperative hydronephrosis provides additional predictive information concerning changes in perioperative renal function. A total of 155 patients who underwent nephroureterectomy for upper tract urothelial carcinoma from 1997 to 2010 were identified. The association between preoperative parameters including the grade of hydronephrosis and perioperative renal function was analyzed. Hydronephrosis was observed in 104 patients. The grade of hydronephrosis was 1, 2, 3 and 4 in 6 (3.9%), 25 (16.1%), 42 (27.1%) and 31 (20.0%) cases. Using a defined cut-off creatinine clearance value of ≥50 ml/min indicating eligibility for cisplatin-based chemotherapy, only 94 patients (60.6%) were eligible in the neoadjuvant setting. Of these 94 patients, 30 (31.9%) were judged to be ineligible in the adjuvant setting. Multivariate analysis demonstrated that patient age ≥70 years [P < 0.001, hazard ratio (HR) 27.9] and the absence of a higher grade hydronephrosis (P = 0.013, HR 7.40) were independent risk factors for predicting patients ineligible to receive adjuvant cisplatin-based chemotherapy. The proportion of patients ineligible to receive cisplatin-based chemotherapy changed from 40.9 to 88.6% following nephroureterectomy in patients aged ≥70 years and those with no or a lower grade hydronephrosis. The status of hydronephrosis is an independent predictor of eligibility to receive adjuvant cisplatin-based chemotherapy. The information on preoperative hydronephrosis and patient age may assist in part of the decision-making when considering neoadjuvant cisplatin-based chemotherapy.

Renal Function and Oncologic Outcomes of Parenchymal Sparing Ureteral Resection Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

We compared renal function and oncologic outcomes of parenchymal sparing ureteral resection with radical nephroureterectomy for the treatment of upper tract urothelial carcinoma confined to the ureter. Review of a large institutional database identified 367 patients treated for primary upper tract urothelial carcinoma with radical nephroureterectomy or parenchymal sparing ureteral resection from 1994 to 2009. Patients with known renal pelvis tumors, muscle invasive urothelial carcinoma, prior cystectomy, contralateral upper tract urothelial carcinoma, metastatic disease or chemotherapy were excluded, leaving 120 patients for analysis. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Recurrence-free, cancer specific and overall survival were estimated using Kaplan-Meier analysis. Radical nephroureterectomy was performed in 87 patients and parenchymal sparing ureteral resection in 33. Median age at surgery was 73 years in the radical nephroureterectomy group (IQR 64-76) vs 70 years (IQR 59-77) in the parenchymal sparing ureteral resection group (p = 0.5). The radical nephroureterectomy and parenchymal sparing ureteral resection cohorts had several disparate clinicopathological variables including preoperative hydronephrosis (80% vs 45%, p = 0.0006), stage (pT3 or greater 26% vs 9%, p = 0.01) and baseline estimated glomerular filtration rate (51 vs 63 ml/minute/1.73 m(2), p = 0.009). Patients who underwent radical nephroureterectomy experienced a significantly greater decrease in estimated glomerular filtration rate after surgery (median -7 vs 0 ml/minute/1.73 m(2), p <0.001). Median followup was 4.2 years. Of the patients 79 experienced cancer recurrence and 44 died (28 of upper tract urothelial carcinoma). There were no obvious differences in the rates of recurrence, cancer specific death or overall death by procedure type. However, due to the limited number of events we cannot exclude the possibility that there are large differences in oncologic outcomes by procedure type. Parenchymal sparing ureteral resection is associated with superior postoperative renal function. However, the impact on cancer control cannot be determined conclusively due to the small sample size and putative selection bias.

FATS expression is associated with cisplatin sensitivity in non small cell lung cancer

BackgroundAlthough the survival benefit of cisplatin-based adjuvant chemotherapy has been proven for patients with non small cell lung cancer (NSCLC), the resistance to cisplatin and its dose-dependent side effects remain a challenge. Improvement in survival and reduction of side effects require a biomarker capable of defining the response to cisplatin treatments in patients with NSCLC. FATS is a newly identified tumor suppressor involved in DNA damage-induced carcinogenesis. In this study, we investigated whether the quantified mRNA expression of FATS can predict cisplatin sensitivity in NSCLC. MethodsThe expression level of FATS mRNA in tumor samples from patients receiving an initial diagnosis of NSCLC (n=89) was determined by quantitative real-time reverse transcription PCR. The histological characteristics of patients were retrospectively reviewed. Cisplatin-induced apoptosis in NSCLC cells was evaluated by flow cytometry after Annexin V staining. ResultsThe mRNA level of FATS was significantly downregulated in NSCLC samples compared with normal tissues from the same patient (P=0.001). Low level of FATS mRNA expression was correlated with poor overall survival in NSCLC (P=0.030). For those NSCLC patients receiving cisplatin-based chemotherapy, the overall survival was significantly longer in FATS-high subgroup than that in FATS-low subgroup (P=0.038). Multivariate analysis revealed the independent value of FATS mRNA in predicting the overall survival for NSCLC patients receiving cisplatin-based chemotherapy. Furthermore, enhanced expression of FATS significantly sensitized NSCLC cells to cisplatin-induced apoptosis. ConclusionThe relatively high expression of FATS mRNA provides a new biomarker for a good outcome in patients receiving cisplatin-based chemotherapy.

Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk Gastric Cancer

To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer. This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36-75 years). Postoperative treatment consisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m²) followed by a bolus of 5-fluorouracil (400 mg/m²) and then a 44-h continuous infusion of 5-fluorouracil (2400-3600 mg/m²) given every 14 days, for three cycles (LV5FU2 protocol). Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy. Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control.

The Relationship Between ERCC1 Expression and Clinical Outcome in Patients With FIGO Stage I to Stage II Uterine Cervical Adenocarcinoma

Several studies have suggested that excision repair cross-complementation group 1 (ERCC1), a protein involved in nucleotide excision repair, is associated with resistance to platinum agent-based chemotherapy or chemoradiotherapy with platinum agents in various types of cancer. Herein we evaluated ERCC1 protein expression in uterine cervical adenocarcinoma and the relationship between this expression, clinicopathological factors, and clinical outcome, particularly in patients receiving adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. Thirty-six patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB to stage IIB cervical adenocarcinoma who underwent radical hysterectomy were evaluated. Excision repair cross-complementation group 1 protein expression was examined by immunohistochemistry in tumor tissues. The relationship between ERCC1 expression levels and clinicopathological factors (age, FIGO stage, histological grade, tumor size, vascular invasion, cervical stromal invasion, and lymph node metastases) and prognosis was evaluated. No significant differences between ERCC1 expression levels and clinicopathological factors were observed. The patients in the ERCC1 high-expression group (n = 7) experienced significantly worse disease-free survival than the patients in the ERCC1 low-expression group (n = 29; P = 0.005). Among the 25 patients who received cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, those with high ERCC1 expression (n = 5) also experienced significantly worse disease-free survival than those with low ERCC1 expression (n = 20; P = 0.002). Moreover, univariate and multivariate analyses revealed that high ERCC1 expression was an independent prognostic factor in patients receiving cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. This is the first analysis of the association between ERCC1 expression and clinical outcomes in patients with uterine cervical adenocarcinoma. High ERCC1 protein expression was revealed to be associated with worse disease-free survival in the patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin and was shown to be an independent prognostic factor. Further evaluation with a larger number of patients is required to confirm these preliminary observations.

Management of early-stage non-small-cell lung cancer (NSCLC)

Approximately 1.5 million new cases of lung cancer are diagnosed annually worldwide. Around 85% of these tumours are non-small-cell lung cancer (NSCLC). The optimal treatment for early-stage NSCLC (i.e. clinical stages I and II) is surgery, mostly lobectomy. In patients with functional limitations, an alternative to surgical resection is radiotherapy, and stereotactic irradiation may play a greater role in the future. Despite optimal local management, five-year survival rate of resected NSCLC ranges between 73% for pathological stage Ia and 25% for pathological stage IIIa. In the early 1990s, a large overview of the role of chemotherapy in NSCLC using updated individual data showed a 13% reduction in the risk of death with adjuvant chemotherapy at five years (P = 0.08), suggesting an absolute benefit of 5% [1]. These results constituted the rationale for a new generation of randomised studies with cisplatin-based regimens. The ALPI trial included patients with resected stage I-IIIa NSCLC. They were randomly allocated to receive either three courses of mitomycin (8mg/m2 day 1); vindesine (3mg/m2 days 1 and 8); cisplatin 100mg/m2 day 1 every three weeks or no adjuvant treatment after complete resection [2]. Overall 1209 patients were enrolled into the study; 1088 patients were analysed with a median followup of 63 months. The hazard ratio (HR) was 0.94 for overall survival and 0.89 for disease-free survival. No statistically significant difference was observed even if the difference was borderline significant for stage II disease. The IALT was a large worldwide randomised study whose aim was to determine the impact on overall survival of three to four cycles of a cisplatin-based chemotherapy (CT) after complete surgical resection in patients with stages I−III NSCLC [3]. Thoracic radiotherapy may be given according to the preregistration policy of each centre. There were 932 patients allocated to CT and 935 patients in the control arm. After a median follow-up of 56 months, there was a significant difference in overall survival between the two arms (HR= 0.86 [0.76–0.98], P < 0.03). Disease-free survival was also significantly different (HR= 0.83 [0.74–0.94], P < 0.003). The effect was no longer significant at 90 months (HR= 0.91 [0.81– 1.02], P = 0.10) owing to a higher rate of non-cancerrelated deaths in the chemotherapy arm. ERCC1 was evaluated by immunohistochemistry in 761 tumour specimens of patients in the IALT-Bio programme [4]. ERCC1 expression was positive in 44% and negative in 56%. A benefit of cisplatin-based adjuvant chemotherapy was associated with the negative expression of ERCC1 (test for interaction, P = 0.009). In the post-operative subgroup of the Big Lung Trial, no benefit from adjuvant chemotherapy was observed among 381 patients, but the population was heterogeneous, in particular concerning the quality of the resection and the compliance with chemotherapy [5]. A Japanese randomised study compared adjuvant tegafur-uracil (UFT) for two years with no treatment in patients with completely resected stage I NSCLC [6]. Among 979 eligible patients, there was a significant advantage in favour of UFT (P = 0.036), but the benefit was restricted to the 27% of patients with T2N0 NSCLC. At the 2004 ASCO meeting, the Japanese adjuvant UFT meta-analysis confirmed a significant advantage of the drug compared with controls in 2003 patients (P < 0.001). The NCI-Canada conducted a phase III trial (JBR 10) comparing surgery alone with surgery followed by adjuvant chemotherapy with cisplatin and vinorelbine in 459 eligible patients with stage Ib and II resected NSCLC [7]. They showed a 15% benefit at five years (P = 0.012). The benefit was restricted to stage II patients. In the ANITA 1 trial, which also concerned patients with completely resected NSCLC, chemotherapy consisted of four cycles of cisplatin-vinorelbine [8]. A total of 831 patients were included. Again, there was a survival advantage for adjuvant chemotherapy (HR: 0.80 [0.66–0.96], P = 0.017).

Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer: Mature Results of the Phase 2 PBM-PFU Protocol

The mature results of the neoadjuvant and adjuvant chemotherapy arms of the nonrandomized, phase 2 Yale University cisplatin, bleomycin, methotrexate, and 5-FU protocol are presented. Sixty-seven patients were prospectively accrued with a median follow-up of 5.4 years, and standard parameters of toxicity and efficacy were studied. Both univariate and multivariate analyses were applied. The 5-year disease-free survival of 78% for the 25 patients in the adjuvant group, of which 80% had high-risk features including positive margins, parametria, and lymph nodes and 28% had adenocarcinomas, was comparable to recent relevant literature. Only 64% of patients in this group received consolidation radiation therapy, which did not impact on survival. Only 12% of patients recurred distantly. Notably, those who received 4 months or more of chemotherapy had prolonged survival (P = 0.012). In the neoadjuvant group, chemotherapy response rate among 42 patients (with stages 1B-IIIB cancer) was 79% (50% partial response, 29% complete response), and no patient progressed. In the subgroup of 22 patients who underwent surgery after chemotherapy, 59% had nonsquamous histology. Forty-five percent of patients with stage IIB cancer were deemed operable after chemotherapy. Ninety-five percent received postoperative radiation therapy. There was a 9% pathologic complete response rate, with positive lymph nodes found in 27%. Notably, those who received 3 months or less of chemotherapy had improved overall survival (P = 0.030). Survival rates of these 22 patients at 3 and 5 years were 73% and 63%, respectively. Although not randomized, these survival rates were similar to those achieved with chemoradiation. Although there are several logistical/design features of the cisplatin, bleomycin, methotrexate, and 5-FU regimen that are not in line with the current chemotherapy era, our experience with this well-tolerated regimen can serve as a proof of principle. Our data suggests that both neoadjuvant and adjuvant cisplatin-based neoadjuvant chemotherapy may have their place. It also raises the possibility that the optimal duration of chemotherapy in adjuvant cases should be longer than in neoadjuvant cases.

1595 EXTENDED LYMPHADENECTOMY AND CHEMOTHERAPY OFFER SURVIVAL ADVANTAGE IN MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Invasive1 Apr 20111595 EXTENDED LYMPHADENECTOMY AND CHEMOTHERAPY OFFER SURVIVAL ADVANTAGE IN MUSCLE-INVASIVE BLADDER CANCER Peter J. Bostrom, Tuomas Mirtti, Martti Nurmi, Matti Laato, Bas W.G van Rhijn, Neil E. Fleshner, Antonio Finelli, Michael A Jewett, and Alexandre R. Zlotta Peter J. BostromPeter J. Bostrom Toronto, Canada More articles by this author , Tuomas MirttiTuomas Mirtti Helsinki, Finland More articles by this author , Martti NurmiMartti Nurmi Turku, Finland More articles by this author , Matti LaatoMatti Laato Turku, Finland More articles by this author , Bas W.G van RhijnBas W.G van Rhijn Toronto, Canada More articles by this author , Neil E. FleshnerNeil E. Fleshner Toronto, Canada More articles by this author , Antonio FinelliAntonio Finelli Toronto, Canada More articles by this author , Michael A JewettMichael A Jewett Toronto, Canada More articles by this author , and Alexandre R. ZlottaAlexandre R. Zlotta Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1645AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The role of extended pelvic lymph node dissection (ePLND) and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer (BC) remain unclear. Our large database from two centers (Turku, Finland and Toronto, Canada) offer an opportunity to study these factors, as there have been different institutional practice policies. In Turku, ePLND was not common practice and adjuvant chemotherapy was nearly never offered whereas standard of care in Toronto included ePLND and adjuvant chemotherapy when indicated. METHODS Consecutive BC patients undergoing radical cystectomy in UHN, Toronto, Canada (1992–2008) and University of Turku, Turku, Finland (1986–2005) were studied. After exclusion of non-urothelial cases and neoadjuvant treatment, 563 patients were available for analysis. Clinicopathological variables, the rate and extent of PLND and the rate of adjuvant cisplatin-based chemotherapy were analyzed using the Chi-squared-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival. RESULTS In the Toronto cohort, patients were older (mean age 68 vs. 63y, p<0.001), had more extensive PLNDs (>10 nodes removed, 58% vs. 8%, p<0.001), had more nodal metastasis (26% vs. 7%, p<0.001), and adjuvant chemotherapy was administered more often (21% vs. 1%, p<0.001). Positive margin rate was similar (4% in both centers). No BC specific survival differences could be demonstrated in ≤ pT2a tumors or in pT4a/b tumors. In contrast, there was a trend for improved survival in pT2b tumors (10y BC specific survival 65% vs. 42%, p=0.23) and a significant difference favouring the Toronto cohort in pT3a and pT3b tumors (55% vs. 31%, p=0.025; 43% vs. 28% p=0.06, respectively). In multivariate analysis, pT-stage (HR 1.8, 95% CI 1.2–2.8; p<0.005), N-stage (HR 2.5, 95% CI 1.5–4.1; p<0001), and ePLND (HR 0.53, 95% CI 0.31–0.93, p=0.026) significantly affected disease specific survival. Adjuvant chemotherapy offered borderline significant benefit (HR 0.61, 95% CI 0.36–1.05, p=0.072). An interaction model combining ePLND and chemotherapy was significant when ePLND with more than 10 nodes removed and adjuvant chemotherapy were combined (HR 0.49, 95% CI 0.26–0.92, p=0.026). CONCLUSIONS With the limitations of not being a randomized study but with an unique setting as our study centers had opposite management in terms of ePLND and adjuvant chemotherapy, our results show that the combination of ePLND and adjuvant chemotherapy offer a survival advantage in muscle-invasive BCs treated with RC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e640 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Peter J. Bostrom Toronto, Canada More articles by this author Tuomas Mirtti Helsinki, Finland More articles by this author Martti Nurmi Turku, Finland More articles by this author Matti Laato Turku, Finland More articles by this author Bas W.G van Rhijn Toronto, Canada More articles by this author Neil E. Fleshner Toronto, Canada More articles by this author Antonio Finelli Toronto, Canada More articles by this author Michael A Jewett Toronto, Canada More articles by this author Alexandre R. Zlotta Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy

BackgroundWe recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy. Patients and methodsIncidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs. ResultsOf 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup. ConclusionsThis study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies.

Editorial Comment

In this issue of Urology, we are provided with provocative additional evidence that should further inform the discussion regarding use of perioperative chemotherapy for muscle-invasive urothelial cancer. Despite level I evidence demonstrating a survival benefit for patients who receive cisplatin-based neoadjuvant chemotherapy compared with those who do not, 1 Grossman H.B. et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003; 349: 859-866 Crossref PubMed Scopus (1958) Google Scholar it is believed that adoption of the use of neoadjuvant chemotherapy, in widespread practice, has been limited. 2 Donat S.M. Integrating perioperative chemotherapy into the treatment of muscle-invasive bladder cancer: strategy versus reality. J Natl Compr Cancer Netw. 2009; 7: 40-47 PubMed Google Scholar , 3 David K.A. et al. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998-2003: a report from the national cancer database. J Urol. 2007; 178: 451-454 Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Multiple factors, reflecting perhaps a hesitance by both patients and surgeons, have been cited as reasons for omission of neoadjuvant chemotherapy. 4 Black P. So A. Perioperative chemotherapy for muscle-invasive bladder cancer. Cancer Urol Assoc J. 2009; 3: S223-S227 PubMed Google Scholar The current article provides a characterization of the most objectively measurable limitation to neoadjuvant cisplatin-based chemotherapy: unfitness of the patient because of poor baseline renal function. The authors found that, in a consecutive cohort of 194 patients, up to 40% would be deemed inappropriate for cisplatin-based therapy using either of the most widely used cutoffs (creatinine clearance <60 mL/min or glomerular filtration rate (GFR) <60 mL/min/1.73 m2). 5 Raj G.V. et al. Formulas calculating creatinine clearance are inadequate for determining eligibility for cisplatin-based chemotherapy in bladder cancer. J Clin Oncol. 2006; 24: 3095-3100 Crossref PubMed Scopus (61) Google Scholar , 6 Dash A. et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006; 107: 506-513 Crossref PubMed Scopus (289) Google Scholar Notably, the authors also found that, in most patients, renal function did not decline after cystectomy and, in some patients, especially those younger than 65 years, it may even improve. This conclusion is supported by similar evidence from Dash et al. in an even larger series of patients. 6 Dash A. et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006; 107: 506-513 Crossref PubMed Scopus (289) Google Scholar Baseline Renal Function Status Limits Patient Eligibility to Receive Perioperative Chemotherapy for Invasive Bladder Cancer and Is Minimally Affected by Radical CystectomyUrologyVol. 77Issue 1PreviewTo evaluate the proportion of patients with muscle-invasive urothelial carcinoma (UC) who would be eligible to receive cisplatin-based chemotherapy before and after radical cystectomy based on renal function. Full-Text PDF

Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA)

BackgroundA recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤1). Post-operative radiotherapy (RT) is optional for pN2 tumours. Patients and methodsTo evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail. ResultsSeventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin–vinorelbine (64%) and cisplatin–gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians. ConclusionsA substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen.

Poly(ADP-Ribose) Polymerase Inhibitors

This session not only described several poly(ADP-ribose) polymerase (PARP) inhibitors but also included talks on the science of nuclear excision repair, an oxidized glutathione, and a heat shock protein (HSP) 90 inhibitor. SUMMARY OF PRESENTATIONS Science of Nuclear Excision Repair Dr. George Simon opened the session by presenting the science of nuclear excision repair. He reviewed preclinical data, including evidence that apoptosis increases in cell lines exposed to cisplatin when excision repair cross-complementation group 1 (ERCC1) siRNA is added. He also reviewed clinical data from the International Adjuvant Lung Trial, in which improved survival with adjuvant cisplatin-based chemotherapy was restricted to tumors with low ERCC1. 1 He then focused on trials that designed to tailor therapy to repair genes. The Spanish Customized Adjuvant Treatment trial randomly assigns postresection patients with positive N1 or N2 nodes to docetaxel cisplatin or an experimental arm. Based on data correlating higher breast cancer 1 (BRCA1) mRNA levels with cisplatin resistance and docetaxel sensitivity, 2 the experimental arm assigns treatment by quartile expression for BRCA1 (lowest: gemcitabine cisplatin; 2‐3: docetaxel cisplatin; and highest: docetaxel). The TAilored post-Surgical Therapy in Early-stage NSCLC (TASTE) trial randomizes postsurgical patients to cisplatin pemetrexed or an experimental arm. In the experimental arm, mutations in the epidermal growth factor receptor (EGFR) lead to treatment with erlotinib, whereas treatment for EGFR wild-type patients are assigned based on ERCC1 status (cisplatin pemetrexed versus observation). He then discussed the MADe IT Trail, in which patients with metastatic disease were assigned treatment regimen based on ERCC1 and ribonucleotide reductase M1 (RRM1) levels (Figure 1). Outcomes in this trial exceeded selected historical controls, and the difference was more apparent for

SEOM clinical guidelines for the treatment of non-small-cell lung cancer: an updated edition

The purpose of this article is to provide updated recommendations for the diagnosis and treatment of patients non-small-cell lung cancer (NSCLC). The staging system for lung cancer has recently been revised by the International Association for Study of Lung Cancer and patients with NSCLC shall now be staged according to the UICC system 7th edition. Recommendations for treatment were based on treatment strategies that improve overall survival. In functionally fit patients with stage I-II disease surgical resection is recommended. Four cycles of adjuvant cisplatin-based chemotherapy is recommended in patients with pathologic stage II-III. For patients with stage IIIA and non-bulky mediastinal lymph node survival was significantly improved with induction chemotherapy plus surgical resection. Patients with unresectable or bulky stage IIIA and those with stage IIIB, should be treated with platinum-based chemotherapy and thoracic radiotherapy. For patients with metastatic disease and performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For elderly patients and those with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with platinum-based chemotherapy, except for patients with certain clinical characteristics. Maintenance therapy with pemetrexed or erlotinib increases survival in patients who did not progress after 4 cycles of a platinum based chemotherapy. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs.

MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only.

Adjuvant cisplatin-based chemotherapy for resected NSCLC: one size fits all?

The standard of care for resected stage II - IIIA non-small-cell lung cancer includes adjuvant chemotherapy based on the results of randomized trials using cisplatin regimens. A recent meta-analysis (Lung Adjuvant Cisplatin Evaluation) showed no survival benefit for this modality in stage IB disease. Therefore, the role for stage IB disease remains controversial. The Lung Adjuvant Cisplatin Evaluation meta-analysis, which is based on pooled data of five randomized trials, has shown a 5.3% absolute survival benefit at 5 years. However, long-term results of the International Adjuvant Lung Cancer Trial evaluating adjuvant cisplatin-based chemotherapy in resected non-small-cell lung cancer indicated a possible late adjuvant chemotherapy-related over-mortality. Tumor stage currently is the benchmark standard use for identifying patients who would benefit from adjuvant treatment. In the knowledge of late adjuvant chemotherapy-related over-mortality it is therefore critical to identify subsets of patients who would or would never benefit from adjuvant cisplatin. This review will discuss the extent to which individualized adjuvant treatment can be provided.

Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going?

Following the 1995 meta-analysis on the role of postoperative chemotherapy in NSCLC, many randomized controlled trials (RCTs) have evaluated the effect of adjuvant cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC), adding substantially to the existing evidence. The LACE pooled analysis included a total of 4584 patients accrued in five recent cisplatin-based adjuvant trials. It confirmed the benefit of adjuvant chemotherapy (P = 0.0043). In addition, it showed that adjuvant cisplatin-based chemotherapy is detrimental in stage IA resected NSCLC; it also indicated that the combination of vinorelbine and cisplatin offered a higher benefit compared with older doublets or triplets. The individual-databased meta-analysis was also updated with a total of >10,000 patients. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy, with an overall significant benefit of 4% at 5 years. The recent results of biological programmes indicate that the expression of some tumour markers including ERCC1 be evaluated in order to determine which patients are more likely to benefit from chemotherapy. If these results are confirmed, tailored therapy might be the next progress for resected NSCLC.

Non–Small-Cell Lung Cancer mRNA Expression Signature Predicting Response to Adjuvant Chemotherapy

Non–Small-Cell Lung Cancer mRNA Expression Signature Predicting Response to Adjuvant Chemotherapy

MDR1 and ERCC1 Expression Predict Outcome of Patients with Locally Advanced Bladder Cancer Receiving Adjuvant Chemotherapy

The role of adjuvant chemotherapy in patients with locally advanced bladder cancer still remains to be defined. We hypothesized that assessing the gene expression of the chemotherapy response modifiers multidrug resistance gene 1 (MDR1) and excision repair cross-complementing 1 (ERCC1) may help identify the group of patients benefiting from cisplatin-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded tumor samples from 108 patients with locally advanced bladder cancer, who had been enrolled in AUO-AB05/95, a phase 3 trial randomizing a maximum of three courses of adjuvant cisplatin and methotrexate (CM) versus methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC), were included in the study. Tumor cells were retrieved by laser-captured microdissection and analyzed for MDR1 and ERCC1 expression using a quantitative real-time reverse transcription-polymerase chain reaction assay. Gene expression levels were correlated with clinical outcomes by multivariate Cox proportional hazards regression analysis. Expressions of MDR1 and ERCC1 were independently associated with overall progression-free survival (P = .001, relative risk = 2.9 and P = .01, relative risk = 2.24, respectively). The correlation of high MDR1 expression with inferior outcome was stronger in patients receiving M-VEC, whereas ERCC1 analysis performed equally in the CM and M-VEC groups. High MDR1 and ERCC1 gene expressions are associated with inferior outcome after cisplatin-based adjuvant chemotherapy for locally advanced bladder cancer. Prospective studies are warranted to define a role for MDR1 and ERCC1 analysis in individualizing multimodality treatment in locally advanced bladder cancer.

A combined strategy of serial analysis of gene expression (SAGE) and quantitative PCR (qPCR) to identify four genes that predict outcome in non-small cell lung cancer patients.

e17502 Background: Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non-small cell lung cancer. However, objective response rates are in the range of 30% to 50%. Thus, prediction of treatment response and outcome before CRT is a major challenge for clinicians. Methods: In a first stage we perfomed a SAGE analysis on snap-frozen surgical specimens from three good responder and three bad responder patients. Response sensibility to cisplatin was evaluated using cytotoxicity assays in primary cultures of tumor cells from the surgical specimens. In a second stage we analyzed the expression of 22 genes and 2 controls using TaqMan low density arrays in snap-frozen surgical specimens from 51 operable stages non-small cell lung cancer patients. Disease-free survival was used as the endpoint of the study. All patients received cisplatin-based adjuvant chemotherapy. Multivariate Cox methods were applied to build an optimized predictor of outcome. Results: The combination of mTOR, TWIST1, AKCR1C2, and HSPB1 gene expression was able to predict clinical outcome in pretreated tissues. In addition, DFS analysis revealed that the gene signature- based score was the only statistically significant prognostic factor remaining in the multivariate analysis. Conclusions: A basal 4-gene signature, obtained from surgical specimens of non-small cell lung cancer, efficiently predicted clinical outcome in the patients. These preliminary results are very encouraging and, if they are validated in larger series, could have clinical implications. No significant financial relationships to disclose.

Individualized adjuvant chemotherapy (ACT) based on quantitative excision repair cross-complementing 1 (ERCC1) mRNA expression: A randomized phase II trial in Japanese patients with completely resected non-small cell lung cancer (NSCLC).

e17506 Background: Cisplatin-based ACT improves survival in patients with completely resected NSCLC. By immunohistochemistry (IHC), cisplatin-based ACT, as compared with observation, significantly ...