Adjuvant Cisplatin-based Chemotherapy Research Articles

Endovascular Treatment of Acute Abdominal Aortic Thrombosis after Cisplatin-Based Chemotherapy

A 75-year-old male received preoperative cisplatin-based adjuvant chemotherapy for advanced gastric cancer. Three days after administration of cysplatin, the patient presented severe abdominal pain and calf claudication. A multi detector computed tomography (MDCT) revealed a floating mass in the infrarenal abdominal aorta. Considering the underlying malignant disease and subsequent laparotomy, we adopted endovascular treatment as a less invasive treatment: Fogarty thrombectomy followed by stent graft exclusion. Although cisplatin-based chemotherapy is known to be a high risk thromboembolic event, acute thrombosis of the aorta is exceedingly rare and its standard therapeutic management is not well established. We believe this procedure will prove to be a reliable less invasive treatment for this entity in cases of high-risk, such as with cancer patients.

The Efficacy of Adjuvant Chemotherapy for Locally Advanced Upper Tract Urothelial Cell Carcinoma

Objective: To evaluate the efficacy of adjuvant cisplatin-based chemotherapy for locally advanced upper tract urothelial cell carcinoma (UTUC) following radical nephroureterectomy with bladder cuff resection (RNU) in terms of survival and recurrence.Materials and methods: Between January 2000 and January 2013, among 145 patients with upper tract urothelial cell carcinoma, a total of 65 patients with locally advanced UTUC (a diagnosis of pT3 or pT4 or pT1-2N1-3) underwent RNU. Of these 65 patients, 36 patients received at least three cycles of adjuvant gemcitabine plus cisplatin chemotherapy and the remaining 29 patient did not receive adjuvant chemotherapy. Clinical characteristics, bladder recurrence, distant metastasis, and cancer-specific survival were retrospectively reviewed.Results: The mean age of the 65 patients was 60.4 (range, 37-87) years and the median follow-up period was 34 (range, 12-114) months. Patent demographics were not statistically different between the two groups. During the follow-up period, 14 patients (21.5%) experienced distant metastasis; 8 (8/36, 22.2%) patients who had undergone adjuvant chemotherapy and 6 (6/29, 20.7%) patients who did not. Bladder recurrence was noted in 17 patients (26.2%), 5 (5/36, 13.9%) of whom received adjuvant chemotherapy while the remaining 12 (12/29, 41.4%) did not. Kaplan-Meire and multivariate analysis showed that the incidence of bladder recurrence was significantly higher in patients who did not undergo adjuvant chemotherapy, and cancer specific survival was not significantly associated with adjuvant chemotherapy.Conclusions: Adjuvant chemotherapy for locally advanced UTUC can prevent bladder recurrence, but has a minimal effect on cancer-specific survival.

Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer

Previously identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. BRCA1 plays a central role in DNA damage response (DDR. It undergoes phosphorylation by various DDR kinases at different serine residues, of which ser1524 is known to be specifically phosphorylated by ATM in response to genotoxic stress. We performed BRCA1 immunohistochemistry on several tissue microarrays (TMAs) of 113 early (I, II stage) and advanced (III, IV stage) NSCLCs, using MS110 antibody against the BRCA1 N-terminal and S1524 antibody against the phosphorylated form of BRCA1 protein at ser1524 (Abcam). Patients with III and IV stage disease were treated by adjuvant cisplatin-based chemotherapy. Staining results were correlated with overall survival (OS), disease free survival (DFS) and with the occurrence of brain metastases. BRCA1 S1524 nuclear positivity was significantly correlated with longer OS and DFS in stage I and II patients (P<0.05), while OS and DFS were shorter in S1524 positive stage III and IV patients (P<0.05). No significant correlation was found with brain metastases. The results show that BRCA1 phosphorylaton, at least in ser1524, differentiates the fate of early and advanced NSCLC as well as response to chemotherapy, but the underlying mechanisms are not completely understood. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC.

P2-036 - Efficacy and Safety of First-Line Platinum-Based Chemotherapy in Patients with Post-Operative Recurrence after Platinum-Based Adjuvant Chemotherapy

ABSTRACT Background and aim Several studies suggest that cisplatin-based adjuvant chemotherapy improves survival in patients with completely resected non-small-cell lung cancer in stage II and III; thus, this chemotherapy is recognized as a global standard regimen. However, the efficacy and safety of first-line platinum-based chemotherapy in patients with post-operative recurrence after platinum-based adjuvant chemotherapy has not yet been fully assessed. The aim of this study is to assess these clinical outcomes of platinum-based chemotherapy in patients with post-operative recurrence. Subjects and methods Clinical records of patients with post-operative recurrence who received platinum-based chemotherapy as first line after platinum-based adjuvant chemotherapy at Juntendo University Hospital and Shizuoka Cancer Center between April 2008 and December 2011 were reviewed, and the clinical efficacy and the toxicity were retrospectively evaluated. Result A total of 11 patients were included in this study. The median age was 61 years (range, 36–71 years). Five patients were female. Eight patients were PS 0, the others were PS 1. Adjuvant chemotherapy regimens were CDDP + VNR in five patients, CBDCA + GEM in four patients, CBDCA + PTX in one patient and CDDP + TS-1 in one patient. 72.7 % of patients received at least three cycles of adjuvant chemotherapy. The median recurrence-free survival was 495 days (range, 98–1358 days). First-line chemotherapy regimens were CDDP + PEM in six patients (including one patient with a combination of VEGF-TKI), CBDCA + PTX + Bev in three patients, CDDP + VNR in one patient and CDDP + DTX in one patient. 63.6% patients received at least three cycles of first-line chemotherapy. The overall response rates and the disease control rates were 27.3 and 72.7% (CR/PR/SD/PD/NE: 0/3/5/0/3), respectively. The median overall survival was 841 days (range, 210–1918). Two patients (16.7%) were dropped out. The receiving dose was reduced because of toxicity in four patients (36.4%). Conclusion The first-line platinum-based chemotherapy was effective, but highly toxic in patients with post-operative recurrence after platinum-based adjuvant chemotherapy.

Treatment of the Future, Today?

DOI: 10.1200/JCO.2012.45.5923 A patient in her early 60s was referred to me for a discussion of adjuvant chemotherapy after she underwent a lobectomy for clinical stage I adenocarcinoma of the lung. Unfortunately, pathologic evaluation revealed hilar lymph node involvement, which upstaged her to pathologic stage II disease. This should have been a fairly routine discussion. Several well-done, phase III randomized clinical trials have demonstrated an improvement in overall survival with the use of adjuvant cisplatin-based chemotherapy versus observation alone after resection of stages II and III non–small-cell lung cancer (NSCLC), and such treatment has been the standard of care since 2004. She was upset by the fact that the cancer was a higher stage than initially thought and was terribly afraid of the potential adverse effects of chemotherapy. She truly saw the higher stage of cancer as a death sentence. I assured her that the complete surgical resection she had already undergone offered her a 50% chance of cure and that adjuvant chemotherapy could improve the cure rate by another 5% to 10%. The chemotherapy would amount to throwing the kitchen sink at the cancer to do all we could to prevent it from recurring. Her husband voraciously wrote down my every word and asked a multitude of pointed questions. Despite my best efforts to explain her situation and my recommendation for adjuvant treatment, they left my office still despondent and unsure of how to proceed, so I suggested a return office visit in a couple of weeks, when she had more fully recovered from surgery and more thoroughly digested the information I had shared with them. The next week, her husband called to tell me that they had sought a second opinion and that this new oncologist had asked for the molecular profile of the tumor (epidermal growth factor receptor (EGFR) mutation, KRAS mutation, and EML4-ALK rearrangement). He was quite upset that I had not discussed molecular analysis during my initial visit with them, and it was clear from his tone that he felt I had not given his wife all of the available options. I could already feel his confidence in my professional abilities eroding. At first, I did not know what to say. I am an academic thoracic oncologist. I keep up on the lung cancer literature. I know that presently, all of the data that justify molecular profiling and the use of targeted therapy, such as gefitinib, erlotinib, and crizotinib, are from studies in patients with metastatic NSCLC. In fact, all of these agents were approved by the US Food and Drug Administration only in the setting of metastatic disease. I assured him that molecular testing was not relevant in his wife’s situation, that there was no proven benefit for targeted therapy in the postoperative setting, and that adjuvant cisplatin-based chemotherapy was still the best option for improving her long-term survival. Despite my explanations of the current state of our knowledge and standard of care, he cancelled the subsequent visit with me and the planned chemotherapy. The tumor tissue had indeed been sent for reflex molecular analysis and was positive for an EGFR sensitizing mutation. It can be rationally argued that reflex molecular analysis based on histology in patients who have undergone potentially curative therapy is not an appropriate use of medical resources, because there are no data justifying the use of adjuvant EGFR inhibitors in patients with completely resected NSCLC. Or are there? The oncologist with whom they had sought a second opinion had offered adjuvant erlotinib, given the patient’s reluctance to receive adjuvant chemotherapy. I felt panicked and uneasy. I knew that, thus far, data were available from only one randomized trial evaluating the adjuvant use of an EGFR inhibitor in patients with resected NSCLC and that this trial had demonstrated no survival benefit, even in the subset of patients with EGFRmutant tumors. Had I somehow missed a practicechanging clinical trial that had demonstrated a survival benefit for adjuvant EGFR inhibitors in patients with resected, EGFR-mutant NSCLC? A quick literature search revealed a recent article entitled, “Impact on Disease-Free Survival of Adjuvant Erlotinib or Gefitinib in Patients With Resected Lung Adenocarcinomas That Harbor EGFR Mutations.” This was a retrospective study in which 56 patients with resected, early-stage, EGFR-mutant NSCLC who had been treated with adjuvant EGFR inhibitors either in a phase II clinical trial or “at the discretion of their physicians” were compared with 111 similar patients who had not received adjuvant JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 30 NUMBER 32 NOVEMBER 1

Phosphorylated AMP-activated protein kinase expression associated with prognosis for patients with gastric cancer treated with cisplatin-based adjuvant chemotherapy

The present study analyzed the expression of phosphorylated AMP-activated protein kinase (pAMPK), Fyn kinase, and pyruvate dehydrogenase kinase-1 (PDK-1) and their impact on the survival of patients with resected gastric cancer who received cisplatin-based adjuvant chemotherapy. Korean patients with stage II-IV (M0) gastric adenocarcinoma who underwent a gastrectomy with D2 lymph node resection and received a combination regimen of cisplatin and S-1 were enrolled. Immunohistochemistry was carried out to determine the expression of pAMPK, Fyn kinase, and PDK-1 in operative specimens of gastric cancer. The expression was divided into two groups according to the intensity score (negative: 0 or 1+ and positive: 2+ or 3+). From January 2006 to July 2010, 73 tumor samples obtained from 74 patients were analyzed. Forty patients were included in the pAMPK-positive group, while 33 patients were included in the pAMPK-negative group. Meanwhile, positive Fyn kinase expression was observed in only 10 patients (13.7%), and there was no or very weak PDK-1 staining. The clinicopathologic characteristics were similar between the two groups according to the expression of pAMPK. With a median follow-up duration of 26.5months (2.6-73.2), the estimated 3-year relapse-free survival (RFS) and overall survival rates were 55.0 and 78.4%, respectively. In a multivariate analysis adjusted for age, sex, Lauren classification, and stage, the pAMPK-negative group was significantly associated with improved RFS (Hazard ratio=0.459, 95% CI 0.109-0.711, P=0.043). A low expression of pAMPK was found to be correlated with better RFS in patients with resected gastric cancer treated with adjuvant cisplatin-based chemotherapy.

A phase II study of docetaxel and oxaliplatin combination in recurrent gastric cancer patients after fluoropyrimidine and/or cisplatin adjuvant treatment: a Korean Cancer Study Group Protocol ST06-02

Surgery alone is no longer an adequate standard of care for patients with resectable gastric cancer. Thus, research efforts should focus on which regimens are the most effective for patients with recurrent gastric cancer after combined treatment with surgery and perioperative or adjuvant chemotherapy. Patients with histologically confirmed and measurable advanced gastric cancer who showed a relapse even after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy received docetaxel (35mg/m(2)) intravenously on day 1 and 8 plus oxaliplatin (100mg/m(2)) intravenously on day 1 every 3weeks until disease progression or unacceptable toxicity. A total of 34 patients with relapsed advanced gastric cancer who had received adjuvant chemotherapy with fluoropyrimidine and/or cisplatin for a median of 6months (range, 1-48months) were enrolled in this trial; 22 (64.7%) patients had been exposed to both agents. Their median age was 58years (range, 50-68years). The overall response rate was 55.9% (95% confidence interval (CI), 38.3-73.5%), including 1 complete response and 18 partial responses. At a median follow-up duration of 28.5months (range, 9.2-50.7months), the median progression-free survival for all patients was 5.3months (95% CI, 4.4-6.1months) and the median overall survival was 13.8months (95% CI, 11.1-16.4months). The most common grade 3 or 4 hematologic and nonhematologic toxicities were neutropenia (47.1%) and diarrhea (17.6%), respectively. Five patients (14.7%) experienced febrile neutropenia. Docetaxel and oxaliplatin combination chemotherapy was active and tolerable in patients with recurrent gastric cancer after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy.

Carboplatin Based Induction Chemotherapy for Nonorgan Confined Bladder Cancer—A Reasonable Alternative for Cisplatin Unfit Patients?

We investigated induction carboplatin based chemotherapy in patients with nonorgan confined urothelial carcinoma who were considered unfit for cisplatin. A comparison was made with patients who received induction cisplatin based combination chemotherapy. We identified 167 patients with nonorgan confined urothelial carcinoma who received induction cisplatin based combination chemotherapy (126) or gemcitabine and carboplatin (41) at our hospital between 1990 and 2010. Of the patients 124 completed 4 cycles of cisplatin based combination chemotherapy or gemcitabine and carboplatin. Clinical response (ycTNM) was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. Radical cystectomy and bilateral extended pelvic lymph node dissection were performed in 106 patients. A pathological complete response was defined as no evidence of disease (ypT0N0). Disease specific survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed. Complete clinical response rates did not differ significantly among the treatment groups. A pathological complete response was seen in 33.7% of specimens in the cisplatin based combination chemotherapy group vs 30.3% in the gemcitabine and carboplatin group (p = 0.808). We found no significant difference in disease specific survival between patients who started cisplatin based combination chemotherapy and those who started gemcitabine and carboplatin. For patients who completed 4 cycles and underwent radical cystectomy there was also no significant difference in disease specific survival between the groups. On multivariate analysis a pathological complete response was the only variable significantly associated with disease specific survival (p <0.045). Induction gemcitabine and carboplatin for nonorgan confined urothelial carcinoma achieves clinical and pathological response rates, and survival outcomes comparable to those of the cisplatin based combination chemotherapy schemes. Our data suggest that a carboplatin based regimen can be considered a reasonable alternative for cisplatin unfit patients in the preoperative setting.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. To evaluate the effectiveness and safety of platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for this update. Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. For this updated version, we identified three additional ongoing trials but no new studies for inclusion. Three trials including 368 evaluable women with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Two trials compared chemotherapy combined with radiotherapy to radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy to radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (risk ratio (RR) 5.66, 95% CI 2.14 to 14.98). We considered this evidence to be of a moderate quality due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no significant difference in disease recurrence between the groups (HR = 1.34; 95% CI 0.24 to 7.66) and OS was not reported. We considered this evidence to be of a low quality.No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long-term due to a lack of long-term data. This evidence is limited by the small numbers and poor methodological quality of included studies. We await the results of three ongoing trials, that are likely to have an important impact on our confidence in this evidence.

P-0064 ERCC1 Overexpression Predicts Poor Prognosis in Patients with Gastric/GE Junction Adenocarcinoma Treated with Adjuvant Cisplatin-Based Chemotherapy

IntroductionAdjuvant chemotherapy is gaining an increasing role after curative resection for gastric cancer. Novel molecular markers could guide treatment decision-making, in order to better select candidates for adjuvant chemotherapy. The objective of our study was to analyze the status of excision repair cross-complementing gene 1 (ERCC1), thymidylate synthetase (TS) e p53, and correlate with outcome of patients who underwent adjuvant chemotherapy after curative resection for locally advanced gastric/GE junction adenocarcinoma. MethodsWe retrospectively evaluated patients with locally advanced gastric/GE junction adenocarcinoma (stage≥IB according to UICC classification), who underwent curative gastrectomy with D2 dissection, followed by adjuvant chemotherapy consisting of 4 to 6 courses of the ECF regimen (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1, 5FU 200 mg/m2 protracted continuous infusion). Molecular analyses were performed on formalin-fixed paraffin-embedded tissues collected from surgical specimens. p53 mutations were analyzed by sequencing exons 4-10. Protein expression of ERCC1 and TS was assessed by immunohistochemistry (IHC), using specific monoclonal antibodies from Neomarkers. Real-time PCR (TaqMan assay) was performed to quantify mRNA ERCC1 expression. Statistical analyses were carried out using both Fisher'exact and Log Rank tests. ResultsSixty-eight patients were eligible for the study. There were 32 women (47%) and 36 men (53%). The median age was 69 (range: 30-74); UICC stage was III in 44 patients (65%). The median number of delivered chemotherapy cycles was 5.1 (range 4-6). With a median f-up was 40.5 months, disease-free and overall survival were 18.0 (95%CI: 13.4-22.76) and 56 months (95%CI: 44.87-67.13), respectively. We identified mutations in p53 in 21 out of 66 (32%) cases. ERCC1 expression was negative (score 0) in 14 out of 67 (21%) cases, whereas a positive score (score 1-3+) was observed in 53 (79%) cases. TS expression was negative (score 0) in 17 out of 67 (25%) cases, while a positive (score 1-3+) was found in 50 (75%) cases. High ERCC1 mRNA level was found in 19 out of 33 (57%) evaluable cases. Median overall survival was significantly longer in patients with ERCC1 negative tumors (p=0.04) by IHC, whilst TS, p53 and ERCC1 mRNA were not significantly associated with survival. ConclusionIn gastric/GE junction cancer patients after curative resection, ERCC1 by IHC might predict who is more likely to benefit from adjuvant platinum-based chemotherapy, according to the better overall survival observed in ERCC1 negative patients. In those exhibiting ERCC1 positive tumors, alternative chemotherapy regimens should be considered.

Compliance with follow-up (f.-up) program and outcome of patients (pts) with stage I nonseminomatous germ cell tumors (NSGCT).

e15025 Background: There are limited data about f.-up quality of pts with stage I NSGCT after orchiectomy (OE) management and their survival. A retrospective analysis was performed to find the impact of compliance with schedule of f.-up on outcome of relapsed pts with stage I NSGCT. Methods: We analyzed data of 261 pts with stage I GCT treated in our department from 1994 to 2010. NSGCT was revealed in 128 (49%) pts. Therapeutic options following OE comprised retroperitoneal lymph node dissection (RPLND) – in 4/128 (3%), adjuvant cisplatin-based chemotherapy (CT) - in 75/128 (58%) and surveillance - in 49/128 (39%). The following procedures were performed in our center during the f.-up: ultrasound of the abdomen and pelvis, serum AFP, HCG and LDH – bimonthly in the 1st year, quarterly in the 2nd year, biannually in the 3rd-4th years and then annually; X-Ray of the chest – thrice-yearly in the 1st year, biannually on the 2nd year and then annually. Median f.-up time was 75 (range 16 - 176) months. Results: No pts had relapse after RPLND, 4/75 (5,3%) pts had relapses after CT, 16/49 (32%) pts – in surveillance group. 17/20 (85%) relapses were revealed in the first 2 years of f.-up. During relapses, 17/20 (85%) pts had good, 2/20 (10%) - intermediate and 1 patient - poor IGCCCG prognosis. The mean number of visits in the 1st year after OE was 3, on the 2nd year -1,4, in the 3rd- 4th years - 1 per year. All relapsed pts received induction CT (EP or BEP regimen). 11/20 (55%) pts were compliant to visits, 9/20 (45%) pts were not. The 5-years overall survival was 90% and 68% (p=0,3); the median size of metastases in RPLN was 2,2 and 5,5 cm (p=0,001), respectively. All pts in intermediate and poor prognosis were in the noncompliant group, whereas all pts, who were compliant were in good prognosis (3/9 (33%) vs 0/11 (0%), p=0,07). Moreover, surgical removal of residual tumor after induction CT was more often performed in the noncompliant group (5/11 (33%) vs 5/9 (71%), р=0.6). Conclusions: Poor compliance with f.-up program in stage I NSGCT results to non significant worse long-term outcome. Also pts, who were compliant had significantly smaller size of metastases in retroperitoneal lymph nodes at relapse and had good IGCCCG prognosis in all case.

Pilot SCAT trial: Spanish customized adjuvant chemotherapy (CT) based on BRCA1 mRNA expression levels (l) in resected stage II-IIIA non-small cell lung cancer (NSCLC) patients (p).

7011 Background: Surgical resection is the standard treatment in early stages of NSCLC. Nonetheless, long-term survival rate even after surgical resection is disappointing. Several randomized trials and meta-analyses confirmed the survival benefit of adjuvant cisplatin-based CT for stage II and IIIA. BRCA1 is a component of multiple DNA repair pathways, functions as a molecular determinant of response to cytotoxic chemotherapeutics agents, and is an independent prognostic variable in resected p. Since BRCA1 mRNA expression has been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 expression may provide additional information for customizing adjuvant CT. Methods: Completely resected p with pathological lymph node involvement (N1, N2) received 4 cycles of customized adjuvant CT according BRCA1 l. Low l: gemcitabine-cisplatin, intermediate l: docetaxel-cisplatin, high l: docetaxel. Overall survival (OS) was the primary endpoint. Multivariate analysis for time to relapse (TTR) and survival was performed. Results: Eighty-three p were elegible. Most of the patients were male (83%). Type of surgery: 23% pneumonectomy, and 77% lobectomy or bilobectomy. Fifty-three per cent had low BRCA1 l, 33,7% intermediate l, and 13,3% expressed high l. Most of the tumors with adenocarcinoma histology had low l (71%). With a median follow-up of 41.6 months (m), median TTP for the whole group was 22.9 m (13.4-32.5): 20.3 m for low l, 56.5 m for intermediate l, and 51.9 m for high l (P=0.31). Median OS for the whole group was 63.6 m (33.3-93.9): 55 m for low l, and not reached for intermediate and high l (P=0.58). Forty-three p (51.8%) are still alive. Conclusions: Selection of customized CT based on BRCA1 expression l is feasible and could increase time to relapse and survival in resected N1-N2 p. No statistical differences for survival: 55 months for gemcitabine-cisplatin, and not reached for docetaxel-cisplatin and for docetaxel as single agent. Randomized phase III SCAT trial with the addition of a non-pharmacogenomic control arm is ongoing (372 patients included).

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies.

1746 AN EVALUATION OF NEOADJUVANT CHEMOTHERAPY ELIGIBILITY RATES AMONG PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR BLADDER CANCER

shown to be beneficial for patients with extravesicular bladder cancer (pT>2, N>0), but the use of nephrotoxic platinum-based regimens is limited by postoperative renal function. We sought to evaluate the eligibility of post-op radical cystectomy patients at our institution for adjuvant chemotherapy. Our single-institution retrospective study shows that 54% of patients that receive radical cystectomy for what turns out to be extravesicular disease are ineligible for cisplatinbased adjuvant chemotherapy based on their post-operative renal function. Furthermore, perioperative morbidity associated with RC ranges from 28% to 64% and in many cases can preclude patients from access to appropriate adjuvant chemotherapy. Older patients and Caucasian patients are more likely to be ineligible than their younger and African American counterparts. New non-nephrotoxic adjuvant chemotherapeutic regimens are needed to ensure that these patients receive chemotherapy to minimize the chance of recurrence in these high risk patients. Raj Kurpad, Ian Udell, Jed Fergueson, Matthew Nielsen, Mathew Raynor, Angela Smith, Eric Wallen, Michael Woods and Raj Pruthi

639 PREOPERATIVE PREDICTORS OF RENAL FUNCTION DECLINE FOLLOWING RADICAL NEPHROURETERECTOMY FOR UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyUrothelial Cancer: Upper Tract Tumors1 Apr 2012639 PREOPERATIVE PREDICTORS OF RENAL FUNCTION DECLINE FOLLOWING RADICAL NEPHROURETERECTOMY FOR UPPER TRACT UROTHELIAL CARCINOMA Matthew Kaag, Landon Trost, R. Houston Thompson, Ricardo Favaretto, Vanessa Elliott, Shahrokh Shariat, Ally Maschino, Jay Raman, and Guido Dalbagni Matthew KaagMatthew Kaag Hershey, PA More articles by this author , Landon TrostLandon Trost Rochester, MN More articles by this author , R. Houston ThompsonR. Houston Thompson Rochester, MN More articles by this author , Ricardo FavarettoRicardo Favaretto New York, NY More articles by this author , Vanessa ElliottVanessa Elliott Hershey, PA More articles by this author , Shahrokh ShariatShahrokh Shariat New York, NY More articles by this author , Ally MaschinoAlly Maschino New York, NY More articles by this author , Jay RamanJay Raman Hershey, PA More articles by this author , and Guido DalbagniGuido Dalbagni New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.718AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical nephroureterectomy (NU) for upper tract urothelial carcinoma (UTUC) may result in a clinically significant decrease in renal function. This loss of glomerular filtration rate (GFR) may impact the ability to adequately deliver postoperative chemotherapy. We developed a model to predict GFR based on interval from NU, and assessed predictors of GFR after surgery. METHODS We identified 370 patients treated with NU for UTUC at 3 centers between 1995 and 2010 who had post-operative laboratory data. Only patients deemed eligible for cisplatin-based chemotherapy before NU (pre-operative GFR>60 ml/min/m2) were included. We created a generalized estimating equations linear model to predict GFR based on the time from surgery. We used univariate linear regression to identify predictors of GFR after NU at early post-operative (1-5 months after NU) and late post-operative (>5 months after NU) time points. RESULTS 163 patients had an eligible early post-NU GFR measurement and 172 had an eligible late post-NU GFR measurement. The median age was 67 (IQR 59, 73) and 154 (72%) were male. The median GFR prior to NU was 72 ml/min/m2 (IQR 64, 80). When modeling GFR after surgery, we did not see evidence that post-NU GFR values changed significantly over time, despite allowing for a possible non-linear relationship in the model. At 2 months the predicted GFR was 52 ml/min/m2 (95% CI: 51, 54); at 6 months it was 51 ml/min/m2 (95% CI: 49, 53). On univariate analysis, age and preoperative GFR were both significant predictors of early (per year: β= -0.4; 95% CI: -0.6, -0.2; p<0.0005 and per 10 ml/min/m2: β= 5.4; 95% CI: 3.7, 7.2; p<0.0005) and late GFR outcomes (per year: β= -0.4; 95% CI: -0.5, -0.2; p<0.0005 and per 10 ml/min/m2: β= 4.1; 95% CI: 2.6, 5.6; p<0.0005). On multivariate analysis, preoperative GFR and age remained significant predictors of both early (p<0.0005 and p=0.004) and late (p=0.001 and p=0.007) GFR after NU. Charlson score was also an independent predictor of late GFR post-NU on multivariate analysis (p=0.004). CONCLUSIONS Renal function decreases after NU and does not show evidence of recovery over time. Pre-NU GFR and patient age are independent predictors of post-NU GFR at early and late time points, while Charlson score predicts only late post-operative GFR. Diminished GFR following NU is likely to limit utilization of adjuvant cisplatin-based chemotherapy. These data underscore the need for clinical trials evaluating neoadjuvant chemotherapy in well-selected patients. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e260 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Matthew Kaag Hershey, PA More articles by this author Landon Trost Rochester, MN More articles by this author R. Houston Thompson Rochester, MN More articles by this author Ricardo Favaretto New York, NY More articles by this author Vanessa Elliott Hershey, PA More articles by this author Shahrokh Shariat New York, NY More articles by this author Ally Maschino New York, NY More articles by this author Jay Raman Hershey, PA More articles by this author Guido Dalbagni New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

AOS22 Expression of excision repair cross complementation group 1 (ERCC1) protein in Indonesian patients with nasopharyngeal carcinoma receiving cisplatin-based adjuvant chemotherapy

Background Overexpression of excision repair cross complementation group 1 (ERCC1) has been reported to be associated with resistance to platinum-based chemotherapy in head and neck cancer. Since cisplatin-based adjuvant chemoradiotherapy is the standard treatment for nasopharyngeal cancer (NPC) in Indonesia, it is important to investigate the role of ERCC1 as a possible predictive marker of disease progression in our patients. Methods Consecutive samples obtained from our pathology archives of NPC from 31 patients who were receiving standard treatment with cisplatin-based chemoradiotherapy were examined for ERCC1 expression by use of immunohistochemistry. A retrospective cohort study was done and overall survival curves (OS) were plotted versus expression of ERCC1. Findings ERCC1 expression was high in 16 (51.6%) patients and low in 15 (48.4%). There were no differences in the baseline characteristics between the two groups (age, sex, and stage of the disease; p > 0.05). Median survival was 15.5 months. Analysis of OS showed a significant difference between the two groups ( p = 0.02). A univariate analysis of the baseline characteristics and ERCC1 in relation to the 1 year OS showed that only ERCC1 was significant. 53.3% (95% confidence interval (CI) 40.4–66.2) of patients in the group with high ERCC1 expression had an OS of 1 year or more, whereas 80% (95% CI 69.7–90.3; p = 0.02) of the group with low ERCC1 expression had an OS of 1 year or more. The median 1 year OS in the high ERCC-1 group was 13.2 months (95% CI 0.0–27.2), whereas it was not achievable in the low ERCC-1 group. Hazard ratio for the group with high expression of ERCC1 was 3.304 (95% CI 1.12–9.71). Interpretation The low expression of ERCC1 might prolong the overall survival in Indonesian patients with NPC who are receiving standard cisplatin-based chemoradiotherapy. The authors declared no conflicts of interest.

Thoracoscopic Mediastinal Lymph Node Dissection for Lung Cancer

One of the main criticisms against lobectomy for lung cancer via video-assisted thoracoscopic surgery (VATS) is that mediastinal nodes are not properly assessed; however, VATS lobectomy permits complete nodal dissection that does not differ from that performed by thoracotomy. 1 Watanabe A. Koyanagi T. Ohsawa H. et al. Systematic node dissection by VATS is not inferior to that through an open thoracotomy: A comparative clinicopathologic retrospective study. Surgery. 2005; 138: 510-517 Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Because recent publications have shown a significant statistical gain in 5-year survival if patients with stage ≥IIa non-small cell lung cancer (NSCLC) are treated with adjuvant chemotherapy, 2 Arriagada R. Bergman B. Dunant A. et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non–small-cell lung cancer. N Engl J Med. 2004; 350: 351-360 Crossref PubMed Scopus (2100) Google Scholar , 3 Douillard J.Y. Rosell R. De Lena M. et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol. 2006; 7: 719-727 Abstract Full Text Full Text PDF PubMed Scopus (1351) Google Scholar a thorough systematic mediastinal lymph node dissection (MLND) is absolutely mandatory to properly stage patients with NSCLC. Stage migration from inadequate mediastinal lymph node assessment has the potential to be detrimental to patients with NSCLC by dictating the wrong postoperative management. In addition, stage migration might lead to completely erroneous survival statistics. It should be kept in mind that randomized controlled trials rely on final histologic staging, which is possible only with an accurate systematic MLND.

Extended lymphadenectomy and adjuvant chemotherapy in muscle-invasive bladder cancer treated by radical cystectomy.

287 Background: Level 1 evidence is weak for adjuvant chemotherapy (AC) after cystectomy, but surveys indicate physicians refer patients for AC more frequently than for neoadjuvant chemotherapy (NC). The exact benefit of an extended pelvic lymph node dissection (ePLND) remains debated. We addressed the issue of AC and ePLND analyzing two academic centers RC databases with opposite approaches, one using ePLND and AC, the other performing a limited lymph node dissection and no AC. Methods: Two ethics approved RC databases including consecutive BC patients undergoing RC at the University Health Network, Canada and the University of Turku, Finland were studied. Excluding non-urothelial cases and patients receiving NC, 563 patients were available for analysis. Clinicopathological variables, rate and extent of PLND and rate of adjuvant cisplatin-based chemotherapy were analyzed using the χ2-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival. Results: In Toronto, patients had more extensive PLNDs (&gt;10 nodes removed, 58% vs. 8%, p&lt;0.001), higher rate of nodal metastases (26% vs. 7%, p&lt;0.001), and received more often AC (21% vs. 1%, p&lt;0.001). Positive margin rates were similar (4% in both centers). No BC specific survival difference was demonstrated in ≤ pT2a or in pT4a tumors. 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, N-stage (HR 2.5, 95% CI 1.5-4.1; p&lt;0001) and ePLND (HR 0.53, 95% CI 0.31-0.93, p=0.026) significantly affected disease specific survival. The benefit of AC did not reach significance (HR 0.61, 95% CI 0.36-1.05, p=0.072). An interaction model combining ePLND and AC was significantly related to improved outcome (HR 0.49, 95% CI 0.26-0.92, p=0.026). Conclusions: Despite not being randomized, using 2 study cohorts that received completely opposite managements in terms of ePLND and AC, our results support that ePLND and AC may offer a survival advantage in T2b and especially in T3 BC treated with RC.

868 Histologic subtypes of bladder cancer influence overall survival of patients treated by radical cystectomy and adjuvant cisplatin-based chemotherapy

868 Histologic subtypes of bladder cancer influence overall survival of patients treated by radical cystectomy and adjuvant cisplatin-based chemotherapy

Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma

PurposeThe optimal treatment of women with advanced adenocarcinoma of uterine cervix is still undefined. We compared concurrent chemoradiation (CCRT) and adjuvant cisplatin-based chemotherapy with CCRT alone for advanced cervical adenocarcinoma in a randomized trial at the Hunan Provincial Tumor Hospital in China. MethodsFrom 1998 to 2007, 880 patients with clinical FIGO stages IIB–IVA cervical adenocarcinoma were randomized to receive either CCRT or chemoradiation with one cycle of neo-adjuvant chemotherapy with Paclitaxel (135mg/m2)+Cisplatin (75mg/m2) before receiving radiation and two cycles of consolidation chemotherapy with the same drugs after radiotherapy in 3-week intervals. The disease control and survival rates were calculated using the Kaplan–Meier method. ResultsAll patients completed the treatment plan. 340 patients have relapsed, with a median follow-up duration of 60months. Patients who received chemoradiation with adjuvant chemotherapy showed a significantly longer disease-free (P<.05), cumulative survival (P<.05) and long-term local tumor control (P<.05). Patients who received CCRT alone had significantly more distant metastasis and pelvic failure than those who received chemoradiation with adjuvant chemotherapy (P<.05). ConclusionIncorporating neo-adjuvant and consolidation chemotherapy with Paclitaxel and Cisplatin into concomitant chemoradiation is highly effective, safe and may be a very promising treatment protocol for advanced cervical adenocarcinoma.