Secondary Endpoint Of Overall Survival Research Articles

LBA22_PR - Temsirolimus vs Sorafenib As Second Line Therapy in Metastatic Renal Cell Carcinoma: Results from the Intorsect Trial

ABSTRACT Background Temsirolimus (TEM) demonstrated an overall survival (OS) benefit vs interferon alfa in previously untreated patients (pts) with advanced renal cell carcinoma (RCC) and poor prognostic features. The efficacy of temsirolimus after VEGF inhibitor therapy is not known. This multicenter, randomized, open-label phase 3 trial compared the efficacy and safety of TEM vs sorafenib (SOR) in pts with metastatic RCC (mRCC) who failed prior sunitinib therapy. Methods RCC pts with disease progression after 1st-line sunitinib therapy and ECOG performance status 0 or 1 were enrolled. Eligible pts, stratified by duration of prior sunitinib therapy (≤ or >6 mo), prognostic risk, histology (clear cell or non–clear cell), and nephrectomy status, were randomized 1:1 to receive TEM 25 mg/wk intravenously or SOR 400 mg bid. Dose reductions were allowed for TEM (to 20 then 15 mg) and for SOR (to 400 mg/d then every other day). Study was powered to detect a 33% improvement in progression-free survival (PFS), the primary end point, by independent central review. Results From Sept 2007 to March 2011, 112 sites in 20 countries enrolled 512 pts; 259 received TEM and 253 received SOR. Baseline demographics were balanced. Median age was 60 y, 75% were male, and 67% were white (Asian, 17%). Histology was clear cell in 422 pts, non–clear cell in 90 pts. At data cutoff for final analysis (May 2012), 389 pts had independently assessed PFS events; 351 pts had died. Median PFS with TEM was 4.28 mo (95% confidence interval [CI]: 4.01, 5.43) and with SOR, 3.91 mo (95% CI: 2.80, 4.21); hazard ratio [HR] = 0.87 (95% CI: 0.71, 1.07; 2-sided P value = 0.1933). Median OS for the TEM group was 12.27 mo (95% CI: 10.13, 14.80); for the SOR group, 16.64 mo (95% CI: 13.55, 18.72); HR= 1.31 (95% CI: 1.05, 1.63; 2-sided P value = .0144). The most common adverse events (all grade, all cause) with TEM were rash, fatigue, diarrhea, anemia, and hyperglycemia; with SOR, they were diarrhea, rash, hand-foot syndrome, and decreased appetite. Conclusions TEM did not show superiority to SOR in the primary end point (PFS [independent]) or in the secondary end point of OS. Safety data were as expected for both agents. Further evaluation is needed to define the optimal sequence after prior sunitinib in advanced RCC pts. Disclosure This study was sponsored by Pfizer Inc. T. Hutson: Dr. Hutson is a Study Investigator for Pfizer Inc. B. Escudier: Advisory role for Aveo, Bayer, GSK, Novartis, Pfizer Inc G.A. Bjarnason: Has received honoraria for talks given, support for travel to meetings and advisory boards, and funding for investigator initiated trials from Pfizer Inc. P. Senico: Employee and stock owner of Pfizer Inc. A. Niethammer: Employee and stock owner of Pfizer Inc. D. Lu: Employee and stock owner of Pfizer Inc. S. Hariharan: Employee and stock owner of Pfizer Inc. R.J. Motzer: Research Funding and Consultancy with Pfizer Inc. All other authors have declared no conflicts of interest.

Adjuvant chemotherapy and chemoradiation following surgery for high-risk endometrial cancer.

5028 Background: Endometrial cancer with adverse pathology has a significant risk of disease relapse if treated with surgery alone. We performed a prospective phase II trial testing the addition of concurrent chemotherapy during adjuvant radiation followed by adjuvant chemotherapy. Methods: Eligible patients had histologically confirmed endometrial cancer following a minimum of TAH-BSO, plus high-risk features of: node-positive disease, grade 3 FIGO 1988 stage Ic or IIb, or any stage III disease. Stage IV disease, serous or clear cell cancer was excluded. Treatment involved 54Gy of external beam radiotherapy (RT) to the pelvis ±extended field (EFRT) with carboplatin AUC 2 weekly × 6 during RT, followed by 4 cycles of carboplatin AUC 5-6 and paclitaxel 175 mg/m2 q3weeks. The primary endpoint was failure-free survival (FFS), with secondary endpoints of overall survival (OS) and toxicity. Results: 41 patients of median age 57 (range 31-79) were enrolled 06/04 to 08/08. 24 (59%) had stage IIIC disease with 11 (27%) having residual measurable disease on post-operative CT. All completed planned RT, including 11 (27%) treated with EFRT. 32 (78%) received all 6 doses of concurrent chemotherapy, 32 all 4 cycles of adjuvant chemotherapy and 28 (68%) received the planned 10 doses. After a median follow-up of 2.34 years, the estimated 3 year FFS rate was 73% (95%CI: 54-87%) and OS rate was 93% (95%CI: 76- 98%). By the study censor date, 9 patients (22%) had a recurrence with only 2 patients relapsing within the RT field. Treatment was well tolerated with no treatment-related deaths. Grade 3 or 4 nonhaematologic toxicity occurred in 14 with 12% grade 3 diarrhoea and 10% grade 3 arthralgia/myalgia. One pt respectively developed febrile neutropenia and grade 3 sensory neuropathy with 4 (10%) developing platinum-hypersensitivity. Conclusions: Adjuvant chemotherapy after chemoradiation for patients with high-risk endometrial cancer is a promising approach, though distant failure remains the dominant site of failure. This regimen was well tolerated but the high number of carboplatin doses resulted in a 10% hypersensitivity rate. Ongoing randomised trials should be supported to determine the optimum adjuvant therapy in endometrial cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study

Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001). Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Eli Lilly.

Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST)

8009 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This phase III study compared the efficacy of vandetanib vs erlotinib in patients (pts) with advanced, previously treated NSCLC. Methods: Eligible pts (stage IIIB/IV NSCLC, PS 0–2, 1–2 prior chemotherapies; all histologies permitted) were randomized 1:1 to receive vandetanib 300 mg/day or erlotinib 150 mg/day until progression/toxicity. The primary objective was to show superiority in progression-free survival (PFS) for vandetanib vs erlotinib. Secondary endpoints included overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS; EORTC QoL Questionnaire) and safety. Results: Between Oct 06-Nov 07, 1240 pts (mean age 61 yrs; 38% female; 22% squamous) were randomized to receive vandetanib (n=623) or erlotinib (n=617). Baseline characteristics were similar in both arms. Median duration of follow-up was 14 months, with 88% pts progressed and 67% dead. There was no difference in PFS for pts treated with vandetanib vs erlotinib (hazard ratio [HR] 0.98, 95.22% CI 0.87–1.10; P=0.721), and no difference in the secondary endpoints of OS (HR 1.01, 95.08% CI 0.89–1.16; P=0.830), ORR (both 12%) and TDS (pain: HR 0.92, P=0.289; dyspnea: HR 1.07, P=0.407; cough: HR 0.94, P=0.455). A preplanned non-inferiority analysis for PFS and OS demonstrated equivalent efficacy for vandetanib and erlotinib. The adverse events (AEs) observed for vandetanib were generally consistent with previous NSCLC studies with vandetanib 300 mg. There was a higher incidence of some AEs (any grade) with vandetanib vs erlotinib, including diarrhea (50% vs 38%) and hypertension (16% vs 2%); rash was more frequent with erlotinib (38% vs 28%). The overall incidence of CTCAE grade ≥3 AEs was also higher with vandetanib (50% vs 40%). The incidence of protocol-defined QTc prolongation in the vandetanib arm was 5%. Conclusions: The study did not meet its primary objective of demonstrating PFS prolongation with vandetanib vs erlotinib in pts with previously treated advanced NSCLC. However, vandetanib and erlotinib showed equivalent efficacy for PFS and OS in a preplanned non-inferiority analysis. [Table: see text]

Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial

4000 Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone. [Table: see text]

Phase 2 study of talabostat/gemcitabine in Stage IV pancreatic cancer

4616 Background: Talabostat is an oral small molecule inhibitor of fibroblast activation protein (FAP), a stromal enzyme with collagenase and dipeptidyl peptidase activity. Talabostat also upregulates cytokine and chemokine production, resulting in immune stimulation. Talabostat is active in pancreatic tumor xenograft models and enhances the activity of gemcitabine in mice. Therefore, a clinical trial in patients with metastatic pancreatic cancer was initiated. Methods: Open-label, single-arm, Phase 2 study in 60 evaluable patients with Stage IV pancreatic cancer. Study treatment is administered in 4 x 4-week cycles; gemcitabine 1g/m2 weekly for 4 weeks in Cycle 1, then once weekly for 3 of 4 weeks. Talabostat 200mcg tablets are given BID for 6 days following each gemcitabine infusion; dose-escalation to 300mcg BID is allowed post-Cycle 1. Either agent alone or in combination can be continued beyond 4 cycles depending on tolerability. Eligible patients have measureable Stage IV pancreatic adenocarcinoma (per RECIST) are chemotherapy-naive, have a KPS ≥50, no CNS metastases, transaminases &lt; 3 X ULN, and total bilirubin &lt; 1.5 X ULN. Primary endpoint is 6-month survival with secondary endpoints of overall survival, PFS, pain, and quality-of-life. Tumor response or PD is assessed per RECIST. Results: As of the cut-off date, 46 patients (30 men, 16 women, median age 66 [range 43–88 years]) have received study treatment. Most patients (76%) were Stage IV at original diagnosis, and 72% have a KPS of 80 or higher. Ten of 21 evaluable patients treated as of June 30, 2006 meet 6-month survival. Median overall survival is currently estimated at 4.8 months (95% CI: 2.9, NE) in all 46 patients, and median PFS at 3.5 months (95% CI: 2.0, 4.9). Tumor responses have been reported in 3 patients: one CR and 2 PRs. Pain and QOL have not yet been analyzed. AEs are consistent with those of gemcitabine, with the exception of edema in 28.3% of patients. Grade 3 anemia, neutropenia, hyponatremia hyperbilirubinemia, and increased alk phos are reported in 2 patients each. No Grade 4 AEs have been reported in more than one patient. Conclusions: Talabostat/gemcitabine shows activity in metastatic pancreatic cancer and can be safety administered. Enrollment completed in early January 2007, and final results will be presented at the annual meeting. No significant financial relationships to disclose.

Phase II trial evaluating capecitabine and irinotecan in patients (pts) with esophago-gastric (E-G) carcinoma having progressed or relapsed within 3 months of platinum-based chemotherapy

4170 Background: To assess the efficacy and toxicity of a 3-weekly regimen containing capecitabine combined with irinotecan (CapeIri) in refractory or relapsed E-G carcinomas. Primary endpoints were response rate (RR) and disease free survival (DFS) with secondary endpoints of overall survival (OS) and toxicity. Methods: 29 pts with locally advanced or metastatic E-G carcinoma (27 adenocarcinoma, 2 squamous carcinoma) with documented progression during or within 3 months of completion of chemotherapy were recruited between January 2003 and November 2004. Capecitabine (2000mg/m2/day Day 1–14) and Irinotecan (250mg/m2 Day 1) (CapeIri) was given every 3 weeks. CT response was assessed at 12 and 24 weeks. Results: Four pts were ineligible due to no measurable disease (number, n=3) and progression > 3 months since platinum therapy (n=1). Median age of the 25 eligible pts was 59 years and 21 pts (84%) had metastatic disease. All pts had previously received platinum although one pt had capecitabine alone immediately prior to study entry. 19/25 (76%) received a 3-drug ECF-like regimen. At present, with a median follow up of 4.3 months, 21 pts are assessable for response. 3 pts responded, RR 14.3% (95% CI 3.1–36.3%) and 3 pts (14.3%) had stable disease. Improvement in the following tumor-related symptoms occurred: dysphagia 43% (3/7 pts), reflux 50% (5/10), anorexia 44% (4/9), weight loss 43% (3/7), vomiting 60% (3/5) and pain 29% (4/14). 8 pts (32%) had grade 3/4 neutropenia and 1 pt (4%) had febrile neutropenia. There were no toxic deaths. Median DFS was 2.8 months and median survival was 6.3 months. Conclusions: Second-line chemotherapy with CapeIri in primary refractory and relapsed esophago-gastric carcinoma is effective, tolerable palliative treatment and warrants further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, sanofi-aventis Roche, sanofi-aventis Roche-educational grant and free drug. Money to research fund, sanofi-aventis towards drug costs, to research fund not myself.

Comparison of two-year and five-year tamoxifen use in Japanese post-menopausal women

Aim Large multicenter, randomized trials have revealed the advantages of using tamoxifen for 5 years vs 2 years in breast cancer patients. The aim of this report is to confirm the optimal duration of tamoxifen administration in a study of Japanese breast cancer patients. Methods Japanese post-menopausal estrogen receptor-positive breast cancer patients treated with mastectomy were randomly assigned to either a 5-year or 2-year course of tamoxifen. The primary endpoint was disease-free survival, with secondary endpoints of overall survival and a reduction in the development of metachronous contra-lateral breast cancer. Results A total of 256 breast cancer patients were randomized to a 5-year or 2-year tamoxifen administration group. After a median follow-up time of 81 months, there were no significant differences seen in terms of disease-free or overall survival ( p=0.65 and 0.56, respectively). Furthermore, the impact of the 5-year use of tamoxifen on the development of contra-lateral breast cancer did not reach statistical significance ( p=0.0511). However, 5-year tamoxifen use was closely associated with gynaecological complications ( p=0.0081). Conclusion We could not show a beneficial effect of using tamoxifen for 5 years over 2 years in Japanese estrogen receptor-positive patients. This is likely due to the small number of patients enrolled in our study; however, racial disparity may influence this result. A reevaluation is necessary to study the advantages of the 5-year use of tamoxifen in the Japanese racial subgroup.

The role of EGFR in predicting clinical outcome in locally advanced rectal carcinoma treated with neoadjuvant chemoradiation

9592 Background: To explore the prognostic role of EGFR (epidermal growth factor receptor) expression in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiation. Methods: 60 pre and post-chemoradiation tumour samples were studied. T stages : T3:21, T4:39. Median age 68 years, male: female ratio 80:20%. Median follow-up 42 months. The radiotherapy dose was 45Gy in 25 fractions over 5 weeks. 5-FU was a 60 minutes infusion days 1–5 and 29–33, at 350mg/m2, following low dose folinic acid. At 6–8 weeks following chemoradiation patients underwent surgery with curative intent. An immunohistochemical analysis was conducted to analyse EGFR expression. The primary endpoint was disease-free survival (DFS), with a secondary endpoint of overall survival (OS). Results: 65% of tumours stained for EGFR, which was predominantly cytoplasmic and there was a strong correlation between intensity and percentage of positive tumour cells (p<0.001). Expression did not significantly change following chemoradiation. EGFR correlated significantly with increasing N stage (p=0.049), suggesting a role in disease progression. EGFR expression also correlated significantly with DFS on univariate analysis, see table, and this significance remained on multivariate analysis (p=0.05). There was no effect on OS. Conclusions: The data suggests that overexpression of EGFR may correlate with disease progression; however DFS in this group improved with increasing EGFR expression. This contradicts other studies in rectal cancer; however these did not include patients receiving neoadjuvant chemoradiation. An interaction between EGFR and pre-operative 5FU chemoradiation may exist, enhancing treatment effect. Larger studies are required to elucidate the clear role of EGFR as a marker of prognosis in patients receiving different treatment modalities in this disease. No significant financial relationships to disclose.

The role of EGFR in predicting clinical outcome in locally advanced rectal carcinoma treated with neoadjuvant chemoradiation

9592 Background: To explore the prognostic role of EGFR (epidermal growth factor receptor) expression in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiation. Methods: 60 pre and post-chemoradiation tumour samples were studied. T stages : T3:21, T4:39. Median age 68 years, male: female ratio 80:20%. Median follow-up 42 months. The radiotherapy dose was 45Gy in 25 fractions over 5 weeks. 5-FU was a 60 minutes infusion days 1–5 and 29–33, at 350mg/m2, following low dose folinic acid. At 6–8 weeks following chemoradiation patients underwent surgery with curative intent. An immunohistochemical analysis was conducted to analyse EGFR expression. The primary endpoint was disease-free survival (DFS), with a secondary endpoint of overall survival (OS). Results: 65% of tumours stained for EGFR, which was predominantly cytoplasmic and there was a strong correlation between intensity and percentage of positive tumour cells (p<0.001). Expression did not significantly change following chemoradiation. EGFR correlated significantly with increasing N stage (p=0.049), suggesting a role in disease progression. EGFR expression also correlated significantly with DFS on univariate analysis, see table, and this significance remained on multivariate analysis (p=0.05). There was no effect on OS. Conclusions: The data suggests that overexpression of EGFR may correlate with disease progression; however DFS in this group improved with increasing EGFR expression. This contradicts other studies in rectal cancer; however these did not include patients receiving neoadjuvant chemoradiation. An interaction between EGFR and pre-operative 5FU chemoradiation may exist, enhancing treatment effect. Larger studies are required to elucidate the clear role of EGFR as a marker of prognosis in patients receiving different treatment modalities in this disease. No significant financial relationships to disclose.