Improvement In Or Overall Survival Research Articles

Abstract PO4-02-04: Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort

Abstract Background: In the PENELOPEB trial, the addition of 1-year of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib to standard endocrine therapy (ET) for women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer at high risk of recurrence after neoadjuvant chemotherapy (NACT) did not improve invasive disease-free survival (iDFS) or overall survival (OS) in the main study analysis. Invasive lobular breast cancer (ILC) accounts for ~15% of all breast cancers (BC) and represents an underinvestigated subtype of BC with typically less sensitivity to (neo)adjuvant chemotherapy, and poor distant disease-free survival (DDFS) irrespective of response to NACT. Here, we report the post-hoc analysis results of iDFS, DDFS and OS in pre- and postmenopausal women enrolled on PENELOPEB and with ILC. Methods: Patients with HR+/HER2-negative BC without pathological complete response (pCR) after taxane-containing NACT and at high risk of relapse (CPS-EG score ≥3, or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 of a 28-day cycle in addition to standard ET with tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age at first diagnosis (< 50 vs. ≥50 years), Ki-67, region, and CPS-EG score. ILC diagnosis was locally assessed and reported by the investigators on the pathology case report form. The primary objective of this post-hoc analysis was to evaluate iDFS, DDFS and OS by treatment arm in patients with high risk ILC. Results: A total of 1,250 patients were randomized, of whom 110 had ILC and were nearly uniformly distributed between both treatment arms (palbociclib n=58 vs. placebo n=52), with a higher proportion of postmenopausal women (58.6% in the palbociclib arm vs. 53.8% in the placebo arm) compared to premenopausal women (41.4% in the palbociclib arm vs. 46.2% in placebo arm). There was no difference in the distribution of AI/TAM use between the treatment arms. An estimated absolute 3-year-iDFS difference of 18.3% with palbociclib compared to placebo (iDFS 88.4% [95% CI 76.0-94.6] vs. 70.1% [95% CI 55.3-80.7]) with a HR of 0.66 [95% CI 0.27 – 1.61, log-rank p=0.354]) was observed. A comparable 3-year-DDFS difference of 16.3% was observed. An estimated 3-year-OS difference of 16.4% (98.0% [95% CI 86.6 – 99.7] vs. 81.6% [95% CI 67.5 – 90.0]) with a hazard ratio (HR) of 0.27 (95% CI 0.05 – 1.43, log-rank p=0.108) was observed. Out of 12 observed deaths (n=2 palbociclib vs. n=10 placebo), 11 (in placebo arm) were related to metastasic BC. Conclusions: In this post-hoc analysis, a trend towards improvement in OS and a trend in favor of iDFS and DDFS for the addition of palbociclib to ET was observed among women with HR+/HER2- ILC at high risk of recurrence after NACT, but these differences were not statistically significant. This could represent a valuable treatment option for patients with high risk ILC. Due to the small sample size of the ILC subgroup, further follow-up evaluation is necessary. Moreover, analyses in the ILC subgroup from other adjuvant CDK4/6 inhibitor trials could substantiate these findings. Table. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort Results of iDFS, DDFS and OS. Citation Format: Hervé Bonnefoi, Frederik Marmé, Miguel Martín, Michael Untch, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Zhe Zhang, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Nader Hirmas, Valentina Nekljudova, Johannes Holtschmidt, Sibylle Loibl. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-04.

CTNI-56. A MULTI-INSTITUTIONAL RETROSPECTIVE SERIES OF ADULT-ONSET MEDULLOBLASTOMA

Abstract Adult-onset medulloblastoma is a rare tumor for which limited data exists. Current treatment is based on data from childhood medulloblastoma. We present a retrospective cohort of 130 consecutive patients age ≥ 18 years and treated at the University of Washington (N = 61), University of Florida (N = 50), and Stanford University (N = 19), from 2000-2021. Median duration of follow-up was 57.3 months. Patients were 57.7% male (75/130), with median age at diagnosis of 29 years. 5 and 10-year overall survival were 78.9% and 67.6% and no recurrence was seen beyond 10 years. 31/130 (23.8%) patients had Chang M1 or greater disease and molecular typing was available for 41/130 patients. There was no improvement in progression-free survival (PFS) or overall survival (OS) either in patients who received proton therapy or those who received concurrent vincristine. There was a trend favoring longer OS in patients receiving radiotherapy within 6 weeks of surgery. A trend towards shorter OS in patients receiving a higher craniospinal radiation dose ( > 30Gy) likely reflected accurate clinical risk stratification. There was no improvement in OS or PFS for adjuvant chemotherapy overall, but patients receiving ≥ 5 cycles had improved PFS (HR 2.10, 95% CI = 1.19 - 3.90, p = 0.038) and a trend to improved OS (HR 2.07, 95%CI = 0.81-5.25, p = 0.125). After first progression, median OS was 20.7 months and both 5 and 10-year survival were 24.8%. We conclude that surveillance past 10 years may be unnecessary and that 1 in 4 patients achieve long-term survival after first relapse. Within the confines of a retrospective study, these data suggest equivalence between proton and photon radiotherapy, no benefit to concurrent vincristine, and that at least 5 cycles of adjuvant chemotherapy are required to delay progression.

Real-world utility of early measurable residual disease assessments by multi-parametric flow cytometry in adult patients with B-lymphoblastic leukemia receiving Hyper-CVAD induction chemotherapy.

Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p= .426) or overall survival (OS) (p= .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p= ·005) and OS (p= .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.

Molecular, Histological, and Clinical Characteristics of Oligodendrogliomas: A Multi-Institutional Retrospective Study.

Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined. To evaluate the role of PIK3CA mutations in mODGs. One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed. The median age was 37 years, and 61 patients (57%) were male. There were 64 (60%) World Health Organization (WHO) grade 2 and 43 (40%) WHO grade 3 tumors. Eighty-two patients (77%) were stratified as high risk (age 40 years or older and/or subtotal resection per Radiation Treatment Oncology Group-9802). Gross-total resection was achieved in 47 patients (45%). Treatment strategies included observation (n = 15), TMZ (n = 11), radiation (n = 13), radiation/TMZ (n = 62), and others (n = 6). Our results show a benefit of TMZ vs observation in progression-free survival (PFS). No difference in PFS or overall survival (OS) was observed between radiation and radiation/TMZ. PIK3CA mutations were detected in 15 (14%) mODG, and shorter OS was observed in PIK3CA-mutant compared with PIK3CA wild-type mODGs (10.7 years vs 15.1 years, P = .009). WHO grade 3 tumors showed a shorter PFS, but no significant difference in OS was observed between WHO grades. Our findings suggest that mODGs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS with TMZ treatment, adjuvant TMZ, radiation, or a combination of the two showed no significant improvement in OS.

Pre-Operative Chemoradiotherapy With or Without Induction Chemotherapy for Operable Locally-Advanced Esophageal Cancer

Following presentation of the CALGB 80803 trial, which demonstrated notably high pathologic complete response (pCR) rates with induction FOLFOX followed by chemoradiotherapy (CRT), our institution more routinely incorporated induction chemotherapy (IC) into the management of LA-EC patients. However, improvements in progression-free (PFS) or overall survival (OS) with this regimen compared to pre-operative CRT alone have not yet been shown. We hypothesized IC-CRT would lead to an improvement in OS and PFS when compared to CRT.Patients with operable LA-EC were eligible for analysis if they received CRT between 2013-2019. The cohort was stratified into two groups, IC-CRT vs. CRT. The Kaplan-Meier method was used to estimate OS and PFS. The cumulative incidences of local recurrence (LR), locoregional recurrence (LRR), and distant metastasis (DM) were reported. The impact of treatment group on pathologic response and surgical outcomes were assessed by Chi-square.95 patients were included for analysis (IC-CRT n = 58; CRT n = 37). Baseline characteristics included median Karnofsky Performance Status 80, median weight loss 5% (IQR 0-9%), with the majority being adenocarcinoma histology (81%), T3-T4 (60%), N+ (79%), located in the distal esophagus or gastroesophageal junction (89%). Patients receiving IC-CRT were more likely to have been treated after 2016 (64% vs 38%, P = 0.021). IC was most commonly FOLFOX (74%) for a median of 3 (IQR 1-3) cycles. CRT was delivered to a median dose of 50 Gy in 25-28 fractions. Surgery was attempted in 60% and 68% of the IC-CRT and CRT cohorts, respectively. Median follow-up was 26 months. ICRT and CRT were associated with similar 2-year OS (66% [95% CI 51-78%] vs 70% [95% CI 52-83%]) and PFS (47% [95% CI 33-59%] vs 48% [95% CI 30-63%]). In the adenocarcinoma subset (n = 77), 2-year OS was 69% (95% CI 52-81%) in the IC-CRT cohort vs 61% (95% CI 40-77%) with CRT. 2-year PFS was 46% (95% CI 31-60%) and 38% (95% CI 20-56%), respectively. IC-CRT was not associated with an OS or PFS benefit among any patient subgroup. Recurrence rates were similar between the cohorts (47%) and first recurrence was most commonly DM (61% IC-CRT vs 65% CRT). Patients receiving IC-CRT compared to CRT had numeric but not statistically significant improvement in pCR (45% vs 29%, P = 0.24) and N-stage regression (72% vs 58%, P = 0.28). There was no difference in the rate of R0 resection, hospitalization, surgical complications, or treatment-related death with use of IC-CRT.IC-CRT was not associated with improved OS or PFS in this small and perhaps underpowered cohort study. Further investigations are needed to explore the impact of IC-CRT on quality of life, symptom burden, and to see if meaningful trends develop with time.

Identification of cancer hallmarks associated with benefit in advanced gastroesophageal adenocarcinoma patients treated with checkpoint blockade.

439 Background: The benefit of checkpoint blockade in advanced gastric cancer is limited and biomarkers related to response are needed. Novel gene expression analysis software was used to identify Hallmarks of Cancer associated with clinical benefit following nivolumab treatment in >2nd line advanced gastroesophageal adenocarcinoma (GEA). Methods: RNA-sequencing data from baseline GEA patient diagnostic tumor samples (103 from NCT02862535; 5 from NCT02862535) were analyzed using the claraT platform (V2.0.0, Almac Diagnostic Services). 62 gene signatures were quantified representing 6 key Hallmarks of Cancer (Avoiding Immune Destruction, Activating Invasion and Metastases, Sustaining Proliferative Signaling, Inducing Angiogenesis, Resisting Cell Death and Genome Instability and Mutation). Clinical benefit (CB) was defined as tumor response or overall survival (OS) > 1 year. HER2 status was from medical records. Survival analyses used cox proportional hazards models. Results: Gene expression signatures (GES) identified 5 molecular subgroups (C1-C5). Rate of CB in each molecular subtype are outlined in Table. C3 and C4 had significantly improved OS compared to C2, (HR = 0.45; p= 0.02 and HR = 0.42; p= 0.02). Greater proportions of HER2+ subjects were present in C4 and C3 vs. C2, with C3 statistically significant (60% vs. 14%; p= 0.012). Gene expression characterized by chromosomal instability (CIN) and homologous recombination repair deficiency (HRD) were associated with HER2(+) (wilcox p= < 0.05). Patients selected by only using CIN & HRD had significant improvement in OS (HR = 0.63; p= 0.03). Conclusions: Interferon-based GES did not predict benefit from immune checkpoint blockade. GES representing HRD and activation of HER2, EGFR and MAPK (each enriched in CIN) were associated with improved survival upon checkpoint blockade in advanced GEA patients. Clinical trial information: NCT02862535 . [Table: see text]

Primary cardiac sarcomas: A multi-national retrospective review.

BackgroundPrimary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort.MethodsClinical records of PCS across six institutions in three continents were reviewed. Kaplan‐Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression‐free survival (PFS) or overall survival (OS).ResultsSixty‐one patients with PCS (1996‐2016) were identified. The median age at diagnosis was 46 (range 18‐79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi‐modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5‐20.6), with seven (11%) patients surviving longer than 36 months. On multi‐variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first‐line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9‐7.7 months). The best response for first‐line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20‐year period of this review.ConclusionYounger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.

Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma.

We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We reviewed the medical records of 72 consecutive patients who had undergone ASCT for relapsed or refractory DLBCL at our institution from 2006 to 2014. Pretransplant conditioning consisted of HDC and total body irradiation. Of the 72 patients, 13 received post-transplant consolidative RT at the discretion of the consulted radiation oncologist. Consolidative RT was associated with significantly improved 2-year locoregional control (LRC) (92% vs. 68%; P= .04). However, no difference was seen in either the 2-year progression-free survival (PFS) (69% vs. 54%; P= .25) or overall survival (OS) (85% vs. 59%; P= .44). Analysis of the subgroup of 19 patients with persistent residual masses≥ 2 cm on post-transplant imaging demonstrated a significant improvement in LRC (100% vs. 36%; P< .01), PFS (88% vs. 27%; P= .01), and OS (100% vs. 45%; P=.02) with consolidative RT. The use of consolidative RT after HDC and ASCT for relapsed or refractory DLBCL appears to significantly improve LRC. For patients with masses≥ 2 cm after ASCT, improved 2-year PFS and OS were seen. Prospective trials are needed to further identify the patients who would derive the most benefit from consolidative RT in the ASCT setting.

Impact of intensity of post-treatment surveillance on survival in colorectal cancer.

10016 Background: The optimal strategy for CRC post-treatment surveillance is unknown. The frequency and type of testing remains controversial, and it is unclear whether surveillance impacts rates of detection or survival. The purpose of this study was to determine if the intensity of post-treatment surveillance is associated with time to recurrence detection, treatment, or overall survival (OS). Methods: Primary records of a random sample of 10,636 Stage I-III CRC patients from Commission on Cancer accredited hospitals (2006-2007) were abstracted, and detailed results of surveillance testing were reviewed. Data was merged with records in the National Cancer Database (NCDB). A predicted and observed number of imaging and CEA tests per patient were determined and clustered by hospital to categorize patients into high (HI, O/E ≥ 1) or low intensity (LI, O/E &lt; 1) categories. Results: 6,279 patients underwent imaging or CEA surveillance in the 3 years after CRC treatment. Patients with HI imaging (50.6%) or CEA (51.2%) had a mean of 2.9 imaging studies and 4.7 CEA tests. Patients with LI imaging underwent a mean of 1.4 imaging studies and 1.6 CEA tests. 5-year recurrence rates did not differ based on intensity of surveillance. Stage II and III patients who underwent HI imaging and CEA testing had a slightly higher resection rate, but this did not translate into an improvement in 5-year OS. Conclusions: High vs. low intensity surveillance was not associated with earlier detection of recurrent disease or improved OS. HI surveillance was associated with a slightly higher resection rate, but this did not result in a survival benefit. Our findings within a national hospital registry cohort failed to demonstrate a survival benefit of HI surveillance and suggest that an effective surveillance strategy may involve less frequent testing. [Table: see text]

Addition of Rituximab to Front-Line-Treatment Highly Improved the Outcome of Elderly Patients with Follicular Lymphoma: a Population Based-Study From the Modena Cancer Registry

AbstractAbstract 5077 Background:The benefit of adding Rituximab to combination chemotherapy in Follicular Lymphoma (FL) has been established in several randomized clinical trials (RCT). All of them have shown improvements in response rates, time to progression or overall survival (OS). The aim of the study was to assess the impact of the introduction of Rituximab in the treatment of FL in the general population of elderly patients, usually not included in RCT. Methods:All FL patients diagnosed in the province of Modena, Italy that had been diagnosed between 1997 and 2010 were identified from the archives of the Modena Cancer Registry that covers a population of approximately 600. 000 people. In the studied region Rituximab was available for first line treatment of FL since 2004. Therefore, for study purposes patients were grouped according to the year of diagnosis in 2 study periods (1997–2003, and 2004–2010). Elderly patients were defined using a cut off for age at 60 years. Clinical and treatment characteristics and also OS were compared according to the period of diagnosis and also, regarding the use or not of Rituximab as part of first line treatment. Moreover, a Cox regression analysis was performed to identify clinical factors and treatment characteristics associated with OS. Results:A total of 340 FL patients were identified of whom 177 (52%) were older than 60 years. No difference was found regarding clinical characteristics at diagnosis (age, gender, stage, bulky disease and LDH level) among study periods. Regarding treatment, no difference was found for the first general approach (watch and wait, chemotherapy or radiotherapy) across time. Among 229 patients initially treated with chemotherapy, antracyclines (ADM) or fludarabine (F)-based-regimens were the most frequently used. However, the use of ADM and/or F-based-regimens decreased from 82% (85/104) in the first period to 66% (83/125) in the last period (p=0. 03). Elderly patients (67%; 83/124) received less frequently ADM or F-based-regimens in comparison with younger patients (81%; 85/105) (P<0. 001). In contrast, the use of Rituximab alone or as part of front line treatment remarkably increased from 15% (16/104) in the first period to 94% (118/125) after 2003 (p<0. 001). This increase was also observed among elderly patients (8% (4/49) in the first period and 92% (69/75) in the last period, p<0. 001). After a median follow up of 68 months (range 8 to 176) for living patients, median OS was not reached. In univariate analysis factors associated with inferior OS were older age (>60), period of diagnosis before 2004, no use of Rituximab and abnormal LDH levels. The 5-years OS increased from 73% to 85% moving from first to second study periods (p=0. 008). In the Cox-Regression analysis, age > 60 (HR 11. 27 95%CI 5–25) and abnormal LDH level (HR 2. 7 95%CI 1. 56–4. 8) at diagnosis were identified as independent adverse risk factors. In contrast, the use of Rituximab yielded a protective effect (HR 0. 4 95%CI 0. 23–0. 79). In multivariate analysis period of diagnosis and use of Rituximab were mutually exclusive. Comparing young with elderly patients, only the latter group had a significant improvement in OS across the study periods: among the young, the 5-years OS in the first and second period was 89% and 98%, respectively, p= 0. 07; and among the elderly the 5-years OS in the first and second period was 58% and 72%, respectively p=0. 02. Conclusion:The present population based study showed a remarkable improvement in OS of FL patients after 2003, as a consequence of introduction of Rituximab as part of first line treatment. This improvement was mostly pronounced in the elderly population. Disclosures:No relevant conflicts of interest to declare.

Follicular Lymphoma: To Treat or Not to Treat Is No Longer the Question

Follicular lymphoma arises from germinal center B cells and is the most common indolent non-Hodgkin lymphoma (1). It has a widely variable clinical course but nearly always presents as advanced disease with asymptomatic lymphadenopathy and has a long median overall survival of 8-10 years or more (2). Treatment before the onset of symptoms or organ dysfunction related to disease progression has not been proven to improve disease-specific survival or overall survival (OS), although early treatment may result in higher complete response rates and may prevent prognos- tically significant histological progression (3,4). However, the introduction of rituximab as a therapy for this disease has changed the landscape of this debate (5). When treatment is indicated, a variety of combination chemotherapeutic regimens have proven efficacy, and although some result in improvements in progression- free (PFS) and event-free survival (EFS), none are superior with respect to OS. The addition of rituximab to these regimens, how- ever, has resulted in a statistically significant improvement in OS in this disease (6-9). Response rates to chemoimmunotherapy are high, but this disease remains, for the most part, incurable and will, with rare exception, relapse. Further attempts to improve PFS and OS have included maintenance therapy with rituximab or con- solidation high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) (10-15). In this issue of the Journal, Al Khabori et al. (16) report the results of a meta-analysis exploring the efficacy and toxicity of HDC-ASCT compared with conventional-dose chemotherapy or chemoimmunotherapy in patients with untreated, advanced-stage follicular lymphoma. Four studies, including 941 patients with a median follow-up of 5-9 years, were identified that met the eligibility criteria; and data regarding OS, EFS, treatment-related mortality, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and secondary malignancies were abstracted (12-15). Only one of these studies included rituximab in both arms (15). There was no difference in OS between HDC-ASCT and con- ventionally treated patients, but EFS was statistically significantly improved following HDC-ASCT compared with conventional treatment. Treatment-related mortality and the rates of sec- ondary solid tumor malignancies were not different between the two arms. The rate of MDS/AML was somewhat higher following HDC-ASCT, although the difference was not statisti- cally significant. In these prospective randomized controlled trials, the 4- to 7-year EFS and OS ranged from 38% to 61% and 76% to 84%, respectively, and were similar whether or not rituximab was part of the therapy in each arm. An EFS benefit despite the absence of an improvement in OS is not insignificant in a disease with a long clinical course, as time off therapy may have an important impact on personal productivity and quality of life. However, the lack of OS benefit seen following HDC-ASCT in untreated patients has often been attributed, in part, to an increased rate of sec- ondary MDS/AML and solid tumors, which have been reported to be as high as 16%-21% at 10 years following total body irradiation-containing regimens (17,18). The lower rate of both secondary MDS/AML (4%) and solid tumors (5%) following HDC-ASCT observed in this meta-analysis may be a reflection of conditioning regimens, as two of the four studies did not include total body irradiation, or it may reflect abbreviated follow-up. An investigation into the efficacy of HDC-ASCT in untreated follicular lymphoma is timely in light of the recent data showing the efficacy of maintenance rituximab in the ECOG1496 and PRIMA trials (10,11). The results of the studies included in this meta-analysis are similar to the 3-year PFS of 68%-75% seen in these two trials of maintenance rituximab. Given the risk of sec- ondary MDS/AML and solid tumors following HDC-ASCT and

Long-term follow-up of dose-dense neoadjuvant chemotherapy in patients with stage II/III breast cancer.

e11048 Background: Prior studies have shown that women with operable breast cancer had no improvement in disease free survival (DFS) or overall survival (OS) having received chemotherapy (AC) either pre or postoperatively. However, they were able to delineate a subset of women who had improvement in DFS and OS. Achieving a pathological complete remission (pCR) was directly proportional to DFS and OS. Dose dense adjuvant chemotherapy (ATC) has shown a statistically significant improvement in DFS and OS. Methods: We performed a single institution review of patients (pts) enrolled in a neoadjuvant trial who received dose dense neoadjuvant chemotherapy (doxorubicin 60mg/m2 IV Q2wks x4, paclitaxel 175mg/m2IV Q2wks x4 and cyclophosphamide 600 mg/m2 IV Q2wks x4) to asses response rates, safety and DFS. Women with newly diagnosed breast cancer T > 3cm, any N, and M0 were enrolled. Results: Since 2/2003, 48 pts were enrolled in a trial at UAB (mean age 48.7, range 28-64) and received dose dense chemotherapy. The median follow up is 67.9 months (range 8-88 months). Forty one pts completed dose dense chemotherapy and underwent surgery. Seventeen (41.4%) pts achieved a pCR in the breast and of those 14 (34%) pts were also pathologically negative in axillary lymph nodes. Ten of the 17 pts with pCR in the breast were triple negative. Nine pts have had disease relapse including one pt (HER2+) who had achieved a pCR. Two pts had febrile neutropenia, 2 pts had grade 3 anemia and none with grade 4 thrombocytopenia or anemia. Non hematological grade 3 or 4 toxicity included: venous thrombosis 3 pts, hyperglycemia 2 pts, syncope 1 pt, varicella zoster 1 pt and neuropathy in 2 pts. Conclusions: Our results show that dose dense neoadjuvant chemotherapy is effective, achieving high number of pCRs (breast and node) in triple negative and HER2+ breast cancer subtypes as opposed to hormone receptor positive cancers, with tolerable toxicity. Achieving a pCR is an important factor predicting the subsequent risk of relapse across all tumor types. Triple-negative HER2+ ER+ Total Number of cases (%) 17 (41) 6 (15) 18 (44) 41 (100) Breast pCR 10 (59) 5 (29) 2 (12) 17 (100) Breast/node pCR 8 (57) 4 (29) 2 (14) 14 (100) Relapses 4 2* 3 9 pCR in relapses None 1 None 1

Postoperative Chemoradiotherapy or Surgery Alone for Gastric Cancer: The Plausibility of the Question and Pertinence of the Answer

TO THEEDITOR:WereadwithgreatinterestthereportbyDikken etal 1 ontheroleofpostoperativechemoradiotherapy(CRT)ingastric cancer.Inthisretrospectivestudy,theauthorscomparedtheoutcome of patients treated with surgery only with that of patients treated with surgeryandadjuvantCRT.Althoughastatisticallysignificantdecrease in the rate of 2-year local recurrence was found in the CRT group (5% v17%), this difference did not translate into a significant benefit in progression-free survival or overall survival (OS). These disappointing results were confirmed in the subgroup analysis, in which— despite a better local control—no survival advantage could be detected for patients with CRT compared with patients who received surgery only, according to the extent of lymph node dissection (D1 v D2)andMaruyamaIndex.Onlythepresenceofmicroscopicresidual diseaseaftersurgerywasfoundtobeapredictorofsurvivaladvantage in CRT, with the significant decrease in rate of local recurrence observed in R1 patients translating into significant improvement in 2-year OS (66% v 29%). Although this study raises the controversial issue of the optimal strategy to use in resectable gastric cancer, we think that it has some important conceptual and methodologic limits that affect its appeal and strength. Thesignificantimprovementinprogression-freesurvivalandOS in resectable gastric cancer deriving from the addition of a multimodalitystrategy,includingpostoperativeCRTandperioperativechemo

Outcome of Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation in the Era of Novel Therapies.

Abstract 1865Poster Board I-890 Background:The incorporation of novel therapies, including thalidomide, bortezomib, and lenalidomide, in the treatment of multiple myeloma as induction, maintenance, or salvage therapy, along with autologous stem cell transplantation (ASCT) is expected to result in improved outcome. The impact of a single regimen or drug on Progression Free Survival (PFS) or overall survival (OS) is difficult to determine because, even within a single institution, these drugs and treatment modalities are used in varying sequences among patients. The goal of this retrospective analysis is to determine the PFS and OS of patients with multiple myeloma treated with ASCT at a single institution, in the era of novel therapeutic agents and to validate the significance of established prognostic factors. Methods:We performed a retrospective analysis of all patients with multiple myeloma who were eligible to undergo ASCT at MSKCC between 2000 and 2007 and received novel therapies including thalidomide, bortezomib, and lenalidomide during the course of their disease. During this period of time, 274 patients were transplanted and were analyzed for overall survival. Among them, a subset of 116 patients who received induction therapy, ASCT, and long term follow up at MSKCC, on whom baseline data and response analysis at all stages of disease was available, was used to analyze prognostic factors. Log-rank test was performed to assess the difference of OS and PFS among subgroups of patients stratified by baseline variables. A time-dependent Cox model was used to assess the effect of post treatment parameters on OS and PFS. Landmark analysis at 6 months after first ASCT was performed to assess the association between post-transplant response and survival endpoints. Results:For the entire study population of MM patients (n=274), with a median follow up of 4 years, the median OS measured from the time of transplant is 7 years [95% CI (6, not reached)]. For the subset of 116 patients treated exclusively at MSKCC, with a median follow up of 5 years, the median OS measured from initial treatment has not been reached and median PFS is 3 years =95% CI (2,4)] Using the subset of 116 patients treated exclusively at MSKCC, several baseline characteristics were analyzed as prognostic factors for OS and PFS including age =median age 57 (32 to 72)] gender =M 73, F 43] type of M-spike =IgGK 49, IgGL 21, FKLC 17, IgAK 13, FLLC 10, IgAL 5, IgMK 1] kappa to lambda ratio at diagnosis =Normal 15, Abnormal 75, Not available 26] ISS stage =I 50, II 49, III 16] and cytogenetic risk =standard 95, high 14, N/A 7] As reported by others, the type of monoclonal protein had a significant impact on OS (P = 0.02) with FKLC and IgAK having the worse prognosis. Other baseline characteristics including age, gender and K/L ratio did not influence OS and none affected the PFS. Several post treatment parameters were also analyzed including response to initial therapy =CR 15, nCR 18, VGPR 20, PR 42, SD 15, POD 5] response to ASCT =CR 73, VGPR 14, PR 29] response conversion =based on response before and after first ASCT: ≥VGPR - ≥ VGPR 51; < VGPR - ≥ VGPR 34, and < VGPR - < 0.0001, and P < 0.0001, respectively). Conclusion:This retrospective study confirms the marked improvement in OS for patients who undergo ASCT in the era of novel anti-myeloma therapies. It is difficult to ascribe this improvement to a specific regimen but rather probably to the abundance of successive options available to myeloma patients in the current era. Interestingly, we find no prognostic value to the response status to initial therapy or to ASCT for overall survival in contrast to PFS. Disclosures:Comenzo:Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Detecting an Overall Survival Benefit that Is Derived From Progression-Free Survival

Whether progression-free survival (PFS) or overall survival (OS) is the more appropriate endpoint in clinical trials of metastatic cancer is controversial. In some disease and treatment settings, an improvement in PFS does not result in an improved OS. We partitioned OS into two parts and expressed it as the sum of PFS and survival postprogression (SPP). We simulated randomized clinical trials with two arms that had respective medians for PFS of 6 and 9 months. We assumed no treatment difference in median SPP. We found the probability of a statistically significant benefit in OS for various median SPP and observed P values for PFS. We compared the sample sizes required for PFS vs OS for various median SPP. We compare our results with the literature regarding surrogacy of PFS for OS by use of the correlation between hazard ratios for PFS and OS. All statistical tests were two-sided. For a trial with observed P value for improvement in PFS of .001, there was a greater than 90% probability for statistical significance in OS if median SPP was 2 months but less than 20% if median SPP was 24 months. For a trial requiring 280 patients to detect a 3-month difference in PFS, 350 and 2440 patients, respectively, were required to have the same power for detecting a real difference in OS that is carried over from the 3-month benefit in PFS when the median SPP was 2 and 24 months. Addressing SPP is important in understanding treatment effects. For clinical trials with a PFS benefit, lack of statistical significance in OS does not imply lack of improvement in OS, especially for diseases with long median SPP. Although there may be no treatment effect on SPP, its variability so dilutes the OS comparison that statistical significance is likely lost. OS is a reasonable primary endpoint when median SPP is short but is too high a bar when median SPP is long, such as longer than 12 months.

Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer

e11566 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy (AC) either pre- or postoperatively; in the study there was no significant difference in disease free survival (DFS) or overall survival (OS) among patients in either group. Pathologic complete response rate (pCR) was directly proportional to DFS and OS. Dose dense adjuvant chemotherapy (ATC) has shown a statistically significant improvement in DFS and OS. Methods: We performed a single institution review of pts enrolled in a neoadjuvant trial and who received dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m2 IV Q2wks x4, paclitaxel 175 mg/m2 IV Q2wks x4, and cyclophosphamide 600 mg/m2 IV Q2wks x4) to assess response rates, safety, and DFS. Women with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were enrolled. Results: Since 02/2003, 43 pts were enrolled (mean age 47.6, range 28–64) and received dose dense chemotherapy. 41.4% of the pts were triple negative and 14.6% were Her2+ by FISH or IHC. The median follow-up is 49 months (range 8–69). Two patients dropped out without finishing therapy. Forty one pts completed dose dense chemotherapy and proceeded to surgery. 17 pts (41.4%) achieved a pCR in the breast and of those 14 pts were also negative in the axillary lymph nodes (34.1% pCR in the breast and lymph nodes). 10 of the 17 pts with pCR in the breast (8 out of the 14 pts with pCR in breast and axillary lymph nodes) were triple negative. 18 pts (43.9%) achieved PR, 3 pts (7.31%) had SD and 3 pts (7.31%) had PD. Up to November 2008, 7 pts who did not have a pCR have relapsed (4 triple negative, 1 Her2+, 1 ER/PR positive and 1 ER negative, PR positive) with a relapsed free survival rate of 85%. Hematologic toxicity consisted of grade 3 anemia in 2 patients with no grade 4 anemia, no G4 thrombocytopenia and febrile neutropenia in 2 pts. Non-hematologic grade 3 or 4 toxicity consisted of mediport thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and varicella zoster in 1 pt. Conclusions: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast + node) in about 1/3 of patients (34%) with tolerable toxicity; although the number of patients is limited, our data suggest that triple negative breast cancer seems to be the most sensitive tumor to this regimen. No significant financial relationships to disclose.

Low dose interferon-α2b (IFN) + thalidomide (T) in patients (pts) with previously untreated renal cell cancer (RCC). Improvement in progression-free survival (PFS) but not quality of life (QoL) or overall survival (OS). A phase III study of the Eastern Cooperative Oncology Group (E2898)

4516 Background: Both low dose IFN and T have anti-angiogenic properties (PNAS U S A. 1995 92:4562 & PNAS U S A. 1994 91:4082). We performed a randomized trial to assess the value of combining these two agents compared to low-dose IFN alone in RCC. Methods: Eligibility included no prior therapy, ECOG PS 0–2 and normal organ function. Treatment consisted of IFN 1 MIU SC BID alone or in combination with T (intra-pt dose escalation from 200 mg/day to 1,000 mg/day maximum). Patients were stratified according to prior nephrectomy, disease-free interval and ECOG performance status (PS). The study was designed to detect an improvement in PFS at 6 months of 35% compared to 20% in the std arm and was re-sized to detect a 50% improvement in median OS from 12 to 18 mos. Results: We enrolled 353 pts of whom 342 were eligible with a median age of 59 years (range 24–84) including 227M:115F with a median ECOG PS 1. 254 pts had undergone a prior nephrectomy and 236 had a disease-free interval of ≤1yr. Fatigue, myelosuppression and thrombotic events (12 vs 4) were greater in I+T arm. There was no difference in response rates or overall survival though progression-free survival was statistically significantly longer in the IFN+T arm (see table). QoL and fatigue scores were worse on the IFN+T arm. Conclusions: The addition of T to this IFN regimen modestly improves PFS but not OS and worsens QoL in RCC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Schering

Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets—men aged 44–57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease—showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 199 6 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 × 10 6 melanoma cells and 10 5.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10 5.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44–57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.