In the largest series of pancreatic cancer SBRT to date, dose-escalated tumor coverage specifically to 40 Gy (BED = 72 Gy) increases the likelihood of surgical resection in patients with upfront BRPC and is associated with improved PFS that is driven by improvement in loco-regional disease control for unresected patients. These data may help to inform the evolving landscape on the use of neoadjuvant and definitive radiotherapy in pancreatic cancer.

Purpose/Objective(s)We hypothesized that the addition of concurrent ipilimumab (IPI) with chemoradiotherapy followed by consolidative nivolumab (NIVO) would be safe and tolerable for patients with unresectable stage III non-small cell lung cancer (NSCLC). We report early outcomes and toxicity associated with this regimen in a phase I/II clinical trial.Materials/MethodsThe study was designed as a prospective, multicenter phase I/II trial. Eligible patients had ECOG 0-1 and unresectable stage III NSCLC. Therapy included a platinum-based chemotherapy doublet with concurrent radiotherapy to 60 Gy in 30 fractions over six weeks and two doses of concurrent IPI (1 mg/kg) given weeks 1 and 4. Maintenance NIVO was initiated 1-3 weeks after completion of chemoradiotherapy/IPI and given every 4 weeks (480 mg) for up to 12 cycles. The primary endpoints were to evaluate the safety and tolerability of the regimen (Phase I) and the 12-month PFS (Phase II). Treatment-related toxicity was assessed according to CTCAE v5.0. Time to event analysis was performed with Kaplan Meier (KM) and Cox proportional hazard (CPH) models. Results are reported with 95% confidence intervals (CI).ResultsNineteen of a planned 55 patients were enrolled in the trial which was discontinued without proceeding to the Phase II component due to exceeding the futility boundary for toxicity. The median follow-up was 21 months by the reverse KM method. The 12-month PFS estimate was 54% (CI 29-78) and the median PFS was 19 months (CI 6-not reached). The 12-month OS estimate was 60% (CI 36-84) while the median OS was not reached. Ten patients (53%, CI 29-76) experienced grade 2 or higher (G2+) pneumonitis. The median time to development of G2+ pneumonitis was 5.5 months and the risk of G2+ pneumonitis at 6- and 12-months was 57% (CI 30-84) and 74% (CI 49-99), respectively. Sixteen patients (84%, CI 68-100) had any G3+ treatment related toxicity. The most common G3+ toxicities were pulmonary (8 patients, 42%, CI 20-67) and cytopenias (7 patients, 37%, CI 16-62). Five patients (26%, CI 6-46) had possible treatment related G5 toxicity, including three patients with possible treatment related G5 pulmonary toxicity (16%, CI 0-32). There was no difference in the mean percent of lung volume receiving 20 Gy (V20) between those with and without G2+ pneumonitis (26%, CI 20-32 vs 21%, CI 16-27, P = 0.18), nor in the mean lung dose (14 Gy, CI 10-17 vs 15 Gy, CI 12-18, P = 0.35). Neither mean lung dose nor lung V20 were associated with time to G2+ pneumonitis on univariable CPH.ConclusionThe combination of concurrent IPI with standard chemoradiation followed by maintenance NIVO for unresectable stage III NSCLC is associated with significant toxicity which may limit opportunities for improved outcomes, although the sample size in this trial is small. Alternative strategies or sequencing should be explored to integrate immunotherapy with cytotoxic chemotherapy and radiation for patients with unresectable stage III NSCLC.

Nearly 50% of patients with colorectal cancer (CRC), one of the most common cancers worldwide, develop metastatic disease. Pre-clinical data suggest that ibrutinib, a BTK inhibitor used in several hematologic malignancies, may counteract the immune tumor escape mechanism in solid tumors. Pembrolizumab, a PD-1 checkpoint inhibitor, is effective in advanced CRC with microsatellite instability, but not microsatellite stable (MSS) disease. Given ibrutinib’s immune-modulatory function, it may display synergy with checkpoint inhibitors. Ibrutinib plus anti-PD-L1 or anti-CTLA-4 has shown enhanced efficacy in multiple cancers including MSS CRC, in various mouse models. This was a phase I/II study with standard 3+3 dose-escalating design in patients with advanced MSS CRC. Patients must have progressed through standard frontline therapies. Cohort 0 received 420mg ibrutinib PO daily and cohort 1 received 560mg ibrutinib PO daily. Both cohorts received 200mg IV pembrolizumab every 3 weeks. The primary endpoints for phase I were safety and establishment of a recommended phase II dose for ibrutinib. In the phase II portion, patients received ibrutinib at maximum tolerated dose (MTD) and 200mg IV pembrolizumab every 3 weeks. The primary endpoint of the phase II portion was disease control rate (DCR= CR + PR + SD) at 4 months. Patients were accrued according to a two-stage Minimax design. At least 1 of 18 patients must have achieved disease control at 4 months in the first stage to proceed to the second stage. In the second stage, at least 4 of 32 patients must have achieved disease control at 4 months for the therapy to be considered effective. Those who received more than one baseline scan were considered evaluable and up to 6 patients treated at MTD from phase I were allowed to count toward the evaluation of primary endpoints in the phase II portion. Eight patients in phase I (75% male, median age 60 years) and 30 patients in phase II received at least one treatment dose (53.3% male, median age 57 years). Median number of prior lines of systemic therapy was 3. In phase I, no dose-limiting toxicities (DLTs) were experienced in either cohort. MTD was 560mg ibrutinib daily and 200mg pembrolizumab every 3 weeks. In the phase II portion, a total of 28 patients (including 4 patients from phase I) were evaluable for primary endpoints. One of 18 patients in the first stage had stable disease at 4 months but no additional patients had disease control in the second stage for a DCR of 3.6% at 4 months and RR of 0%. Median OS was 5.32 months (95% CI: 3.35-8.41) and median PFS was 1.54 months (95% CI: 1.41-1.71). The most common grade 3/4 AEs overall were anemia (21.1%), increased alkaline phosphatase (7.9%), and fatigue (7.9%). Ibrutinib and pembrolizumab in combination appear to be well tolerated with no DLTs identified at MTD. However, low DCR does not warrant further study of this combination in advanced MSS CRC.

Patients with extensive stage small cell lung cancer (ES-SCLC) typically receive first line treatment with platinum doublet chemotherapy (CT). Consolidative thoracic radiotherapy (TRT) has also been shown to improve outcomes for patients with ES-SCLC. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve the 6 month progression free survival (PFS, primary endpoint) and 12 month overall survival (OS, secondary endpoint) for patients with ES-SCLC and stable disease or better after at least 4 cycles of platinum CT. This prospective single arm Phase I/II study enrolled 21 patients. Eligible patients demonstrated stable disease or better following platinum CT. Study therapy included consolidative TRT to a total dose of 30Gy in 10 fractions targeting any residual primary tumor and all initially involved regional lymph node stations. Two weeks after TRT, patients received concurrent IPI (3mg/kg) and NIVO (1mg/kg) every 3 weeks for 4 planned doses followed by NIVO monotherapy (480mg) every 4 weeks until progression or up to 1 year. Archival tissue from initial diagnosis (n=15) and peripheral blood (n=20) were collected at serial time points for research purposes. The study planned to enroll up to 52 patients but was discontinued early due to a planned interim analysis after 21 patients had enrolled. The initial 6 patient safety lead in demonstrated an acceptable toxicity profile with the study therapy. The 6 month (mo) PFS estimate was 24% (95% CI: 9%-43%). The median PFS estimate was 4.5 mo (95% CI: 2.7-4.6). The median PFS follow up for those patients who have not progressed is 11.1 mo. The 12 mo OS estimate was 47% (95% CI 25%-66%). The median OS estimate was 11.7 mo (95% CI: 4.7-16.0). The median OS follow up for patients who remain alive is 14.4 mo. 52% of patients had at least 1 grade 3 or higher immune related adverse event (IRAE) possibly or definitely attributable to study therapy. Grade 3 pulmonary and GI IRAEs possibly or definitely attributable to study therapy were recorded in 19.1% and 23.8% of patients respectively. The only grade 4 IRAE toxicity was thrombocytopenia. One patient died without progression at 4.6 mo due to lung aspergillosis infection secondary to steroid and infliximab therapy delivered for treatment of study related grade 3 diarrhea. Consolidative IPI and NIVO after platinum based CT and TRT demonstrated a toxicity profile consistent with the known AEs attributable to IPI and NIVO. The study regimen did not significantly improve the 6 mo PFS compared to historic estimates. The OS estimate at 1 year compares favorably with historic estimates. Biomarkers including tissue PD-L1 and estimation of tumor mutational burden, as well as flow cytometric characterization of the peripheral T cells and myeloid cells at baseline and during the treatment course will be presented.

Improved pathologic complete response with preoperative radiation dose escalation has been reported in locally advanced rectal cancer (LARC), but risk stratification to personalize radiation dose prescription has not been explored. We modeled genomic-based radiation dose-response utilizing the previously validated radiosensitivity index (RSI) and the clinically actionable genomic-adjusted radiation dose (GARD). We hypothesized that optimal therapeutic gain could be achieved in LARC stratified by genomic heterogeneity and RSI-based dose prescription (RxRSI). We assessed the patterns of pathologic response in a cohort of LARC patients treated with neoadjuvant chemoradiotherapy (NACRT) (cohort 1). Tumor regression grade (TRG) was analyzed for complete (TRG 0; pCR), favorable (TRG 1, moderate response), and poor (TRG 2 and 3) responders. We characterized the tumor genomics in a separate cohort of 113 rectal cancer tissue samples (cohort 2) to calculate tumor specific RSI, from which a tumor specific α was derived to generate GARD. RxRSI was modeled using the GARD threshold for which the percentile of RSI distribution mirrored the patterns of pathologic response in cohort 1. In cohort 1, the primary tumor stage was T3 (84%). The majority of patients (82%) received an RT dose of 50.4 Gy with concurrent 5-FU or Capecitabine. The rates of complete, favorable and poor responders were 21%, 53%, and 26%, respectively. The RSI of rectal cancer ranged from 0.19 to 0.81 in a bimodal distribution. A pCR rate of 21% would be achieved in tumors with RSI < 0.31 at a minimal GARD of 29.76 when modeling RxRSI to the commonly prescribed physical dose of 50.4 Gy. Modeling RxRSI dose escalation to 55 Gy in tumors with an RSI 0.31-0.34 would lead additional 10% tumors to achieve a pCR, whereas some radioresistant tumors would require much higher genomic-based dose to achieve pCR. For example, in our model, 105 Gy would be required for a tumor with an RSI of 0.57 to achieve a complete response. In regards to modeling RxRSI for a favorable response, tumors with RSI 0.32-0.51 would have TRG 1 in response to 50.4 Gy at a minimal GARD of 16.9. RxRSI dose escalation to 60 Gy could potentially bring 95% tumors (RSI <0.57) to a favorable response. We modeled personalized dose escalation in rectal cancer based on genomic expression profiling. This study could provide a theoretical platform for the development of an RxRSI-based prospective trial in rectal cancer. We anticipate individualizing radiation dose selection for each patient and optimizing patient selection for nonoperative management.

Radiation therapy, the most commonly utilized therapeutic agent in oncology, has not yet entered the era of precision medicine. We hypothesize that a patient specific molecular signature of radiation sensitivity, together with the canonical equations governing radiation response, can form the basis for precision medicine in radiation oncology. We used a clinically validated genomic radiation sensitivity index (RSI) to evaluate 8,271 primary tumors from 20 disease sites from a prospective observational trial. All tumor samples were arrayed on Affymetrix Hu-RSTA-2a520709. RSI was determined using the previously described rank-based algorithm. To make RSI comparisons we used an arbitrary RSI = 0.37 and the Fisher Exact test. The genomic adjusted radiation dose (GARD) is calculated using the linear quadratic model, the individual RSI, and the radiation dose/fractionation for each patient. The association between clinical outcome and GARD was evaluated in five separate RT-treated patient cohorts (breast n = 263, breast n = 77, pancreas n = 40, lung n = 60, and GBM n = 98) with multivariable Cox proportional hazards regression. In line with previous observations, we demonstrate disease-site is associated with radioresistance. For example, glioma, sarcoma, and melanoma had the highest (most resistant) RSI scores and overrepresented the radioresistant peak for the whole cohort (P < 0.0001). In contrast, cervical and oropharyngeal-head and neck cancer were radiosensitive (P < 0.001). However, within tumor types, we observe wide heterogeneity, highlighting the opportunity for precision radiation therapy. In a breast cancer cohort (n = 263), GARD is an independent predictor of outcome (HR = 2.11 [1.13, 3.94], P = 0.01). Backward elimination with candidate variables (ER/PR status, T stage, age, GARD, BED2.88 and RSI) demonstrated GARD (P = 0.008) was the only remaining significant variable in the model. To further validate GARD, we show that it is the strongest independent predictor of clinical outcome in four other independent cohorts, including breast cancer (relapse-free survival, HR = 7.4 [1.4, 138], P = 0.01), lung cancer (local control, HR = 1.9 [1.1-3.1], P = 0.02), GBM (overall survival, HR = 3.2 [1.5-6.9], P = 0.004 and pancreas cancer (overall survival, HR = 2.6 [1.1-6.0], P = 0.03). Finally, a GARD based model identifies sub-populations that derive differential benefit from RT, can be utilized to individualize radiation dose to account for tumor radiosensitivity and allows for genomic stratification in radiation-based clinical trials. GARD provides the first clinically actionable genomic biomarker to personalize radiation dose and provides a new paradigm for precision genomic radiation therapy.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches ( n =531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race ( P <0.0001) were more likely to find a donor. Younger age ( P =0.01), Caucasian race ( P =0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk ( P =0.005), and 8/8 HLA matching ( P =0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63–1.2), P =0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90–100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38–0.90, P =0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

In a consecutive series of unrelated donor searches conducted from March, 2006 through December, 2009 at Moffitt Cancer Center, we studied the following: (1) likelihood of finding a suitable (7-8/8) high-resolution matched unrelated donor; (2) factors associated with reaching transplant (HCT) among those with a donor; and (3) the effect of unrelated donor vs. no donor status on survival by intention to treat (ITT) analysis. Those with a fully HLA-A, -B, -C, and –DRB1 (8/8) matched or single locus (7/8) mismatched unrelated donor were defined as donor (n = 448), while those without were no donor (n = 83). Median time from search initiation to donor identification was 21 days; 95% of these values were within 59 days. While race/ethnicity (p<0.0001) and disease (p = 0.01) were associated with finding a donor, other variables (age, gender, CIBMTR risk, CMV, KPS, socio-economic status) were not. Among those with a donor, logistic regression modeling identified increasing age (p = 0.02), non-Caucasian race/ethnicity (p = 0.002), and high CIBMTR risk (p = 0.007) as associated with decreased odds for reaching HCT. Among 448 patients in the donor group, 239 underwent HCT. Of those in the no donor group, a total of 14 underwent double umbilical cord blood transplant (dUCBT). In the primary ITT analysis, we studied outcome according to donor vs. no donor status from time of search initiation using a time-dependent Cox model. Compared to no donor, donor status had reduced hazard for mortality (HR of 0.85, 95% CI 0.63 -1.2, p = 0.3). Accounting for interaction, those with KPS 90-100 and donor had significantly reduced hazard (HR 0.59, 95% CI 0.38 - 0.90, p = 0.02) compared to no donor. Secondary analyses examined outcome by treatment received: Those who received the intended HCT in the donor group had significantly reduced hazard (HR 0.64, 95% CI 0.46 – 0.89, p = 0.009) compared to no donor. In a separate analysis, donor, dUCBT, and no donor/no UCBT were treated as time-varying covariates, demonstrating significantly reduced hazard for donor vs. no donor (HR 0.57, 95% CI 0.43-0.76, p = 0.0001). No significant effect of matching (7/8 vs. 8/8) was detected in any analyses. In total, these data provide new insight into factors associated with unrelated donor identification according to high-resolution typing methods, identify factors relevant to reaching HCT among those with a suitable donor, and speak to the efficacy of unrelated donor HCT.

6607 Background: It is often not known if harms were considered in the overall benefit-risk evaluation in deciding about the superiority of treatments. Here we present a study examining the relationship between researchers’ conclusions about the superiority of treatment with quality of treatment-related harms reporting. Methods: We reviewed all consecutive phase III randomized clinical trials (RCTs) conducted by Southwest Oncology Group from 1960 to 2003 (117 RCTs involving 139 comparisons enrolling 58,908 patients). We extracted data on primary outcomes [overall survival (OS), event free survival (EFS)], and treatment-related mortality (TRM). We classified the quality of reporting as good, intermediate or poor. Association of superiority of treatment and harms reporting was evaluated using chi-square test and meta-analytic techniques. Results: 76% of studies (106/139) reported TRM. Of these, the quality of reporting of harms was considered as “good” in 36% (38/106) of studies, “intermediate” in 55% (58/106), and “poor” in 9% (10/106). Investigators judged experimental treatments to be superior in 34% of trials (48/139) while standard treatment was superior in 66% (91/139). TRM data was reported in 75% (36/48) of results favoring experimental treatments and 78% (70/91) of results favoring standard treatments. There was no association between superiority of a treatment and TRM reporting (p = 0.80) or quality of harms reporting (p = 0.83). The pooled hazard ratio (HR) for OS in RCTs reporting TRM was 0.94 (95% CI: 0.90, 0.99) and for RCTs not reporting TRM was 0.99 (95% CI: 0.89, 1.09) (test of heterogeneity p = 0.06). The pooled HR for EFS among RCTs reporting TRM was 0.88 (95% CI: 0.83, 0.94) and for RCTs not reporting TRM it was 1.01 (95% CI: 0.79, 1.29) (test of heterogeneity p = 0.07). Additionally, the pooled HR for OS and EFS did not show any bias in reporting of harms according to harms reporting quality. Conclusions: Investigators’ conclusion regarding the superiority of experimental or standard treatment does not appear to be associated with outcome reporting bias for harms. Investigators judge both harms and benefits when they draw conclusions about treatment superiority. No significant financial relationships to disclose.

8033 Background: RRM1 and ERCC1 mRNA and/or protein levels are molecular predictors of G and C efficacy. Prior studies had been performed under highly controlled conditions in tertiary referral centers. We prospectively assessed if RRM1 and ERCC1 protein levels are predictive of response in a community-based randomized phase III trial of GC vs G. Patients and Methods: 170 pts with NSCLC were enrolled from 3/04–12/06. All had IIIB/IV, PS 2, and no prior therapy. Routine diagnostic pretreatment tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression by an automated quantitative immunofluorescence-based technology (AQUA, HistoRx). Full section specimens were analyzed individually, and expression data were adjusted by using a standardized control TMA that was included in each analysis. Results: Tumor specimens were received from 91 pts. 69 were of sufficient quality for expression analysis (76% of specimens, 41% of all pts). These pts included 34 treated with GC, 35 with G; 34 women, 35 men; age 49–85 y; 5 stage IIIB, 64 stage IV; 43 adeno-, 13 squamous, 13 other cas. Adjusted RRM1 values ranged from 5.3- 105.6 (median 34.1). Adjusted ERCC1 values ranged from 10.4 -262.6 (median 69.4). RRM1 and ERCC1 expression levels were significantly correlated (p=0.001, r=0.39). They were marginally associated with pts’ age (p=0.05 and p=0.11). Neither was significantly associated with gender (p=0.73 and p=0.39) or histology (p=0.77 and p=0.91). RRM1 and ERCC1 protein values were significantly and inversely correlated with disease response (p=0.001, r=0.41 for RRM1; p=0.003, r=0.39 for ERCC1) in all pts; i.e., response was better for pts with low levels of expression. There was no significant interaction between either RRM1 or ERCC1 and best response by treatment arm. Conclusion: Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens from pts with advanced NSCLC is possible in most cases in a community setting. RRM1 and ERCC1 expression are predictive of response to G and GC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly, sanofi-aventis

MCL is an aggressive and incurable B-cell malignancy with an intrinsic characteristic to relapse after an initial good response to treatment. Manipulation of the immune system to unleash its well-known specificity and long-lasting protective effect might provide a unique opportunity to induce more durable responses in MCL. In previous studies in an A20 B-cell lymphoma murine model we have demonstrated that augmentation of the antigen-presenting cell function of the malignant B-cell is required for elicitation of an effective anti-lymphoma immunity1. Inhibition of Stat3 signaling, a negative regulator of inflammatory responses, and modulation of histone deacetylases function were identified as two novel targets to augment the immunogenicity of the malignant B-cell. In this study we determined therefore whether manipulation of these intracellular pathways in murine and human MCL cells could result in priming of antigen-specific T-cells and/or restoration of the responsiveness of tolerant T-cells. First, in vitro treatment of FC-muMCL1 cells - cell line derived from a MCL tumor that arise following pristine injection into Em-cyclin D1 transgenic mice- with increasing concentrations of the Stat3 inhibitors, Cucurbitacin I (CuI) or CPA-7 resulted in an enhanced presentation of OVA-peptide to naive CD4+ T-cells specific for a MHC class II restricted epitope of Ovalbumin (OT-II cells). Indeed, these antigen-specific T-cells produce higher levels of IL-2 and IFN-gamma compared to anti-OVA T cells that encountered cognate antigen in FC-muMCL1 cells treated with LPS alone. Similarly, we found that culture of the human MCL cells JEKO or Z138 with allogeneic human peripheral blood mononuclear cells in the presence of increasing concentrations of the Stat3 inhibitors also resulted in increased IL-2 production by T-cells. In the next set of experiments, we determined whether treatment of FC-muMCL1 cells with the hydroxamic acid analogue pan-HDAC inhibitor LAQ824 could influence their antigen-presenting capabilities and their ability to activate T-cell responses. Unlike, MCL cells treated with LPS alone, FC-muMCL1 cells treated with LPS and LAQ824 effectively prime antigen-specific CD4+ T-cells as determined by their production of both IL-2 and IFN-gamma in response to cognate peptide. Furthermore, in vitro treatment of Z138 MCL cells with LAQ824 also led to enhanced IFN-gamma production by allogeneic human PBMCs. Taken together, our findings points to inhibition of Stat3 signaling and inhibition of histone deacetylases as appealing molecularly based immunotherapeutic strategies to augment the immunogenicity of MCL cells.

You have accessJournal of UrologyDiscussed Poster, Sunday, May 22, 2005, 1:00 - 5:00 pm1 Apr 2005413: Androgen Tissue Levels in Recurrent Prostate Cancer using Liquid Chromatography Tandem Mass Spectrometry Mark Titus, Liguo Song, Michael Schell, Kenneth Tomer, and James Mohler Mark TitusMark Titus More articles by this author , Liguo SongLiguo Song More articles by this author , Michael SchellMichael Schell More articles by this author , Kenneth TomerKenneth Tomer More articles by this author , and James MohlerJames Mohler More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34666-4AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "413: Androgen Tissue Levels in Recurrent Prostate Cancer using Liquid Chromatography Tandem Mass Spectrometry." The Journal of Urology, 173(4S), p. 113 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 113 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Mark Titus More articles by this author Liguo Song More articles by this author Michael Schell More articles by this author Kenneth Tomer More articles by this author James Mohler More articles by this author Expand All Advertisement PDF DownloadLoading ...

Extensive-stage small cell lung cancer (ES-SCLC) remains a therapeutic challenge to the medical oncologists. We evaluated the triplet combination of paclitaxel (175 mg/m(2) over 1 h), ifosfamide (2.5 gm/m(2) over 1 h) and carboplatin (AUC=6 over 0.5 h) (PIC) all given on day 1 of a 21 day schedule. Thirty-five patients were entered with a median age of 59 years (range 40-79). The ECOG PS was 0-1 in 86%. A median of 6 cycles were delivered (range 1-6). The principal toxicity was neutropenia with 66% of patients experiencing grade 4 neutropenia. Only 9% of patients experienced febrile neutropenia. One treatment-related death (3%) due to neutropenic sepsis occurred. Non-hematologic toxicity was minimal. The overall response rate was 71% (15% complete response, 56% partial responses). Quality of life appeared to be stable across time. The median survival time was 9.5 months (95% confidence interval (CI), 6.7-13.2 months) with a 1- and 2-year survival rates of 43% (95% CI, 26-59%) and 16% (95% CI, 2-30%). PIC has activity in ES-SCLC and is associated with a response rate and survival profile similar to other combinations in this disease setting. This regimen has a tolerable toxicity profile and a favorable and convenient administration schedule.

We evaluated the performance of a regression model in predicting enrollment status in a chemoprevention trial for breast cancer using a population independent of that from which the model was derived. In years 1 and 2 of recruitment, questionnaires were completed by eligible participants following attendance at informational meetings about the Breast Cancer Prevention Trial. The variables in the original model, based on women recruited in year 1, included not being able to take estrogen replacement therapy (ERT), concern about the side effects of tamoxifen, the possibility of getting a placebo, the out-of-pocket expenses associated with the trial, and disagreement with the statement "significant others would be reassured if the respondent was taking tamoxifen." These variables were used to predict enrollment status of women newly recruited to the trial in year 2. Among the 89 women in the study population who responded to the questionnaire, 66% did not enroll in the trial. By applying the original logistic regression model, enrollment status in the trial was correctly predicted for 72% of year 2 questionnaire respondents. Age and risk scores, as binary variables, were used in a derived logistic model to determine whether they provided additional predictive information on enrollment status. The resulting four-factor model, which predicted nonenrollment, included: age of > or = 50 years, not being able to take ERT, expressed concern that significant others would not be reassured if the respondent was taking tamoxifen, and concern about out-of-pocket expenses associated with the trial. This model correctly classified 76% of the respondents. The logistic regression models performed reasonably well in predicting enrollment status. Not being able to take ERT remained the strongest factor predicting nonenrollment. More research is needed to evaluate factors that motivate persons to seek participation in primary chemoprevention trials in culturally diverse populations.