Summary of efficacy in the urothelial carcinoma and NSCLC cohorts

Summary of reductions in tumor size and durations of PFS or response. A, Best percentage change from baseline in target lesions (green bars) and PFS in responding patients (gray bars) in the urothelial carcinoma cohorts.aB, DOR in responding patients and change in tumor size over time in all patients in the urothelial carcinoma cohorts. C, Best percentage change from baseline in target lesions (green bars) and PFS in responding patients (gray bars) in the NSCLC cohorts. TMB high represents >10 mut/Mb. In urothelial carcinoma cohorts, PD-L1–positive status was defined using an algorithm that combines assessments of PD-L1 staining on tumor and immune cells, which were scored by pathologists (30); in NSCLC cohorts, PD-L1–positive status was defined as PD-L1 expression on ≥1% of tumor cells. PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; FGFR, fibroblast growth factor receptor. aTwo patients with no postbaseline tumor assessments who were receiving avelumab 1,200 mg were excluded.

AbstractPurpose: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non–small cell lung cancer (NSCLC). Materials and Methods: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). Results: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1–80.8) and 39.0% (24.2–55.5) in urothelial carcinoma, and 50.0% (11.8–88.2) and 33.3% (4.3–77.7) in NSCLC. Conclusions: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. Significance: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

BACKGROUND:Priapism is a very rare complication of malignancy and is usually accompanied by locally advanced or widely metastatic disease. We describe a case of priapism arising in a 46-year-old male with localised rectal cancer that was responding to therapy.CASE PRESENTATION:This patient had just completed two weeks of neoadjuvant, long-course chemoradiation when he presented with persistent painful penile erection. Assessment and diagnosis were delayed for more than 60 h, and although a cause could not be determined from imaging, a near complete radiological response of the primary rectal cancer was seen. His symptoms were refractory to urologic intervention and were associated with extreme psychological distress. He re-presented shortly thereafter with extensively metastatic disease in the lungs, liver, pelvis, scrotum, and penis; additionally, multiple venous thromboses were identified, including in the dorsal penile veins. His priapism was not reversible and was associated with a considerable symptom burden for the remainder of his life. His malignancy did not respond to first-line palliative chemotherapy or radiation, and his clinical course was further complicated by obstructive nephropathy, ileus, and genital skin breakdown with a suspected infection. We initiated comfort measures, and he ultimately died in hospital less than five months after his initial presentation.CONCLUSION:Priapism in cancer is usually related to tumour infiltration of the penis and corporal bodies resulting in poor venous and lymphatic drainage. The management is palliative and can include chemotherapy, radiation, surgical shunting, and potentially penectomy; however, conservative penis-sparing therapy may be reasonable in patients with limited life expectancy.

Background: Globally there is a move to adopt competency-based medical education (CBME) at all levels of the medical training system. Implementation of a complex intervention such as CBME represents a marked paradigm shift involving multiple stakeholders. Methods: This article aims to share tips, based on review of the available literature and the authors’ experiences, that may help educators implementing CBME to more easily navigate this major undertaking and avoid “black ice” pitfalls that educators may encounter. Results: Careful planning prior to, during and post implementation will help programs transition successfully to CBME. Involvement of key stakeholders, such as trainees, teaching faculty, residency training committee members, and the program administrator, prior to and throughout implementation of CBME is critical. Careful and selective choice of key design elements including Entrustable Professional Activities, assessments and appropriate use of direct observation will enhance successful uptake of CBME. Pilot testing may help engage faculty and learners and identify logistical issues that may hinder implementation. Academic advisors, use of curriculum maps, and identifying and leveraging local resources may help facilitate implementation. Planned evaluation of CBME is important to ensure choices made during the design and implementation of CBME result in the desired outcomes. Conclusion: Although the transition to CBME is challenging, successful implementation can be facilitated by careful design and strategic planning.

The post-graduate medical programs at Queen’s University transitioned to a competency-based medical education framework on July 1, 2017. In advance of this transition, the Medical Oncology program participated in a pilot of six Entrustable Professional Activities (EPAs) focused workplace-based assessment (WBA) tools with faculty and residents. The purpose of this sequential explanatory mixed method study was to determine the extent to which these WBAs provided quality feedback for residents. The WBAs were introduced into daily clinical practice and, once completed, were collected by the research team. A resident focus group (n = 4) and faculty interviews (n = 5) were also conducted. Focus group and interview data were analyzed using an emergent thematic analysis. Data from the completed assessment tools were analyzed using both descriptive statistics and a literature-informed framework developed to assess the quality of feedback. Six main findings emerged: Verbal feedback is preferred over written; providing both written and verbal feedback is important; effective feedback was seen as timely, specific, and actionable; the process was conceptualized as coaching rather than high stakes; there were logistical concerns about the WBAs, and additional clarification about the WBA tools is needed. This study provides insight into faculty and resident perceptions of quality feedback and the potential for WBA tools to assist in providing effective feedback to residents as we shift to competency-based medical education in Canada. Our results suggest the need for additional faculty development around the use of the tools, and their intended role, and the elements of quality feedback.

As part of a university-wide initiative, competency-based medical education (CBME) was implemented in the Medical Oncology training program at Queen’s University in July 2017. Stages, entrustable professional activities (EPAs), and required training experiences established by the Royal College of Physicians and Surgeons of Canada (RCPSC) national subspecialty committee were adopted. Entrada (Elentra), the electronic portfolio developed at Queen’s University, was used for assessment collection. Between July 2017 and December 2018, participating faculty members completed 157 assessments. Eighty-nine percent were EPA assessments with a median of 16 assessments per faculty member (range 1–40). Ninety-five percent of assessments included written “Comments” or “Next steps” with 56% of all assessments including specific or actionable feedback. Discussions between the program director, residents, program administrator, CBME education consultant, and CBME lead led to the identification of 9 lessons learned during implementation. These centered on (1) faculty and resident development and engagement; (2) sharing the work of CBME; (3) collaboration and communication; (4) global assessment; (5) assessment plan challenges; (6) burden of CBME; (7) limitations of e-portfolio; (8) importance of early tracking of resident progress; and (9) culture change. This article describes the experience of the authors and considers strategies that may be helpful to programs implementing CBME in their teaching and learning environment.

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du)+/- tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du +/- Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nabpaclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were <= grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly <= grade 2; the most frequent (occurring >= 10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatmentrelated deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI= 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI= 5.5-9.4 months) and 19.8 months (95 % CI= 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials.

BACKGROUND Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS We conducted a randomized, placebo‐controlled, double‐blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate‐to‐high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow‐up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS Of the 574 patients who underwent randomization, 563 were included in the modified intention‐to‐treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention‐to‐treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P=0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate‐to‐high‐risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol‐Myers Squibb–Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.)

PURPOSE: Timely lung cancer care has been associated with improved clinical outcomes and patient satisfaction. We identified improvement opportunities in lung cancer management pathways at Kingston Health Sciences Centre. Quality improvement strategies led to the implementation of a multidisciplinary lung cancer clinic (MDC). METHODS: We set an outcome measure of decreasing the time from diagnosis to first cancer treatment by 10 days within 6 months of clinic implementation. We implemented a weekly MDC that involved respirologists, medical oncologists, and radiation oncologists at which patients with new lung cancer diagnoses were offered concurrent oncology consultation. We used Plan-Do-Study-Act cycles to guide our improvement initiatives. A total of five Plan-Do-Study-Act cycles spanned 14 months and consisted of an MDC pilot clinic, large-scale MDC launching, debriefing meetings, and clinic expansion. Pre-MDC data were analyzed retrospectively to establish baseline and prospectively for improvement. Statistical Process Control XmR(i) charts were used to report data. RESULTS: Since MDC initiation, 128 patients have been seen in 34 MDC clinics (3.8 patients per clinic). Mean days from diagnosis to first oncology assessment decreased from 12.4 days to 3.9 days, and mean days from diagnosis to first cancer treatment decreased from 39.5 to 15.0 days, both of which demonstrated special cause variation. Time to assessment and treatment improved for patients with every stage of lung cancer and for both small-cell and non–small-cell subtypes. CONCLUSION: MDC shortens the time from lung cancer diagnosis to oncology assessment and treatment. Time to treatment improved more than time to oncology assessment, which suggests the improvement is related to benefits beyond faster oncology assessment.

10536 Background: This original research assesses Canadian Medical Oncology (MO) residents’ perceptions and satisfaction with their education and preparedness for practice prior to initiation of Competency Based Medical Education (CBME). Methods: Digital surveys were sent to MO residents in Canadian training institutions yearly from 2014–2017. Because of lower than expected response rates, invitations were subsequently extended to recent graduates completing training between 2009–2014. Ethics and funding were granted by Queen’s University. Results: A total of 71 surveys were received with representation from 11 training programs. Preparedness for Practice: Current trainees and recent graduates ranked preparedness for practice similarly in all assessment domains except Medical Expert (trainee mean 3.50, graduate mean 4.45, p=0.004; 1=not prepared, 5=well prepared). Means for the combined cohort shown in table. Usefulness of teaching modalities: Participants ranked learning in a clinical setting as most useful (6.53/8, 1=least useful, 8=most useful) and educational sessions by residents (4.24/8) and Journal Club (3.74/8) as least useful. Most participants felt their training was a shared learner-teacher responsibility (56.1%) or was learner-centered (22.5%). Quality of teaching: Participants reported similar levels of satisfaction with teaching across domains except for Manager which scored lowest (3.46/5, 1=poor, 5=excellent). Self-assessment of skills: Participants were most satisfied by their ability to assess their own performance and competence at the end of training (7.16/10, 1=not satisfied, 10= very satisfied). The degree to which their programs set expectations about required knowledge, skills, or attitudes at various points in training (6.63/10) and participants abilities to self-assess these skills during their training (6.64/10) scored lower. Conclusions: Participants reported low satisfaction with their ability to self-assess during their training and their training programs’ ability to communicate expectations. Transition to CBME training may address these issues, and follow-up is required.[Table: see text]

25 Background: NCRT followed by surgery per the CROSS trial regimen is an accepted standard of care in the treatment of EC and GEJC. When treatments are used in the real-world setting, there are often patient, treatment and potential outcome differences compared to the original clinical trial. The study aim was to assess the real-world application and outcomes of the CROSS trial protocol. Methods: A retrospective chart review was undertaken of 83 patients (pts) with EC or GEJC who were treated from June 2012 to June 2018 with CRT. 65 pts were with NCRT intent to proceed to surgery. Pts’ demographics, clinical, pathological, treatment and surgical characteristics were assessed and exploratory analyses were conducted to review these factors and outcomes. Analyses included Chi-square, t-tests and Kaplan-Meier. Results: For pts who underwent NCRT (n = 65): median age was 68 yrs (range 52-80), male 79%, adenocarcinoma 82%, median (m) tumor length 5 cm, GERD 43%, clinical stage II/III 95%, and BMI > 30 in 37%. 80% completed CRT with RT ≥ 41.4 Gy; of these 88% had ≥ 50.4 Gy. Delay/interruption in chemotherapy occurred in 46% and in RT 37%. Pts who underwent surgery were younger (p = 0.04) and weighed more (p = 0.05). mOS was 37 months (M) v 14 M in those who started CRT ≤ 8 weeks (w) from diagnosis v > 8 w (p = 0.10). The median time from CRT to surgery was 8.9 w. 40 pts had surgery with a complete response in 38% and a R0 resection in 98%. Postoperative major and minor complications occurred in 67%. Those < 75 yrs v ≥ 75 yrs had a mOS of 32 M v 15 M respectively (log rank p = 0.46). 25 pts did not get surgery; 28% was due to death/progression. Pts who proceeded to surgery had a mOS of 35 M v 12 M in pts who did not go to surgery (log rank p = 0.002). Further correlative outcome data will be presented. Conclusions: Real-world data in our center showed patient, tumor and treatment differences compared to the CROSS trial protocol. Despite the broadening of eligibility and treatment criteria, survival in a single institution setting is maintained with trimodality therapy compared to NCRT alone. Real-world data is of value in the assessment of therapeutic validity of clinical trial data.

BACKGROUND:Oncolytic reovirus pelareorep might preferentially infect and destroy rat sarcoma (RAS)-activated cells, and has preclinical and early clinical activity against colorectal cancer (CRC). PATIENTS AND METHODS:After a 6-patient safety run-in, 103 patients with metastatic CRC were randomly assigned to standard first-line leucovorin/5-FU/oxaliplatin (FOLFOX6)/bevacizumab (FOLFOX/BEV) every 2 weeks with (n = 51) or without (n = 52) pelareorep 3 × 1010 tissue culture infective dose 50 on days 1 to 5 (cycles 1, 2, 4, and alternate cycles thereafter). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life, and correlative analyses. RESULTS:At 13 months' median follow-up, PFS was inferior in the pelareorep arm (median 7 vs. 9 months; hazard ratio [HR], 1.59 [80% confidence interval (CI), 1.18-2.15]; P = .046). There was no statistical difference in OS (median, 19.2 vs. 20.1 months; HR, 1.22; P = .38). An increased ORR was observed with pelareorep (adjusted odds ratio, 2.52 [80% CI, 1.44-4.41]; P = .03), but with a shorter median duration of response (5 vs. 9 months; P = .028). Pelareorep patients experienced more hypertension and proteinuria, and were more likely to omit bevacizumab before progression. A trend to lower dose intensity and shorter oxaliplatin and bevacizumab treatment duration was observed with pelareorep. CONCLUSION:Combination pelareorep with FOLFOX/BEV was tolerable with an increased ORR, but PFS was inferior. Subgroup analysis of baseline variables including Kirsten rat sarcoma oncogene did not identify subgroups with PFS benefit. Decreased treatment intensity with standard agents likely contributed to the lack of benefit with pelareorep. Future studies might consider alternate pelareorep/chemotherapy strategies or combination therapy with novel agents.

3546 Background: Reo, a serotype 3 reovirus, may preferentially infect and destroy cells with RAS activation. This trial evaluated the progression-free survival (PFS) of untreated mCRC pts treated with FOLFOX6/bevacizumab (q2 weekly) alone or with Reo (3x1010TCID50 on day 1-5 [cycles 1, 2, 4, 6, 8 then alternate cycles]). Methods: The trial had 80% power to detect improvement in PFS from 8.5 to 15.5 mo [Hazard ratio (HR) 0.55, α = 0.1]. Primary analysis adjusted for stratification factors (prior adjuvant chemotherapy, KRAS status) with sensitivity analyses (SA) adjusted for additional prespecified factors (gender, age, baseline LDH and Alk Phos). Secondary endpoints included overall response rate (RR), quality of life (EORTC QLQ C30), overall survival (OS). Results: Following safety run-in of 6 pts, 103 pts were randomized to FOLFOX6/bevacizumab with (n = 51) or without (n = 52) Reo. Pt characteristics: median age 60 (range 31-79), male (61.2%), ECOG 0: 45.6%, 1: 50.5% and 2: 3.9%. At median follow-up 13 months, PFS was significantly shorter in the Reo arm [median 7.3 vs 9.1 mo, HR 1.59 (95% CI 1.00 - 2.53) p = 0.046; SA HR 1.65, p = 0.04]. RR was higher in Reo treated pts [52.9 vs 34.6%, OR 2.09 (95% CI 0.96-4.55), p = 0.06; SA p = 0.03], but with a shorter median duration of response (5.1 versus 8.5 mo, p = 0.028). In subgroup analysis female pts had higher RR and longer OS than male pts but test for interaction was significant only for RR. There was no significant difference in hepatectomy rate (Reo 7.8% vs 3.8%), median OS (p = 0.48), or relative dose intensity of FOLFOX6 or bevacizumab. Reo pts had worse QLQ C30 physical functioning (mean change score from baseline -3.9 vs. 1.94; p = 0.008). The most common adverse events (AEs) of any grade attributed to Reo were fatigue (51%), fever (49%), chills (44%), and anorexia (33%). With respect to grade 3+ AEs, pts on Reo experienced more hypertension (26.3 vs 3.8%, p = 0.001), more proteinuria (22.8 vs 1.9%, p = 0.001); and less abdominal pain (3.5 vs 17.3, p = 0.02) than the control arm. Conclusions: While the addition of Reo to FOLFOX6/bevacizumab increased RR; PFS, toxicity and QoL were significantly worse. Further follow-up of maturing OS data is planned. Clinical trial information: NCT01622543.

8046 Background: Selumetinib (AZD6244, ARRY-142886, S) is a potent inhibitor of MEK, with promising activity with docetaxel in pts with previously treated NSCLC. Non-clinical data suggest potential negative interaction with platin. We conducted a phase Ib study testing continuous or intermittent S with either cisplatin/pemetrexed (CPe; non-squamous) or carboplatin/paclitaxel (CPa) in previously untreated NSCLC. Methods: Pts received CPa (C AUC 6; Pa 200mg/ m2) or CPe (C 75mg/ m2 ; Pe 500mg/ m2) or for 4-6 21day cycles; single-agent S continued. A 3+ 3 design was used, dose levels (DL) were: DL1 50mg bid d2-19, DL2 75 mg bid d2-19, DL3 75 mg bid d1-21 (continuous) with an expansion cohort at RP2D. DLTs were assessed in cycle 1. Results: 30 pts were enrolled and 27 currently evaluable for adverse events (AE). In both cohorts, the most common S related toxicities were mild GI and skin. For CPa, 11 pts were treated, and no DLTs were seen at any DL. CPa related AEs were as expected. 2 pts had dose reductions of S (1 each of fatigue, skin toxicity). Most AEs related to S were grade (G) 1-2 and included gastrointestinal and skin. 4 pts had ≥ G3 AEs considered related to S (includes 1 pt with fatal lung infection also related to CPa and 1 pt with fatal stroke also related to disease & CPa). 2 pts had G3 neutropenia; 1 pt had G4 thrombocytopenia; 1 pt had G3 LFTs. For CPe, 16 pts are currently evaluable; 2 possible DLTs were seen at the continuous DL (vomiting but inadequate antiemetics). Expansion to that DL ongoing. CPe related AEs were as expected. 3 pts had dose reductions of S (1 each of CPK, fatigue, dehydration). 3 additional pts had G3 AE (retinal vascular disorder, thromboembolism, diarrhea/dehydration/ hypertension) related to S. There were no S related G5 events. There were no G4 hematologic toxicities. One pt had a G3 increase in CPK. Conclusions: S can be given in combination with CPe or CPa at full single agent doses, with generally mild incremental GI and skin toxicity. Patients continue to be enrolled to the RP2D expansion cohorts at a dose of 75 mg bid d1-21. NCIC CTG plans further P2 studies of CPe with S in NSCLC. Clinical trial information: NCT01783197.

3602 Background: The CO.17 trial demonstrated that the addition of cetuximab monotherapy (C) to best supportive care (BSC) improves OS and progression-free survival (PFS) in patients (pts) with ACRC. We compared tumour measurement as a continuous variable and visualized by waterfall plot vs. categorized as response based on RECIST as potential early predictors of OS benefit.METHODSOf the 572 randomized, 216 pts on C and 142 on BSC had tumor assessment at baseline and 8 weeks and are included in this analysis. Response at 8 weeks was assessed using standard RECIST criteria and categorised as partial response, stable disease or progressive disease. Continuous tumour size measurement was also assessed using waterfall plot, The absolute difference in logarithm transformed sum of the longest tumor diameters (LSLD) between 8 weeks and baseline were calculated for the entire group and the KRAS wild-type (WT) and mutant (MUT) subgroups and correlated with OS in a multivariate analysis including difference in LSLD, RECIST response and other prognostic factors as covariates.RESULTSThe increase of tumor size (cm) from baseline of pts treated by C was significantly smaller than those that received BSC (mean difference in LSLD 0.02 vs. 0.23; p < 0.0001), and this remained significant after adjusting for baseline prognostic factors (p<0.0001). In a multivariate analysis of pts treated by C, difference in LSLD was significantly associated with OS (HR 14.84, per ln(cm) of increase, 95% CI 4.31 to 51.08; p<0.0001), whilst RECIST defined response was not. Results were similar for WT pts: HR 14.30 per ln(cm) of increase in LSLD, 95% CI 1.32 to 96.5; p=0.03. For MUT pts, neither change in LSLD nor RECIST response was associated with OS.CONCLUSIONSChange of tumor size at 8 weeks following commencement of C using a waterfall plot analysis was a better predictor of OS than standard RECIST categories. This may be a better early signal of treatment efficacy for molecular targeted therapies in ACRC.

BACKGROUND:Blood levels of the extracellular domain of HER-2/neu (ECD/HER2) have been suggested to have potential as a tumor marker in breast cancer. Our aim was to assess the prognostic value of baseline levels of ECD/HER2, but more importantly changes in levels over time, in women with metastatic breast cancer.METHODS:Baseline and serial levels of ECD/HER2 were measured in 158 women with newly-diagnosed metastatic breast cancer, in whom we previously performed serial measurement of plasma osteopontin. ECD/HER2 was measured in 1,282 serum samples using a validated ELISA at baseline and every 3-12 weeks during and after therapy until death (median, n=8 samples per patient). Multivariate time-dependent survival analyses were conducted using models that right-censored patient outcomes 3, 6 and 12 months after last known ECD/HER2 measurement.RESULTS:Thirty-four patients (22%) had elevated baseline ECD/HER2 (median 10.2 ng/ml: range 4.1-40.4 ng/ml). In univariate analysis, elevated baseline ECD/HER2 was associated with short survival (P=0.001). In a multivariate model incorporating standard clinical prognostic factors, baseline ECD/HER2 was significantly associated with survival duration (RR 1.029; P=0.020). Presence of visceral metastases and ECOG status 2-4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential ECD/HER2 levels, an ECD/HER2 increase of >12 ng/ml at any time was the variable with most prognostic value for poor survival (RR 6.10; P=0.0003); poor ECOG status also retained significance.CONCLUSION:Increases over time of ECD/HER2 levels were strongly associated with poor survival in this cohort of women with metastatic breast cancer.

PURPOSE:Osteopontin is a malignancy-associated protein measurable in blood and tumor tissue. To evaluate its prognostic value in advanced disease, we conducted a prospective clinical study measuring serial osteopontin plasma levels in women with metastatic breast cancer throughout the course of their disease.EXPERIMENTAL DESIGN:One hundred fifty-eight women with newly diagnosed metastatic breast cancer were enrolled in the study. Plasma osteopontin was measured using our validated ELISA, at baseline and every 3 to 12 weeks during and after therapy until death. Multivariate time-dependent survival analyses were conducted using models that right censored patient outcomes 3, 6, and 12 months after the last known osteopontin measurement.RESULTS:Osteopontin was measured in 1,378 samples (median, 9 per patient). Ninety-nine patients had elevated baseline osteopontin (median, 177 ng/mL; range, 1-2,648 ng/mL). In univariate analysis, elevated baseline osteopontin was associated with short survival (P = 0.02). In a multivariate model incorporating standard prognostic factors, baseline osteopontin was significantly associated with survival duration (relative risk, 1.001; P = 0.038). Metastasis-free interval, visceral metastases, and Eastern Cooperative Oncology Group status 2 to 4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential osteopontin levels, an osteopontin increase of >250 ng/mL at any time was the variable with the most prognostic value for poor survival (relative risk, 3.26; P = 0.0003), and poor Eastern Cooperative Oncology Group status also retained significance.CONCLUSIONS:This is the first study to show that in women with metastatic breast cancer, increases in osteopontin levels over time are strongly associated with poor survival. Sequential monitoring of osteopontin may have use in making treatment decisions for these patients.

PURPOSE:To look for survival differences between men and women with limited stage small cell lung cancer (LS-SCLC) by examining stratified variables that impair treatment efficacy.METHODS:A retrospective review of 215 LS-SCLC patients treated from 1989 to 1999 with concurrent chemotherapy-radiotherapy modelled on the 'early-start' thoracic radiotherapy arm of a National Cancer Institute of Canada randomized trial.RESULTS:Of 215 LS-SCLC patients, 126 (58.6%) were men and 89 (41.4%) were women. Smoking status during treatment for 186 patients (86.5%) was: 107 (58%) nonsmoking (NS) (76 [71%] male [M]; 31 [29%] female [F]) and 79 (42%) smoking (S) (36 M [46%]; 43 F [54%]) (continuing-to-smoke F versus M, P=0.001). Fifty-six patients (26%) had radiotherapy interruptions (RTI) during chemotherapy-radiotherapy because of toxicity. Radiotherapy breaks were not associated with sex (P=0.95). Survival by sex and smoking status at two years was: F + NS = 38.7%; F + S = 21.6%; M + NS = 22.9%; and M + S = 9.1% (P=0.0046). Survival by sex and RTI status at two years was: F + no RTI = 32.4%; F + RTI = 23.6%; M + no RTI = 23.0%; and M + RTI = 3.8% (P=0.0025). Diffusion capacity for carbon monoxide (DLCO) was recorded for 86 patients (40%) and median survival by sex and DLCO was F = 16.7 months and M = 12.1 months for a DLCO less than 60%; and for a DLCO 60% or more, F = 15.1 months and M = 15.3 months. First relapses were recorded in 132 cases (61%), with chest failure in men (45%) greater than for women (35%) and cranial failure rates similar between sexes (48%). Upon multivariable analysis, continued smoking was the strongest negative factor affecting survival.CONCLUSIONS:In LS-SCLC, women overall do better than men, with or without a negative variable. The largest quantifiable improvement in survival for women came from smoking cessation, and for men from avoidance of breaks during treatment.

Purpose: To determine the impact of continued smoking by patients receiving chemotherapy (CHT) and radiotherapy (RT) for limited-stage small-cell lung cancer (LSCLC) on toxicity and survival. Patients and Methods: A retrospective review was carried out on 215 patients with LSCLC treated between 1989 and 1999. Treatment consisted of six cycles of alternating cyclophosphamide, doxorubicin, vincristine and etoposide, cisplatin (EP). Thoracic RT was concurrent with EP (cycle 2 or 3) only. Patients were known smokers, with their smoking status recorded at the start of chemoradiotherapy (CHT/RT). RT interruption during concurrent CHT/RT was used as the marker for treatment toxicity. Results: Of 215 patients, smoking status was recorded for 186 patients (86.5%), with 79 (42%) continuing to smoke and 107 (58%) abstaining during CHT/RT. RT interruptions were recorded in 38 patients (20.5%), with a median duration of 5 days (range, 1 to 18 days). Median survival for former smokers was greater than for continuing smokers (18 v 13.6 months), with 5-year actuarial overall survival of 8.9% versus 4%, respectively (log-rank P .0017). Proportion of noncancer deaths was comparable between the two cohorts. Continuing smokers did not have a greater incidence of toxicity-related treatment breaks (P .49), but those who continued to smoke and also experienced a treatment break had the poorest overall survival (median, 13.4 months; log-rank P .0014). Conclusion: LSCLC patients who continue to smoke during CHT/RT have poorer survival rates than those who do not. Smoking did not have an impact on the rate of treatment interruptions attributed to toxicity. J Clin Oncol 21:1544-1549. © 2003 by American Society of Clinical Oncology.