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Background: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. Methods: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. Findings: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23–31) greater accuracy than that of conventional imaging (92% [88–95] vs 65% [60–69]; p

Aims This multicenter phase II trial evaluates the efficacy of everolimus in poor prognosis grade 2 (G2) pancreatic neuroendocrine tumors (PNETs), defined by 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) avidity. FDG-PET avidity in NETs is associated with a significantly higher risk of death, outperforming Ki-67 index or liver metastases as a poor prognostic factor. We hypothesized that everolimus has efficacy in patients with FDG-PET-avid G2 PNETs and prospectively evaluated progression-free survival (PFS) and response in the first-line setting. Methods Patients with FDG-PET-avid G2 advanced PNET received everolimus 10 mg daily until disease progression. Patients were staged every 12 weeks with CT/MRI and FDG-PET and every 24 weeks with Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) PET. The primary endpoint was PFS at 6 months. Overall survival rate, PET/structural imaging response and toxicity were also measured. Results Nine patients were accrued from December 2012 to February 2015. Median treatment duration was 13.8 months. The estimated PFS rate at 6 months was 78%. The best response on CT/MRI was stable disease in nine patients (100%) and partial response on FDG-PET in five patients (55.5%). Treatment-related adverse effects were consistent with previous studies of everolimus. Conclusion Everolimus is active with prolonged disease control in poor prognosis FDG-avid G2 PNETs. Treatment individualization based on functional imaging warrants further evaluation.

Purpose: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. Materials and methods: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/− TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. Results: 1608 women were enrolled from 11 countries between 2007 and 2014. 85–90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). Conclusions: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-04.

Summary Objective Diaphragmatic herniation is a rare complication following esophagectomy, associated with risks of aspiration pneumonia, bowel obstruction, and strangulation. Repair can be challenging due to the presence of the gastric conduit. We performed this systematic review and meta-analysis to determine the incidence and risk factors associated with diaphragmatic herniation following esophagectomy, the timing and mode of presentation, and outcomes of repair. Methods A systematic search using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was performed using four major databases. A meta-analysis of diaphragmatic herniation incidence following esophagectomies with a minimally invasive abdominal (MIA) approach compared with open esophagectomies was conducted. Qualitative analysis was performed for tumor location, associated symptoms, time to presentation, and outcomes of postdiaphragmatic herniation repair. Results This systematic review consisted of 17,052 patients from 32 studies. The risk of diaphragmatic herniation was 2.74 times higher in MIA esophagectomy compared with open esophagectomy, with pooled incidence of 6.0% versus 3.2%, respectively. Diaphragmatic herniation was more commonly seen following surgery for distal esophageal tumors. Majority of patients (64%) were symptomatic at diagnosis. Presentation within 30 days of operation occurred in 21% of cases and is twice as likely to require emergent repair with increased surgical morbidity. Early diaphragmatic herniation recurrence and cardiorespiratory complications are common sequelae following hernia repair. Conclusions In the era of MIA esophagectomy, one has to be cognizant of the increased risk of diaphragmatic herniation and its sequelae. Failure to recognize early diaphragmatic herniation can result in catastrophic consequences. Increased vigilance and decreased threshold for imaging during this period is warranted.

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. Significance: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies. This article is highlighted in the In This Issue feature, p. 983

Background: MYB is a transcription factor that is overexpressed in colorectal cancer (CRC) and also a driver mutation in adenoid cystic carcinoma (AdCC). Therefore, the MYB protein is an ideal target to vaccinate against to aid recruitment of tumour infiltrating lymphocytes (TILs) against these tumours. The Peter MacCallum Cancer Centre (Melbourne, Australia) has engineered a DNA vaccine, TetMYB, based on the pVAX1 plasmid vector carrying a fusion construct consisting of the universal tetanus toxin T-cell epitopes flanking an inactivated MYB gene. Methods: This prospective first-in-human phase I single-arm multi-centre clinical trial involves patients with metastatic CRC or AdCC. Stage 1 will evaluate the safety profile of escalating doses of TetMYB vaccine, given sequentially and in combination with an anti-PD-1 inhibitory antibody, to determine the maximum tolerated dose (MTD). Stage 2 will assess the MTD in an expanded cohort. The calculated sample size is 32 patients: 12 in Stage 1 and 20 in Stage 2. The expected total duration of the trial is 3 years with 15 months of recruitment followed by a minimum of 18 months follow-up. Discussion: MYB transcription factor is aberrantly overexpressed in a range of epithelial cancers, not limited to the above tumour types. Based on promising pre-clinical data of vaccine-induced tumour clearance and establishment of anti-tumour memory, we are embarking on this first-in-human trial. If successful, the results from this trial will allow progression to a Phase II trial and validation of this breakthrough immunotherapeutic approach, not only in CRC and AdCC, but other MYB over-expressing cancers. Trial registration: ClinicalTrials.gov ID: NCT03287427. Registered: September 19, 2017. Keywords: Colorectal neoplasms, Adenoid cystic carcinoma, Glandular and epithelial neoplasms, Cancer vaccine, Immunotherapy, Immune checkpoint therapy

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.

SUMMARY Oral contrast studies are used to detect anastomotic leak (AL) postesophagectomy. However, recent evidence suggests oral contrast studies have low sensitivity in detecting ALs, and their false positive results can lead to unnecessary prolonged hospital stay. The objective of this study was to determine if oral contrast studies should be used routinely post-esophagectomy for cancer. A systematic literature search was conducted for studies published between January 1990 and June 2018. Data extracted for analyses included type of esophagectomy, operative morbidity (such as AL and pneumonia), mortality rates, timing of contrast study, and type of oral contrast used. The sensitivity, specificity, and positive and negative predictive values of routine oral contrast studies to detect AL were calculated using the aforementioned variables. Two hundred and forty-seven studies were reviewed with 16 studies included in the meta-analysis. Postoperative oral contrast study was performed in 94.0% of cases between day 5 and 7. The rates of early and delayed leaks were 2.4% (1.8%–3.3%) and 2.8% (1.8%–4.4%), respectively. Routine contrast studies have a sensitivity and specificity of 0.44 (0.32–0.57) and 0.98 (0.95–0.99), respectively. Analysis of covariates revealed that sensitivity is reduced in centers with a higher volume of cases (greater than 15 per year: 0.50 [0.34–0.75; p = 0.0008]) and specificity was higher in centers with a lower leak rate. Given its poor sensitivity and inability to detect early/delayed AL, oral contrast study should be used selectively with endoscopy and/or computerized tomography scan to assess surgical anastomoses following esophagectomy.

4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.

485 Background: In patients (pts) with muscle invasive bladder (MIBC) suitable for curative definitive chemoradiotherapy (CRT), we hypothesise that the addition of pembrolizumab may be safe and improve efficacy. A pre-planned safety analysis was performed after the first 10 of planned 30 pts were enrolled and completed treatment. Methods: Patients with maximally resected non-metastatic MIBC and ECOG 0-1, who desire bladder preservation or are ineligible for cystectomy were treated with 64Gy in 32 daily radiation fractions to the whole bladder alone over 6.5 weeks in combination with 6 concurrent doses of weekly cisplatin at 35mg/m2 IV. Pembrolizumab was commenced concurrently with radiation and given flat-dose 200mg IV q21 days for 7 doses. Surveillance cystoscopy, urine cytology and CT chest-abdomen-pelvis were performed 12 & 24 weeks post CRT. The primary endpoint is feasibility, defined by a satisfactory low rate of unacceptable toxicity of a) G3-4 non-urinary adverse events (AE) or b) failure of completion of planned CRT according to defined parameters. Secondary endpoints include complete cystoscopic response without metastatic disease at 12 & 24 weeks, loco-regional PFS, metastatic DFS, and overall survival. A 2-stage design was planned, with accrual to be halted if >5 of the first 10 pts experienced unacceptable toxicity up to 12 weeks post treatment. Results: All 10 pts completed the course of CRT and pembrolizumab without alteration in radiation dose or schedule. 1 patient had a dose of cisplatin withheld. 4/10 pts experienced G3-4 non-urinary adverse events within 12 weeks of completing treatment. One immune related AE interrupted pembrolizumab delivery (G2 nephritis). By week 24, 9/10 pts achieved a complete cystoscopic response to treatment post CRT and were free of distant metastatic disease. Conclusions: Interim results indicate that pembrolizumab and CRT shows satisfactory safety, and promising efficacy. There were no unexpected safety signals. Follow up of these and additional pts will better define the efficacy and safety of the combination. Enrolment is ongoing with 20 pts recruited out of a planned total of 30. Clinical trial information: NCT02662062.

5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK)/pharmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies. Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0–2, and adequate organ function, were eligible. Patients had blood samples taken at t = 0, mid infusion (if feasible) then 2 h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated. Twenty patients (12 male; 8 female), median age 62, (range 37–71) had samples taken. Twenty (100%) feasibility forms were available for assessment. Blood samples were taken at 51/69 (74%) specified time points. Ease of sample processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood samples analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1 g/m2 with platinum: 35.8 h mg/L (range 28.56–44.26), mean Css 372.2 µg/L (range 297.5–461.0); 5FU 600 mg/m2 with platinum: 12.42 h mg/L (range 6.91–18.29), mean Css 111.0 µg/L (72.0–190.5) and 5FU 2400 mg/m2 as part of FOLFOX ± bevacizumab: 14.75 h mg/L (range 6.74–22.93), mean Css 320.70 µg/L (range 146.5–498.5). One patient had grade 4 neutropenia and one patient without PK parameters experienced febrile neutropenia (grade 4 neutropenia). Mucositis was observed in two patients: [5FU/platinum (1), grade 1, FOXFOX ± bevacizumab (1) grade 1]. Diarrhoea was reported in three patients [5FU/platinum (2) grade 1–2, FOXFOX ± bevacizumab (1) grade 1]. Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m(2) ; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m(2) ; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m(2) ) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched-analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24-0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35-0.72, P = 0.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy.

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 μg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.

Objectives/Hypothesis Immunosuppression in organ transplant recipients increases the incidence and aggressiveness of cutaneous squamous cell carcinoma. However, there are little clinical data on cutaneous squamous cell carcinoma in patients with immunosuppression due to chronic lymphocytic leukemia. In this study we evaluated the clinical features, patterns of recurrence, and outcomes of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. Study Design Retrospective cohort study. Methods A review was performed of 42 consecutive patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia presenting to our institution between July 2000 and July 2010. Baseline characteristics, treatment details, and outcomes were analyzed. Results Thirty-four patients presented with primary cutaneous squamous cell carcinoma (33 node negative, 1 node positive), and eight patients presented with nodal disease without a simultaneous index primary. The 2-year cumulative incidence of local recurrence for primary cutaneous squamous cell carcinoma was 15%. Nodal recurrence occurred in 36% of node-negative patients. The 3-year overall and cause-specific survival rate for all patients was 37% and 65%, respectively. In patients managed curatively for nodal disease at presentation or relapse (n = 17), the 3-year overall and cause-specific survival rate was 21% and 53%, respectively. Conclusions Patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia experience higher rates of skin cancer recurrence and death than expected in an immunocompetent population. Novel strategies are needed to improve outcomes. Level of Evidence 4. Laryngoscope, 124:2043–2048, 2014

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Despite successful treatments for primary UM, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Treatment options are limited after development of hepatic metastasis, and the median survival of patients is reported to be 6 to 12 months. Immune-checkpoint blockades have not proved effective in the management of metastatic UM. We have conducted a phase 2 clinical trial using 90Y resin microspheres (radiosphere) (SIR-Spheres, Sirtex Medical) for uveal melanoma patients with liver-dominant metastasis [NCT NCT01473004]. In this clinical trial, patients with liver dominant metastasis were enrolled to arm A (n=24): no previously liver-direct treatment, and arm B (n=23): second line treatment after failing immunoembolization (IE). Blood samples were collected and processed before therapy (baseline), 1 hour after completion of therapy, at 1 month, and 3 months after therapy. Serum levels of cytokines and chemokines were analyzed by Bead-based Multiplex assay using the Luminex technology (MilliporeSigma). All of the samples were tested using a panel of 11 cytokines: interleukin (IL)-10, IL-1 beta, IL-6, IL-8, IP-10, MCP-1, TNF-alpha, TGF-beta1, CXCL9, HMGB-1, and HGF by Luminex FLEXMAP 3D. IL-8 levels were increased at 1 and 3 months after radiosphere (RE) treatment in both arms compared to baseline (paired T-test, P Citation Format: Mizue Terai, Emma Link, Carin F. Gonsalves, David J. Eschelman, Rober D. Adamo, Meggie Danielson, Marlana M. Orloff, Takami Sato. Cytokines and chemokines production after radiosphere treatment for uveal melanoma patients with hepatic metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4052.

TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.

Background Previous studies have suggested that patients with occult peritoneal metastases not seen on preoperative imaging have poor prognosis. In this study, we aim to evaluate the utility and impact of staging laparoscopy and peritoneal cytology in patients with gastric adenocarcinoma. Methods A retrospective analysis of patients with gastric adenocarcinoma managed at two major metropolitan hospitals in Melbourne, Australia, between January 1999 and July 2010 was undertaken. The main outcome measures were the number of patients in whom laparoscopy and/or peritoneal cytology changed treatment intent, and the overall survival of patients with occult metastases detected by laparoscopy/cytology. Results Staging laparoscopy as an independent procedure was performed in 74.3% (148/199) of patients who had neither unequivocal metastases (M1) on preoperative imaging nor early T1 disease on endoscopic ultrasound. Laparoscopy/cytology detected occult metastases in 38 (25.6%) patients (27 macroscopic M1 and 11 microscopic M1 with positive peritoneal cytology only), leading to change in the treatment intent in 37 cases. The median overall survivals of patients with metastatic disease detected at staging laparoscopy (8.3 months, 95% confidence interval (CI) 5.4–16.5) or on peritoneal cytology (4.9 months, 95% CI 4.2–48) were as poor as those with M1 disease seen on preoperative imaging (6.7 months, 95% CI 4.2–8.9), P = 0.97. Conclusions Laparoscopy and peritoneal cytology add incremental value to modern imaging in the staging of gastric adenocarcinomas by detecting occult metastatic disease. Their utility needs to be optimized to allow better treatment selection for gastric cancer patients.

Single agent azacitidine or immunomodulatory drugs are effective in myelodysplastic syndrome (MDS), with differing target mechanisms and toxicities. Objectives of this ALLG MDS3 study in clinically advanced MDS, AMML and low blast AML were to establish safety, response and quality of life of azacitidine and thalidomide. Patients received azacitidine (75mg/m2/d sc 7days every 28 days), and oral thalidomide up to 100mg/d for maximum 12months. Eighty patients registered; median age 68 years (range 42-82), 49% IPSS int2-high. With 36.5 months follow up, patients received median 9 cycles azacitidine, 6.1mths thalidomide. Nonhematologic toxicity grade 3+ in 85%, commonly infections. Overall response rate was 63%; 26% CR were unaffected by IPSS. Median response duration 26.3months; overall survival was 28.1months. This combination azacitidine and thalidomide in clinically advanced MDS, CMML and low-blast AML was tolerable without unexpected toxicity and encouraging responses support further investigation of combination approaches with hypomethylating agent and immunomodulatory drug.

Purpose To evaluate cosmetic outcome and its association with breast wound seroma after breast-conserving surgery (BCS) with targeted intraoperative radiation therapy (tIORT) boost for early breast cancer. Methods and Materials An analysis of a single-arm prospective study of 55 patients with early breast cancer treated with BCS and tIORT boost followed by conventional whole breast radiation therapy (WBRT) between August 2003 and January 2006 was performed. A seroma was defined as a fluid collection at the primary tumor resection site identified clinically or radiologically. Cosmetic assessments using the European Organization for Research and Treatment of Cancer rating system were performed at baseline before BCS and 30 months after WBRT was completed. Results Twenty-eight patients (51%) developed a seroma, with 18 patients (33%) requiring at least 1 aspiration. Tumor location was significantly associated with seroma formation ( P =.001). Ten of 11 patients with an upper inner quadrant tumor developed a seroma. Excellent or good overall cosmetic outcome at 30 months was observed in 34 patients (62%, 95% confidence interval 53%-80%). Seroma formation was not associated with the overall cosmetic result ( P =.54). Conclusion BCS with tIORT boost followed by WBRT was associated with an acceptable cosmetic outcome. Seroma formation was not significantly associated with an adverse cosmetic outcome.

BackgroundChemotherapy has in some series been linked with increased morbidity after a hepatectomy. Hepatic injuries may result from the treatment with chemotherapy, but can also be secondary to co-morbid diseases. The aim of the present study was to draw correlations between clinical features, treatment with chemotherapy and injury phenotypes and assess the impact of each upon perioperative morbidity.Patients and methodsRetrospective samples (n= 232) were scored grading steatosis, steatohepatitis and sinusoidal injury (SI). Clinical data were retrieved from medical records. Correlations were drawn between injury, clinical features and perioperative morbidity.ResultsInjury rates were 18%, 4% and 19% for steatosis, steatohepatitis and SI, respectively. High-grade steatosis was more common in patients with diabetes [odds ratio (OR) = 3.33, P= 0.01] and patients with a higher weight (OR/kg = 1.04, P= 0.02). Steatohepatitis was increased with metabolic syndrome (OR = 5.88, P= 0.02). Chemotherapy overall demonstrated a trend towards an approximately doubled risk of high-grade steatosis and steatohepatitis although not affecting SI. However, pre-operative chemotherapy was associated with an increased SI (OR = 2.18, P= 0.05). Operative morbidity was not increased with chemotherapy, but was increased with steatosis (OR = 2.38, P= 0.02).ConclusionsDiabetes and higher weight significantly increased the risk of steatosis, whereas metabolic syndrome significantly increased risk of steatohepatitis. The presence of high-grade steatosis increases perioperative morbidity, not administration of chemotherapy per se.

We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with > 1 prior therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS). The MTD identified was bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12), and romidepsin 10 mg/m2 (days 1, 8, and 15) every 28 days. Thrombocytopenia (64%) was the most common ≥ grade 3 hematologic toxicity. Peripheral neuropathy occurred in 76% of patients (n = 19) (≥ grade 3, 8%; 95% confidence interval [CI] 1%-26%). Maintenance romidepsin 10 mg/m2 (on days 1 and 8 of a 28-day cycle) proved feasible, with 12 patients receiving a median of 7.5 cycles (range: 1-29). An OR (M-protein) of > minor response (MR) was seen in 18 of 25 patients (72%); 2 (8%) had complete remissions (CRs) and 13 (52%) had partial responses (PRs), including 7 (28%) with very good PRs (VGPRs). The median TTP was 7.2 (95% CI: 5.5-19.6) months, and the median OS was > 36 months. This regimen shows activity with manageable toxicity and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as NCT00431990.

IntroductionChemotherapy-induced hepatic injuries (CIHI) are an increasing problem facing hepatic surgeons. It may be possible to predict the risk of developing CIHI by analysis of genes involved in the metabolism of chemotherapeutics, previously established as associated with other forms of toxicity.MethodsQuantitative reverse transcriptase-polymerase chain reaction methodology (q-RT-PCR) was employed to quantify mRNA expression of nucleotide excision repair genes ERCC1 and ERCC2, relevant in the neutralization of damage induced by oxaliplatin, and genes encoding enzymes relevant to 5-flurouracil metabolism, [thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)] in 233 hepatic resection samples. mRNA expression was correlated with a histopathological injury scored via previously validated methods in relation to steatosis, steatohepatitis and sinusoidal obstruction syndrome.ResultsLow-level DPD mRNA expression was associated with steatosis [odds ratio (OR) = 3.95, 95% confidence interval (CI) = 1.53–10.19, P < 0.003], especially when stratified by just those patients exposed to chemotherapy (OR = 4.48, 95% CI = 1.31–15.30 P < 0.02). Low expression of ERCC2 was associated with sinusoidal injury (P < 0.001). There were no further associations between injury patterns and target genes investigated.ConclusionsPredisposition to the development of CIHI may be predictable based upon individual patient expression of genes encoding enzymes related to the metabolism of chemotherapeutics.

Universal screening for chronic hepatitis B virus (HBV) before chemotherapy has been recommended by the Centers for Disease Control. We sought to determine the prac- tice of Australian oncologists with regard to HBV screening in patients with solid tumors (STs) and their clinical experience of HBV reactivation (HBVR). Methods: A survey was sent to all consultant members of the Medical Oncology Group of Australia. One hundred eighty-eight responses (63% response rate) were received. We also reviewed the incidence of HBV in patients with STs screened at the Peter MacCallum Cancer Centre (Melbourne, Australia). Results: Fifty-three percent of medical oncologists screen for HBV, but only 19% screen all patients. The most common rea- sons given for performing screening were anecdotal experience of HBVR (46%) and perceived sufficient evidence for screening of some patient subgroups (42%). Sixty-five percent of those who screened did so only in subgroups, usually selecting patients on the basis of ethnicity (82%). Oncologists who did not screen most commonly cited inadequate evidence for a benefit of screening (72%). Twenty-two percent of oncologists had wit- nessed one or more HBVR events, representing one event per 45 years of respondents' practice. HBVR events reported (n 54) consisted of asymptomatic liver test abnormalities only (44%), symptomatic hepatitis (28%), decompensated liver failure (19%), and death (7%). In 206 patients with STs screened for HBV, 1.0% (n 2) were HBV surface antigen positive, and 14.9% hepatitis B core antibody positive. Conclusion: The majority of Australian medical oncologists have not adopted universal HBV screening before chemothera- py. Further evidence of the benefit and cost effectiveness of universal screening in patients with STs will be required to alter practice.

Summary Background It has been suggested that inflammation status, as assessed by C-reactive protein (CRP) concentration, modifies the vascular protective effects of statin therapy. In particular, there have been claims that statins might be more beneficial in people with raised CRP concentrations, and might even be ineffective in people with low concentrations of both CRP and LDL cholesterol. This study aimed to test this hypothesis. Methods In 69 UK hospitals, 20 536 men and women aged 40–80 years at high risk of vascular events were randomly assigned to simvastatin 40 mg daily versus matching placebo for a mean of 5·0 years. Patients were categorised into six baseline CRP groups (

Uveal (eye) melanoma (UM) is the most common primary eye malignancy in adults. Despite effective treatments for primary UM, up to 50% of patients subsequently develop systemic metastasis, predominantly in the liver. Once hepatic metastasis develops, the survival of UM patients is generally short and currently available treatments fail to show meaningful improvement of their survival. Metastatic uveal melanoma (MUM) is highly resistant to traditional systemic therapies, including immunotherapy. Immune checkpoint blockades approved for metastatic cutaneous melanoma (MCM) such as anti-CTLA4 antibody and anti-PD-1 antibody have shown only marginal clinical benefit in MUM (response rates = 1 RPKM), while TDO2 message is not present in 1/3 of the samples. Expression of TDO2 in primary UM correlated to poor survival (Cox regression hazard ratio 0.7, p=0.04). Moreover, TDO2 expression correlated to patients with BAP1 mutations (p=0.00071) and differences between patients with monosomy 3 and disomy 3 (p=0.00017). We further investigated whether MUM cell lines and MUM tumor specimens express TDO. We detected TDO protein in all of 4 MUM cell lines by Western blotting. Although inducible by exogenous IFN-gamma, IDO1 protein was not detected in any of these MUM cell lines without stimulation. TDO mRNA was increased 3.5 fold by stimulating MUM cells with recombinant human TNF-alpha. All MUM cell lines possess TNF-alpha receptors. We have also investigated TDO and IDO1 proteins in 10 MUM specimens obtained from hepatic metastasis by immuno-histochemical staining. TDO was positive in both normal hepatocytes as well as tumor themselves in all MUM specimens. Interestingly, the intensity of TDO staining is much stronger in MUM, compared to the surrounding liver tissues. On the other hand, IDO1 protein was not positive in any of MUM tissues obtained from liver metastasis. These results indicate that expression of TDO by MUM cells might be one of the key mechanisms for escape from T-cell immune surveillance in hepatic metastasis from primary UM. Citation Format: Mizue Terai, Emma Link, Eric Link, Bao Lam, Marlana Orloff, Takami Sato. Expression of tryptophan -2, 3-dioxygense (TDO) in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3805.

Standard pretreatment staging for gastric cancer includes CT of the chest, abdomen, and pelvis; gastroscopy; and laparoscopy. Although 18F-PET combined with CT has proven to be a useful staging tool in many cancers, some gastric cancers are not 18F-FDG–avid and its clinical value is still debatable. Methods: Gastric cancer patients who underwent staging 18F-FDG PET scans from 2002 to 2013 at the Peter MacCallum Cancer Center were retrospectively analyzed, and a systematic review was also conducted using PubMed between 2000 to March 2014 to investigate clinicopathologic parameters associated with 18F-FDG avidity. A pretreatment PET scoring system was developed from predictors of 18F-FDG avidity. Results: Both the retrospective analysis of the patients and the systematic literature review showed similar significant predictors of 18F-FDG avidity, including large tumor size, non–signet ring cell carcinoma type, and glucose transporter 1–positive expression on immunohistochemistry. A PET scoring system was developed from these clinicopathologic parameters that allowed 18F-FDG–avid tumors to be detected with a sensitivity of 85% and a specificity of 71%. Conclusion: A pretreatment PET scoring system can assist in the selection of patients with gastric adenocarcinoma when staging 18F-FDG PET is being considered.

Background. Chemoradiotherapy (CRT) for squamous cell carcinoma of the anus (SCCA) may cause significant toxicity, and concerns exist about its tolerability in the elderly. The authors compared tolerability and outcomes across the age groups following CRT for SCCA.Methods. Single-institution retrospective analysis of patients with localized SCCA treated with CRT. CRT was standardized at 50.4–54 Gy, with concurrent infusional 5-fluorouracil and mitomycin C. Patients were arbitrarily categorized into three groups: Group 1 – age < 50 years; Group 2 – age ≥ 50 and < 70 years; and Group 3 – age ≥ 70 years.Results. Of 284 patients identified, 278 were evaluable. The number of patients in each age group was: Group 1 – 51; Group 2 – 140; and Group 3 – 93. Baseline and treatment characteristics, tumor stage, rates of overall acute toxicity, need for unplanned treatment breaks and chemotherapy delivery were largely similar across the age groups. However, nine patients in Group 3 did not complete CRT, compared with five and none in Groups 1 and 2, respectively (p = 0.006). In addition, five patients in Group 3 had diarrhea requiring treatment break, compared with none in the other two groups (p = 0.004). At a median follow-up 5.3 years, there was no significant difference in overall survival (p = 0.11), disease-free survival (p = 0.22) or local-recurrence free survival (p = 0.34), across the three age groups.Conclusions. CRT is safe and tolerable in the elderly age group, and provides equivalent disease control rates compared with the younger age group. Age alone should therefore not preclude aggressive curative treatment.

Partial breast irradiation (PBI) after lumpectomy may be an option for selected patients with early breast cancer. A feasibility study of accelerated PBI delivered using external beam 3-dimensional conformal radiation therapy (RT) was undertaken at 8 Australasian centers. The present study evaluated the impact of patient, tumor, and RT technique-related factors on the quality of RT plans as determined by the dose-volume parameters of organs at risk.Forty-eight patients were enrolled in the study. All RT plans were centrally reviewed using predefined dosimetric criteria before commencement and after completion of protocol therapy. The RT plans of 47 patients met the dose-volume constraints, and all 47 patients received PBI to a prescribed dose of 38.5 Gy in 10 fractions. The RT plan quality was determined by volumes of the ipsilateral whole breast, lung, and heart that received 50% and 95%; 30%; and 5% of the prescribed dose, respectively. Patient, tumor, and RT technique-related factors were investigated for association with the parameters of RT plan quality.The ratio of the planning target volume to the ipsilateral whole-breast volume was significantly associated with the ipsilateral breast doses on multiple variable analyses. The distance of the postlumpectomy surgical cavity from the heart and lung were predictive for heart and lung doses, respectively. A distance between surgical cavity and heart of4 cm typically resulted in1% of the heart volume receiving 5 Gy or less. It was more difficult to meet the heart dose constraint for left-sided and medially located tumors.Partial breast irradiation using 3-dimensional conformal RT was feasible within the study constraints. The ratio of planning target volume to ipsilateral whole-breast volume and the distance of surgical cavity from the heart were significant predictors of the quality of treatment plan for external beam PBI.

We investigated the incremental management impact and prognostic value of staging with (18)F-FDG PET/CT in patients with non-small cell lung cancer (NSCLC) being considered for potentially curative therapies.Information on 168 consecutive patients with NSCLC being considered for surgery or definitive radiotherapy with curative intent before PET/CT was entered into a prospective database. The pre-PET/CT management plan, based on conventional imaging (conventional CT, appropriately supplemented by bone scintigraphy or other modalities), was defined prospectively by referring clinicians before PET/CT results became available. After PET/CT, actual clinical management was recorded, and patients were followed up until 5 y or death. The appropriateness of PET/CT management plans was assessed by biopsy when available, clinical follow-up, and survival analysis.Stage was discordant on PET/CT and conventional imaging in 50.6% of patients (41.1% upstaged, 9.5% downstaged), with high management impact (change in treatment modality or curative intent) in 42.3% of patients. Both conventional imaging stage and PET/CT stage were strongly predictive of overall survival (OS) but there were greater differences between hazard rates and separations in the OS curves for stage groupings determined using PET/CT. OS was also strongly predicted by PET/CT-directed choice of therapy (P0.0001).PET/CT frequently affects patient management and strongly predicts OS in NSCLC, supporting the appropriateness of such changes.

Background: The pivotal phase III MM009 and MM010 trials have established standard dose lenalidomide (len; 25mg daily, days 1-21 of 28 day cycle) and high-dose dexamethasone (dex; 40mg daily, days 1-4,9-12,17-20) [RD] as effective treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, moderate toxicities were seen with RD that necessitated dose reduction in 76% and treatment cessation in 20% of patients. We prospectively investigated lower dose len-dex (rd) in a group of patients who were deemed at higher risk of myelosuppression and compared this to a matched cohort of patients who received RD in the MM009 and MM010 trials. Methods: RevLite was a multicentre phase II single-arm study across 12 centres in Australia and New Zealand of patients with RRMM, who were aged ≥60 years and/or with CrCL 20-59ml/min and/or platelets ≤75x109/L. Patients received rd (len 15mg daily, day 1-21 of a 28 day cycle and dex 20mg daily, days 1-4,9-12,17-20) until disease progression. The primary end point was overall response rate (ORR) and secondary endpoints were progression free survival (PFS) and adverse events (AE). A matched cohort of patients who received RD was extracted from the MM009/010 trials. Toxicities and survival outcome were compared between the cohort of patients receiving rd and RD. Results: A total of 149 patients (median age 69 years; male 60%) received rd in the RevLite trial. 65% of patients had prior thalidomide and 49% had at least 3 prior lines of treatment. ORR was 69.1% with CR 14.1%. With a median follow up of 28.4 months (0.2-63.5), median PFS was 8.9 months (95% confidence interval (CI): 6.9-11.5) and median OS was 30.5 months (20.0-36.2). Data of a total of 255 patients were extracted from the RD cohort in the MM009 and MM010 trials. Patients from the rd vs. RD cohort were similar in age, sex, ISS stage and CrCL. There was a higher prior exposure to thalidomide in the rd cohort (65% vs. 36% (RD)). ORR was similar between rd (69%; CR 14.1%) and RD (60%; CR 13.7%). No difference was seen in PFS (p=0.34) and OS (p=0.21). On multivariate analysis, after adjusting for other baseline prognostic factors, there was a trend for better OS with RD (HR 0.76 (95%CI 0.57-1.01), p=0.058). Grade 3-4 toxicities were lower with rd, mainly lower neutropenia (29 vs. 41%), infections (23.3 vs. 31.4%), and VTE (3 vs. 13%). Patients who were still on treatment after 3 years were on an average daily dose of 15mg in both groups. Conclusion: Lower dose len-dex is less toxic but remains efficacious in patients with RRMM who are at higher risk of myelosuppression. While this trial was not powered to detect non-inferiority of rd vs RD with respect to PFS and OS, rd was shown to induce a meaningful depth of response and PFS that was comparable to that seen with standard dose len-dex in patients who are aged ≥60 years and/or with renal impairment and/or with thrombocytopenia. These results reinforce the growing recognition of treatment attenuation in elderly or frail patients, and confirm that such practice with len-dex will not likely compromise patient response or survival outcome. Disclosures Quach: Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Harrison:Celgene: Honoraria, Research Funding. Li:Celgene Corp: Employment, Equity Ownership. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Prince:Celgene Corp, Amgen, Janssen: Honoraria, Research Funding.

Background: The aim was to investigate the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. Methods: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan–Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. Results: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P

Purpose To evaluate the prognostic factors, patterns of failure, and late toxicity in patients treated with chemoradiation (CRT) for anal cancer. Methods and Materials Consecutive patients with nonmetastatic squamous cell carcinoma of the anus treated by CRT with curative intent between February 1983 and March 2008 were identified through the institutional database. Chart review and telephone follow-up were undertaken to collect demographic data and outcome. Results Two hundred eighty-four patients (34% male; median age 62 years) were identified. The stages at diagnosis were 23% Stage I, 48% Stage II, 10% Stage IIIA, and 18% Stage IIIB. The median radiotherapy dose to the primary site was 54 Gy. A complete clinical response to CRT was achieved in 89% of patients. With a median follow-up time of 5.3 years, the 5-year rates of locoregional control, distant control, colostomy-free survival, and overall survival were 83% (95% confidence interval [CI] 78–88), 92% (95% CI, 89–96), 73% (95% CI, 68–79), and 82% (95% CI, 77–87), respectively. Higher T stage and male sex predicted for locoregional failure, and higher N stage predicted for distant metastases. Locoregional failure occurred most commonly at the primary site. Omission of elective inguinal irradiation resulted in inguinal failure rates of 1.9% and 12.5% in T1N0 and T2N0 patients, respectively. Pelvic nodal failures were very uncommon. Late vaginal and bone toxicity was observed in addition to gastrointestinal toxicity. Conclusions CRT is a highly effective approach in anal cancer. However, subgroups of patients fare relatively poorly, and novel approaches are needed. Elective inguinal irradiation can be safely omitted only in patients with Stage I disease. Vaginal toxicity and insufficiency fractures of the hip and pelvis are important late effects that require prospective evaluation.

Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy.The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer.Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival.: Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis.Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival compared with patients with no metabolic response. Metabolic response may be used to stratify prognosis in patients with rectal cancer.

e22212 Background: Ribosome biogenesis driven by RNA polymerase 1 (Pol1) is a fundamental cellular process increased in malignancy. We have shown that CX-5461, a small molecule inhibitor of Pol1, s...

Abstract 4046 Background: TP53, a tumour suppressor gene, has critical functions regulating normal cellular homeostasis and when inactivated can enhance oncogenesis and disease progression. TP53 deletion as detected by FISH is recognized to occur in approximately 10% of MM patients. Mutations in TP53 in MM are uncommon in de novo disease, 0–3%, while in advanced disease have been reported in up to 25% of patients. Currently the prognostic importance of TP53 mutations in the setting of IMiD therapy for MM is unknown. Our aim was to study the incidence and clinical relevance of TP53 mutations using high resolution melting (HRM) analysis and sequencing in patients with relapsed/refractory MM treated with thalidomide. Patients and Methods: Stored patient samples were obtained with ethics approval. All patients had been enrolled in either of two previously published multicentre phase II trials with thalidomide +/− IFNa-2B (MMThal) (Mileshkin L et al. Blood 2003) or celecoxib-thalidomide (CEThal) (Prince et al. Clin Cancer Res. 2005). Steroid treatment was not a part of either regimen. Bone marrow DNA was extracted from pre-treatment archived bone marrow aspirate samples and screened for TP53 mutations using HRM analysis targeting exons 5–9. Subsequent positive cases underwent confirmatory testing with sequencing of amplicons with aberrant melting patterns. The IARC TP53 database was used for sequence analysis interpretation. Results: 55 (of 141 patients accrued) samples were available and have been analysed to date for TP53 mutations in exons 5–9. Median age is 65 years (range 36–85), 32 males. Median plasma cell differential on bone marrow aspirate smears was 16% (1-96). Median serum β2 microglobulin (β2m) was 3.3 (1.37-12.8), median Hb 107 g/L (60-145) while patients had received a median of 3 prior treatments (1-8) and 16% had refractory disease. 40/141 (28%) had received a prior autograft. Median follow up was 73 months and 46 months for MMTHAL and CETHAL, respectively, while PFS was 24% and 39% at 1 yr for the 2 trials, respectively. 8/55 (14.5%) had abnormal melts detected by HRM with 5 mutations confirmed by sequencing, and 3 awaiting sequence confirmation. Additionally two SNP's were detected. We believe the mutation rate is an under-representation given low tumour burden ( Conclusions: TP53 mutations were detected in the DNA binding domain (exons 5–9) in 14.5% (8/55) of our cohort studied to date. 4/8 patients with mutated TP53 had a CR/PR suggesting that thalidomide is a useful agent in this context, although further evaluation is required for confirmation of these findings, as would exploration of similar relationships in lenalidomide-treated patients. Both avenues of experimentation are ongoing. Disclosures: Westerman: Celgene Pty Ltd: Research Funding. Lynch:Celgene Pty Ltd: Employment, Equity Ownership. Prince:Celgene Pty Ltd: Honoraria, Research Funding.

4105 Background: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) improves the accuracy of staging and radiotherapy planning in anal cancer, and in other malignancies has prognostic val...