E. van Werkhoven

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: A single institution experience

AIM To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery. METHODS All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC). RESULTS In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001). CONCLUSIONS Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: A comparison with the radioguided occult lesion localization with 99m technetium

BACKGROUND Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL. METHODS We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen. RESULTS Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21). CONCLUSION Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy.

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

Background:Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with ‘luminal’-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half.Methods:Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a ‘favourable response’ on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an ‘unfavourable response’, using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival.Results:Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%.Conclusion:The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

Phase I dose-escalation study and population pharmacokinetic analysis of fixed dose rate gemcitabine plus carboplatin as second-line therapy in patients with ovarian cancer

OBJECTIVE This phase I study of fixed dose rate (FDR) gemcitabine and carboplatin assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profile and preliminary anti-tumor activity in patients with recurrent ovarian cancer (OC). METHODS Patients with recurrent OC after first line treatment were treated with carboplatin and FDR gemcitabine (infusion speed 10mg/m(2)/min) on days 1, 8 and 15, every 28 days. Pharmacokinetics included measurement of platinum concentrations in plasma ultrafiltrate (pUF) and plasma concentrations of gemcitabine (dFdC) and metabolite dFdU. Intracellular levels of dFdC triphosphate (dFdC-TP), the most active metabolite of gemcitabine, were determined in peripheral blood mononuclear cells (PBMCs). Population pharmacokinetic modeling and simulation were performed to further investigate the optimal schedule. RESULTS Twenty three patients were enrolled. Initial dose escalation was performed using FDR gemcitabine 300 mg/m(2) (administered at infusion speed of 10 mg/m(2)/min) combined with carboplatin AUC 2.5 and 3. Excessive bone marrow toxicity led to a modified dose escalation schedule: carboplatin AUC 2 and dose escalation of FDR gemcitabine (300 mg/m(2), 450 mg/m(2), 600 mg/m(2) and 800 mg/m(2)). DLT criteria as defined per protocol prior to the study were not met with carboplatin AUC 2 in combination with FDR gemcitabine 300-800 mg/m(2) because of myelosuppressive dose-holds (especially thrombocytopenia and neutropenia). CONCLUSIONS FDR gemcitabine in combination with carboplatin administered in this 28 days schedule resulted in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine. A two weekly schedule (chemotherapy on days 1 and 8) would be more appropriate.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies

BACKGROUND Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorffs α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER NCT01566279.

Effect of preservation of the right gastro-epiploic artery on delayed gastric emptying after cytoreductive surgery and HIPEC: A randomized clinical trial☆

BACKGROUND Delayed gastric emptying (DGE) is a main complication with unknown origin after a cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy (CRS-HIPEC). The aim of this study was to investigate if preservation of the right gastro-epiploic artery (GEA) during standard omentectomy would have a positive effect on gastric emptying after CRS-HIPEC. METHODS Forty-two patients subjected to a CRS-HIPEC were randomized into two groups perioperatively before performing an omentectomy: in Group I (N = 21) omentectomy was performed with preservation of the GEA; in Group II (N = 21) omentectomy was performed with resection of the GEA. The primary endpoint was the number of days to full oral intake of solid food. Secondary endpoints were number of days to intended occlusion of gastrostomy catheter and total hospital admission time. RESULTS No significant differences were discovered between both groups in any of the study endpoints after CRS-HIPEC. No significant differences were observed in patient or operation characteristics between the randomized groups. CONCLUSIONS No association was demonstrated between preservation of the gastro-epiploic artery during omentectomy and gastric emptying after CRS-HIPEC. The extensive intestinal manipulation or the heated intra-peritoneal chemotherapy during surgery are more plausible causes of this phenomenon. This clinical trial was registered in the Netherlands at the Central Committee on Research involving Human Subjects (CCMO) under registration number P06.0301L.

Identifying pathologic complete response of the breast after neoadjuvant systemic therapy with ultrasound guided biopsy to eventually omit surgery: Study design and feasibility of the MICRA trial ( M inimally I nvasive C omplete R esponse A ssessment)

PURPOSE Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). The MICRA trial (NTR6120) aims at identifying pCR with post-NST biopsies. Here, we report the study design and feasibility. METHODS The MICRA-trial is a multi-center prospective cohort study. Patients with a pre-NST placed marker and radiologic complete (rCR) or partial response on MRI after NST are eligible for inclusion. Ultrasound guided biopsy of the original tumor area is performed. Pathology results of the biopsies and surgery specimens are compared. The primary endpoint is false-negative rate of biopsies in identifying pCR. RESULTS During the first year of the trial 58 patients with rCR were included. One patient was a screening failure and excluded for analysis. Twenty-one percent had hormone receptor (HR)+/HER2- tumors, 21% HR+/HER2+ tumors, 18% HR-/HER2+ tumors and 40% TN tumors. Overall pCR was 68%. In seven patients biopsies could not be obtained: in 6 patients, the marker could not be identified on ultrasound in the OR and in 1 patient there were technical difficulties. A median of eight biopsies was obtained (range 4-9). The median of histopathological representative biopsies was 4 (range 1-8). CONCLUSION Ultrasound guided biopsy of the breast in patients with excellent response on MRI after NST is feasible. Accuracy results of the MICRA trial will be presented after inclusion of 525 patients to determine if ultrasound guided biopsy is an accurate alternative to surgical resection for assessment of pCR after NST.

Abstract OT2-01-11: Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment

Background: The combination of PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant (MUT) PI3Kα isoforms than wild-type (WT) via a unique mechanism. Phase Ib data of POSEIDON with Taselisib + tamoxifen (TAM) demonstrated encouraging activity in patients with heavily pre-treated MBC, with an acceptable toxicity profile (Baird et al, ASCO 2016). The recommended phase II dose (RP2D) was Taselisib 4mg plus TAM 20mg, both administered on a daily continuous schedule. ctDNA monitoring may have value in drug development by (1) assessing predictive biomarkers to therapy, (2) providing an early indication of treatment response, and (3) shedding light on potential mechanisms of acquired drug resistance. In some patients included in phase Ib of POSEIDON, tumor response was preceded by a corresponding early change in plasma PIK3CA ctDNA levels. Methods: The phase II portion of the POSEIDON trial is a two-arm, randomized, double blind study of Taselisib plus TAM versus placebo (PLA) plus TAM in pre- and postmenopausal women with HR+/HER2- MBC. In the first part of the Phase II, 180 patients will be randomized (1:1) to receive continuous TAM with either Taselisib at the RP2D or PLA until disease progression, unacceptable toxicity or patient / physician decision. Crossover is allowed upon progressive disease in those patients receiving PLA plus TAM, after collection of tumor and blood samples for exploratory biomarker analysis. Stratification is based on menopausal status, histology [lobular breast cancer (LBC) vs. ductal/others], PIK3CA mutation (WT vs. exon 9 vs. exon 20), prior everolimus, timing of recurrence/progression after prior endocrine therapy, number of prior chemotherapy (CT) lines, and treatment center. After recruiting the initial 180 patients, trial will focus in LBC, until a total number of 110 patients with LBC are enrolled. Other key eligibility criteria include presence of measurable or evaluable disease (RECIST 1.1), prior progression to endocrine treatment, maximum of 5 prior CT lines in the metastatic setting, absence of diabetes under medical treatment, and absence of chronic inflammatory bowel disease. Primary endpoint is investigator-assessed PFS. Key secondary endpoints are PFS in LBC, objective response rate, clinical benefit rate, safety, and exploratory biomarker analysis (including ctDNA). The study has a 90% power at a two-sided log-rank test significance level of 0.2 to detect an HR of 0.64, which corresponds to an increase in median PFS from 4.5 months in the PLA plus TAM arm to 7 months in the Taselisib plus TAM arm. Enrollment to POSEIDON Phase II started in June 2016 (Clinicaltrials.gov NCT02285179). Citation Format: Oliveira M, Baird RD, van Rossum AGJ, Beelen K, Garcia-Corbacho J, Mandjes IAM, Vallier AL, van Werkhoven E, Garrigos L, Kumar S, van Tinteren H, Munoz S, Linossi C, Rosing H, Miquel JM, Schrier M, de Vries Schultink A, Saura C, Gallagher WM, Bernards R, Tabernero J, Cortes J, Caldas C, Linn SC. Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-11.

Abstract P4-11-01: Factors influencing patient reported cosmetic outcome: Results of the Young Boost trial

Purpose The Young Boost trial (YBT), a multicenter RCT (NCT00212121), investigates whether a higher boost dose leads to a lower recurrence rate in young patients treated with breast conserving therapy. Cosmetic outcome is the secondary objective. The aim of the current analysis is to investigate which factors influence the patients9 opinion about cosmesis. Patients & methods From 2004-2011, 2421 breast cancer patients ≤ 50 yrs were included in The Netherlands, France, and Germany. All patients were treated with lumpectomy, followed by 50 Gy whole breast irradiation. Patients were randomized to receive a standard 16 Gy (n=1211) or a high 26 Gy boost (n=1210) to the tumour bed. Cosmesis was scored prior to radiation therapy, at 1 year and at 4 years follow-up according to the following three scoring systems: 1. BCCT.core: Digital photographs were analyzed using a software program to extract an overall cosmetic score: excellent, good, fair or poor. This score is based on symmetry, skin colour and scar visibility. The 7 features of symmetry in the BCCT.core program are:  pBRA (nipple position)  pLBC (level of lower breast contour)  pUNR (level of nipple)  pBCE (distance from nipple to inframammary fold)  pBCD (length of breast contour)  pBAD (area of the breast)  pBOD (non overlapping area between left and right breast) 2. Physician9s score: excellent, good, fair or poor 3. Patients9 score using a validated patient9s questionnaire about the breast appearance, including an overall score: very satisfied, satisfied, not dissatisfied, dissatisfied or very dissatisfied. Very satisfied and satisfied were grouped as satisfactory. At the same time points fibrosis was scored by the physician on a 4-point scale. The presence of rib pain was scored as well. First, we analyzed the correlation between the 3 scoring methods. Secondly, we analyzed the 7 features of BCCT.core in a proportional odds model, to investigate which parameters are related to the patients9 opinion about cosmesis at 4 years. Also, we analyzed whether fibrosis score or presence of rib pain are related to the patients9 opinion on cosmetic outcome. Results At 4 years, the agreement between the different scoring methods was low. The agreement between the physician and the patient was the highest (kappa 0.42), compared to the agreement between the patient and BCCT.core (kappa 0.26) or between BCCT.core and physician (kappa 0.39). Of the 7 BCCT.core parameters, pBCE and pBCD are significantly related to patients9 score at 4 years (table 1). Further, patients with any fibrosis interpret their cosmesis worse than patients without fibrosis, even when the objective score (i.e. BCCT.core) was similar. This effect was larger by increasing grade of fibrosis. The presence of rib pain had no influence. Conclusion The patients 9opinion on cosmetic outcome was significantly related to the score on pBCE and pBCD, and to the severity of fibrosis. The correlation between objective score and subjective scores (patient and physician) was low. Citation Format: Brouwers P, van Werkhoven E, van Loon J, Leer JW, Poortmans P, Bartelink H, Boersma L. Factors influencing patient reported cosmetic outcome: Results of the Young Boost trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-01.