Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

A Prospective Study of Arterial Spin Labelling in Paediatric Posterior Fossa Tumour Survivors: A Correlation with Neurocognitive Impairment.

AIMS: Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population. MATERIALS AND METHODS: Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus. RESULTS: Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20-30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5-10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04). CONCLUSIONS: These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit.

Evaluation of two modalities of perioperative treatment in the management of extremity and truncal soft tissue sarcomas: neoadjuvant concurrent chemoradiotherapy and sequential treatment.

PURPOSE: Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS: We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS: A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p < 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days, p < 0.01), with no impact on the surgical procedure or postoperative complications. CONCLUSION: cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.

Quality of life and functional outcomes after radical cystectomy with ileal orthotopic neobladder replacement for bladder cancer: a multicentre observational study.

PURPOSE: Ileal orthotopic neobladder (IONB) reconstruction is the preferred urinary diversion among selected patients who have undergone radical cystectomy (RC) for bladder cancer (BCa). There is insufficient data regarding patients' quality of life (QoL), sexual and urinary outcomes. Our objectives were to assess QoL in a multicentre cohort study, and to identify related clinical, oncological and functional factors. METHODS: Patients who underwent RC with IONB reconstruction for BCa from 2010 to 2017 at one of the three French hospitals completed the following self-reported questionnaires: European Organization for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and bladder cancer specific instruments (QLQ-BLM30). To assess urinary symptoms, patients completed the Urinary Symptom Profile questionnaire (USP) and a three-day voiding diary. Univariate and multivariate analyses were computed to identify clinical, pathological, and functional predictors of global QoL score. RESULTS: Seventy-three patients completed questionnaires. The median age was 64 years and 86.3% were men. The median interval between surgery and responses to questionnaires was 36 months (range 12-96). Fifty-five percent of patients presented a high global QoL (EORTC-QLQC30, median score 75). A pre-RC American Society of Anesthesiologists score > 2, active neoplasia, sexual inactivity, and stress urinary incontinence were associated with a worse QoL. After a multivariate analysis, sexual inactivity was the only independent factor related to an altered QoL. CONCLUSION: Patients with IONB reconstruction after RC have a high global QoL. Sexual activity could independently impact the global QoL, and it should be assessed pre- and post-operatively by urologists.

[Orthotopic neobladder reconstruction for bladder cancer: robotic-assisted versus open-radical cystectomy for perioperative outcomes, functional results and quality of life]. / Morbidité, résultat fonctionnel, et qualité de vie des néovessies après cystectomie pour cancer : comparaison de la voie ouverte vs robotique.

INTRODUCTION: Open radical cystectomy (ORC) is the gold standard technique for carcinologic cystectomies. Robotic-assisted radical cystectomy (RARC) was introduced in 2003 and its development is booming. OBJECTIVE: To compare ORC and RARC with totally intracorporal (IC) orthotopic neobladder (ONB) reconstruction, in terms of perioperative outcomes, morbidity, functional results and quality of life (Qol). PATIENTS AND METHODS: From February 2010 to February 2017, a French multicentric, prospective study on patients who had a RC and ONB reconstruction for bladder cancer was performed. All patients completed the following questionnaires: the European Organization for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and the bladder cancer specific instruments (QLQ-BLM30). To assess urinary symptoms, patients also completed the Urinary Symptom Profile questionnaire (USP) and a three-day voiding diary. Patients were divided in two groups: ORC and RARC. RESULTS: We included 72 patients: 55 in the ORC group (76,4%) and 17 (33,6%) in the RARC group. Operative time was longer in RARC group (median 360 vs 300min; P<0.001) but length of stay was 5 days shorter (median 12 vs 17 days; P<0,05). Patients in RARC group had less blood transfusion (0 vs 23.6%; P<0.05), but a higher rate of uretero-ileal anastomosis stenosis and eventration at long term (respectively 25.5 vs 3.6% et 23 vs 2%; P<0.05). No statistical differences were found concerning quality of life items and functional results between the groups. CONCLUSION: RARC with totally IC ONB reconstruction lead to less perioperative morbidity with a reduced rate of blood transfusion and a reduced hospital length of stay. At long term, RARC could provide higher rates of uretero-ileal stenosis and eventration. RARC and ORC do not have any differences in terms of functional outcomes and Qol at long term after ONB reconstruction. LEVEL OF EVIDENCE: 3.

Designing phase II clinical trials to target subgroup of interest in a heterogeneous population: A case study using an R package.

Phase II trials that evaluate target therapies based on a biomarker must be well designed in order to assess anti-tumor activity as well as clinical utility of the biomarker. Classical phase II designs do not deal with this molecular heterogeneity and can lead to an erroneous conclusion in the whole population, whereas a subgroup of patients may well benefit from the new therapy. Moreover, the target population to be evaluated in a phase III trial may be incorrectly specified. Alternative approaches are proposed in the literature that make it possible to include two subgroups according to biomarker status (negative/positive) in the same study. Jones, Parashar and Tournoux et al. propose different stratified adaptive two-stage designs to identify a subgroup of interest in a heterogeneous population that could possibly benefit from the experimental treatment at the end of the first or second stage. Nevertheless, these designs are rarely used in oncology research. After introducing these stratified adaptive designs, we present an R package (ph2hetero) implementing these methods. A case study is provided to illustrate both the designs and the use of the R package. These stratified adaptive designs provide a useful alternative to classical two-stage designs and may also provide options in contexts other than biomarker studies.

The importance of jointly analyzing treatment administration and toxicity associated with targeted therapies: a case study of regorafenib in soft tissue sarcoma patients.

Background: Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting. Patients and methods: The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib. Results: Only 4.6% of progression-free patients developed mucositis/stomatitis (grade ≥2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm. Conclusion: This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit-risk ratio of therapies in their treatment choice. Clinical trial: NCT01900743.

Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review.

PURPOSE: As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients. METHODS: An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review. RESULTS: The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs. CONCLUSIONS: Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).

How to report toxicity associated with targeted therapies?

BACKGROUND: In the era of personalized medicine, molecularly targeted therapies (MTT) have modified the outcome of some cancer types. The price of tumor control needs to be balanced with toxicity since these new therapies are administered continuously for several months or sometimes for several years. For cytotoxic drugs, the incidence of adverse event (AE) was traditionally reported as frequency and intensity. This simple measure is not sufficient to capture the recurrent nature and duration of AE. This paper presents two methods to better describe the toxicity burden across the time: prevalence and Q-TWiST. PATIENTS AND METHODS: Limitation of worst-grade method and advantages of prevalence and Q-TWiST in the analysis of toxicity were illustrated using data from a phase II trial and a hypothetically simulated clinical trial. RESULTS: Prevalence integrates the recurrent nature of AE. Using prevalence, it is possible to obtain a time profile of AE. Q-TWiST method evaluates the weighted time spent in each health state and also considers the recurrent nature of side-effects in order to assess the 'risk-benefit' ratio of a treatment. When interpreting Q-TWiST results, it is necessary to take into account overall survival and progression-free survival and to define a clinically relevant difference according to the setting. CONCLUSION: The two methods presented here capture different effects. They are helpful for physicians in their treatment choice (balance benefit risk), to counsel patients and to optimize supportive care. In order to ensure consistency and provide critical information required for medical decision-making, it is important to encourage the use of alternative statistical methods in the analysis of toxicities associated with MTT. CLINICAL TRIAL: NCT00541008.

Prediction of long-term cumulative incidences based on short-term parametric model for competing risks: application in early breast cancer.

Use of parametric statistical models can be a solution to reduce the follow-up period time required to estimate long-term survival. Mould and Boag were the first to use the lognormal model. Competing risks methodology seems more suitable when a particular event type is of interest than classical survival analysis. The objective was to evaluate the ability of the Jeong and Fine model to predict long-term cumulative incidence. Survival data recorded by Institut Curie (Paris) from 4761 breast cancer patients treated and followed between 1981 and 2013 were used. Long-term cumulative incidence rates predicted by the model using short-term follow-up data were compared to non-parametric estimation using complete follow-up data. 20- or 25-year cumulative incidence rates for loco-regional recurrence and distant metastasis predicted by the model using a maximum of 10 years of follow-up data had a maximum difference of around 6 % compared to non-parametric estimation. Prediction rates were underestimated for the third and composite event (contralateral or second cancer or death). Predictive ability of Jeong and Fine model on breast cancer data was generally good considering the short follow-up period time used for the estimation especially when a proportion of patient did not experience loco-regional recurrence or distant metastasis.

Assessment of health status over time by Prevalence and Weighted Prevalence functions: Interface in R.

The importance of evaluating complications and toxicity during and following treatment has been stressed in many publications. In most studies, these endpoints are presented descriptively and summarized by numbers and percentages but descriptive methods are rarely sufficient to evaluate treatment-related complications. Pepe and Lancar developed Prevalence and Weighted Prevalence functions which take into account the duration and the severity of complication unlike conventional methods of survival analysis or competing risks which are limited to the time to first event. The purpose of this paper is to describe features and use of two R functions, main.preval.func and main.wpreval.func, which were designed for the analysis of survival adjusted for quality of life. These functions compute descriptive statistics, survival and competing risks analysis and especially Prevalence and Weighted Prevalence estimations with confidence intervals and associated test statistics. The use of these functions is illustrated by several examples.