Katarzyna Jóźwiak

Prediction of Hearing Loss Due to Cisplatin Chemoradiotherapy

IMPORTANCE Patients with head and neck cancer may experience chemoradiotherapy-induced hearing loss, but the weighing of involved variables has been subjective. Identification of patient and treatment characteristics to predict the absolute posttreatment hearing level is important for effective counseling of patients undergoing chemoradiotherapy. OBJECTIVE To predict treatment-induced hearing loss among patients with head and neck cancer. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was performed at The Netherlands Cancer Institute. One hundred and fifty-six patients with head and neck cancer treated with concomitant chemoradiotherapy as the primary treatment modality from January 1, 1997, through December 31, 2011, were enrolled. Follow-up was complete on March 1, 2012, and data were analyzed from April 1, 2011, through November 5, 2013. INTERVENTIONS High-dose intravenously administered cisplatin-based concomitant chemoradiotherapy. Cisplatin, 100 mg/m2, was administered in 3 courses on days 1, 22, and 43 during 7 weeks of radiotherapy (total radiation dose, 70 Gy in 35 fractions). MAIN OUTCOMES AND MEASURES Posttreatment bone conduction hearing threshold at pure-tone average frequencies of 1, 2, and 4 kHz, based on pure-tone audiometry after completion of treatment. Predictors included baseline hearing levels, radiation dose to the cochlea, and cisplatin dose. A multilevel mixed-effects linear regression model for predicting whether or not posttreatment hearing was at least 35 dB was established, and cross-validated sensitivity and specificity were obtained. RESULTS Of 156 patients who received high-dose concomitant chemoradiotherapy, 15 were missing the exact radiation dose to the cochlea and 41 had no data on posttreatment pure-tone audiometry. Nineteen patients had a hearing level of at least 35 dB for at least 1 ear before the treatment. The remaining 81 patients (162 ears) had a total cumulative cisplatin dose ranging from 315 to 600 (median, 546) mg. The radiation dose to the cochlea ranged from 1.1 to 70.9 (median, 13.6) Gy. Based on data from the 81 patients (162 ears), the area under the receiver operating characteristic curve was 0.68, with a sensitivity of 29% (95% CI, 13%-51%) and a specificity of 97% (95% CI, 88%-100%), resulting in a positive predictive value of 78%. CONCLUSIONS AND RELEVANCE Patient and treatment characteristics can be used to predict hearing level after concomitant chemoradiotherapy for head and neck cancer. This step may constitute the first in evidence-based individual counseling for treatment-induced hearing loss.

Cosmetic outcome and quality of life are inextricably linked in breast-conserving therapy

Cosmetic results and quality of life (QoL) are increasingly important in the treatment of breast cancer. This study was designed to determine the relationship between QoL and both subjectively and objectively measured cosmetic outcomes of breast‐conserving therapy (BCT), and its course over time.

Timing of Systemic Chemotherapy in Patients With Colorectal Peritoneal Carcinomatosis Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BACKGROUND: Timing of systemic chemotherapy in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is controversial. Preoperative systemic chemotherapy may offer benefits. OBJECTIVE: The purpose of this study was to evaluate the effect of timing of systemic chemotherapy on survival. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from January 2004 until June 2015 were included. MAIN OUTCOME MEASURES: The influence of patient-related, tumor-related, and treatment-related factors on survival were investigated using Cox regression models. Main outcome was overall survival. RESULTS: A total of 280 consecutive patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. In group A, 78 patients (28%) were treated with preoperative or perioperative chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. In group B, 169 patients (60%) were intentionally treated with cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and adjuvant chemotherapy. In group C, 33 patients (12%) had received their chemotherapy before peritoneal carcinomatosis was diagnosed. Median overall survival was 36.9 months (interquartile range, 20.6–79.7 mo) in group A, 43.1 months (interquartile range, 25.7–95.9 mo) in group B, and 34.0 months (interquartile range, 20.0–53.7 mo) in group C (p = 0.19). The extent of peritoneal carcinomatosis (region count of 3–5, HR = 1.58 (95% CI, 1.02–2.45), and 6–7, HR = 3.34 (95% CI, 1.66–6.72) vs 1–2 regions), a higher lymph node ratio (HR = 7.96 (95% CI, 2.16–29.31)), and cycles of systemic chemotherapy (0 cycles, HR = 2.52 (95% CI, 1.48–4.29)) and partial chemotherapy (HR = 2.15 (95% CI, 1.27–3.65) vs complete chemotherapy) were associated with poorer overall survival. LIMITATIONS: Selection bias is present because of the retrospective design of this study. CONCLUSIONS: Timing of systemic chemotherapy does not appear to have impact on survival in patients with colorectal peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Tumor Resection Margin Definitions in Breast-Conserving Surgery : Systematic Review and Meta-analysis of the Current Literature

&NA; Worldwide, various guidelines recommend what constitutes an adequate margin of excision for invasive breast cancer or for ductal carcinoma‐in‐situ (DCIS). We evaluated the use of different tumor resection margin guidelines and investigated their impact on positive margin rates (PMR) and reoperation rates (RR). Thirteen guidelines reporting on the extent of a positive margin were reviewed along with 31 studies, published between 2011 and 2016, reporting on a well‐defined PMR. Studies were categorized according to the margin definition. Pooled PMR and RR were determined with random‐effect models. For invasive breast cancer, most guidelines recommend a positive margin of tumor on ink. However, definitions of reported positive margins in the clinic vary from more than focally positive to the presence of tumor cells within 3 to 5 mm from the resection surface. Within the studies analyzed (59,979 patients), pooled PMRs for invasive breast cancer ranged from 9% to 36% and pooled RRs from 77% to 99%. For DCIS, guidelines vary between no DCIS on the resection surface to DCIS cells found within a distance of 2 mm from the resection edge. Pooled PMRs for DCIS varied from 4% to 23% (840 patients). Given the differences in tumor margin definition between countries worldwide, quality control data expressed as PMR or RR should be interpreted with caution. Furthermore, the overall definition for positive resection margins for both invasive disease and DCIS seems to have become more liberal.

Definitive (chemo)radiotherapy is a curative alternative for standard of care in advanced stage squamous cell carcinoma of the oral cavity

OBJECTIVE To compare outcome after definitive (chemo)radiotherapy (CRT group) with standard of care (surgery group) for advanced stage oral cavity carcinoma (OCC). Although definitive (chemo)radiotherapy is assumed to be inferior to surgery with regard to disease control, data on outcome of this approach are scarce. METHODS Retrospective analysis by chart review (2000-2013). Endpoints were locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS). RESULTS Between the CRT-group (n = 100) and Surgery-group (n = 109), baseline characteristics were equally distributed except stage and local tumor diameter (all p ≤ .001). In the CRT group, at 5 years the LRC rate was 49%, DFS 22%, DSS 39% and OS 22%. In the surgery group, at 5 years the LRC rate was 77%, DFS 45%, DSS 64% and OS 45%. The survival curves of the two groups significantly differed for LRC (p < .001), DFS and DSS (p = .001) and OS (p = .002). After adjusting for confounders and prognostic factors, we found a significant difference between the treatment groups in LRC (adjusted HR = 2.88, 95%CI 1.35-6.16, p = .006). Within 100 days, 5 patients (5%) died from treatment-related toxicity in CRT group and 1 patient after surgery (p = .21). CONCLUSIONS Although surgery with adjuvant radiotherapy for advanced stage OCC results in favorable locoregional control, definitive (chemo)radiotherapy is a curative alternative in patients often considered beyond cure and should be considered when surgery is not feasible.

Clinical prognostic markers in stage IIIC melanoma

Although the EORTC 18071‐trial has shown a clear survival benefit for adjuvant ipilimumab, accurately selecting patients for this toxic adjuvant therapy is important. We aimed to identify prognostic factors for death and disease recurrence in AJCC stage IIIC melanoma patients.

Using DRS during breast conserving surgery: identifying robust optical parameters and influence of inter-patient variation.

Successful breast conserving surgery consists of complete removal of the tumor while sparing healthy surrounding tissue. Despite currently available imaging and margin assessment tools, recognizing tumor tissue at a resection margin during surgery is challenging. Diffuse reflectance spectroscopy (DRS), which uses light for tissue characterization, can potentially guide surgeons to prevent tumor positive margins. However, inter-patient variation and changes in tissue physiology occurring during the resection might hamper this light-based technology. Here we investigate how inter-patient variation and tissue status (in vivo vs ex vivo) affect the performance of the DRS optical parameters. In vivo and ex vivo measurements of 45 breast cancer patients were obtained and quantified with an analytical model to acquire the optical parameters. The optical parameter representing the ratio between fat and water provided the best discrimination between normal and tumor tissue, with an area under the receiver operating characteristic curve of 0.94. There was no substantial influence of other patient factors such as menopausal status on optical measurements. Contrary to expectations, normalization of the optical parameters did not improve the discriminative power. Furthermore, measurements taken in vivo were not significantly different from the measurements taken ex vivo. These findings indicate that DRS is a robust technology for the detection of tumor tissue during breast conserving surgery.

Breast-specific factors determine cosmetic outcome and patient satisfaction after breast-conserving therapy: Results from the randomized COBALT study

To identify breast‐specific factors and the role of tumor, treatment, and patient‐related items in influencing patient opinion on cosmesis and satisfaction after breast‐conserving therapy (BCT).

The Prognostic Value of Immune Factors in the Tumor Microenvironment of Penile Squamous Cell Carcinoma

The host’s immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV− tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV− cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.

Inter-observer variation in the histopathology reports of head and neck melanoma; a comparison between the seventh and eighth edition of the AJCC staging system

BACKGROUND TNM staging of melanoma has recently been altered by the introduction of the 8th edition of the AJCC Cancer Staging manual. The purpose of this study is to analyze the inter-observer variation of histopathology reports and its effect on recommended treatment policy. METHODS We retrospectively analyzed 296 cases, diagnosed as primary cutaneous head and neck melanoma (2005-2016), referred to the Netherlands Cancer Institute (NCI) for treatment after prior diagnosis in another hospital (non-NCI). All reports were analyzed for patients demographics, tumor characteristics and histopathologic features. RESULTS In 53% and 40% of the cases, the histopathologic parameters were discordant, according to AJCC 7th and 8th edition, respectively. This indicated a perfect inter-observer agreement for the measurement of Breslow thickness (Intraclass correlation coefficient (ICC) = 0.981) and a substantial agreement for subtype (kappa statistic (κ) = 0.648) and ulceration (κ = 0.802), while only moderate for dermal mitotic activity (κ = 0.472). After NCI review, recommended treatment policies were changed in 13% and 11% of the patients when applying TNM 7 and TNM 8, respectively. Scheduling sentinel lymph node biopsy (SLNB) changed in 14 (5%) and 10 (3%) cases when using TNM 7 and TNM 8, respectively. CONCLUSION Review by a NCI pathologist of histopathologic parameters of primary cutaneous head and neck melanoma led to significant changes in treatment decision. Introduction of the AJCC 8th edition led to slightly less discordances between NCI and non-NCI reports and consequently smaller impact on treatment planning. Expert review remains indicated when a SLNB is considered for additional staging in selected cases.