Secondary analyses of the randomized phase III Stop&Go study: efficacy of second-line intermittent versus continuous chemotherapy in HER2-negative advanced breast cancer

Background: Previously, we showed that reintroduction of the same (first-line) chemotherapy at progression could only partially make up for the loss in efficacy as compared to continuously delivered first-line chemotherapy. Here, we report the probability of starting second-line study chemotherapy in the Stop&Go trial, and the progression-free survival (PFS) and overall survival (OS) of patients who received both the first- and second-line treatment in an intermittent versus continuous schedule. Methods: First-line chemotherapy comprised paclitaxel plus bevacizumab, second-line capecitabine or non-pegylated liposomal doxorubicin, given per treatment line as two times four cycles (intermittent) or as eight consecutive cycles (continuous). Results: Of the 420 patients who started first-line treatment within the Stop&Go trial (210:210), a total of 270 patients continued on second-line study treatment (64% of all), which consisted of capecitabine in 201 patients and of non-pegylated liposomal doxorubicin in 69 patients, evenly distributed between the treatment arms. Median PFS was 3.7 versus 5.0 months (HR 1.07; 95% CI: 0.82–1.38) and median OS 10.9 versus 12.4 months (HR 1.27; 95% CI: 0.98–1.66) for intermittent versus continuous second

Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours

Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)0–48, AUC0–inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC0–48 and AUC0–inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. ClinicalTrials.gov Identifier: NCT03147378, date of registration: May 10 2017

Plasma thymus and activation‐regulated chemokine (TARC) as diagnostic marker in pediatric Hodgkin lymphoma

Abstract Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed‐Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is “thymus‐and‐activation‐regulated chemokine” (TARC). The objectives of this study were to define normal TARC values in non‐cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non‐cHL patients (n = 81). TARC levels were measured by enzyme‐linked immunosorbent assay. The non‐cHL patients had a median plasma TARC value of 71 pg/mL (range: 18‐762), compared to 14 619 pg/mL (range: 380‐73 174) in cHL patients (P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998‐1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B‐symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work‐up for pediatric patients with lymphadenopathy

Gastric and duodenal cancer in individuals with Lynch syndrome:a nationwide cohort study

Background:Lynch syndrome increases the risk of gastric cancer (GC) and duodenal cancer (DC), particularly in individuals with MLH1 and MSH2 pathogenic variants (PVs). To provide further insight into whether, and from what age, esophagogastroduodenoscopy (EGD) surveillance may be beneficial, we evaluated the cumulative incidence and tumour characteristics of GC and DC in a large nationwide cohort of Dutch individuals with LS. Methods: For this retrospective nationwide cohort study, clinical data of individuals with LS registered at the Dutch Hereditary Cancer Registry were matched with pathology reports filed by the Dutch Pathology registry. All individuals registered between Jan 1, 1989 and Dec 31, 2021 with proven or putative PVs in one of the mismatch repair genes were included. Cumulative incidences of GC and DC were estimated for high-risk (MLH1, MSH2 and EpCAM) and low-risk (MSH6 and PMS2) PVs using competing risk methodology (Fine and Gray method) with death due to other causes as competing risk. Findings: Among 1002 individuals with high-risk and 765 individuals with low-risk PVs, 29 GCs (1.6%) and 39 DCs (2.2%) were diagnosed. Cumulative incidence of GC and DC under the age of 50 was very low (≤1%) for all individuals. At age 70 and 75, cumulative incidence of GC was 3% [95% CI 1%–5%] and 5% [3%–8%] for high-risk PVs and 1% [0%–2%] and 1% [0%–2%] for low-risk PVs (p = 0.006). For DC, cumulative incidence at age 70 and 75 was 5% [3%–7%] and 6% [3%–8%] in high-risk, 1% [0%–1%] and 2% [0%–4%] in low-risk PVs, respectively (p = 0.01). Primary tumour resection was performed in 62% (18/29) of GCs and 77% (30/39) of DC cases. Early-stage GC, defined as TNM stage I, was found in 32% (9/28) of GCs. Early-stage DC, defined as TNM stage I-IIa, was found in 39% (14/36) of DCs. Interpretation: Individuals with MLH1, MSH2, and EpCAM PVs have an increased risk of developing GC and DC at the age of 70 years, but this risk is very low before the age of 50 years. The age of onset of surveillance, the yield of GC and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies. </p

Adjuvant photodynamic therapy in head and neck cancer after tumor-positive resection margins

ObjectiveIn case of close or positive resection margins after oncological resection in head and neck surgery, additional treatment is necessary. When conventional options are exhausted, photodynamic therapy (PDT) can play a role in achieving clear margins. The purpose of the current study was to evaluate the clinical benefit of PDT as adjuvant therapy next to surgery with positive resection margins. The role of the time interval between surgery and PDT on survival outcomes also was investigated. Study DesignRetrospective cohort analysis. MethodsAdjuvant PDT was performed in patients with a malignancy in the head and neck region with close or positive resection margins who were not eligible for conventional treatment options. The primary endpoint was progression-free survival. Secondary endpoints were disease-free survival, overall survival, and optimal time interval between surgery and PDT. ResultsFifty-four patients were treated with surgery followed by meta-tetrahydroxyphenylchlorin-mediated PDT. There was a large diversity in tumor location and histopathology, as well as in time interval between surgery and PDT. The 2-year progression-free survival rate was 30%; 2-year disease-free survival rate was 28%; and 2-year overall survival was 51%. Disease-free survival was significantly better when the time interval between surgery and PDT was 6 weeks (P = 0.02). ConclusionPDT can be applied as adjuvant therapy after surgery in cases of a malignancy with close or positive tumor resection margins. However, the clinical benefits are yet to be determined. There is a significantly better disease-free survival with a time interval between surgery and PDT of minimal 6 weeks. Level of Evidence4. Laryngoscope, 128:657-663, 201

Oral and oropharyngeal squamous cell carcinoma in young patients: the Netherlands Cancer Institute experience

Head and neck squamous cell carcinoma (HNSCC) mainly affects patients between the fifth and seventh decade of life but is increasingly seen in young patients ( <40 years old). Controversy exists in the literature regarding outcomes for younger patients with HNSCC. A retrospective cohort analysis was performed comparing survival of 54 early-onset ( <40 years) and 1708 older patients with oral and oropharyngeal squamous cell carcinomas (SCC) treated at The Netherlands Cancer Institute between 1977 and 2008. Survival analysis was performed using univariable and multivariable weighted Cox proportional hazards regression. The primary endpoint for the survival analysis was disease-specific survival (DSS). There was no difference in DSS between patients who were 40 years or younger and those older than 40 years (p = .878), although young patients had significantly better overall survival (OS). In this series, patients younger than 40 years with oral and oropharyngeal SCC showed no significant difference in DSS compared with patients older than 40 years, even when adjusted for tobacco and alcohol consumptio

Safety and efficacy of RFA versus MWA for T1a renal cell carcinoma: a propensity score analysis

OBJECTIVES: Percutaneous radiofrequency ablation (RFA) is stated as a treatment option for renal cell carcinoma (RCC) smaller than 4 cm (T1a). Microwave ablation (MWA) is a newer technique and is still considered experimental in some guidelines. The objective of this study was to compare the safety and efficacy of RFA and MWA for the treatment of RCC. METHODS: Patients with T1a RCC treated by RFA or MWA in two referral centers were retrospectively analyzed. Patient records were evaluated to generate mRENAL nephrometry scores. Local tumor progression (LTP) was considered when new (recurrence) or residual tumor enhancement within/adjacent to the ablation zone was objectified. Differences in LTP-free interval (residual + recurrence) between ablation techniques were assessed with Cox proportional hazards models and propensity score (PS) methods. RESULTS: In 164 patients, 87 RFAs and 101 MWAs were performed for 188 RCCs. The primary efficacy rate was 92% (80/87) for RFA and 91% (92/101) for MWA. Sixteen patients had residual disease (RFA (n = 7), MWA (n = 9)) and 9 patients developed recurrence (RFA (n = 7), MWA (n = 2)). LTP-free interval was significantly worse for higher mRENAL nephrometry scores. No difference in LTP-free interval was found between RFA and MWA in a model with inverse probability weighting using PS (HR = 0.99, 95% CI 0.35-2.81, p = 0.98) and in a PS-matched dataset with 110 observations (HR = 0.82, 95% CI 0.16-4.31, p = 0.82). Twenty-eight (14.9%) complications (Clavien-Dindo grade I-IVa) occurred (RFA n = 14, MWA n = 14). CONCLUSION: Primary efficacy for ablation of RCC is high for both RFA and MWA. No differences in efficacy and safety were observed between RFA and MWA. KEY POINTS: • Both RFA and MWA are safe and effective ablation techniques in the treatment of T1a renal cell carcinomas. • High modified RENAL nephrometry scores are associated with shorter local tumor progression-free interval. • MWA can be used as heat-based ablation technique comparable to RFA for the treatment of T1a renal cell carcinomas

Incidence Changes of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma and Effects on Survival in the Netherlands Cancer Institute, 1980-2009

Aim: Human papillomavirus (HPV) is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence. The present study aimed to determine the changing incidence of HPV in patients with OPSCC in the period 1980-2009 and its influence on survival. Patients and Methods: We randomly sampled 158 patients from a cohort of 828 patients with OPSCC stratified by decade (1980-1989, 1990-1999, 2000-2009). Formalin-fixed paraffin-embedded material was tested for HPV DNA by SPF-10 polymerase chain reaction (PCR) and immuno histo chemically stained for p16 and p53. Results: DNA from 146 patients was suitable for HPV detection. HPV DNA was detected in 13/47 (28%), 18/47 (38%), and 20/52 (38%) patients in the cohorts of 19801989, 1990-1999, and 2000-2009, respectively (p-value for trend= 0.269). Lack of further increase during the most recent decade is inconsistent with the rising incidence and higher prevalence reported in other Western countries. Patients with HPV-positive OPSCC had a better survival in spite of higher tumor stag

Cochlea sparing effects of intensity modulated radiation therapy in head and neck cancers patients: a long-term follow-up study

Radiation to the inner ear may lead to (irreversible) sensorineural hearing loss. The purpose of this study was to evaluate the long-term effect of radiotherapy on hearing in patients treated with Intensity Modulated Radiation Therapy (IMRT), sparing the inner ear from high radiation dose as much as possible. Between 2003 and 2006, 101 patients with head and neck cancer were treated with IMRT. Audiometry was performed before, short-term, and long-term after treatment. Data were compared to normal hearing levels according to the International Organisation for Standardization (ISO). Statistical analysis was done using repeated measurements. None of the patients received chemotherapy. In 36 patients an audiogram at long-term follow-up (median 7.6 years) was available. The mean dose to the cochlea was 17.8 Gy (1.0-66.6 Gy). A hearing deterioration of 1.8 dB at Pure Tone Average (PTA) 0.5-1-2 kHz (p = 0.11), 2.3 dB at PTA 1-2-4 kHz (p = 0.02), and 4.4 dB at PTA 8-10-12.5 kHz (p = 0.01) was found. According to the ISO, the expected age-related hearing loss was 2.7, 4.8, and 8.8 dB at PTA 0.5-1-2 kHz, 1-2-4 kHz, and 8-10-12.5 kHz, respectively. After IMRT with radiation dose constraint to the cochlea, potential long-term adverse effects of IMRT remained subclinical. The progressive hearing loss over time was mild and could be attributed to the natural effects of ageing. Therefore, we recommend that a dose constraint to the cochlea should be incorporated in the head and neck radiotherapy protocol