Kees Verhoef

A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities

Abstract Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting. Methods. Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5–7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II). Results. A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24–78 years, median tumor size 9 cm, range 5–15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases. Conclusion. Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.

Isolated limb perfusion for melanoma in-transit metastases: developments in recent years and the role of tumor necrosis factor alpha.

Purpose of review The treatment of in-transit metastasis of melanoma remains challenging and is essentially dictated by the biological behavior of melanoma. When lesions are large or numerous, isolated limb perfusion (ILP) is an attractive treatment modality. In this review an overview of literature on treatment options of melanoma in-transit metastases will be discussed. Recent findings Most recent studies report on tumor necrosis factor (TNF) and melphalan based ILP (TM-ILP) series or mixed series of TM-ILP and melphalan only based ILP (M-ILP). After TM-ILP complete response rates of 70% (range 44–90%) have been reported, while for M-ILP this is lower with complete response rates of 54% (range 40–76%). The only randomized trial comparing TM-ILP and M-ILP revealed no clear benefit of TNF at 3 months, but improved outcome at 6 months and in patients with bulky disease. Reports on isolated limb infusion (ILI) with melphalan and actinimycin D indicate lower response rates, but similar local control rates as M-ILP at lower cost. Summary ILP is an attractive treatment option in melanoma patients with multiple in-transit metastases. In our opinion TM-ILP is superior to M-ILP as it achieves higher response rates, especially in patients with bulky disease. When lesions are small and in the distal two-thirds of the leg only, ILI is a valuable alternative.

A Novel Less-invasive Approach for Axillary Staging After Neoadjuvant Chemotherapy in Patients With Axillary Node-positive Breast Cancer by Combining Radioactive Iodine Seed Localization in the Axilla With the Sentinel Node Procedure (RISAS): A Dutch Prospective Multicenter Validation Study

Background In 1 of 3 patients with initial lymph node‐positive (cN+) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax‐pCR). This urges the need for a less‐invasive axillary staging method. Recently introduced less‐invasive procedures have been insufficient in accurately identifying ax‐pCR. Therefore, we propose a novel less‐invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB). Patients and Methods In the present open single‐arm multicenter validation study, 225 cN+ (biopsy‐proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine‐125 seed before NAC. After NAC completion, this iodine‐125 seed‐marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false‐negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported. Conclusion The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN+ patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax‐pCR confirmed using the RISAS procedure.

Implementation of the 7th edition AJCC staging system: Effects on staging and survival for pT1 melanoma. A Dutch population based study.

In the 7th edition of the AJCC staging system, the mitotic rate criterion replaced Clark level to increase correct classification of high‐risk thin melanoma patients (pT1B). Additionally, sentinel node biopsy (SNB) was recommended for nodal staging of pT1B melanomas. The aim of this article was to evaluate the effects on pT1 substaging and clinical implications in the national pT1 melanoma population. All pT1 melanomas diagnosed in the Netherlands between 2003 and 2014 were selected from the Netherlands Cancer Registry (IKNL). Patients were stratified by cohort according to AJCC edition: (1) 2003–2009 (6th) and (2) 2010–2014 (7th). Relative survival was calculated to estimate melanoma‐specific survival. A total of 29.546 pT1 melanoma patients were included. The pT1b proportion increased from 10.1% in Cohort 1 to 21.5% in Cohort 2. The proportion of performed SNBs per cohort increased: for pT1b melanomas alone from 4.5% to 13.0%. SNB positivity rate decreased from 10.5% to 8.8% for the entire pT1 population, and for pT1b melanomas from 11.3% to 8.6%. At 5 years, the relative survival rate was similar for pT1a and pT1b in both cohorts, namely, pT1a 100% vs pT1b 97% (Cohort 1), and pT1a 100% vs pT1b 98% (Cohort 2). The 7th edition of the AJCC staging system has caused an increased number of patients to undergo SNB, without an increase in SNB positivity rate. Survival between pT1 subgroups remains similar. The mitotic rate criterion for pT1b classification and the recommendation to perform SNB for pT1b melanomas should be reconsidered.

Pigmentation in the sentinel node correlates with increased sentinel node tumor burden in melanoma patients.

The prognosis of sentinel node (SN)-positive melanoma patients is predicted by a number of characteristics such as size and site of the metastases in the SN. The pathway and prognosis of strong pigmentation of melanoma metastases in the SN is unclear. The aim of this study is to evaluate the role of pigmentation and growth pattern of metastases in the SN with respect to survival. A total of 389 patients underwent an SN procedure (1997–2011). Ninety-five patients had a positive SN and material from 75 patients was available for review. The median follow-up time was 75 months (range 6–164). Pigmentation was scored from 0 to 2 using the following scale: 0=absent, 1=slight, and 2=strong. Growth pattern was scored as either eccentric (1) or infiltrative (2). SN tumor burden was measured according to the Rotterdam criteria. The primary melanoma had a median Breslow thickness of 2.90 mm (0.8–12.00 mm). Ulceration was present in 34 patients (45.3%). There was a median SN tumor burden of 0.5 mm (0.05–7.00 mm). In a total of 75 patients, 59 patients (79%) had no pigmentation, 13 patients (17%) had slight pigmentation, and three patients (4%) had strong pigmentation in the SN. Because of the small numbers, the classification was modified to either absent 59 (79%) or present 16 (21%) pigmentation, respectively. The SN tumor burden was significantly higher (P=0.031) for patients with pigmentation. Patients with pigmentation had a 5-year melanoma-specific survival (MSS) of 47% and a 10-year MSS of 33%. Patients without pigmentation had a 5-year MSS of 70% and a 10-year MSS of 59% (P=0.06). There was no difference in MSS for patients with an eccentric or an infiltrative growth pattern, nor did it correlate with other prognostic factors. Multivariate analysis for MSS showed five significant factors associated with worse prognosis: male sex (P=0.036), nodular melanoma (P=0.001), truncal site (P=0.0001), SN tumor burden more than 1.0 mm (P=0.022), and positive completion lymph node dissection (P=0.004). The 5-year MSS for SN tumor burden is 94% for 0.1 mm or less, 66% for 0.1–1.0 mm, and 41% for more than >1.0 mm (P<0.001). The 10-year MSS for SN tumor burden is, respectively, 94, 51, and 35% (P<0.001). This preliminary exploratory retrospective study showed that pigmentation within the SN seems to correlate with increased SN tumor burden.

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.