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To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.

PURPOSE: To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20).METHODS: Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified.RESULTS: CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi-factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy.CONCLUSIONS: Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months [n=30; 95% confidence interval (CI): 6.8-15.7], 8.8 months for dabrafenib alone (n=31; 95% CI: 3.9-13.7), and 5.7 months for vemurafenib (n=85; 95% CI: 4.6-6.8). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group (hazard ratio for death, 0.52; 95% CI: 0.30-0.89; P=0.02). Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months (95% CI: 3.2-8.5), 5.7 months (95% CI: 3.0-8.4) for dabrafenib, and 3.6 months (95% CI: 3.5-3.8) for vemurafenib (P=0.54). A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

Composite scales such as the Total Neuropathy Score clinical version (TNSc(©) ) have been widely used to measure neurological impairment in a standardized manner but they have been criticized due to their ordinal setting having no fixed unit. This study aims to improve impairment assessment in patients with chemotherapy-induced peripheral neuropathy (CIPN) by subjecting TNSc(©) records to Rasch analyses. In particular, we wanted to investigate the influence of factors affecting the use of the TNSc(©) in clinical practice. TNSc(©) has 7 domains (sensory, motor, autonomic, pin-prick, vibration, strength, and deep tendon reflexes [DTR]) each being scored 0-4. Data obtained in 281 patients with stable CIPN were subjected to Rasch analyses to determine the fit to the model. The TNSc(©) did not meet Rasch model's expectations primarily because of misfit statistics in autonomic and DTR domains. Removing these two, acceptable model fit and uni-dimensionality were obtained. However, disordered thresholds (vibration and strength) and item bias (mainly cultural) were still seen, but these findings were kept to balance the assessment range of the Rasch-Transformed TNSc(©) (RT-TNSc(©) ). Acceptable reliability findings were also obtained. A 5-domains RT-TNSc(©) may be a more proper assessment tool in patients with CIPN. Future studies are needed to examine its responsive properties.

Reports on the outcome of patients with primary central nervous system lymphoma (PCNSL) are mainly based on results obtained in the context of clinical trials. However, due to poor performance status and cognitive impairment, most patients are actually treated outside clinical studies. The aim of this retrospective study was to get more insight into the outcome of HIV-negative PCNSL patients, treated between 2000-2010 in two hospitals (one academic centre and one categorical cancer centre). Fifty-two patients were identified. Eight patients were treated with corticosteroids only. Sixteen patients received high-dose methotrexate (MTX)-based chemotherapy, ten received radiotherapy and 18 patients were treated with a combination of MTX-based chemotherapy and radiotherapy. At a median follow-up of 63.1 months, the median overall survival for all patients was 24.4 months (95% CI: 11.5-39.8 months), with an event-free survival of 14 months (95% CI: 7.3-24.4 months). Causes of death were progressive PCNSL in 29 patients, MTX toxicity in four patients and epileptic seizures in one patient. These results are comparable with the outcome of prospective clinical trials in this disease, which still has a relatively poor prognosis.

Biomarkers as biological signposts of cancer have become an essential component of oncology drug development. The importance of biomarkers in oncology has grown substantially due to the advent of targeted anti-cancer therapies, which are directed against a specific biological target that tumor cells rely on for their growth. In clinical cancer trials, biomarkers are used for the selection of patients most likely to benefit from a certain (personalized) treatment. Biomarkers can also facilitate the early detection of treatment outcome, which may provide essential guidance for treatment modification or discontinuation. For these reasons, the interest in the use of biomarkers in cancer trials has grown considerably over the past 60 years. Many challenges are encountered in the development of reliable and robust methods used for the measurement of biomarkers. Firstly, biomarkers need to be detected in patient material such as body fluids and tissue that contain a complex mixture (the matrix) of similar endogenous molecules. Secondly, endogenous compounds may affect the stability of a biomarker, or the biomarker is susceptible to post-translational modification. Thirdly, obtaining biomarker-free matrices for the method development is often impossible. Lastly, sometimes a pure and certified biomarker is not available to serve as reference standard. The level of purification of these reference standards may vary considerably between manufacturers, resulting in high lot-to-lot variation of 76% in a European Bioanalysis Forum case study. In this thesis, we focus on the development and validation of diagnostic and pharmacodynamic biomarker methods for the support of (pre)clinical cancer studies. Diagnostic biomarkers provide essential insight into the patient’s disease condition, for instance whether metastases are present. In contrast, pharmacodynamic biomarkers are used to establish whether a cancer drug is hitting its pharmacological target and thereby help to guide the clinical decision making about drug dose and optimal administration schedule. In regard to the importance of biomarkers, laboratory methods for their measurement need to be extensively validated to ensure that the used methods are specific, accurate, precise, and robust. We found, however, that only 13% of the pharmacodynamic biomarker methods used in clinical cancer trials for the past 7 years were fully validated. The majority of biomarker methods used in clinical trials have only partly been validated, which may explain why these methods not always perform as expected in the clinic. It may also be an important factor in the relatively low approval rate of 27% for new cancer drugs in 2018. This lack of validation for clinical cancer biomarker methods may be explained by the absence of international guidelines for their validation. However, since 2018 recommendations for the validation of biomarker methods have existed from the Food and Drug administration. Here, we demonstrate the development of seven cancer biomarker methods, and show that full validation of these biomarker methods is possible. These biomarker methods were designed for high sensitivity and precision to further enhance their clinical usefulness. We successfully applied these fully validated biomarker methods in (pre) clinical cancer studies. The clinical chemistry laboratory of our hospital, Antoni van Leeuwenhoek, has implemented our biomarker method for the detection of epithelial circulating tumor cells as a standard diagnostic tool for the diagnosis of leptomeningeal metastases.

PhD Defence: Clinical pharmacology of anticancer agents with focus on neuro-oncology and biomarker assessment Patients with leptomeningeal metastases have a poor prognosis with a one year survival rate of 16-24%. Metastases to the leptomeninges, the lining of the brain and spinal cord, surrounded by cerebrospinal fluid (CSF), are difficult to detect with the currently used techniques. New methods to detect circulating tumour cells in CSF are presented. Circulating tumour cells in CSF were isolated via magnetism and subsequently stained. The cells were counted one by one with a laser and a detector. In addition we were able to analyse the cells genetically which opens possibilities for targeted therapies. In patients with an epithelial tumor (e.g. breast- or lung cancer) and a clinical suspicion on leptomeningeal metastases circulating tumour cells were found in the CSF of 94% of the patients who were finally diagnosed with the disease. The diagnosis could be made in 76% of the patients with the method used in clinical practice, viz. microscopic examination of the CSF by the pathologist. The clinical pharmacology of anticancer agents is described in part II. Generally it is assumed that large molecules like antibodies cannot penetrate and pass the blood brain barrier. However, encouraging results have been reported for immunotherapy with the antibodies nivolumab and ipilimumab in patients with melanoma brain metastases. We could detect nivolumab in the CSF and gave a perspective on the pharmacology of nivolumab and ipilimumab in melanoma brain metastases. Finally, potential novel drugs and novel combinations of drugs were investigated in phase I clinical trials and are described in this thesis.

This thesis focused on different aspects of melanoma treatment with immunotherapy and targeted therapy. In chapter 2 we search for biomarkers that could be associated with overall survival in patients treated with ipilimumab. In chapter 3 we describe diarrea, a commonly seen side effect of immunotherapy. Here we show that there is no significant correlation between grade of diarrhea and severity of colitis as seen during endoscopy. Chapters 4 and 5 describe patients with brain metastases and/or leptomeningeal metastases. In chapter 4 we show the difference in overall survival in patients treated with vemurafenib, dabrafenib or the combination of dabrafenib + trametinib. Chapter 5 focusses on the treatment of leptomeningeal metastases. Here a significant difference in overall survival was noted between treated and untreated patients. Furthermore LDH was a predictive biomarker for overall survival. In chapter 6 we show that treating patients with vemurafenib beyond progression of disease has a significant impact on overall survival. Lastly in chapter 7 we review the past, present and future of treating patients with different kinds of cancer with tumor-infiltrating lymphocytes.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. Patients and methods After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. Results Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test–retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. Conclusion Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Chemotherapy is a very frequently used therapy in patients with advanced tumors with or without central nervous system (CNS) metastases or primary brain tumors. Despite the significant progress in drug development, the survival of patients is limited with an unmet need for more effective chemotherapeutics that have an acceptable safety profile. This thesis presents I/II clinical phase studies with an aim to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and the preliminary anti-tumor activity of novel anti-cancer drugs or new combinations of drugs already in use. During the research we were able to recommend dosing schedules and dose-levels of the (combination of) drug(s) for further clinical studies and confirmed drug-drug interactions or food-effects. The second part of this thesis presents pharmaceutical/nanomedicine strategies and laboratory assays in the treatment, diagnosis and drug-monitoring of central nervous system (CNS) tumors. We represent the review of the literature that discusses new drug strategies of targeting blood-brain barrier (BBB) by active chemo- and immunotherapies. Due to the presence of the blood-brain barrier (BBB) only few systemic drugs can be used to treat brain tumors. As treatment of systemically metastasized cancer patients becomes more effective and prolongs patient’s survival, CNS metastases are more frequently observed. Recently, using nanotechnology active chemotherapeutics can be safely transported across the barriers (BBB and blood-cerebrospinal fluid barrier (BCSFB)) and target brain and CSF, respectively. Further studies on improving the brain-penetration of potentially effective drugs for brain tumors is warranted. In the line with this we describe two clinical studies with a novel strategy consisting of administration of glutathione liposomal PEGylated doxorubicin (2B3-101) as a treatment of patients with solid tumors and brain metastases or recurrent malignant glioma and leptomeningeal metastases from breast cancer. Doxorubicin is a well- known, frequently used chemotherapeutic agent in various tumor types, such as breast cancer and lung cancer. Glioblastoma cell lines showed to be sensitive to doxorubicin, however, without the carrier, doxorubicin cannot pass the BBB. The first study with 2B3-101 demonstrated that treatment of patients with solid tumors and brain metastases or malignant gliomas with 2B3-101 showed a dose-dependent PK profile and is safe and relatively well tolerated with both as single agent and with trastuzumab co-administration. Intracranial and extracranial preliminary anti-tumor activity was observed in patients with (HER2+) breast cancer with brain metastases and malignant glioma. In the second study using 2B3-101 in patients with leptomeningeal metastases (LM) from breast cancer, doxorubicin concentrations in the CSF were within the reported IC50, a measure of effectiveness in-vitro in two out of three patients. One of the three treated patients with LM showed stable disease for 10 cycles and progression free survival for more than six months. Further we demonstrate the clinical application of the circulating tumor cell assay (CTC) for EPCAM-positive cells (an epithelial tumor cell marker) to be more sensitive in diagnosing leptomeningeal metastases in CSF (100%), than the standard CSF cytology method (71%) in patients with clinically suspected LM or with already diagnosed LM, while both methods showed a very high specificity (100%).

Chemotherapy is a very frequently used therapy in patients with advanced tumors with or without central nervous system (CNS) metastases or primary brain tumors. Despite the significant progress in drug development, the survival of patients is limited with an unmet need for more effective chemotherapeutics that have an acceptable safety profile. This thesis presents I/II clinical phase studies with an aim to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and the preliminary anti-tumor activity of novel anti-cancer drugs or new combinations of drugs already in use. During the research we were able to recommend dosing schedules and dose-levels of the (combination of) drug(s) for further clinical studies and confirmed drug-drug interactions or food-effects. The second part of this thesis presents pharmaceutical/nanomedicine strategies and laboratory assays in the treatment, diagnosis and drug-monitoring of central nervous system (CNS) tumors. We represent the review of the literature that discusses new drug strategies of targeting blood-brain barrier (BBB) by active chemo- and immunotherapies. Due to the presence of the blood-brain barrier (BBB) only few systemic drugs can be used to treat brain tumors. As treatment of systemically metastasized cancer patients becomes more effective and prolongs patient’s survival, CNS metastases are more frequently observed. Recently, using nanotechnology active chemotherapeutics can be safely transported across the barriers (BBB and blood-cerebrospinal fluid barrier (BCSFB)) and target brain and CSF, respectively. Further studies on improving the brain-penetration of potentially effective drugs for brain tumors is warranted. In the line with this we describe two clinical studies with a novel strategy consisting of administration of glutathione liposomal PEGylated doxorubicin (2B3-101) as a treatment of patients with solid tumors and brain metastases or recurrent malignant glioma and leptomeningeal metastases from breast cancer. Doxorubicin is a well- known, frequently used chemotherapeutic agent in various tumor types, such as breast cancer and lung cancer. Glioblastoma cell lines showed to be sensitive to doxorubicin, however, without the carrier, doxorubicin cannot pass the BBB. The first study with 2B3-101 demonstrated that treatment of patients with solid tumors and brain metastases or malignant gliomas with 2B3-101 showed a dose-dependent PK profile and is safe and relatively well tolerated with both as single agent and with trastuzumab co-administration. Intracranial and extracranial preliminary anti-tumor activity was observed in patients with (HER2+) breast cancer with brain metastases and malignant glioma. In the second study using 2B3-101 in patients with leptomeningeal metastases (LM) from breast cancer, doxorubicin concentrations in the CSF were within the reported IC50, a measure of effectiveness in-vitro in two out of three patients. One of the three treated patients with LM showed stable disease for 10 cycles and progression free survival for more than six months. Further we demonstrate the clinical application of the circulating tumor cell assay (CTC) for EPCAM-positive cells (an epithelial tumor cell marker) to be more sensitive in diagnosing leptomeningeal metastases in CSF (100%), than the standard CSF cytology method (71%) in patients with clinically suspected LM or with already diagnosed LM, while both methods showed a very high specificity (100%).

Background: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. Patients and methods: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc (c)), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). Results: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. Conclusion: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.