Understanding the tumor-host interaction, the key to more effective anti-cancer treatment

Chemotherapy is the main treatment modality for patients with metastatic disease. Unfortunately, response to chemotherapy is only transient and eventually almost all tumors become resistant to chemotherapy. Development of resistance to chemotherapy is therefore one of the major obstacles in the effective treatment of cancer patients with metastatic disease. In addition to conventional chemotherapy, more and more targeted therapies are directed against specific properties of the tumor cell itself, against the cells in the immediate vicinity of the tumor or to certain growth factors that are known to stimulate tumor growth. This thesis focuses on the tumor-host interaction, it examines the role of different bone marrow derived cells (BMDCs) in tumor growth, metastasis formation and response to therapy in order to find new targets to improve anti-cancer therapy in patients. The clinical implications of this thesis mainly consist of optimizing the effect of current treatments by better combining agents and identifying new targets for therapy. Based on our results, combining conventional chemotherapy with targeted therapies, in order to prevent the systemic host-repair response, seems promising to enhance chemotherapy efficacy. Various combinations with agents targeting the different aspects of the tumor-host interaction could be explored. Conventional chemotherapy can potentially be combined with agents targeting the various growth factors and cytokines involved in the release or homing of BMDC to the tumor, including VEGF and SDF1α. Secondly, agents blocking the downstream effects of the BMDCs, including inhibition of the production of the identified PIFAs as described in chapter 2 and antibodies against e.g. Il-6, CCL5, VEGFR-1, can potentially enhance the efficacy of chemotherapy. Thirdly, more general modulators of the micro-environment like erlotinib, imatinib or hedgehog inhibitors are promising targets to enhance conventional chemotherapy. Notably, besides choosing the right combination of drugs, the timing of the different drugs is also essential to optimize efficacy by preventing the chemotherapy-induced host response in time. In the design of new clinical studies, this concept of enhancing conventional chemotherapy by blunting the host-repair response should be further explored. Concluding, this thesis shows that in addition to the direct anti-tumor effect of the chemotherapy, chemotherapy elicits a protective host response that actually promotes tumor growth. The outcome will therefore be determined by the balance between the cytotoxic effects of chemotherapy on one hand versus the activation of the microenvironment on the other hand, which might obfuscate the benefits of treatment and may actually induce resistance. Clinical studies are needed to evaluate the relative importance of this mechanism in the treatment of patients with cance

Correlation of Immunological and Histopathological Features with Gene Expression-Based Classifiers in Colon Cancer Patients

The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers-(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients. Contingency tables were constructed and a chi 2 test was used to test for statistical significance. Odds ratios with 95% confidence intervals were calculated. The presence of tumor infiltrating lymphocytes and a mucinous phenotype (>50% mucinous surface area) were strongly correlated with CMS1 (p = 10%) was associated with CMS3: mucus was present in 64.1% of all CMS3 tumors (p < 0.001). Although a clear association between tumor-stroma ratio and CMS4 was established in this study (p = 0.006), still 32 out of 61 (52.5%) CMS4 tumors were scored as stroma-low, indicating that CMS4 tumors cannot be identified solely based on stromal content. Higher budding counts were seen in CMS4 and CRIS-B tumors (p = 0.045 and p = 0.046). No other associations of the measured parameters were seen for any of the other CRIS subtypes. Our analysis revealed clear associations between histopathologic features and CMS or CRIS subtypes. However, identification of distinct molecular subtypes solely based on histopathology proved to be infeasible. Combining both molecular and morphologic features could potentially improve patient stratification

Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT)

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022

Multicentre study of short-course radiotherapy, systemic therapy and resection/ablation for stage IV rectal cancer

Background The optimal treatment sequence for patients with rectal cancer and synchronous liver metastases remains unclear. The aim of this study was to evaluate the feasibility and effectiveness of short-course pelvic radiotherapy (5 x 5 Gy) followed by systemic therapy and local treatment of all tumour sites in patients with potentially curable stage IV rectal cancer in daily practice.Methods This was a retrospective study performed in eight tertiary referral centres in the Netherlands. Patients aged 18 years or above with rectal cancer and potentially resectable liver +/- extrahepatic metastases, treated between 2010 and 2015, were eligible. Main outcomes included full completion of treatment schedule, symptom control and survival.Results In total, 169 patients were included with a median follow-up of 49 center dot 5 (95 pr cent c.i. 43 center dot 6 to 55 center dot 6) months. The completion rate for the entire treatment schedule was 65 center dot 7 per cent. Three-year progression-free survival and overall survival (OS) rates were 24 center dot 2 (95 per cent c.i. 16 center dot 6 to 31 center dot 6) and 48 center dot 8 (40 center dot 4 to 57 center dot 2) per cent respectively. Median OS of patients who responded well and completed the treatment schedule was 51 center dot 5 months, compared with 15 center dot 1 months for patients who did not complete the treatment (P < 0 center dot 001). Adequate symptom control of the primary tumour was achieved in 87 center dot 0 per cent of all patients.Conclusion Multimodal treatment is palliative in most patients, and associated with good survival rates in those able to complete the schedule.Experimentele farmacotherapi

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era

Contains fulltext : 230109.pdf (Publisher’s version ) (Closed access)BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients