Rectal cancer: steps towards tailored treatment

Treatment options for rectal cancer include surgery, radiation therapy and chemotherapy. In recent years, there has been an increased interest in organ-saving treatment of rectal cancer. This dissertation is aimed at tailoring the treatment of patients with rectal cancer. Three aspects were studied, namely the use of PET scans to make radiation therapy more accurate, the development of models to predict reactions to radiation therapy and the intensifying of radiation therapy to increase the chances of the tumour reacting to treatment. PET imaging proved to be useful in making radiation therapy more accurate. Furthermore, it was found that reactions to radiation therapy can be predicted by using PET scans and blood samples, among other things

Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer

PURPOSE: To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced cancer. MATERIAL AND METHODS: Twelve patients were treated with to 50.4Gy combined with capecitabine 825mg/m2 BID. Three dose levels nelfinavir were tested: 750mg BID (DL1), 1250mg BID (DL2) and an level of 1000mg BID (DL3). Surgery was performed between 8 and 10weeks completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), any grade 3 or higher non-hematological or grade 4 or higher toxicity. RESULTS: Eleven patients could be analyzed: 5 were treated in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase patient had a gr 3 cholangitis with unknown cause. An intermediate dose tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 3 transaminase elevation and gr 4 post-operative wound complication. patients achieved a pathological complete response (pCR). CONCLUSIONS: 750mg BID was defined as the recommended phase II dose in combination capecitabine and 50.4Gy pre-operative radiotherapy in rectal cancer. response evaluations are promising, but a further phase II study is more information about efficacy of this treatment regimen

Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma (Withdrawn Paper, art. no. CD006377, 2010)

Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervical carcinoma (LACC).To assess whether adding hyperthermia to standard radiotherapy for LACC has an impact on (1) local tumour control, (2) survival and (3) treatment related morbidity.The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 1, 2009) and Cochrane Gynaecological Cancer Groups Specialised Register, MEDLINE, EMBASE, online databases for trial registration, handsearching of journals and conference abstracts, reviews, reference lists, and contacts with experts were used to identify potentially eligible trials, published and unpublished until January 2009.RCTs comparing radiotherapy alone (RT) versus combined hyperthermia and radiotherapy (RHT) in patients with LACC.Between 1987 and 2009 the results of six RCTs were published, these were used for the current analysis.74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 1 to 3). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p <0.001), a significantly reduced local recurrence rate at 3 years (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p <0.001) and a significanly better overall survival (OS) at three years following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments.The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervical carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity

Whole breast and regional nodal irradiation in prone versus supine position in left sided breast cancer

Background: Prone whole breast irradiation (WBI) leads to reduced heart and lung doses in breast cancer patients receiving adjuvant radiotherapy. In this feasibility trial, we investigated the prone position for whole breast + lymph node irradiation (WB + LNI). Methods: A new support device was developed for optimal target coverage, on which patients are positioned in a position resembling a phase from the crawl swimming technique (prone crawl position). Five left sided breast cancer patients were included and simulated in supine and prone position. For each patient, a treatment plan was made in prone and supine position for WB + LNI to the whole axilla and the unoperated part of the axilla. Patients served as their own controls for comparing dosimetry of target volumes and organs at risk (OAR) in prone versus in supine position. Results: Target volume coverage differed only slightly between prone and supine position. Doses were significantly reduced (P < 0.05) in prone position for ipsilateral lung (Dmean, D2, V5, V10, V20, V30), contralateral lung (Dmean, D2), contralateral breast (Dmean, D2 and for total axillary WB + LNI also V5), thyroid (Dmean, D2, V5, V10, V20, V30), oesophagus (Dmean and for partial axillary WB + LNI also D2 and V5), skin (D2 and for partial axillary WB + LNI V105 and V107). There were no significant differences for heart and humeral head doses. Conclusions: Prone crawl position in WB + LNI allows for good breast and nodal target coverage with better sparing of ipsilateral lung, thyroid, contralateral breast, contralateral lung and oesophagus when compared to supine position. There is no difference in heart and humeral head doses

Impact of the COVID-19 Pandemic on Colorectal Cancer Care in the Netherlands: A Population-based Study

Contains fulltext : 283493.pdf (Publisher’s version ) (Open Access)INTRODUCTION: The COVID-19 pandemic disrupted health care services worldwide. In the Netherlands, the first confirmed COVID-19 infection was on February 27, 2020. We aimed to investigate the impact of the pandemic on colorectal cancer care in the Netherlands. METHODS: Colorectal cancer patients who were diagnosed in 25 hospitals in weeks 2 to 26 of the year 2020 were selected from the Netherlands Cancer Registry (NCR) and divided in 4 periods. The average number of patients treated per type of initial treatment was analyzed by the Mantel-Haenszel test adjusted for age. Median time between diagnosis and treatment and between (neo)adjuvant therapy and surgery were analyzed by the Mann Whitney test. Percentages of (acute) resection, stoma and (neo)adjuvant therapy were compared using the Chi-squared test. RESULTS: In total, 1,653 patients were included. The patient population changed during the COVID-19 pandemic regarding higher stage and more clinical presentation with ileus at time of diagnosis. Slight changes were found regarding type of initial treatment. Median time between diagnosis and treatment decreased on average by 4.5 days during the pandemic. The proportion of colon cancer patients receiving a stoma significantly increased with 6.5% during the pandemic. No differences were found in resection rate and treatment with (neo)adjuvant therapy. CONCLUSION: Despite the disruptive impact of the COVID-19 pandemic on global health care, the impact on colorectal cancer care in the Netherlands was limited

A facile and green route to terpene derived acrylate and methacrylate monomers and simple free radical polymerisation to yield new renewable polymers and coatings

We present new acrylic monomers derived directly from abundant naturally available terpenes via a facile, green and catalytic approach. These monomers can be polymerised to create new polymers with a wide range of mechanical properties that positions them ideally for application across the commodity and specialty plastics landscape; from packaging, cosmetic and medical, through to composites and coatings. We demonstrate their utility through formation of novel renewable polymer coatings

Treatment and overall survival of four types of non-metastatic periampullary cancer:nationwide population-based cohort study

Background: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin. Methods: Patients diagnosed with non-metastatic periampullary cancer in 2012–2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan–Meier analysis and multivariable Cox regression analyses, stratified by origin. Results: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55–0.69) and DC (HR = 0.69; 95% CI 0.48–0.98), but not AC (HR = 0.87; 95% CI 0.62–1.22) and DA (HR = 0.85; 95% CI 0.48–1.50). Conclusion: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA

Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours