Chemotherapy and Chemoradiotherapy Studies in Oesophageal Cancer

The aim of this thesis was, first, to explore the use of preoperative chemoradiotherapy and palliative chemotherapy in the treatment of oesophageal cancer. Furthermore, the effects of a chemoradiotherapy regimen on histopathological and psychological and social level were studied. Chapter 2 provides a review of the literature on systemic treatment for oesophageal cancer. An overview is given for preoperative and postoperative chemotherapy, preoperative chemoradiotherapy, definitive chemoradiotherapy, and palliative chemotherapy. In Chapter 3 the efficacy and safety of preoperative chemoradiotherapy consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable oesophageal cancer is studied. Chapter 4 describes the histopathological effects of the above mentioned chemoradiotherapy regimen and correlates the effect of specific pathologic and clinical findings to overall survival. In Chapter 5 the health related quality of life up to one year after surgery, in patients with oesophageal cancer treated with curative intent with neoadjuvant chemoradiotherapy consisting of the above mentioned regimen followed by oesophagectomy is evaluated. Finally, in Chapter 6 the analysis of a phase II study evaluating the safety and efficacy of the combination of oxaliplatin and capecitabine in patients with metastatic or local-regional unresectable carcinoma of the oesophagus, oesophagogastric junction, and cardia is given. In addition, the effect of this regimen of the patients’ well-being is evaluated by performing a quality of life analysis on these patients during the treatment. The studies described in this thesis are summarized in Chapter 7. Furthermore, potential directions for future studies are addressed

Relation between body composition and severe diarrhea in patients treated with preoperative chemoradiation with capecitabine for rectal cancer:a single-centre cohort study

BACKGROUND: Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. METHODS: A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. RESULTS: A total of 746 patients were included. Median age was 64 years (interquartile range 57–71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54–7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85–5.87) were the only risk factors for severe diarrhea. CONCLUSIONS: Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea

Catalytic activity of the membrane-bound methylcholanthrene-inducible cytochrome P-450

AbstractThe benzopyrene hydroxylase activity of the methylcholanthrene-inducible form of cytochrome P-450 (P-448) has been studied in native and reconstituted liver microsomal membranes. The data obtained show that the molecular catalytic activity of membrane-bound cytochrome P-448 depends on the molar ratio of the cytochrome to NADPH-cytochrome P-450 reductase and that the optimal ratio for maximal activity of cytochrome P-448 in the microsomal membrane essentially differs from the equimolar one

Treatment of Inguinal Lymph Node Metastases in Patients with Rectal Adenocarcinoma

Background Inguinal lymph node metastases (ILNM) from rectal adenocarcinoma are rare and staged as systemic disease. This study aimed to provide insight into the treatment and prognosis of ILNM from rectal adenocarcinoma. Methods All patients with a diagnosis of synchronous or metachronous ILNM from rectal adenocarcinoma between January 2005 and March 2017 were retrospectively reviewed. Result

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m−2 and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3–4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing

Diagnostic performance of FDG-PET/CT of post-transplant lymphoproliferative disorder and factors affecting diagnostic yield

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT. METHODS: This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed. RESULTS: The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04). CONCLUSION: FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield

Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma:a Dutch population-based study

In 2017, the European Medicines Agency approved rituximab biosimilars (R-biosimilars) for treatment of diffuse large B-cell lymphoma (DLBCL). Thereafter, the Netherlands was one of the first countries to implement R-biosimilars, given lower costs compared with rituximab originator (R-originator). This study's objective was to investigate whether overall survival (OS) of patients with DLBCL receiving R-biosimilars is similar to patients treated with R-originator. DLBCL patients ≥18 years, diagnosed between 2014 and 2018, who received at least 1 cycle of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were identified in the Netherlands Cancer Registry. Patients were categorized into R-originator or R-biosimilars groups based on data from a central repository of the Dutch medicinal drug market. The primary end point was 3-year OS, defined as the time between diagnosis and all-cause death. By the end of 2018, 91% of purchased rituximab were biosimilars. In total, 4429 patients were identified with 876 in the R-biosimilars group and 3553 in the R-originator group. Patients in the R-biosimilars group less frequently received .6 cycles of R-CHOP compared with patients treated with R-originator (24% vs 30%, P 5 .003). The 3-year OS did not differ between patients treated with R-originator or R-biosimilars (73% vs 73%, P = .855). This was confirmed with a multivariable Cox regression analysis accounting for sex, age, International Prognostic Index score, and number of R-CHOP cycles. In conclusion, the 3-year OS is similar for patients treated with CHOP in combination with R-originator or R-biosimilars and, therefore, favors the use of R-biosimilars in DLBCL treatment management

Value of bronchoscopy after EUS in the preoperative assessment of patients with esophageal cancer at or above the carina

Introduction: Esophageal cancer is an aggressive disease with a strong tendency to infiltrate into surrounding structures. The aim of the present study is to determine the additional value of bronchoscopy for detecting invasion of the tracheobronchial tree after endoscopic ultrasonography (EUS) in the preoperative assessment of patients with esophageal cancer at or above the carina. Materials and Methods: Between January 1997 and December 2006, 104 patients were analyzed for histologically proven esophageal cancer at or above the carina. All patients underwent both EUS and bronchoscopy (with biopsy on indication) in the preoperative assessment of local resectability. Results and Discussion: After extensive diagnostic workup, 58 of 104 patients (56%) were eligible for potentially curative esophagectomy; nine of these 58 patients (9/58, 15%) appeared to be incurable peroperatively because of ingrowth in the tracheobronchial tree (five patients), ingrowth in other vital structures (two patients) or distant metastases (two patients). Of the 46 non-operable patients, local irresectability (T-stage 4) was identified in 26 patients (26/46, 57%) due to invasion of vital structures on EUS: invasion of the aorta in six patients, invasion of the lung in 11 patients; in 12 patients invasion of the tracheobronchial tree was described, which was confirmed by bronchoscopy in only five patients. No patients with T4 were identified by bronchoscopy alone. Conclusion: For patients with esophageal tumors at or above the carina, no additional value of bronchoscopy (with biopsy on indication) to exclude invasion of the tracheobronchial tree was seen after EUS in a specialized centre. Although based on relatively small numbers, we conclude that bronchoscopy is not indicated if no invasion of the airways is identified on EUS

First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study

This phase II study assessed the safety and efficacy of oxaliplatin and capecitabine in patients with advanced oesophageal cancer. Fifty-one eligible patients received oxaliplatin 130 mg m−2 intravenously on day 1 and capecitabine 1000 mg m−2 orally twice daily on days 1 to 14 in a 21-day treatment cycle as first-line treatment for advanced oesophageal cancer. Grade 3 neutropenia was seen in one patient and anaemia in another patient. No grade 4 haematological toxicities were observed. Grade 4 non-haematological toxicity (lethargy) occurred in one patient (2%). Grade 3 non-haematological toxicity was seen in 14 (27%) patients (vomiting and polyneuropathy (8%); nausea (6%); lethargy and hand–foot syndrome (4%); and anorexia, diarrhoea, and hyperbilirubinaemia (each in one patient)). In 22% of the patients, toxicity was the reason for stopping the treatment. The overall response rate was 39%. The median overall survival was 8 months; the 1-year survival rate was 26%. In the quality of life (QoL) analysis, the emotional well-being improved during treatment, but the physical functioning scores declined. The fatigue score on the symptom scales increased. Overall, the global QoL score did not change during treatment. In conclusion, the activity of oxaliplatin and capecitabine is comparable with other chemotherapy regimens in advanced oesophageal cancer with a low frequency of grade 3/4 toxicity. Because this treatment can be given on an outpatient basis, it is probably less toxic than cisplatin-based therapy and preserves QoL during treatment, it is a viable treatment option in patients with advanced oesophageal cancer