Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant. Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005). Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.

Harnessing Integrative Omics to Facilitate Molecular Imaging of the Human Epidermal Growth Factor Receptor Family for Precision Medicine.

Cancer is a growing problem worldwide. The cause of death in cancer patients is often due to treatment-resistant metastatic disease. Many molecularly targeted anticancer drugs have been developed against 'oncogenic driver' pathways. However, these treatments are usually only effective in properly selected patients. Resistance to molecularly targeted drugs through selective pressure on acquired mutations or molecular rewiring can hinder their effectiveness. This review summarizes how molecular imaging techniques can potentially facilitate the optimal implementation of targeted agents. Using the human epidermal growth factor receptor (HER) family as a model in (pre)clinical studies, we illustrate how molecular imaging may be employed to characterize whole body target expression as well as monitor drug effectiveness and the emergence of tumor resistance. We further discuss how an integrative omics discovery platform could guide the selection of 'effect sensors' - new molecular imaging targets - which are dynamic markers that indicate treatment effectiveness or resistance.

Niacin (Vitamin B3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor.

BACKGROUND/AIMS: Tryptophan is the precursor of serotonin and niacin (vitamin B3). The latter is critical for normal cellular metabolism. Tryptophan and niacin can be deficient in patients with serotonin-producing neuroendocrine tumors (NETs). Niacin deficiency may lead to severe symptoms including pellagra. In patients with serotonin-producing NET, data on niacin status are scarce and niacin supplementation hardly receives attention. We aimed to assess the niacin status before and after supplementation in these patients. METHODS: We identified serotonin-producing NET patients who had received oral niacin supplementation (mean dose 144 mg daily) for tryptophan deficiency and/or pellagra-associated symptoms. Presupplementation plasma tryptophan levels and niacin status based on the urinary niacin metabolite N1-methylnicotinamide (N1-MN) before (n = 42) and after the start of the supplementation (in 34 paired samples) were assessed. Reference values for urinary N1-MN levels were established in 133 healthy individuals. RESULTS: The mean presupplementation plasma tryptophan level was 31.8 ± 9.7 µmol/l (reference value 40.0-70.0). Presupplementation urinary N1-MN levels were lower in patients (median 17.9 µmol/24 h, range 2.6-70.3) compared to healthy controls (median 43.7 µmol/24 h, range 9.5-169.3, p < 0.0001) and below normal in 45% of the patients. Niacin supplementation increased urinary N1-MN levels to high normal levels (median 55.5 µmol/24 h, range 7.4-489.0) in 86% of the niacin-deficient patients. CONCLUSION: In serotonin-producing NET patients, niacin deficiency is prevalent. Therefore, urinary N1-MN deserves to be included in their standard biochemical evaluation. Niacin supplementation normalizes the niacin status in most niacin-deficient serotonin-producing NET patients. A prospective study is warranted.

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.

INTRODUCTION: BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. METHODS: Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. RESULTS: Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH tumors were ER-positive. CONCLUSIONS: Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).

Toward molecular imaging-driven drug development in oncology.

With current testing strategies, the number of novel targeted anticancer agents will exceed our drug selection capacity. Molecular imaging is a powerful additional tool that can assist us in selecting effective drugs and help patients benefit from targeted agents. Moreover, measurement of the functional effects of such targeted agents could permit dynamic tuning of treatment selection at the earliest time point at which loss of functional effects is observed.

TNF-related apoptosis-inducing ligand cooperates with NSAIDs via activated Wnt signalling in (pre)malignant colon cells.

TNF-related apoptosis-inducing ligand (TRAIL) receptor agonistic agents and non-steroidal anti-inflammatory drugs (NSAIDs) are interesting agents for the chemoprevention and treatment of colorectal cancer. We investigated whether NSAIDs sensitize colon cancer and adenoma cell lines and ex vivo cultured human adenomas to recombinant human (rh)TRAIL. Involvement of the crucial Wnt signalling pathway in the sensitization of colon cancer cells was examined. Five colon cancer and two adenoma cell lines, human ex vivo adenomas and normal colonic epithelium were treated with aspirin or sulindac combined with rhTRAIL. Apoptosis levels, expression of intracellular proteins and TRAIL receptor membrane expression were assessed. Ls174T cells stably transfected with an inducible dominant negative TCF-4 (dnTCF-4) construct served to analyse the role of Wnt pathway activation. Both rhTRAIL-sensitive and -resistant colon cancer cell lines were strongly sensitized to rhTRAIL by aspirin (maximum enhancement ratio, 7.1). Remarkably, in adenoma cell lines sulindac enhanced rhTRAIL-induced apoptosis most effectively (maximum enhancement ratio, 2.5). Although membrane TRAIL receptor expression was not affected by NSAIDs, caspase-8 activation was enhanced by combinational treatment. Several proteins from different biological pathways were affected by NSAIDs, indicating complex mechanisms of sensitization. Elimination of TCF-4 completely blocked the sensitizing effect in colon cancer cells. In ex vivo adenomas the combination of sulindac and rhTRAIL increased apoptosis from 18.4% (sulindac) and 17.8% (rhTRAIL) to 28.0% (p = 0.003 and p = 0.005, respectively). It was concluded that NSAID-induced sensitization to rhTRAIL requires TCF-4 activity. Thus, the combination of TRAIL-receptor agonistic agents and NSAIDs is a potentially attractive treatment option for (pre)malignant tumours with constitutively active Wnt signalling, such as colorectal tumours.

Prospective study of long-term impact of adjuvant high-dose and conventional-dose chemotherapy on health-related quality of life.

PURPOSE: To evaluate and compare health-related quality of life (HRQOL) after conventional- and high-dose adjuvant chemotherapy in patients with high-risk breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to either a conventional or high-dose chemotherapy regimen; both regimens were followed by radiotherapy and tamoxifen. HRQOL was evaluated until disease progression using the Short Form-36 (SF-36), Visual Analog Scale, and Rotterdam Symptom Checklist and assessed every 6 months for 5 years after random assignment. For the SF-36, data from healthy Dutch women with the same age distribution served as reference values. RESULTS: Eight hundred four patients (conventional-dose chemotherapy, n = 405; high-dose chemotherapy, n = 399) were included. Median follow-up time was 57 months. Directly after high-dose chemotherapy, HRQOL decreased more compared with conventional chemotherapy for all SF-36 subscales. After 1 year, the reference value of healthy women was reached in both groups. Small differences were observed between the two groups in the role-physical and role-emotional subscales, but 1 year after treatment, these differences were minor and not clinically relevant. During follow-up, patients with a lower educational level and many complaints before chemotherapy experienced a worse HRQOL. CONCLUSION: Shortly after high-dose chemotherapy, HRQOL was more affected than after conventional-dose chemotherapy. One year after random assignment, differences were negligible. Identifying patients who have a higher chance of persistent impaired quality of life after treatment (which, in the present study, included patients with a lower educational level and many complaints before chemotherapy) is important and may open the way for better patient-tailored prevention strategies.

The relation between soluble apoptotic proteins and subclinical cardiotoxicity in adjuvant-treated breast cancer patients.

BACKGROUND: Circulating apoptotic proteins are increased in heart failure patients. We evaluated whether circulating soluble apoptosis-related protein levels change after anthracycline-containing chemotherapy and radiotherapy in relation to cardiac dysfunction or the applied treatment. PATIENTS AND METHODS: Circulating apoptotic proteins were measured with immunoassay in 40 breast cancer patients following surgery (TO), one month (T1) and one year (T2) after epirubicin-based chemotherapy. Standard-dose (n=21) or high-dose (n=19) myeloablative chemotherapy, preceded irradiation and tamoxifen. Circulating apoptotic proteins were compared with previous cardiac evaluations. RESULTS: Soluble tumor necrosis factor receptor 1 (+30%), 2 (+43%) and Fas (+40%) were transiently increased at T1 compared to T0, whereas Fas ligand (-64%) was transiently decreased, especially in the high-dose group. Apoptosis markers were not associated with cardiac dysfunction. CONCLUSION: Significant, but transient changes in soluble apoptotic protein levels were observed, particularly after high-dose chemotherapy. No relation was found between apoptosis-related proteins and cardiotoxicity.

Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma.

BACKGROUND: Consultant gynecologic oncologists from the regional Comprehensive Cancer Center assisted community gynecologists in the surgical treatment of patients with ovarian carcinoma when they were invited. For this report, the authors evaluated the effects of primary surgery by a gynecologic oncologist on treatment outcome. METHODS: The hospital files from 680 patients with epithelial ovarian carcinoma who were diagnosed between 1994 and 1997 in the northern part of the Netherlands were abstracted. Treatment results were analyzed according to the operating physician's education by using survival curves and univariate and multivariate Cox regression analyses. RESULTS: Primary surgery was performed on 184 patients by gynecologic oncologists, and on 328 patients by general gynecologists. Gynecologic oncologists followed surgical guidelines more strictly compared with general gynecologists (patients with International Federation of Gynecology and Obstetrics [FIGO] Stage I-II disease, 55% vs. 33% [P=0.01]; patients with FIGO Stage III disease, 60% vs. 40% [P=0.003]) and more often removed all macroscopic tumor in patients with FIGO Stage III disease (24% vs. 12%; P=0.02). When patients were stratified according to FIGO stage, the 5-year overall survival rate was 86% versus 70% (P=0.03) for patients with Stage I-II disease and 21% versus 13% (P=0.02) for patients with Stage III-IV disease who underwent surgery by gynecologic oncologists and general gynecologists, respectively. The hazards ratio for patients who underwent surgery by gynecologic oncologists was 0.79 (95% confidence interval [95%CI], 0.61-1.03; adjusted for patient age, disease stage, type of hospital, and chemotherapy); when patients age 75 years and older were excluded, the hazards ratio fell to 0.71 (95% CI, 0.54-0.94) in multivariate analysis. CONCLUSIONS: The surgical treatment of patients with ovarian carcinoma by gynecologic oncologists occurred more often according to surgical guidelines, tumor removal more often was complete, and survival was improved.

Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer: a population-based study.

PURPOSE: Adjuvant 'classical' oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective audit of treatment guideline adherence and quality of CMF in hospitals in the CCCN area. METHODS: The CMF treatment data of 251 consecutive axillary lymph node-positive breast cancer patients <50 years old, diagnosed between 1993 and 1996, were analyzed. RESULTS: Ninety-four patients (42%) completed adjuvant CMF without dose adjustment or delay. Overall median relative dose intensity (RDI) was 92.6 (IQR 85.5-97.7). Sixty patients (24%) had an RDI <85, and 7% had an RDI <65. Myelotoxicity was the main reason for reductions and delays. Of 176 irradiated patients, 96% received radiotherapy simultaneously with CMF. Median CMF dose intensity nor median duration differed between patients who underwent mastectomy, mastectomy and radiotherapy, or breast-conserving therapy. Radiotherapy did not influence the median RDI (94 without versus 92 with radiotherapy). G-CSF, administered at least once to 76 patients, did not result in a higher median RDI. Median RDI was slightly higher when >3 patients/year (P=0.014) were treated by one specialist or >10 patients classified for adjuvant chemotherapy yearly in a hospital (P=0.037). CONCLUSION: The adherence to CMF treatment guidelines was generally good. Simultaneous radiotherapy did not affect the median RDI of CMF. G-CSF had no impact on the median RDI but patient volume did influence the RDI.

Diagnostic I-131 scintigraphy in patients with differentiated thyroid cancer: no additional value of higher scan dose.

OBJECTIVE: After initial treatment with total thyroidectomy and radioiodine ablation, most follow-up protocols for patients with differentiated thyroid carcinoma contain cyclic diagnostic I-131 imaging and serum thyroglobulin measurements. The applied diagnostic I-131 doses vary between 37 and 370 MBq. The aim of this study was to determine the yield of a diagnostic scan with 370 MBq I-131 in patients with a negative diagnostic scan with 74 MBq I-131. METHODS: Retrospective evaluation of 158 patients who received a high-dose diagnostic scan with 370 MBq I-131 because of a negative low-dose diagnostic scan with 74 MBq I-131. Special attention was paid to the patients with positive high-dose diagnostic scanning and undetectable serum thyroglobulin levels after thyroid hormone withdrawal. RESULTS: In 127 (80%) of patients the 370 MBq I-131 scan was negative, just like the preceding low-dose scan. In 31 (20%) of patients abnormal uptake was present on the 370 MBq diagnostic scan. In 19 of these 31 patients serum thyroglobulin was undetectable. In 15/19 the high-dose diagnostic scan proved either false positive or demonstrated clinically irrelevant minor ablation rests. In only four patients (2.5%) did the high-dose diagnostic scans reveal possibly relevant uptake caused by residual differentiated thyroid cancer. CONCLUSION: In 98% of patients a 370 MBq dose of I-131 for diagnostic WBS had no additional value. The combination of a low-dose diagnostic I-131 scan using only 74 MBq combined with a serum Tg level measurement proved sufficient for correct clinical decision making regarding whether the patient requires additional I-131 therapy.

Calcium or resistant starch does not affect colonic epithelial cell proliferation throughout the colon in adenoma patients: a randomized controlled trial.

Patients with a history of sporadic adenomas have increased epithelial cell proliferative activity, an intermediate risk marker for colorectal cancer. Reduction of proliferation by dietary intervention may reflect a decreased colorectal cancer risk. To evaluate whether calcium or resistant starch could reduce proliferative activity throughout the colon, we performed a randomized controlled trial in 111 sporadic adenoma patients. Patients received two placebos, 1 g of calcium + placebo, or 30 g of amylomaize (19 g of resistant starch) + placebo. After 2 mo, biopsies were collected from the cecum, transverse and sigmoid colon, and rectum during colonoscopy. Epithelial cell proliferation was determined by dividing the number of 5-bromo-2-deoxyuridine-labeled nuclei by the total number of nuclei x 100 (labeling index, LI). LI of luminal, mid, and basal compartments was determined. Twenty-five patients dropped out. In the remaining 86 patients (28 treated with placebo, 30 with calcium + placebo, and 28 with resistant starch + placebo), no difference was observed in total LI, the LI of the three compartments, or the crypt length in the four areas of the colorectum. Colonic epithelial cell proliferative activity throughout the colon of sporadic adenoma patients is not affected by supplementation with 1 g of calcium or 19 g of resistant starch.