A conceptual framework for cautious escalation of anticancer treatment: How to optimize overall benefit and obviate the need for de-escalation trials.

BACKGROUND: The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability. METHODS: In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers. RESULTS: The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes.

Twelve ESMO Congress 2022 breakthroughs: practicing oncologists' perceptions and potential application on presented data.

BACKGROUND: During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical oncologist, it is important to structure these data in a way that facilitates a trade-off between treatment burden and benefit. MATERIALS AND METHODS: To illustrate this, we carried out a narrative non-systematic review of 12 selected oral presentations with potential impact on future daily practice, focusing on trial methodology, possible study flaws, reported clinical benefit and implementability. RESULTS: The selected presentations encompassed 10 phase III trials, 1 randomized phase II trial and 1 phase II trial. In 7 out of 12 trials, quality of life and/or patient-reported outcomes had been evaluated. None of the trials, which reported progression-free survival (PFS) data, provided information, which could exclude informative censoring bias. In none of the trials reporting overall survival (OS) data, potential flaws due to undesirable crossover and imbalance between study groups regarding post-progression treatments were addressed. For the 11 reviewed randomized trials, the ESMO-Magnitude of Clinical Benefit Scale (MCBS) grade achieved with the new intervention was calculated based on the presented data. The MCBS grade varied from 1 to 5. CONCLUSIONS: Our review confirms the high-quality standard of current cancer research and the clinical relevance of the research questions answered. However, during presentation of PFS and/or OS data, factors known to affect PFS and OS analysis should be structurally addressed. In order to keep cancer care affordable and sustainable, it could be considered to include an ESMO-MCBS threshold in the drug appraisal process of regulatory authorities.

11 ESMO 2021 breakthroughs: practicing oncologist's perceptions on data presentation.

BACKGROUND: The European Society for Medical Oncology (ESMO) 2021 conference provided a high number of randomized phase III trial reports, many of which were claimed to be practice changing. Given the short time available for conference presentations, results and conclusions tend to have greatest priority with less time remaining for study background and study methodology. PURPOSE: On behalf of the ESMO Practicing Oncologists Working Group, 11 potentially practice-changing reports were selected and screened for three main questions: (i) Did the investigators provide sufficient details with regard to Patients and Methods to make the results comprehensible? (ii) Were there any reasons to consider bias? (iii) To which extent did the results presented translate to clinical benefit? RESULTS: In 2 out of 11 trials, the study design presented differed considerably from the study design described at ClinicalTrials.gov. Allocation concealment was not carried out in 6 out of 11 trials. In none of the trials reporting progression-free survival was informative censoring considered an issue. In none of the trials reporting overall survival was desirable crossover considered an issue. Defined trial outcome measures depicted at ClinicalTrials.gov, which could boost or weaken the ESMO-Magnitude of Clinical Benefit Scale score, were often lacking in the presentation. Study success was claimed in a heterogeneous manner, which was often not clearly linked to overall clinical benefit. CONCLUSION: ESMO conference presentations can inform the scientific community and catalyze further research but cannot replace the full papers in peer-reviewed journals, which are needed to estimate the thoroughness of the results, the overall impact on clinical benefit and the consequences for future treatment guidelines.

[Myocardial ischaemia as a result of treatment with capecitabine]. / Myocardischemie als gevolg van behandeling met capecitabine.

A 53-year-old man and a 76-year-old woman were treated with the cytotoxic drug capecitabine as palliative treatment and adjuvant treatment, respectively, because of colorectal carcinoma. Both developed myocardial ischaemia within a few days. In the man, the capecitabine dosage was reduced and metoprolol was prescribed, while in the woman the capecitabine was stopped. According to the literature, the risk of myocardial ischaemia during treatment with capecitabine is approximately 0.4%, irrespective of the patient's medical history. Except in clinical trials, a history of coronary disease is not considered a contraindication for capecitabine treatment. In case stable angina pectoris develops during treatment, continuation of treatment with a reduced dosage of capecitabine can be considered. A switch to treatment with an alternative fluoropyrimidine, such as fluorouracil or raltitrexed, also appears to be safe. However, raltitrexed is no longer available in The Netherlands.

Effect of adjuvant chemotherapy on recurrence-free survival varies by neo-adjuvant treatment in patients with stage III rectal cancer.

INTRODUCTION: Adjuvant chemotherapy still is a controversial therapy for rectal cancer patients. The aim of this study was to analyze the effect of adjuvant chemotherapy on recurrence-free survival (RFS) for patients with stage III rectal cancer treated in clinical practice, taking into account which neo-adjuvant treatment patients received. METHODS: Patients from regions in the Netherlands diagnosed between 1996 and 2013 with pathological stage III rectal cancer who received short-course radiotherapy, chemoradiation or no neo-adjuvant treatment and who underwent surgery were included. After stratification by neo-adjuvant treatment, 5-year RFS according to adjuvant chemotherapy receipt was calculated using Kaplan-Meier curves. Cox regression was used to discriminate the independent effect of adjuvant chemotherapy on the risk of recurrence/death. RESULTS: The study population consisted of 829 patients, of whom 537 (65%) patients received short-course radiotherapy, 128 (15%) patients received chemoradiation and 164 (20%) patients received no neo-adjuvant treatment. Adjuvant chemotherapy was administered to 152 (18%) patients. Adjuvant chemotherapy was associated with improved 5-year RFS for patients who received short-course radiotherapy (61% vs. 46%, p = 0.005) and for patients who did not receive any neo-adjuvant treatment (70% vs. 28%, p < 0.0001). In multivariable analyses, adjuvant chemotherapy was associated with a reduced risk of recurrence/death for patients treated with short-course radiotherapy (HR 0.65, 95% CI 0.46-0.93) and for patients without neo-adjuvant treatment (HR 0.35, 95% CI 0.18-0.71), but not for patients treated with chemoradiation (HR 1.11, 95% CI 0.51-2.41). CONCLUSION: Among patients with stage III rectal cancer, the effect of adjuvant chemotherapy on RFS seems to vary by neo-adjuvant treatment.

Risk factors for the development of oesophageal cancer as a second primary tumour.

Exposure to irradiation or chemotherapy as well as prolonged exposure to risk factors, such as alcohol and tobacco, may induce a second primary carcinoma of the oesophagus. To estimate the potential risk of previous treatment regimens, we performed a case-control study. In the Tumour Registry of The Netherlands Cancer Institute, from 1955, 27 cases of squamous cell carcinoma of the oesophagus were identified following treatment for malignant lymphoma (n = 11), breast cancer (n = 8) and lung cancer (n = 8). The median interval was 6.6 years (range 1-16). Preferably 3 controls from the same tumour registry were matched to each case on the basis of sex, age, primary tumour, location of primary treatment (academic or general hospital), calendar year at diagnosis of primary tumour and duration of follow-up. Clinical data and details of treatment were obtained from the medical records. In patients who had smoked for more than 5 years, there was a 3.2-fold increased risk of oesophageal carcinoma (P = 0.04); for those with a regular alcohol intake the relative risk was 3.3 (P = 0.01). There was no significant relationship between irradiation of the mediastinum and subsequent risk for oesophageal cancer. The number of chemotherapy-treated patients was too small to calculate the relative risk associated with cytostatic drugs. In conclusion, oesophageal cancer as second primary cancer is extremely rare. Risk factors include the well known abuse of alcohol and tobacco. No significant relationship with previous mediastinal irradiation could be demonstrated.

Pulmonary resection for metastases of colorectal origin.

STUDY OBJECTIVE: To develop selection criteria for pulmonary metastasectomy in patients with metastases of colorectal cancer confined to the lungs. DESIGN: A retrospective study. SETTING: Medical records of all patients operated on for this condition in the Netherlands in the period 1982 to 1992 (n = 38). INTERVENTION: Evaluation by means of Cox's proportional hazards regression analysis of factors, which might relate to postthoracotomy disease-free survival and/or postthoracotomy survival. MEASUREMENTS AND RESULTS: The 5-year disease-free survival was 31%, and the overall 5-year survival was 43% (Kaplan-Meyer). Multivariately, a number of three or fewer metastases (p = 0.012) and a short delay between detection of pulmonary metastases and resection (p = 0.05) related to a longer postthoracotomy disease-free interval. A longer interval between resection of the primary tumor and detection of lung metastases related to a longer postthoracotomy survival (p = 0.021). CONCLUSIONS: Patients with three or less pulmonary metastases of colorectal origin may benefit from resection; once metastases have been detected, resection should not be postponed.

Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

Surgical intervention for complications caused by late radiation damage of the small bowel: a retrospective analysis.

We studied the records of 46 patients who had been operated on between 1974 and 1990 in The Netherlands Cancer Institute because of complications due to late radiation damage of the small bowel. Data were collected on preoperative history, surgical intervention, postoperative complications and survival. By means of Cox's proportional hazards regression analysis we sought to identify factors that contribute to complication-risk and survival. The following factors led to an increase in complication-risk: hypoalbuminemia, more than one laparotomy prior to irradiation and a short interval (< 12 months) between irradiation and surgical intervention. The following factors related to a poorer survival: incomplete resection of the primary tumor and a short interval (< 12 months) between irradiation and surgical intervention. The type of surgical intervention did not have cumulative prognostic value in relation to complication-risk or survival. As patients undergoing resections differed considerably from patients undergoing bypass-procedures, no conclusions could be drawn about the superiority of one technique over the other. We think that both types of intervention have their own field of indication.

Anaemia prior to operation is related with poorer long-term survival in patients with operable rectal cancer.

PURPOSE: Local hypoxia has been linked to a higher risk of metastasis in patients with cancer of the uterine cervix and a haemoglobin concentration of 7.45 mmol/l or less. It is unknown whether the same holds true for rectal cancer. We evaluated the independent impact of pre-operative anaemia on survival in patients with rectal cancer. PATIENTS AND METHODS: A random set of 144 patients diagnosed with Dukes' A, B or C rectal cancer in the period 1995-1999 and registered in the database of the Eindhoven Cancer Registry was included in a survival analysis. Parameters tested were gender, age, pre-operative haemoglobin concentration, tumour stage and therapy. The ones that showed a relation with survival (log-rank test, p<0.1) were entered in a multivariate analysis. RESULTS: For patients without pre-operative anaemia, the hazard ratio of death was 0.35 (95% confidence interval 0.19-0.65, p=0.001), which indicates a three times higher mortality risk. For patients with a higher tumour stage (Dukes' B vs. Dukes' A or Dukes' C vs. Dukes' B) the hazard ratio of death was 1.52 (95% CI 1.04-2.23, p=0.03). For older patients (64-73 years vs. <64 years or >73 years vs. 64-73 years) the hazard ratio of death was 1.85 (95% CI 1.29-2.63, p=0.001). CONCLUSION: Long-term survival was significantly affected in rectal cancer patients with pre-operative anaemia. Further study on the relation between anaemia, tumour oxygenation and prognosis is needed, as it may have implications for future therapy.

Cancer cachexia: what is known about its etiology and what should be the current treatment approach?

Cancer cachexia, defined as involuntary weight loss and tissue wasting due to cancer, negatively influences physical condition, quality of life and prognosis. Well known causes, such as ileus or hypercalcemia, do not suffice to explain the entire phenomenon. Metabolic changes induced by the tumor and/or host are supposed to play a deciding role. In the present review current insights into the etiology and treatment are discussed.

Advanced colorectal cancer, refractory to infusional fluorouracil treatment: efficacy of second line fluorouracil in combination with a different biochemical modulation.

BACKGROUND: Currently there is no standard second line treatment for patients with advanced colorectal cancer (ACC). Previous reports have demonstrated that some patients may benefit from second line infusional 5-fluorouracil (5-FU) after failing 5-FU bolus treatment. PATIENTS AND METHODS: We retrospectively studied the efficacy and toxicity of infusional 5FU regimens given in second line, which only differed from the first line regimen in the type of biochemical modulation and compared these results in a non-randomized fashion to the outcome of patients receiving supportive care only in second line. RESULTS: Sixty six patients with ACC were treated in first line with an infusional 5-FU-based schedule. At the time of disease progression 38 patients received supportive care only. The remaining 28 patients continued treatment with the same 5-FU regimen, but with another biochemical modulator. Fourteen patients achieved stable disease for a median duration of 6 months and one patient achieved a complete remission which lasted 34 months. The median survival from the time of disease progression on first line treatment was 7 months for patients who received second line treatment, whereas those who received supportive care survived for a median period of 3 months (p < 0.05). CONCLUSION: Changing the type of biochemical modulation of infusional 5-FU as a second line treatment-alternative may be of some benefit to a subgroup of patients with ACC.

The impact of 5-FU-based bolus chemotherapy on survival in patients with advanced colorectal cancer.

BACKGROUND: An analysis was performed to evaluate whether bolus chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) improves survival for patients with advanced colorectal cancer (ACC). PATIENTS AND METHODS: Two groups of patients were selected from a database which included all patients with colorectal cancer treated in our hospital since 1984. The first group consisted of all patients with irresectable metastases diagnosed between January 1984 and December 1989, who had a performance status of 0 or 1, and were younger than 76 years old. The second group consisted of all patients with irresectable metastases--younger than 76 years old and with a performance status of 0 or 1--who were started on chemotherapy between January 1994 and December 1997. In the first period chemotherapy was never given and in the second period chemotherapy was given to all motivated patients. None of the patients had received a previous metastasectomy or isolated liver perfusion. For chemotherapy, age, location of the metastases, type of surgical intervention for the primary tumor, Hemoglobin, Lactate Dehydrogenase and Carcinoembryonic Antigen concentration we evaluated the relationship with survival. Variables which showed a significant relation with survival in the univariant analysis (logrank test, p < 0.05) were entered into a proportional hazards regression analysis. RESULTS: In the univariant analysis chemotherapy and location of metastases showed a significant relation with survival. The median survival was 11 months for patients who had received chemotherapy and 8 months for untreated patients (p = 0.009). Chemotherapy and location of metastases both retained their significance in a proportional hazards regression analysis. CONCLUSION: In our study group chemotherapy added 3 months to the median life expectancy for patients with ACC.

Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism.

A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia. In growing tumours the O(2) concentration is critically low. Mammalian cells need O(2) for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O(2) they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O(2). Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate. In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.

Colorectal cancer in 2003: old principles, new strategies.

In the last two decades the prognosis of colorectal cancer has improved for two reasons: (i) the proportion of patients with localized disease has increased and treatment has been standardized, and (ii) new chemotherapeutic agents have led to a longer life expectancy for patients with advanced disease. In this review the current insights in disease etiology and treatment of localized and disseminated colorectal cancer are discussed.

Association of H-ras mutations with adenocarcinomas of the parotid gland.

We have examined 17 adenocarcinomas and 2 mixed tumors of the salivary glands for mutational activation of the oncogenes H-ras, K-ras and N-ras. The presence of mutations was determined by in vitro amplification of gene fragments spanning codons 12, 13 and 61 and the use of mutation-specific oligonucleotide hybridization. ras mutations were present in 3 of 13 adenocarcinomas (23%) of the parotid gland. The mutations were confirmed and characterized by means of cycle sequencing of polymerase chain reaction (PCR) fragments. In all 3 cases, the mutation was an A:T to G:C transition at the second position of codon 61 of the H-ras gene. This rather unusual ras mutation could provide a clue to identify one or more carcinogens involved in the pathogenesis of parotid cancer.

Spontaneous regression of hepatocellular carcinoma.

A 72-year-old Caucasian woman suffered from histologically-proven advanced hepatic cancer, for which she received no treatment. She had been a regular drinker for a long time. Serologic markers for hepatitis B and C were negative. In spite of her poor prognosis, she remained in good clinical condition and at 14 months of follow up the hepatocellular carcinoma could not be visualised any more radiologically. At that time the serum alpha foetoprotein concentration was normal. At present, 28 months after diagnosis, the patient is doing well and her tumour still appears to be in complete spontaneous remission.