Interactions in cancer treatment considering cancer therapy, concomitant medications, food, herbal medicine and other supplements.

PURPOSE: The aim of our study was to analyse the frequency and severity of different types of potential interactions in oncological outpatients' therapy. Therefore, medications, food and substances in terms of complementary and alternative medicine (CAM) like dietary supplements, herbs and other processed ingredients were considered. METHODS: We obtained data from questionnaires and from analysing the patient records of 115 cancer outpatients treated at a German university hospital. Drug-drug interactions were identified using a drug interaction checking software. Potential CAM-drug interactions and food-drug interactions were identified based on literature research. RESULTS: 92.2% of all patients were at risk of one or more interaction of any kind and 61.7% of at least one major drug-drug interaction. On average, physicians prescribed 10.4 drugs to each patient and 6.9 interactions were found, 2.5 of which were classified as major. The most prevalent types of drug-drug interactions were a combination of QT prolonging drugs (32.3%) and drugs with a potential for myelotoxicity (13.4%) or hepatotoxicity (10.1%). In 37.2% of all patients using CAM supplements the likelihood of interactions with medications was rated as likely. Food-drug interactions were likely in 28.7% of all patients. CONCLUSION: The high amount of interactions could not be found in literature so far. We recommend running interaction checks when prescribing any new drug and capturing CAM supplements in medication lists too. If not advised explicitly in another way drugs should be taken separately from meals and by using nonmineralized water to minimize the risk for food-drug interactions.

Complementary and alternative medicine (CAM) supplements in cancer outpatients: analyses of usage and of interaction risks with cancer treatment.

PURPOSE: The aim of our study was to analyze the use of complementary and alternative medicine (CAM) supplements, identify possible predictors, and analyze and compile potential interactions of CAM supplements with conventional cancer therapy. METHODS: We included outpatient cancer patients treated at a German university hospital in March or April 2020. Information was obtained from questionnaires and patient records. CAM-drug interactions were identified based on literature research for each active ingredient of the supplements consumed by the patients. RESULTS: 37.4% of a total of 115 patients consumed CAM supplements. Potential interactions with conventional cancer treatment were identified in 51.2% of these patients. All types of CAM supplements were revealed to be a potential source for interactions: vitamins, minerals, food and plant extracts, and other processed CAM substances. Younger age (< 62 years) (p = 0.020, φc = 0.229) and duration of individual cancer history of more than 1 year (p = 0.006, φc = 0.264) were associated with increased likelihood of CAM supplement use. A wide range of different CAM supplement interactions were reviewed: effects of antioxidants, cytochrome (CYP) interactions, and specific agonistic or antagonistic effects with cancer treatment. CONCLUSION: The interaction risks of conventional cancer therapy with over-the-counter CAM supplements seem to be underestimated. Supplements without medical indication, as well as overdoses, should be avoided, especially in cancer patients. To increase patient safety, physicians should address the risks of interactions in physician-patient communication, document the use of CAM supplements in patient records, and check for interactions.

Acute postoperative pain in 23 procedures of gynaecological surgery analysed in a prospective open registry study on risk factors and consequences for the patient.

Effective perioperative pain management is essential for optimal patient recovery after surgery and reduces the risk of chronification. However, in clinical practice, perioperative analgesic treatment still needs to be improved and data availability for evidence-based procedure specific analgesic recommendations is insufficient. We aimed to identify procedures related with high pain scores, to evaluate the effect of higher pain intensity on patients and to define patient and intervention related risk factors for increased pain after standard gynaecological and obstetrical surgery. Therefore, we performed a prospective cross-sectional study based on the German registry for quality in postoperative pain (QUIPS). A cohort of 2508 patients receiving surgery between January 2011 and February 2016 in our tertiary referral centre (university departments of gynaecology and obstetrics, respectively) answered a validated pain questionnaire on the first postoperative day. Maximal pain intensity was measured by means of a 11-point numeric rating scale (NRS) and related to procedure, perioperative care as well as patient characteristics. The interventions with the highest reported pain scores were laparoscopic removal of ovarian cysts (NRS of 6.41 ± 2.12) and caesarean section (NRS of 6.98 ± 2.08). Factors associated with higher pain intensity were younger age (OR 1.75, 95% CI 1.65-1.99), chronic pain (OR 2.08, 95% CI 1.65-2.64) and surgery performed outside the regular day shift (OR 1.67, 95% CI 1.09-2.36). Shorter duration of surgery, peridural or local analgesic and preoperative sedation reduced postoperative pain. Patients reporting high pain scores (NRS ≥ 5) showed relevant impairment of daily activities and reduced satisfaction. Caesarean section and minimal invasive procedures were associated with the highest pain scores in the present ranking. Pain management of these procedures has to be reconsidered. Younger age, receiving surgery outside of the regular shifts, chronic pain and the surgical approach itself have a relevant influence on postoperative pain intensity. When reporting pain scores of 5 or more, patients were more likely to have perioperative complications like nausea or vomiting and to be impaired in mobilisation. Registry-based data are useful to identify patients, procedures and critical situations in daily clinical routine, which increase the risk for elevated post-intervention pain. Furthermore, it provides a database for evaluation of new pain management strategies.

CAMK2N1/RUNX3 methylation is an independent prognostic biomarker for progression-free and overall survival of platinum-sensitive epithelial ovarian cancer patients.

BACKGROUND: To date, no predictive or prognostic molecular biomarkers except BRCA mutations are clinically established for epithelial ovarian cancer (EOC) despite being the deadliest gynecological malignancy. Aim of this biomarker study was the analysis of DNA methylation biomarkers for their prognostic value independent from clinical variables in a heterogeneous cohort of 203 EOC patients from two university medical centers. RESULTS: The marker combination CAMK2N1/RUNX3 exhibited a significant prognostic value for progression-free (PFS) and overall survival (OS) of sporadic platinum-sensitive EOC (n = 188) both in univariate Kaplan-Meier (LogRank p < 0.05) and multivariate Cox regression analysis (p < 0.05; hazard ratio HR = 1.587). KRT86 methylation showed a prognostic value only in univariate analysis because of an association with FIGO staging (Fisher's exact test p < 0.01). Thus, it may represent a marker for EOC staging. Dichotomous prognostic values were observed for KATNAL2 methylation depending on BRCA aberrations. KATNAL2 methylation exhibited a negative prognostic value for PFS in sporadic EOC patients without BRCA1 methylation (HR 1.591, p = 0.012) but positive prognostic value in sporadic EOC with BRCA1 methylation (HR 0.332, p = 0.04) or BRCA-mutated EOC (HR 0.620, n.s.). CONCLUSION: The retrospective analysis of 188 sporadic platinum-sensitive EOC proved an independent prognostic value of the methylation marker combination CAMK2N1/RUNX3 for PFS and OS. If validated prospectively this combination may identify EOC patients with worse prognosis after standard therapy potentially benefiting from intensive follow-up, maintenance therapies or inclusion in therapeutic studies. The dichotomous prognostic value of KATNAL2 should be validated in larger sample sets of EOC.

Extensive endometriosis surgery: rASRM and Enzian score independently relate to post-operative complication grade.

PURPOSE: We aimed to assess post-operative complications based on the Clavien-Dindo classification system following routine laparoscopic treatment of all stages of endometriosis. METHODS: A retrospective cohort study was carried out to identify women who underwent laparoscopic complete resection of newly diagnosed endometriosis between 2013 and 2016. 401 patients were identified using hospital database search software, and electronic files were reviewed. The stages of endometriosis had been classified according to the revised score of the American Society of Reproductive Medicine (rASRM) and the Enzian classification in cases of deep infiltrating endometriosis. Post-operative complications were recorded based on the Clavien-Dindo classification. Multivariate regression analysis was used to investigate the impact of the stages of endometriosis and surgical steps on complications. RESULTS: Grade III complications requiring surgical, endoscopic, or radiological intervention occurred in only 1.7% of patients and were significantly associated with rASRM stage IV (OR 1.8). Grade II complications (blood transfusion, total parenteral nutrition) occurred in 18.7% of patients. rASRM stage IV (OR 2.0), hysterectomy (OR 3.2), conversion to laparotomy (OR 11.1), and bowel resection (OR 27.6) were significantly associated with increased risk of grade II complications. rASRM stages I-III did not show an effect on post-operative complications or hospital stay. CONCLUSIONS: Clavien-Dindo complication grading was readily applicable to laparoscopic removal of endometriosis of all stages. Higher Clavien-Dindo grades correctly reflected clinically relevant complications and were associated with deep infiltrating endometriosis, stage IV endometriosis, bowel surgery, or hysterectomy. Clavien-Dindo classification can be recommended for evaluation of laparoscopic endometriosis surgery outcome.

p53-autoantibody may be more sensitive than CA-125 in monitoring microscopic and macroscopic residual disease after primary therapy for epithelial ovarian cancer.

PURPOSE: To evaluate the use of p53-autoantibodies (p53-aab) for monitoring minimal disease after standard therapy of advanced epithelial ovarian cancer (EOC). METHODS: Retrospective analysis of p53-aab in preoperative and long-term follow-up serum samples from 10 patients selected for representing three relevant EOC subgroups: platinum-sensitive disease after macroscopic complete debulking (n = 4) and platinum-sensitive (n = 3) or platinum-resistant disease (n = 3), both after suboptimal debulking with residual tumor of <1 cm diameter. p53-aab levels were quantified by a sandwich ELISA in two independent experiments. CA-125 values of all samples and clinical information were retrieved from medical records. RESULTS: Patients with early relapse (median PFS 7 months, n = 8) had high p53-aab levels throughout follow-up while CA-125 values had dropped below the cut-off after primary surgery during or after chemotherapy in these cases. Patients with seroconversion to p53-aab negativity experienced prolonged PFS (n = 2; #1: 50 months, #2: no evidence of disease for 36 months until last follow-up). Continued p53-aab positivity was not related to the resection status or platinum sensitivity. CONCLUSIONS: p53-autoantibodies may be a highly sensitive marker for minimal residual tumor mass after surgery and/or chemotherapy rather than standard CA-125, possibly due to the different nature of these markers. CA-125 released by cancer cells is related to tumor mass, whereas p53-aab levels can indicate the presence of few tumor cells due to amplification by the immune system. Seroconversion of p53-aab could be associated with long-term survival.

An increase in cell number at completion of therapy may develop as an indicator of early relapse: quantification of circulating epithelial tumor cells (CETC) for monitoring of adjuvant therapy in breast cancer.

PURPOSE: Treatment efficiency of adjuvant therapy in breast cancer is only revealed after several years by statistical evaluation and gives no answer for the individual patient. We here present a method to analyze the response to adjuvant chemotherapy online in individual patients. METHODS/RESULTS: In 25 consecutive non-metastatic primary breast cancer patients adjuvant fluorouracil/epirubicin/cyclophosphamid (FEC) or EC followed by taxane (EC-T) or cyclophosphamid/methotrexate/fluorouracil (CMF) therapy were given. Circulating epithelial tumor cells (CETC) were quantified before and after each second cycle of the therapy regimen, between the anthracycline and the taxane block of the regimen and in some cases repeatedly during CMF treatment. Independent of the initial cell number CETC numbers showed a decline, no change or a minor increase in 15 patients of which 14 remained in complete remission and 1 suffered local relapse. Ten patients showed an increase at the end of therapy of which 4 have relapsed during the observation time of between 2 months and up to 54 months. This patient group was compared to a previously published group of 25 patients who have all reached a follow-up of 4.5 years or until relapse. CONCLUSION: As in the previous report, Kaplan-Meier analysis revealed a high correlation between the response of CETC to therapy and relapse (p < 0.0001) and curves of both patient groups were super imposable. Multivariate analysis revealed the response of CETC to therapy to be an independent predictive marker for relapse.

Quantification of circulating tumour cells for the monitoring of adjuvant therapy in breast cancer: an increase in cell number at completion of therapy is a predictor of early relapse.

Treatment efficiency of adjuvant therapy in breast cancer is revealed after several years by statistical evaluation, but this gives no answer for the individual patient. Having shown that circulating epithelial tumour cells (CETC) respond to neoadjuvant therapy in exactly the same way as the tumour, we monitored adjuvant therapy in 25 non-metastatic breast cancer patients. Nineteen patients with a decline or no change in number of CETC showed no relapse whereas six patients with a more than ten-fold increase had five distant and one local relapse, indicating that the dynamic of CETC in the individual patient is predictive of outcome.

Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells.

BACKGROUND: Surgery of malignant tumors has long been suspected to be the reason for enhancement of growth of metastases with fatal outcome. This often prevented surgeons from touching the tumor if not absolutely necessary. We have shown in lung cancer patients that surgery, itself, leads to mobilization of tumor cells into peripheral blood. Some of the mobilized cells finding an appropriate niche might grow to form early metastases. Monitoring of tumor cell release during and the fate of such cells after surgery for breast cancer may help to reveal how metastases develop after surgery. METHOD: We used the MAINTRAC analysis, a new tool for online observation of circulating epithelial cells, to monitor the number of epithelial cells before, 30 min, 60 min, three and seven days after surgery and during subsequent variable follow up in breast cancer patients. RESULTS: Circulating epithelial cells were already present before surgery in all patients. During the first 30-60 min after surgery values did not change immediately. They started increasing during the following 3 to 4 days up to thousand fold in 85% of treated patients in spite of complete resection of the tumor with tumor free margins in all patients. There was a subsequent re-decrease, with cell numbers remaining above pre-surgery values in 58% of cases until onset of chemotherapy. In a few cases, where no further therapy or only hormone treatment was given due to low risk stage, cell numbers were monitored for up to three years. They remained elevated with no or a slow decrease over time. This was in contrast to the observation in a patient where surgery was performed for benign condition. She was monitored before surgery with no cells detectable. Epithelial cells increased up to more than 50,000 after surgery but followed by a complete reduction to below the threshold of detection. CONCLUSION: Frequently before but regularly during surgery of breast cancer, epithelial cells are mobilized into circulation. Part of these cells, most probably normal or apoptotic cells, are cleared from the circulation as also shown to occur in benign conditions. After resection even if complete and of small tumors, cells can remain in the circulation over long times. Such cells may remain "dormant" but might settle and grow into metastases, if they find appropriate conditions, even after years.