Approximately 7% of pancreatic cancers occur in patients with a germline mutation in
BRCA1
or
BRCA2
, an alteration that compromises DNA repair. In a randomized trial in patients with metastatic ...pancreatic cancer that had responded to platinum-based chemotherapy, progression-free survival was nearly twice as long with olaparib than with placebo (7.4 months vs. 3.8 months).
PURPOSE
This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, ...open-label, phase II trial in patients with untreated RAS wild-type (WT) metastatic colorectal cancer.
PATIENTS AND METHODS
The primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI mFOLFOXIRI plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival.
RESULTS
A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3% v 60.6%; odds ratio, 4.469; 95% CI, 1.61 to 12.38; P = .004). The secondary resection rate was improved with the addition of panitumumab (33.3% v 12.1%; P = .02). Progression-free survival was similar in the study arms, whereas overall survival showed a trend in favor of the panitumumab-containing arm (hazard ratio for death, 0.67; 95% CI, 0.41 to 1.11; P = .12).
CONCLUSION
The addition of panitumumab to mFOLFOXIRI in patients with RAS WT metastatic colorectal cancer improved the ORR and rate of secondary resection of metastases and represents a treatment option in selected and fit patients in need of highly active first-line therapy. Future studies should determine whether the addition of panitumumab to mFOLFOXIRI prolongs survival.
Background
Physicians' clinical expertise forms an exclusive body of competences, which helps them to find the appropriate diagnostics and treatment for each individual patient. Empirical evidence, ...however, suggests that there is an inverse relationship between the number of years in practice and the quality of care provided by a physician. Knowledge and adherence to professional standards (such as clinical guidelines) are often used as indicators in previous research.
Methods
Semistructured interviews and the Q method were used for an explorative study on oncologists' views on the interplay between their own clinical expertise, intuition, and the external evidence incorporated in clinical guidelines. The interviews were audio recorded, transcribed ad verbatim, and analysed using qualitative content analysis.
Results
Data analysis shows the complex character of clinical expertise with respect to experience, professional development, and intuition. An irreplaceable role is attributed to personal and bodily experience during the providing of care for a patient. Professional experience becomes important, particularly in those situations that lie out of the focus of “guideline medicine.” Intuition is regarded as having a strong emotional component and helps for deciding which therapeutic option the patient can deal with.
Conclusions
Using measurable knowledge and adherence to standards as indicators does not account for the complexity of clinical expertise. Other factors, such as the importance of bodily experience and physicians' intuitive knowledge, must be considered, also with respect to the occurrence of treatment biases.
An accurate blood‐based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti‐EGFR therapy would benefit clinical practice by better informing decisions ...to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood‐based RAS mutation testing is a viable alternative to standard‐of‐care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin‐fixed paraffin‐embedded) tumor samples. Discordant tissue RAS results were re‐examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood‐based RAS mutation testing is a viable alternative to tissue‐based RAS testing.
Implementation of circulating tumor DNA testing in clinical practice has been hindered by the variable performance of available methods. Here, we demonstrate that plasma mutation testing using BEAMing as a standardized platform is comparable to tumor tissue testing and can be useful in the clinic to select patients with metastatic colorectal cancer for targeted therapy.
Cancer-related fatigue (CRF) is defined as a "distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is ...not proportional to recent activity and interferes with usual functioning." CRF is frequently observed in cancer patients even before the initiation of tumor therapy. Its cause is not clear, but in addition to primary effects of therapy, a tumor-induced elevated level of inflammatory cytokines may play a role. Transcutaneous auricular vagal nerve stimulation (taVNS) is a noninvasive way to activate central nervous pathways and modulate pain perception and the immune system. It has positive effects on autoimmune conditions and can also improve fatigue associated with Sjogren's syndrome. It is the main purpose of this feasibility study to investigate the feasibility of daily taVNS against CRF. Therefore, the stimulation protocol of the newly introduced smartphone app of the manufacturer is evaluated. Additionally, the effect taVNS on CRF and quality of life (QoL) shall be evaluated.
Thirty adult patients with gastrointestinal tumors during or after treatment, relevant CRF (Hornheide questionnaire) and life expectancy > 1 year, are enrolled. Patients are randomized to treatment or sham arm and be informed that they will either feel the stimulation or not. Treatment group will receive left-sided tragus above-threshold stimulation with 25 Hz, 250 µs pulse width, and 28-s/32-s on/off paradigm for 4 h throughout the day for 4 weeks. Sham group will receive no stimulation via a nonfunctional electrode. A daily stimulation protocol with time and average intensity is automatically created by a smartphone app connected to the stimulator via Bluetooth®. Multidimensional Fatigue Inventory-20, Short-Form 36 and Beck Depression Inventory questionnaires will be filled out before and after 4 weeks of stimulation.
Primarily, the patients' daily stimulation time and intensity will be evaluated through the electronic protocol after 4 weeks. Secondarily, the effect of taVNS on cancer-related fatigue and QoL will be measured through the questionnaires. As taVNS seems to modulate inflammatory cytokines, this noninvasive method may - if accepted by the patients - be a promising adjunct in the treatment of cancer-related fatigue.
The study was approved by local ethics committee (21-7395) and registered at the DRKS database (DRKS00027481).
Background
Shared decision‐making (SDM) has been advocated as an ethical framework for decision‐making in cancer care. According to SDM, patients make decisions in light of their values and based on ...the available evidence. However, SDM is difficult to implement in cancer care. A lack of applicability in practice is often reported. This empirical‐ethical study explores factors potentially relevant to current difficulties in translating the concept of SDM into clinical practice.
Methods
This study was conducted with nonparticipant observation of the decision‐making process in patients with gastrointestinal cancers for whom the benefit of adjuvant chemotherapy was uncertain according to clinical guidelines. Triangulation of qualitative data analysis was conducted by means of semistructured interviews subsequent to the observation. Observation notes and interview transcripts were analyzed according to the principles of grounded theory.
Results
Deviating from the concept of SDM, oncologists initiated a process of eliciting values and medical information prior to conveying information. The purpose of this approach was to select and individualize information relevant to the treatment decision. In doing so, the oncologists observed used two strategies: “biographical communication” and a “metacommunicative approach.” Both strategies could be shown to be effective or to fail depending on patients’ characteristics such as their view of the physicians’ role and the relevance of value‐related information for medical decision‐making.
Conclusion
In contrast to the conceptual account of SDM, oncologists are in need of patient‐related information prior to conveying information. Both strategies observed to elicit such information are in principle justifiable but need to be adapted in accordance with patient preferences and decision‐making styles.
Implications for Practice
This study showed that knowledge of patients’ values and preferences is very important to properly adapt the giving of medical information and to further the process of shared decision‐making. Shared decision‐making (SDM) trainings should consider different strategies of talking about values. The right strategy depends largely on the patient's preferences in communication. To be aware of the role of values in SDM and to be able to switch communicative strategies might prove to be of particular value. A more systematic evaluation of the patient's decision‐making preferences as part of routine procedures in hospitals might help to reduce value‐related barriers in communication.
Although shared decision making is advocated in most fields of medicine, implementation in oncology is challenging. Considering the importance of patient involvement in the era of individualized oncology, this article analyzes barriers to shared decision making.
Summary Background The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no ...continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. Methods In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00973609. Findings Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5–25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1–8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3–7·4) for the bevacizumab alone group, and 6·4 months (4·8–7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio HR 1·08 95% CI 0·85–1·37; p=0·53; upper limit of the one-sided 98·8% CI 1·42), whereas no treatment was not (HR 1·26 0·99–1·60; p=0·056; upper limit of the one-sided 98·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 19% patients in the fluoropyrimidine plus bevacizumab group, 67 43% in the bevacizumab monotherapy group, and 73 46% in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 13% of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 14% of 156 patients in the bevacizumab alone group, and 12 8% of 158 patients in the no treatment group). Interpretation Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies. Funding RochePharma AG and AIO Studien gGmbH.
Improved non‐invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non‐coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as ...biomarkers for non‐invasive cancer diagnosis. Analyzing serum derived from nude mice implanted with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR‐1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR‐1246 assays with RNA fragments derived from U2 small nuclear RNA (RNU2‐1). Importantly, we found that the assay signal discriminating tumor from controls was derived from U2 small nuclear RNA (snRNA) fragments (RNU2‐1f) and not from miR‐1246. In addition, we observed a remarkable stability of RNU2‐1f in serum and provide experimental evidence that hsa‐miR‐1246 is likely a pseudo microRNA. In a next step, RNU2‐1f was measured by qRT‐PCR and normalized to cel‐54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity and specificity of 97.7% 95% CI = (87.7, 99.9) and 90.6% 95% CI = (80.7, 96.5), respectively area under the ROC curve 0.972. Of note, patients with CRC were detected with our assay as early as UICC Stage II with a sensitivity of 81%. In conclusion, this is the first report showing that fragments of U2 snRNA are highly stable in serum and plasma and may serve as novel diagnostic biomarker for PDAC and CRC for future prospective screening studies.
What's new?
Non‐coding RNAs hold significant promise as biomarkers for noninvasive early cancer detection, but their utility has not yet been demonstrated. Here, fragments of the non‐coding U2 small nuclear RNA (RNU2) were found to be highly preserved and abundant in serum and plasma from pancreatic ductal adenocarcinoma and colorectal cancer patients. Reliable detection of the fragments, particularly for UICC stage II colorectal cancers, suggests that RNU2 may be a valuable screening marker for these cancers.
Detection of methylated free‐circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we ...analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO‐KRK‐0207, mfcDNA was isolated from plasma samples at different time points and bisulfite‐treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37–2.53). About 2–3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non‐detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00–2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86–3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3–4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.
What's new?
Tumor cells of primary tumors and metastases are constantly turned over with their DNA being released into blood circulation. Here the authors quantified circulating DNA of the hyperplastic polyposis 1 (HPP1) gene, which is frequently methylated in colorectal tumors, in a prospective clinical study of combination chemotherapy in patients with metastatic colorectal cancer. They confirmed their previous finding that HPP1 methylated free‐circulating DNA (mfcDNA) is a prognostic marker for progression‐free and overall survival in these patients. In addition, HPP1 mfcDNA served as a marker differentiating between chemotherapy responders and non‐responders, underscoring the usefulness of DNA‐based biomarkers in cancer treatment.
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