Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Learning techniques that medical students use for long-term retention: A cross-sectional analysis.

BACKGROUND: Reviews and meta-analysis conclude that distributed practice and practice testing are deemed the most effective learning techniques among undergraduate students, while rereading, underlining, and summarisation are the most known and less effective ones. However, this evidence is gathered from short-term retention studies prior to 2014, and there are other techniques with promising effect (metacognition, retrieval, concept mapping, setting learning goals) that were not included. Also, there is little real-settings evidence regarding what works best for long-term retention in medical students. METHODS: A cross-sectional analysis was carried out in a sample of 155 of second and third-year students of the Degree in Medicine at Universidad de Navarra in September 2020. The aim was to evaluate the impact the use of different learning techniques had on academic performance of undergraduate medical students, assessing up to three months of retention. A subgroup analysis was performed based on learning approach, spacing of the learning sessions, and academic results. RESULTS: Rereading, highlighting, and summarisation were the most known and used techniques among medical students, with detrimental effects on academic outcomes. Metacognition was the most effective technique, but up to 92% of the students didn't know what it was. No single learning technique seemed to improve results in below-average students. CONCLUSIONS: University curricula should promote the use of more efficient techniques, particularly metacognition, to help students become lifelong learners. More studies are needed to confirm these findings. Below-average students remain a challenging population.

"What medical students with better academic results do: a cross-sectional analysis".

BACKGROUND: With university material doubling over time, medical students need to learn how to become successful life-long learners. Overall a Deep Approach (DA) to learning, and Self-Regulation (SR) skills are among the elements with a potential to accelerate learning, and Student Engagement (SE) has been associated with better university outcomes. However, specific recommendations concerning what students should do are lacking. The aim of this study was to identify above-average students' specific attitudes and strategies toward learning. METHODS: A cross-sectional analysis of the answers to the validated questionnaires Revised Study Process Questionnaire (R-SPQ-2F), SE, and Motivated Strategies for Learning Questionnaire (MSLQ) of 155 s and third-year students included in a prospective interventional study in the University of Navarre in September 2020 was performed. Students were stratified according to their standardized average mean in above-average (mean > 0) and below-average (mean ≤ 0). RESULTS: Overall, 67.1% of students scored higher in DA than in Surface Approach (SA) and had very high Intrinsic Value (IV, median 5.9). A higher proportion of above-average students had DA > SA score (72.7% vs 57.1%, p = 0.05), and showed higher scores in SR (median 4.9 vs 4.3, p = 0.007) compared to below-average, while the latter scored higher in SA (median 24.5 vs 23, p = 0.04), and surface motive (median 11 vs 9, p = 0.007). No differences were found in SE, and both groups had average scores in the cooperative dimension. Differences were rooted to hard work, interest over material and prioritizing understanding over rote-learning motives and aligned strategies. CONCLUSIONS: Curricula design and assessment should be aligned to promote DA and SR skills among learners. Furthermore, it is paramount that teachers help instill students with interest over material and encourage understanding and hard work, since are traits associated with better results. More studies concerning metacognition and other promising traits for becoming life-long learners and prepared professionals should be made.

Role of histological regression grade after two neoadjuvant approaches with or without radiotherapy in locally advanced gastric cancer.

BACKGROUND: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. METHODS: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A-D) were assessed. Grade A-true negative lymph nodes (LNs); grade B and C-infiltrated LNs with any or little evidence of nodal response; and grade D-complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia-b and grade D. RESULTS: From 2004 to 2014, 80 patients with GC (cT3-4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia-b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3%; P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). CONCLUSIONS: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

Technical flaws in multiple-choice questions in the access exam to medical specialties ("examen MIR") in Spain (2009-2013).

BACKGROUND: The main factor that determines the selection of a medical specialty in Spain after obtaining a medical degree is the MIR ("médico interno residente", internal medical resident) exam. This exam consists of 235 multiple-choice questions with five options, some of which include images provided in a separate booklet. The aim of this study was to analyze the technical quality of the multiple-choice questions included in the MIR exam over the last five years. METHODS: All the questions included in the exams from 2009 to 2013 were analyzed. We studied the proportion of questions including clinical vignettes, the number of items related to an image and the presence of technical flaws in the questions. For the analysis of technical flaws, we adapted the National Board of Medical Examiners (NBME) guidelines. We looked for 18 different issues included in the manual, grouped into two categories: issues related to testwiseness and issues related to irrelevant difficulties. RESULTS: The final number of questions analyzed was 1,143. The percentage of items based on clinical vignettes increased from 50% in 2009 to 56-58% in the following years (2010-2013). The percentage of items based on an image increased progressively from 10% in 2009 to 15% in 2012 and 2013. The percentage of items with at least one technical flaw varied between 68 and 72%. We observed a decrease in the percentage of items with flaws related to testwiseness, from 30% in 2009 to 20% in 2012 and 2013. While most of these issues decreased dramatically or even disappeared (such as the imbalance in the correct option numbers), the presence of non-plausible options remained frequent. With regard to technical flaws related to irrelevant difficulties, no improvement was observed; this is especially true with respect to negative stem questions and "hinged" questions. CONCLUSION: The formal quality of the MIR exam items has improved over the last five years with regard to testwiseness. A more detailed revision of the items submitted, checking systematically for the presence of technical flaws, could improve the validity and discriminatory power of the exam, without increasing its difficulty.

Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases.

BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the analmargin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016).

Impact of a longitudinal course on medical professionalism on the empathy of medical students.

OBJECTIVE: Medical education should enhance empathy. We examined, using self-assessment instruments and standardized patients (SPs), the impact on empathy, of a multi-year intervention (years 4-6 of medical training) that uses reflective learning approaches. METHODS: 241 final-year medical students participated; 110 from the 2018 graduation class (non-intervention group) and 131 from the 2019 graduation class (intervention group). Participants completed two self-reported empathy questionnaires - the Jefferson Scale of Empathy-Students (JSE-S) and the Interpersonal Reactivity Index (IRI) - and a personality questionnaire, the NEO Five-Factor Inventory. Additionally, SPs in a simulated station assessed participants' empathy with two patient-reported instruments: the Consultation and Relational Empathy (CARE) scale and the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE). RESULTS: Empathy scores were significantly higher in the intervention group compared to the non-intervention group when assessed by the SP (p < 0.001). No differences were found in self-reported questionnaires between the two groups. CONCLUSION: A longitudinal, multi-year reflection-based intervention enhanced empathy amongst medical students as assessed by SPs, but not when assessed by student self-reported measures. PRACTICE IMPLICATIONS: Multi-year reflective learning interventions during clinical training nurture empathy in medical students. Assessments completed by SPs or patients may enhance the evaluation of empathy.

Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy.

BACKGROUND: Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). METHODS: We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. RESULTS: Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed. CONCLUSIONS: A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.

Prognosis factors for recurrence in patients with locally advanced rectal cancer preoperatively treated with chemoradiotherapy and adjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence risk factors. RESULTS: The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II: OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1-2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis (OR = 7.73) predicted lung recurrence. LIMITATIONS: This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted.

Current treatment of rectal cancer adapted to the individual patient.

Preoperative radiochemotherapy and total mesorectal excision surgery is a recommended standard therapy for patients with locally advanced rectal cancer. However, some subgroups of patients benefit more than others from this approach. In order to avoid long-term complications of radiation and chemotherapy, efforts are being made to subdivide T3N0 stage using advanced imaging techniques, and to analyze prognostic factors that help to define subgroup risk patients. Long-course radiochemotherapy has the potential of downsizing the tumor before surgery and may increase the chance of sphincter preservation in some patients. Short-course radiotherapy (SCRT), on the other hand, is a practical schedule that better suits patients with intermediated risk tumors, located far from the anal margin. SCRT is also increasingly being used among patients with disseminated disease, before resection of the rectal tumor. Improvements in radiation technique, such as keeping the irradiation target below S2/S3 junction, and the use of IMRT, can reduce the toxicity associated with radiation, specially long-term small bowel toxicity.

Impact of perineural invasion on the outcome of patients with synchronous colorectal liver metastases treated with neoadjuvant chemotherapy and surgery.

PURPOSE: To analyze the prognostic value of variables of the primary tumor in patients with synchronous liver metastases in colorectal cancer (CLRMs) treated with neoadjuvant chemotherapy and surgery. METHODS/PATIENTS: From a prospective database, we retrospectively identified all patients with synchronous CLRMs who were treated with neoadjuvant chemotherapy and liver resection. Using univariate and multivariate analyses, we identified the variables associated with tumor recurrence. Overall survival and disease-free survival were calculated using the Kaplan-Meier method with differences determined by the Cox multiple hazards model. Results were compared using the log-rank test. RESULTS: Ninety-eight patients with synchronous CLRMs were identified. With a median follow-up of 39.8 months, overall survival and disease-free survival at 5 and 10 years were 53%, 41.7%, 29% and 29%, respectively. Univariate analysis identified three variables associated with tumor recurrence: location in the colon (p = 0.025), lymphovascular invasion (p = 0.011) and perineural invasion (p = 0.005). Multivariate analysis identified two variables associated with worse overall survival: perineural invasion (HR 2.36, 95% CI 1.162-4.818, p = 0.018) and performing frontline colectomy (HR 3.286, 95% CI 1.256-8.597, p = 0.015). Perineural invasion remained as the only variable associated with lower disease-free survival (HR 1.867, 95% CI 1.013-3.441, p = 0.045). Overall survival at 5 and 10 years in patients with and without perineural invasion was 68.2%, 54.4% and 29.9% and 21.3%, respectively (HR 5.920, 95% CI 2.241-15.630, p < 0.001). CONCLUSIONS: Perineural invasion in the primary tumor is the variable with most impact on survival in patients with synchronous CLRMs treated with neoadjuvant chemotherapy and surgery.

Accuracy of endoscopic ultrasound to assess tumor response after neoadjuvant treatment in rectal cancer: can we trust the findings?

BACKGROUND: The finding that some rectal cancers respond to neoadjuvant chemoradiation is broadening new surgical options for the treatment of some of these tumors that, until now, required a total mesorectal excision. Nevertheless, a fine match between clinical and pathological response is required when planning conservative surgical approaches. OBJECTIVE: This study aims to prospectively validate the use of endoscopic ultrasound as a predictor of clinical and pathological tumor response in patients with locally advanced rectal cancer. DESIGN: : This is an observational study of a cohort of patients undergoing chemoradiation followed by surgery. SETTINGS: This study was conducted at a tertiary medical center. PATIENTS: A total of 235 consecutive patients who underwent chemoradiation followed by surgery at a single institution during a 7-year period were included. MAIN OUTCOME MEASURES: All tumors were staged and restaged at 4 to 6 weeks after neoadjuvant treatment. Downsizing and downstaging were calculated between the initial and posttreatment measures and correlated to the pathological stage. The accuracy of endoscopic ultrasound to predict response was determined. RESULTS: Findings after chemoradiation showed T-downstaging in 54 patients (23%) and N-downstaging in 110 (47%). Overstaging occurred in 88 (37%) patients and was more commonly observed than understaging (21 patients; 9%). Related to the pathological report, endoscopic ultrasound correctly matched the T stage in 54% and the N stage in 75% of tumors. Sensitivity, specificity, and positive and negative predictive values to predict nodal involvement were 39%, 91%, 67%, and 76%. Accuracy was not influenced by such factors as age, distance of the tumor from the anal verge, or time to surgery. LIMITATIONS: This study was limited by the lack of comparison with other imaging methods. CONCLUSIONS: Endoscopic ultrasound allows prediction of involved lymph nodes in 75% of the cases; however, 1 in 5 patients are missclassified as uN0 after neoadjuvant treatment. In our point of view, this percentage is too high to rely only on this diagnostic modality to support a "wait and see" approach.

A phase II trial of less than 7 weeks of concomitant cisplatin-paclitaxel chemoradiation in locally advanced cervical cancer.

OBJECTIVES: This study was undertaken to determine the tolerability of a 7-week schedule of external beam radiation therapy, high-dose-rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix. METHODS: Twenty-nine patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m per week of intravenous (i.v.) cisplatin and 50 mg/m per week of i.v. paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 30 Gy of high-dose-rate brachytherapy. RESULTS: Eleven patients (37.9%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5 (range, 2-7). Thirty-five (20.1%) of 174 cycles of chemotherapy were not given because of toxicity. The median dose intensity of cisplatin was 31 mg/m per week (95% confidence interval [CI], 25.2-36.8); that of paclitaxel was 44 mg/m per week (95% CI, 39.9-48.3). Twenty-two patients (78.6%) were able to complete the planned radiation course in less than 7 weeks. Median radiation treatment length was 45 days (95% CI, 43.4-46.6). After a median follow-up of 48 months, 7 patients (24.1%) experienced severe (Radiation Therapy Oncology Group grade 3 or higher) late toxicity. No fatal events were observed. Seven patients have failed, 1 locally and 6 at distant sites. The 8-year local/pelvic control rate was 95.7%, and the 8-year freedom from systemic failure rate was 76.1%. Eight-year actuarial disease-free survival and overall survival were 63.1% and 75.9%, respectively. CONCLUSIONS: This study demonstrated unacceptable toxicity of combining the stated doses of concurrent cisplatin and paclitaxel chemotherapy with definitive radiotherapy for patients with advanced cervical cancer. Additional phase I/II trials are recommended to clearly establish the recommended phase II dose for these drugs.

Student's Inventory of Professionalism (SIP): A Tool to Assess Attitudes towards Professional Development Based on Palliative Care Undergraduate Education.

Introduction: Quality medical education, centered on a patient's needs, is crucial to develop the health professionals that our society requires. Research suggests a strong contribution of palliative care education to professionalism. The aim of this study was to design and validate a self-report inventory to measure student's professional development. Method: Sequential exploratory strategy mixed method. The inventory is built based on the themes that emerged from the analysis of four qualitative studies about nursing and medical students' perceptions related to palliative care teaching interventions (see Ballesteros et al. 2014, Centeno et al. 2014 and 2017, Rojí et al. 2017). The structure and psychometrics of the inventory obtained is tested in two different surveys with two different groups of medical students. Inventory reliability and construct validity are tested in the first survey group. To verify the inventory structure, a confirmatory factor analysis is performed in a second survey group. Results: The inventory has 33 items and seven dimensions: a holistic approach, caring for and understanding the patient, personal growth, teamwork, decision-making, patient evaluation, and being a health care professional. Cronbach's-alpha was 0.73-0.84 in all seven domains, ICC: 0.95. The confirmatory factor analysis comparative fit index (CFI) was 1 with a standardized root mean square Index 0.088 (SRMR) and obtained a 0.99 goodness-of-fit R-square coefficient. Conclusions: this new inventory is grounded on student's palliative care teaching experiences and seems to be valid to assess student's professional development.

Long-term results of Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiation in adult patients with soft tissue sarcomas of the extremities and the superficial trunk: Final results of a prospective controlled study.

BACKGROUND: To analyze toxicity, patterns of failure, and survival in 106 adult patients with soft tissue sarcomas of the extremity and the superficial trunk treated in a prospective controlled trial of combined Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiotherapy (EBRT). METHODS: Patients were treated with surgical resection and 16 Gy or 24 Gy of PHDRB for negative or close/positive margins, respectively. EBRT (45 Gy) was added postoperatively. Adjuvant chemotherapy was given to selected patients with high-grade tumors. RESULTS: The median follow-up was 7.1 years (range, 0.6-16.0). Grade ≥3 adverse events were observed in 22 patients (20.8%), and grade ≥4 events in 14 patients (13.2%). No grade 5 events were noted. Multivariate analysis (p = 0.003) found that Grade ≥3 toxic events increased with increasing implant volume (TV100). Local control, locoregional control, and distant control rates at 5 and 10 years were 89% and 87%, 82% and 80% and 75% and 69%, respectively. Multivariate analysis (p = 0.024) found that positive margins correlated with decreased local control. Disease-free survival and overall survival rates at 5 and 10 years were 64% and 59% and 73% and 62%, respectively. In multivariate analysis, disease-free survival rates decreased with increasing tumor size (p = 0.0001) and inadequate margins (p = 0.024), and overall survival decreased with increasing tumor size (p = 0.001) and male gender (p = 0.039). CONCLUSIONS: The combination of conservative surgery, high-dose PHDRB, and EBRT produces adequate function and local control in the majority of patients with soft tissue sarcomas of the extremities and the superficial trunk, including a substantial percentage of cases with positive margins. Patients with larger tumors are at a higher risk of complications, treatment failure, and cancer-related death and require an individualized treatment approach.

Correction: Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

[This corrects the article DOI: 10.1371/journal.pone.0217881.].

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

BACKGROUND: Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients. METHODS: Patients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks. RESULTS: A low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage ≥3 and linitis plastica absence, were correlated to a higher risk of death. CONCLUSION: Our model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

BACKGROUND: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. MATERIAL AND METHODS: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. RESULTS: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. CONCLUSIONS: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.

Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced rectal cancer.

PURPOSE: To identify the maximal tolerated dose level of preoperative intensity-modulated radiotherapy combined with capecitabine and oxaliplatin and to evaluate the efficacy. PATIENTS AND METHODS: Patients with rectal T3-T4 and/or N0-N+ rectal cancer received capecitabine 825 mg/m(2) twice daily Monday through Friday and oxaliplatin 60 mg/m(2) intravenously on Days 1, 8, and 15, concurrently with intensity-modulated radiotherapy. The radiation dose was increased in 5.0-Gy steps in cohorts of 3 patients starting from 37.5 Gy in 15 fractions (dose level [DL] 1). DL2 and DL3 were designed to reach 42.5 Gy in 17 fractions and 47.5 Gy in 19 fractions, respectively. RESULTS: No dose-limiting toxicity was observed at DL1 or DL2. Of the 3 patients treated at DL3, 1 presented with Grade 3 diarrhea, which was considered a dose-limiting toxicity, and 3 additional patients were added. Of the 6 patients treated at DL3, no new dose-limiting toxicities were observed, and DL3 was identified as the recommended dose in this study. Eight additional patients were treated at 47.5 Gy. Grade 2 proctitis was the most frequent adverse event (40%); Grade 3 diarrhea occurred in 2 patients (10%). All patients underwent surgery, and 17 patients (85%) underwent R0 resection. Four patients (20%) presented with a histologic response of Grade 4, 11 (55%) with Grade 3+, 2 (15%) with Grade 3, and 2 patients (10%) with Grade 2. CONCLUSION: The maximal tolerated dose in this study was 47.5 Gy. The high rates of pathologic response of Grade 3+ and 4 must be confirmed through the accrual of new patients in the Phase II study.

Impact of perineural invasion on the outcome of patients with synchronous colorectal liver metastases treated with neoadjuvant chemotherapy and surgery

Purpose To analyze the prognostic value of variables of the primary tumor in patients with synchronous liver metastases in colorectal cancer (CLRMs) treated with neoadjuvant chemotherapy and surgery. Methods/Patients From a prospective database, we retrospectively identified all patients with synchronous CLRMs who were treated with neoadjuvant chemotherapy and liver resection. Using univariate and multivariate analyses, we identified the variables associated with tumor recurrence. Overall survival and disease-free survival were calculated using the Kaplan–Meier method with differences determined by the Cox multiple hazards model. Results were compared using the log-rank test. Results Ninety-eight patients with synchronous CLRMs were identified. With a median follow-up of 39.8 months, overall survival and disease-free survival at 5 and 10 years were 53%, 41.7%, 29% and 29%, respectively. Univariate analysis identified three variables associated with tumor recurrence: location in the colon (p = 0.025), lymphovascular invasion (p = 0.011) and perineural invasion (p = 0.005). Multivariate analysis identified two variables associated with worse overall survival: perineural invasion (HR 2.36, 95% CI 1.162–4.818, p = 0.018) and performing frontline colectomy (HR 3.286, 95% CI 1.256–8.597, p = 0.015). Perineural invasion remained as the only variable associated with lower disease-free survival (HR 1.867, 95% CI 1.013–3.441, p = 0.045). Overall survival at 5 and 10 years in patients with and without perineural invasion was 68.2%, 54.4% and 29.9% and 21.3%, respectively (HR 5.920, 95% CI 2.241–15.630, p < 0.001). Conclusions Perineural invasion in the primary tumor is the variable with most impact on survival in patients with synchronous CLRMs treated with neoadjuvant chemotherapy and surgery (AU)