"A prospective study of assessment of neurocognitive function in illiterate patients with gliomas treated with chemoradiation": Assessment of neurocognitive function in gliomas.

OBJECTIVE: Neurocognitive functioning (NCF) is an important component of quality of life (QoL) in glioma patients. The neurocognitive toxicity from irradiation of brain tumours may be related to damage to neural progenitor cells (NPC). The aim of our study was to assess the NCF in illiterate glioma patients. METHODS: This was a prospective study done in glioma patients admitted for adjuvant treatment. Illiterate and semiliterate post op glioma patients with ECOG PS ≤ 3 were included. Neurocognitive assessment was done using Addenbrooke's Cognitive Examination (ACE-III) questionnaire prior to the start of RT and at 6month and 12 month follow up. The scores were correlated to the doses to sub ventricular zone (SVZ) and sub granular zone (SGZ) regions. RESULTS: 20 patients were recruited.16 patients were illiterate and four patients were semiliterate. Median of the mean dose to the SVZ I/L (ipsilateral) was 48.5 Gy and SGZ I/L was 39.5 Gy. In patients who received ≤49 Gy mean dose to SVZ I/L, there was statistically significant improvement in memory, fluency, language and total ACE scores at six months. In patients with SGZ I/L mean dose ≤40 Gy, there was improvement in memory, language, and total ACE score at six months. Similar trend continued at 12 months follow up. CONCLUSIONS: NCF assessment by ACE III questionnaire is a useful tool even in illiterate patients. Lower RT doses to the ipsilateral SVZ and SGZ showed significant improvement in total ACE scores at 6 months and improvement in specific domains at 6 and 12 months.

Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx.

PURPOSE: De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273. METHODS AND MATERIALS: MC1273 is a prospective, phase 2 study evaluating adjuvant CRT to 30 to 36 Gy plus docetaxel for HPV+ OPSCC after surgery for high-risk patients. Matched standard-of-care control groups were retrospectively identified for patients treated with definitive CRT or adjuvant RT. Standardized costs were evaluated before radiation, during treatment (during RT), and at short-term (6 month) and long-term (7-24 month) follow-up periods. RESULTS: A total of 56 definitive CRT, 101 adjuvant RT, and 66 MC1273 patients were included. The CRT arm had more T3-4 disease (63% vs 17-21%) and higher N2c-N3 disease (52% vs 20-24%) vs both other groups. The total treatment costs in the CRT, adjuvant RT, and MC1273 groups were $47,763 (standard deviation [SD], $19,060], $57,845 (SD, $17,480), and $46,007 (SD, $9019), respectively, and the chemotherapy and/or RT costs were $39,936 (SD, $18,480), $26,603 (SD, $12,542), and $17,864 (SD, $3288), respectively. The per-patient, per-month, average short-term follow-up costs were $3860 (SD, $10,525), $1072 (SD, $996), and $972 (SD, $833), respectively, and the long-term costs were $978 (SD, $2294), $485 (SD, $1156), and $653 (SD, $1107), respectively. After adjustment for age, T-stage, and N-stage, treatment costs remained lower for CRT and MC1273 versus adjuvant RT ($45,450 and $47,114 vs $58,590, respectively; P < .001), whereas the total per-patient, per-month follow-up costs were lower in the MC1273 study group and adjuvant RT versus CRT ($853 and $866 vs $2030, respectively; P = .03). CONCLUSIONS: MC1273 resulted in 10% and 20% reductions in global costs compared with standard-of-care adjuvant RT and definitive CRT treatments. Substantial cost savings may be an added benefit to the already noted low toxicity and maintained quality of life of treatment per MC1273.

Brief Hospital Supervision of Exercise and Diet During Adjuvant Breast Cancer Therapy Is Not Enough to Relieve Fatigue: A Multicenter Randomized Controlled Trial.

Supervised exercise dietary programs are recommended to relieve cancer-related fatigue and weight increase induced by adjuvant treatment of early breast cancer (EBC). As this recommendation lacks a high level of evidence, we designed a multicenter randomized trial to evaluate the impact of an Adapted Physical Activity Diet (APAD) education program on fatigue. We randomized 360 women with EBC who were receiving adjuvant chemotherapy and radiotherapy to APAD or usual care at eight French cancer institutions. Data were collected at baseline, end of chemotherapy, end of radiotherapy, and 6 months post-treatment. The primary endpoint was the general cancer-related fatigue score using the MFI-20 questionnaire. Fatigue correlated with the level of precariousness, but we found no significant difference between the two groups in terms of general fatigue (p = 0.274). The APAD arm has a smaller proportion of patients with confirmed depression at the end of follow-up (p = 0.052). A transient modification in physical activity levels and dietary intake was reported in the experimental arm. However, a mixed hospital- and home-based APAD education program is not enough to improve fatigue caused by adjuvant treatment of EBC. Cancer care centers should consider integrating more proactive diet-exercise supportive care in this population, focusing on precarious patients.

Toxicity after adjuvant therapy for stage III uterine cancer.

OBJECTIVE: The optimal adjuvant therapy for stage III endometrial cancer is unknown. Studies have suggested that combination therapy with chemotherapy and radiation is associated with improved survival. We examined early and late-term toxicities associated with chemotherapy (CT), external beam radiotherapy (RT), or combination chemoradiotherapy for stage III uterine cancer. METHODS: The SEER-Medicare database was used to identify women age ≥ 65 years with stage III uterine cancer who received adjuvant CT, RT, or chemoradiotherapy from 2000 to 2015. The associations between therapy and early and late-term toxicities identified with billing claims, hospitalizations and emergency department visits were examined using multivariable regression models. RESULTS: A total of 2185 patients were identified including 574 (26.3%) who received CT, 636 (29.1%) who received RT, and 975 (44.6%) who received chemoradiotherapy. The proportion of patients receiving chemoradiotherapy or CT increased over time. During the first 6 and 12 months of adjuvant therapy, RT was associated with a lower risk of early-term toxicity compared to chemoradiotherapy (aRR = 0.59, 95%CI 0.49-0.70 and aRR = 0.76, 95%CI 0.67-0.86, respectively) while CT shared a similar risk of early toxicities as chemoradiotherapy. CT and RT shared a similar risk of late-term toxicities compared to chemoradiotherapy. CT and RT alone were associated with a higher hazard for overall mortality than chemoradiotherapy (aHR = 1.27, 95% CI 1.10-1.47 and aHR = 1.25, 95% CI 1.08-1.44, respectively). CONCLUSION: Chemoradiotherapy is associated with lower mortality compared to single modality therapy and has a similar risk of early and late term toxicities compared to CT, though higher risk of early toxicities compared to RT.

Avoidance of Overtreatment of Rectal Cancer by Selective Chemoradiotherapy: Results of the Optimized Surgery and MRI-Based Multimodal Therapy Trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer carries a high risk of adverse effects. The aim of this study was to examine the selective application of nCRT based on patient risk profile, as determined by MRI, to find the optimal range between undertreatment and overtreatment. STUDY DESIGN: In this prospective multicenter observational study, nCRT before total mesorectal excision (TME) was indicated in high-risk patients with involved or threatened mesorectal fascia (≤1 mm), or cT4 or cT3 carcinomas of the lower rectal third. All other patients received primary surgery. RESULTS: Of the 1,093 patients, 878 (80.3%) were treated according to the protocol, 526 patients (59.9%) underwent primary surgery, and 352 patients (40.1%) underwent nCRT followed by surgery. The 3-year locoregional recurrence (LR) rate was 3.1%. Of 604 patients with clinical stages II and III, 267 (44.2%) had primary surgery; 337 (55.8%) received nCRT followed by TME. The 3-year LR rate was 3.9%, without significant differences between groups. In patients with clinical stages II and III who underwent primary surgery, 27.3% were diagnosed with pathological stage I. CONCLUSIONS: The results justify the restriction of nCRT to high-risk patients with rectal cancer classified by pretreatment MRI. Provided that a high-quality MRI diagnosis, TME surgery, and standardized examination of the resected specimen are performed, nCRT, with its adverse effects, costs, and treatment time can be avoided in more than 40% of patients with stage II or III rectal cancer with minimal risk of undertreatment. (clinicaltrials.gov NCT325649).

Cost-effectiveness analysis of endocrine therapy alone versus partial-breast irradiation alone versus combined treatment for low-risk hormone-positive early-stage breast cancer in women aged 70 years or older.

PURPOSE: We performed a cost-effectiveness analysis of three strategies for the adjuvant treatment of early breast cancer in women age 70 years or older: an aromatase inhibitor (AI-alone) for 5 years, a 5-fraction course of accelerated partial-breast irradiation using intensity-modulated radiation therapy (APBI-alone), or their combination. METHODS: We constructed a patient-level Markov microsimulation from the societal perspective. Effectiveness data (local recurrence, distant metastases, survival), and toxicity data were obtained from randomized trials when possible. Costs of side effects were included. Costs were adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALY) were calculated using utilities extracted from the literature. RESULTS: The strategy of AI-alone ($12,637) was cheaper than both APBI-alone ($13,799) and combination therapy ($18,012) in the base case. All approaches resulted in similar QALY outcomes (AI-alone 7.775; APBI-alone 7.768; combination 7.807). In the base case, AI-alone was the cost-effective strategy and dominated APBI-alone, while combined therapy was not cost-effective when compared to AI-alone ($171,451/QALY) or APBI-alone ($107,932/QALY). In probabilistic sensitivity analyses, AI-alone was cost-effective at $100,000/QALY in 50% of trials, APBI-alone in 28% and the combination in 22%. Scenario analysis demonstrated that APBI-alone was more effective than AI-alone when AI compliance was lower than 26% at 5 years. CONCLUSIONS: Based on a Markov microsimulation analysis, both AI-alone and APBI-alone are appropriate options for patients 70 years or older with early breast cancer with small cost differences noted. A prospective trial comparing the approaches is warranted.

Neoadjuvant Chemoradiation Therapy Is Associated with Adverse Outcomes in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Cancer.

The use of neoadjuvant chemoradiation therapy in patients with pancreatic adenocarcinoma is emerging as an acceptable therapy option. The effects of neoadjuvant therapy on 30 days' outcomes in patients with pancreatic cancer are not well defined in the literature. NSQIP (2009-2012) was used. Only patients with a diagnosis of pancreatic cancer and those who underwent a Whipple were included in the analysis. Patient who underwent neoadjuvant chemoradiation therapy were compared with those who did not receive therapy. Main outcome measures were as follows: complications, ≥2 units of blood transfusions, length of stay, readmission rates, return to the operating room, and 30-day mortality. A total of 1445 patients (395: neoadjuvant chemoradiation and 1050: no neoadjuvant therapy) were identified. The mean age was 67 ± 12 years, and 51 per cent of the patients were male. Neoadjuvant chemoradiation therapy was associated with increase in readmission rates (18% vs 12.2%, P 0.02), unanticipated return to the operating room (2.3% vs 1.1%, P 0.03) with no difference in mortality rates. Neoadjuvant chemoradiation therapy is associated with increase in inhospital complications. These differences in outcomes may be explained by the more advance stage of pancreatic cancer in these subsets of patients. Resource utilization and preoperative rehabilitation are of utmost significance to overcome this rise in complications associated with neoadjuvant chemoradiation therapy.

Comparative effectiveness of upfront esophagectomy versus induction chemoradiation in clinical stage T2N0 esophageal cancer: A decision analysis.

OBJECTIVES: We compared the effectiveness of upfront esophagectomy versus induction chemoradiation followed by esophagectomy for overall survival in patients with clinical T2N0 (cT2N0) esophageal cancer. We also assessed the influence of the diagnostic uncertainty of endoscopic ultrasound on the expected benefit of chemoradiation. METHODS: We created a decision analysis model representing 2 treatment strategies for cT2N0 esophageal cancer: upfront esophagectomy that may be followed by adjuvant therapy for upstaged patients and induction chemoradiation for all patients with cT2N0 esophageal cancer followed by esophagectomy. Parameter values within the model were obtained from published data, and median survival for pathologic subgroups was derived from the National Cancer Database. In sensitivity analyses, staging uncertainty of endoscopic ultrasound was introduced by varying the probability of pathologic upstaging. RESULTS: The baseline model showed comparable median survival for both strategies: 48.3 months for upfront esophagectomy versus 45.9 months for induction chemoradiation and surgery. The sensitivity analysis demonstrated induction chemoradiation was beneficial, with probability of upstaging > 48.1%, which is within the published range of 32% to 65% probability of pathologic upstaging after cT2N0 diagnosis. The presence of any of 3 key variables (size larger than 3 cm, high grade, or lymphovascular invasion) was associated with > 48.1% risk of upstaging, thus conferring a survival advantage to induction chemoradiation. CONCLUSIONS: The optimal treatment strategy for cT2N0 esophageal cancer depends on the accuracy of endoscopic ultrasound staging. High-risk features that confer increased probability of upstaging can inform clinical decision making to recommend induction chemoradiation for select cT2N0 patients.

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy. METHODS/DESIGN: TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. DISCUSSION: The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

Unmet needs mediate the relationship between symptoms and quality of life in breast cancer survivors.

PURPOSE: This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling. METHODS: In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up. RESULTS: The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors' physical and mental QoL after adjustment for survival time, and the models showed a good fit. CONCLUSIONS: Results suggest that breast cancer survivors continue to endure many symptoms independent of the survivorship period. The unmet needs mediate the relationship between symptom burden and survivors' QoL.

Assessment of radiotherapy combined with adjuvant chemotherapy in the treatment of patients with advanced nasopharyngeal carcinoma: a prospective study.

PURPOSE: To explore the clinical efficacy of radiotherapy combined with concurrent combination chemotherapy in the treatment of patients with advanced nasopharyngeal carcinoma (NPC). METHODS: Two hundred patients with stage III/IV NPC were randomly allocated into the treatment group (N=100) and the control group (N=100). Patients in the control group received conventional fractionated radiotherapy, while patients in the treatment group received conventional fractionated radiotherapy combined with concurrent combination chemotherapy with cisplatin and 5-fluorouracil (5-FU). Short-term efficacy, radiotherapy toxicity, shortand long-term survival were compared. RESULTS: The short-term response rate of the treatment group was 96%, which was significantly higher than that of the control group (87%, p<0.05). The local radiation toxicity of the treatment group was similar to that of the control group p>0.05), but the hematological and gastrointestinal toxicities were significantly higher in the treatment group p<0.05). The 1-, 3- and 5-year overall survival rates were 87, 80, and 76%, respectively, in the treatment group and 74, 64, and 51%, respectively, in the control group, significantly favoring the treatment group p<0.05). CONCLUSION: Radiotherapy with concurrent combination chemotherapy can improve the prognosis of patients with advanced NPC but at the cost of significant toxicity.

A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12 months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74 % of AI-users reported new/worsened musculoskeletal complaints compared with 37 % in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p = 0.0002). 15 % of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p = 0.0107). Young age (p = 0.0135), taxane-based chemotherapy (p = 0.0223), and baseline VAS score >4 (p = 0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p = 0.0090) and probability of discontinuation was observed (p = 0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

Adjuvant treatment for elderly patients with early-stage lung cancer treated with limited resection.

OBJECTIVES: Limited resection is commonly used for treating older patients with early-stage non-small cell lung cancer (NSCLC) who cannot tolerate lobectomy. However, parenchymal-sparing procedures leave patients at increased risk of recurrence. The role of postoperative radiotherapy (PORT) and chemotherapy after limited resection is not established. METHODS: We identified 1,929 patients with stage I-II (≤ 5 cm in size) NSCLC who underwent limited resection (wedge or segmentectomy) from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Using propensity score methods, we compared toxicity and survival of patients treated with limited resection alone, PORT, adjuvant chemotherapy, or PORT and chemotherapy. We conducted secondary analysis stratifying the sample by size (>2-5 cm), stage (IA vs. IB/IIA), and type of limited resection (wedge resection vs. segmentectomy). MEASUREMENTS AND MAIN RESULTS: Overall, 1,656 (85.8%), 159 (8.3%), 74 (3.8%), and 40 (2.1%) patients were treated with limited resection alone, PORT, adjuvant chemotherapy, or PORT and chemotherapy, respectively. Adjusted analysis using inverse probability weighting showed that PORT (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45-1.69), adjuvant chemotherapy (HR, 1.48; 95% CI, 1.36-1.61), and PORT and chemotherapy (HR, 1.73; 95% CI, 1.61-1.86) were associated with worse survival compared with limited resection alone. Similar results were obtained in secondary analyses. Compared with limited resection alone, the adjusted odds ratios for toxicity were 1.97 (95% CI, 1.6-2.4), 3.15 (95% CI, 2.58-3.85), 2.59 (95% CI, 2.0-3.4) for PORT, chemotherapy, and PORT and chemotherapy, respectively. CONCLUSIONS: PORT and adjuvant chemotherapy are not beneficial and appear to be associated with increased toxicity and worse survival after limited resection in elderly patients with early-stage NSCLC. Alternative strategies should be explored to improve local control.