Contemporary Role of Radiation Therapy in Testicular Cancer.

Testicular cancer is a rare but curable male malignancy. Seminoma represents the majority of germ cell tumors and is considered radiation sensitive. Radiation treatment plays a role in adjuvant therapy after orchiectomy of stage I, IIA, and IIB seminomas. Radiation dose de-escalation has been effective in preventing tumor recurrences while also limiting acute and long-term toxicities. However, long-term risks, including the prevailing concern of secondary malignancy risk, between adjuvant radiation and chemotherapy play a role in recommendations. Ongoing work continues to be performed to reduce radiation field and dose in combination with chemotherapy while still maintaining excellent outcomes.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Robotic Stereotactic Radiotherapy for Intracranial Meningiomas-An Opportunity for Radiation Dose De-Escalation.

OBJECTIVE: To evaluate the possibility of dose de-escalation, with consideration of the efficacy and safety of robotic stereotactic CyberKnife radiotherapy in patients diagnosed with intracranial meningiomas. METHODS: The study group consisted of 172 patients (42 men and 130 women) treated in III Radiotherapy and Chemotherapy Clinic of Maria Sklodowska-Curie National Research Institute of Oncology in Gliwice between January 2011 and July 2018. The qualification for dose de-escalation was based on MRI (magnetic resonance imaging) features: largest tumor diameter less than 5 cm, well-defined tumor margins, no edema, and no brain infiltration. The age of patients was 21-79 years (median 59 years) at diagnosis and 24-80 years (median 62 years) at radiotherapy. Sixty-seven patients (Group A) were irradiated after initial surgery. Histopathological findings were meningioma grade WHO 1 in 51 and WHO 2 in 16 cases. Group B (105 patients) had no prior surgery and the diagnosis was based on the typical features of meningioma on MRI. All patients qualified for the robotic stereotactic CyberKnife radiotherapy, and the total dose received was 18 Gy in three fractions to reference isodose 78-92%. RESULTS: Follow-up period was 18 to 124 months (median 67.5 months). Five- and eight-year progression free survival was 90.3% and 89.4%, respectively. Two patients died during the follow-up period. Progression of tumor after radiotherapy was registered in 16 cases. Four patients required surgery due to progressive disease, and three of them were progression free during further follow-up. Twelve patients received a second course of robotic radiotherapy, 11 of them had stable disease, and one patient showed further tumor growth but died of heart failure. Crude progression free survival after both primary and secondary treatment was 98.8%. Radiotherapy was well-tolerated: acute toxicity grade 1/2 (EORTC-RTOG scale) was seen in 10.5% of patients. We did not observe any late effects of radiotherapy. CONCLUSION: Stereotactic CyberKnife radiotherapy with total dose of 18 Gy delivered in three fractions showed comparable efficacy to treatment schedules with higher doses. This could support the idea of dose de-escalation in the treatment of intracranial meningiomas.

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Radiotherapy dose de-escalation in patients with high grade non-Hodgkin lymphoma in a real-world clinical practice.

PURPOSE: The standard treatment of non-Hodgkin lymphoma (NHL) comprises combined modality treatment, radiotherapy (RT), and chemotherapy with rituximab which has significantly improved both disease-free survival (DFS) and overall survival (OS). However, there is no uniformity in radiation dose usage in these patients. In this retrospective study, we compared lower radiation dose with higher in patients with aggressive NHL. MATERIALS AND METHODS: From 2007 to 2017, treatment records of all high-grade NHL or diffuse large B-cell lymphoma and non-central nervous system NHL were included. We compared response rates, OS and DFS of patients who received ≤30 Gy RT to those with >30 Gy. Univariate and multivariate analyses were done to determine factors affecting prognosis, i.e., age, sex, stage, International Prognostic Index (IPI), adding rituximab, and radiation dose. RESULTS: A total of 184 NHL patients treated with combined modality or radiation alone having complete follow-up details were analyzed. At median follow-up of 66.8 months, 5-year OS was 72.8% in high-dose group versus 69.9% in low-dose group (p = 0.772) and 5-year DFS 64.7% versus 64.1% (p = 0.871). Patients having early-stage disease receiving low dose and those with advanced disease treated with >30 Gy had better OS and DFS though not statistically significant. Adding rituximab was associated with significantly better OS and DFS irrespective of radiation dose delivered. High IPI score and omitting rituximab were the only factors that significantly worsened both OS and DFS. Acute radiation toxicities were comparable in both groups (p = 0.82). Among late toxicities, no patient developed a second malignancy and 5% died due to cardiovascular complications (p = 0.595) though only two patients (1.1%) had received thoracic radiation. CONCLUSION: The two groups had comparable response rates, acute toxicities, DFS and OS. This study suggests that RT dose reduction may be possible in high-grade NHL without compromising the DFS and OS.

Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).

BACKGROUND: This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS: The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION: The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).

Effects of dose de-escalation following testosterone treatment and evoked resistance exercise on body composition, metabolic profile, and neuromuscular parameters in persons with spinal cord injury.

The dose de-escalation (DD) effects of testosterone and evoked resistance training (RT) on body composition, cardiometabolic, and neuromuscular variables were investigated. Thirteen men with chronic complete spinal cord injury (SCI) were followed for additional 16 weeks after receiving either testosterone treatment only (TT) or TT+RT. During the 16-week DD period, the TT+RT group underwent a program of once weekly electrical stimulation with gradually decreasing ankle weights and testosterone patches of 2 mg day-1 (TT+RT group). The TT only group did not receive any intervention throughout the detraining period (no-TT group). Body composition was tested using anthropometrics, dual energy X-ray absorptiometry, and magnetic resonance imaging. After an overnight fast, basal metabolic rate (BMR), lipid panel, serum testosterone, inflammatory biomarkers, glucose effectiveness, and insulin sensitivity were measured. Finally, peak isometric and isokinetic torques were measured only in the TT+RT group. All measurements were conducted at the beginning and at the end of DD. Absolute thigh muscle cross-sectional areas (CSAs) demonstrated interaction effects (p < 0.05) between the TT+RT (-8.15%, -6.5%) and no-TT (2.3%, 4.4%) groups. Similarly, absolute knee extensor muscle CSA demonstrated interaction effects (p < 0.05) between the TT+RT (-11%, -7.0%) and no-TT (2.6%, 3.8%) groups. There was a trend (p = 0.07) of increasing visceral adipose tissue (VAT) CSAs in the TT+RT (18%) and in the no-TT (16% cm2 ) groups. There was an interaction (p = 0.005) between TT+RT (decreased by 3.7%) and no-TT groups (increased by 9.0%) in BMR. No interactions were evident between groups over time for biomarkers related to carbohydrate, lipid metabolism, or inflammation. Finally, there were no changes (p > 0.05) in peak isometric or isokinetic torques and rise time following 16 weeks of the DD period in the TT+RT group. TT+RT during 16 weeks of DD was minimally effective at preventing detraining relative to no-TT on muscle size, BMR, and VAT. However, neuromuscular gains were successfully maintained.

De-escalation of anti-CD20 monoclonal antibody (Rituximab) protocols in Pemphigus Vulgaris - a systematic review.

Introduction: This review assesses current evidence supporting dose de-escalated rituximab therapy in pemphigus vulgaris, compared to standard protocols. Primary outcome measures were remission and relapse rates. Adverse effects, cumulative steroid dosages, and serological markers of disease activity were also reported.Areas covered: A literature search was performed to look for reports describing the use of de-escalated rituximab therapy in pemphigus vulgaris. Results from heterogenous studies showed a large variation in remission and relapse rates. Complete remission rates from de-escalated treatment ranged from 41.7 to 100.0%, while rates in the control groups ranged from 60.0 to 90.9%. Relapse rates varied from 8.0 to 81.3% in the de-escalated group and from 0.0 to 72.4% in the control group. Of the 165 patients included in this report, only two major adverse effects were reported.Expert Opinion: Overall, dose de-escalated rituximab protocols reported to date appear effective and safe. However, it is unclear if treatment effect parallels that of standard regimens in regard to disease control in the long term. A lower limit of effective dosing for rituximab in pemphigus vulgaris has not yet been reached or defined. The role for and timing of repeated cycles of low-dose rituximab therapy require further exploration.

A single-arm feasibility study of gradual dose de-escalation of antiemetic dexamethasone for older patients receiving chemotherapy.

OBJECTIVES: To investigate whether discontinuation of prophylactic dexamethasone by gradual dose de-escalation is practicable in older patients with cancer undergoing moderately emetogenic chemotherapy. MATERIALS AND METHODS: This single-arm, feasibility study prospectively enrolled 40 patients (≥70 years old) with colorectal cancer, who were scheduled to undergo adjuvant FOLFOX chemotherapy, and ten patients ≤60 years old to serve as a control group for pharmacokinetic study. All patients received an antiemetic regimen consisting of intravenous dexamethasone 8 mg and palonosetron at day 1 of the first cycle and underwent phone interviews using symptom questionnaires at day 7 of each cycle. Dexamethasone was tapered off through gradual de-escalation by 2 mg per cycle, when complete response (CR; no emesis and no rescue therapy) was achieved. Primary endpoint was the proportion of patients who discontinued dexamethasone completely. RESULTS: The median age of the patient was 74 years, and 50% were male. Of the 40 patients, 36 completed twelve cycles of chemotherapy, and 73% (N = 29) were able to discontinue dexamethasone completely. The mean (±SD) dose of dexamethasone per cycle was 3.0 mg (±2.4 mg), which was reduced to 37.5% of the initial dose level. The severity of patient-reported nausea did not significantly change over chemotherapy cycle. Geriatric assessment revealed no decline in any domain and fasting blood glucose and hemoglobin A1c levels were not elevated after twelve cycles of chemotherapy, compared to the baseline. CONCLUSION: Gradual dose de-escalation and discontinuation of prophylactic dexamethasone is feasible without compromising its antiemetic effect in older patients undergoing chemotherapy.

Stereotactic Radiosurgery for Vestibular Schwannomas: Reducing Toxicity With 11 Gy as the Marginal Prescribed Dose.

BACKGROUND: Stereotactic radiosurgery (SRS) is a common treatment option for vestibular schwannomas. Historically, a dose de-escalation of the marginal prescribed dose from 16 Gy to 12-13 Gy has been done to limit toxicity without reducing local control (LC). We aimed to retrospectively report outcomes of Linac-based SRS for vestibular schwannomas treated with different doses. METHODS: Included in the study were 97 stage 1 (1%), 2 (56%), 3 (21.5%), and 4 (21.5%) vestibular schwannomas treated with Linac-based (Novalis®) SRS from 1995 to 2019. No margin was added to the GTV to create the PTV. The median marginal prescribed dose was 14 Gy (range: 12-16 Gy) before 2006 and then 11 Gy for all patients (61 pts). Mean tumor volume was 1.96 cm3, i.e., about 1.6 cm in diameter. Mean follow-up was 8.2 years. RESULTS: Following SRS, LC at 3, 5, and 10 years was 100%, 98.4%, and 95.6%, respectively [100% for those with ≤ 13 Gy as the marginal prescribed dose (NS)]. Toxicity to the trigeminal nerve was reported in 7.2% of cases (3.3% and 0% for transient and permanent toxicity for 11 Gy). The marginal prescribed dose was the only significant predictive factor in univariate and multivariate analysis (HR = 1.77, 95% CI = 1.07-3.10, p = 0.028). Toxicity to the facial nerve was reported in 6.2% of cases. The marginal prescribed dose was again the only significant predictive factor in univariate and multivariate analysis (HR = 1.31, 95% CI = 0.77-2.23, p = 0.049). CONCLUSION: Linac-based SRS for stages 1-3 vestibular schwannomas provides excellent outcomes: a 10-year LC rate of over 95%, with a permanent facial or trigeminal toxicity rate of under 5%. A marginal prescribed dose of 11 Gy seems to decrease nerve toxicity and facial toxicity in particular, without reducing LC. Prospective studies with longer follow-up are needed.

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results.

BACKGROUND: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Treatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. RESULTS: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. CONCLUSIONS: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Practice patterns and outcomes following radiation dose de-escalation for oropharyngeal cancer.

OBJECTIVES/HYPOTHESIS: Numerous trials are evaluating radiotherapy (RT) de-escalation for human papillomavirus (HPV)-mediated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Herein, we evaluated the degree to which de-escalated RT is delivered in the United States, as well as comparative outcomes with full-dose RT as stratified for HPV status. STUDY DESIGN: Retrospective database review. METHODS: We identified patients diagnosed with OPSCC in the National Cancer Database, excluding those with stage I/II disease, unknown HPV status, receiving surgery or not receiving external beam radiation therapy to the primary site, receipt of radiation doses >75 or <54 Gy, radiation treatment course duration <25 or >75 days, and unknown or inadequate (<2 months) follow-up. Multivariable logistic regression analysis identified variables associated with delivery of de-escalated RT (<66 Gy). Overall survival of HPV+ and non-HPV-mediated (HPV-) disease was compared between full-dose and de-escalated approaches. RESULTS: Altogether, 617 and 551 patients were HPV+ and HPV-, respectively. De-escalated RT was delivered in 16.9% HPV+ and 15.2% of HPV- disease, respectively. Older patients and omission of systemic therapy were more likely to receive de-escalated RT. In HPV+ patients, 3- and 5-year survival rates were 83% and 80% in the de-escalated cohort versus 83% and 78% in the full-dose group (P = .83). In HPV- patients, corresponding 3- and 5-year survival rates were 29% and 23% versus 61% and 51% (P = .001). CONCLUSIONS: National utilization of de-escalated RT for OPSCC is low (15%-20%), but does not seem to impact overall survival in HPV+ (but not HPV-) patients. The caveats of this heterogeneous, retrospective analysis require corroboration from a number of ongoing randomized trials. LEVEL OF EVIDENCE: 2c Laryngoscope, 130:E171-E176, 2020.

Safety and Effectiveness of De-escalated Radiation Dose in T1-3 Nasopharyngeal Carcinoma: A Propensity Matched Analysis.

Backgrounds: With the excellent local control in T1 to T3 nasopharyngeal carcinoma (NPC) treated with intensity modulated radiotherapy (IMRT), the importance of toxicities is increasingly being recognised. This retrospective propensity score analysis sought to assess whether moderate dose reduction compromised long-term outcome compared with standard dose in T1-3 NPCs. Materials and Methods: A total of 266 patients (67 female, 199 male) with a median age of 50 years between June 2011 and June 2015 were analysed. All were treated with IMRT, with or without systemic chemotherapy. The prescription radiation dose to gross tumor is 70Gy/2.12Gy/33F in our institution. Results: With a median follow-up time of 50 months, the 5-year loco-regional failure-free survival (LRFS) and overall survival (OS) were 93.5% and 81.8%, respectively. 32 patients received radiation dose less than prescription dose, with a median dose of 63.6Gy (53-67Gy). Another 234 patients received exactly the prescription dose of 70Gy. Propensity scores were computed (32 patients treated with de-escalated dose and 64 patients with standard dose), there was no significant difference in 5-year LRFS and 5-year OS between the two groups (92.5% and 91.7% with standard dose; 82.1% and 85.7% with de-escalation dose; p=0.863 for LRFS and 0.869 for OS). No independent prognostic factor was associated with loco-regional failure in univariate analysis. Conclusions: T1-3 nasopharyngeal carcinoma presenting with superior locoregional control, a moderately reduced dose (about 10%) delivered with IMRT resulted in comparable prognosis to those with prescription dose of 70Gy.

Postoperative Radiotherapy for Multiple Myeloma of Long Bones: Should the Entire Rod Be Treated?

PURPOSE: To characterize local relapse after surgical fixation and postoperative radiotherapy (RT) for multiple myeloma (MM) with cortical involvement of long bones. PATIENTS AND METHODS: We retrospectively identified patients with MM involving cortical long bones treated with surgical fixation followed by postoperative RT at our institution. Local failures, defined as radiographic recurrence along the surgical hardware, were documented, and potential associations of independent variables (RT dose, fractionation, and extent of hardware coverage) with local failure were assessed by univariate Cox regression. RESULTS: We identified 33 patients with 40 treated sites with a median follow-up of 25.7 months; 68% of treatments were for pathologic fracture, and 32% were for impending fracture. The most common dose and fractionation were 20 to 25 Gy in 8 to 12 fractions. On average, 76% of the surgical hardware was covered by the postoperative RT field (median, 80%; range, 28%-100%). Local failure was observed in 5 cases (12.5%), 2 within the RT field and 3 out of field. None of the relapses resulted in hardware failure, and 2 were retreated with RT. The extent of hardware coverage predicted disease relapse along the hardware (hazard ratio = 6.44; 95% confidence interval, 1.09-37.97; P = .04); however, total RT dose, biologically effective dose, and number of fractions did not. CONCLUSION: After internal fixation of long bones with MM, full hardware coverage with the RT field could reduce the risk, though small, of disease developing in the future in the proximate hardware. Postoperative RT doses of 20 to 25 Gy in 8 to 10 fractions can achieve excellent local control.

Radiation therapy dose de-escalation compared to standard dose radiation therapy in definitive treatment of HPV-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Despite existing evidence that human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis compared to HPV-negative OPSCC, randomized studies have yet to report the effect of de-escalating radiation therapy (RT) dose for definitive treatment. The aim of this study was to assess the effectiveness of dose de-escalated RT (DDRT) vs. standard dose RT (SDRT) in patients with HPV-positive OPSCC. METHODS: This was an observational study using the National Cancer Database (Year 2010-2014) to identify patients who had HPV-positive OPSCC and were treated with definitive RT or chemo-RT. Patients undergoing surgery were excluded. Patients receiving ≥50 Gy, but <66 Gy were categorized as receiving DDRT. Patients receiving ≥66 Gy were categorized as receiving SDRT. Inverse probability of treatment weighting (IPTW) using propensity scores was used to balance the two groups. Kaplan-Meier analysis was used to estimate overall survival (OS). Subset analyses in patients receiving RT alone and concurrent chemo-RT were also performed. Multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. RESULTS: 759 patients with HPV-positive OPSCC were identified: 104 received DDRT and 655 received SDRT. The median follow-up was 30.5 (2.4-81.4) months. After IPTW-adjusted analysis, there was no difference in the 3-yr OS between the two groups (82.2% vs. 79.3%; P = 0.85). In the subset of patients receiving concurrent chemoradiotherapy, IPTW-adjusted analysis also did not show a difference in the 3-yr OS between the two groups (83.1% vs. 79.6%; P = 0.83). On multivariable analysis, DDRT was not associated with an inferior OS (HR 0.88; 95% CI, 0.53-1.47; P = 0.63). CONCLUSIONS: In this study, DDRT was not associated with an inferior OS compared to SDRT in patients with HPV-positive OPSCC. Randomized clinical trials to address DDRT in this patient population are currently ongoing.

The efficacy of 40 mg versus dose de-escalation to less than 40 mg of afatinib (Giotrif) as the first-line therapy for patients with primary lung adenocarcinoma harboring favorable epidermal growth factor mutations.

The choice of a first-line therapy for lung cancer is a crucial decision that can impact the survival as well as the quality of life of a patient. Inhibitors of epidermal growth factor receptor (EGFR) such as afatinib, erlotinib, and gefitinib have previously been used to treat non-small cell lung cancer harboring favorable EGFR mutations. Although afatinib has greater efficacy than other EGFR inhibitors, adverse events related to its use can result in the discontinuation of the therapy. In this study, we compared the therapeutic efficacy in lung cancer patients of a regimen of 40 mg/day of afatinib with that of a lower dose regimen of <40 mg/day resulting either from a lower starting dose of 30 mg/day or dose adjustment. Seventy-nine patients were treated with 40 mg/day and 67 received de-escalated doses of <40 mg/day. There was no significant difference in the clinical characteristics of the two groups except that the proportion of patients with a body weight of 50 kg or more was greater in the 40 mg/day group. Otherwise, there were no significant differences between the two groups in the average time to treatment failure (TTF), the rates at which the administration of a second-line therapy was necessary, or the frequency and severity of adverse events. Overall, these results suggest that it is possible to calibrate the dosage of afatinib to suit individual patient parameters such as low body weight, and that such calibration can be advised based on the given patient's individual experience of the drug.

bDMARD Dose Reduction in Rheumatoid Arthritis: A Narrative Review with Systematic Literature Search.

INTRODUCTION: Although bDMARDs are effective in the treatment of RA, they are associated with dose-dependent side effects, patient burden, and high costs. Recently, many studies have investigated the possibility of discontinuing or tapering bDMARDs when patients have reached their treatment goal. The aim of this review is to provide a narrative overview of the existing evidence on bDMARD dose reduction and to provide answers to specific dose-reduction-related questions that are of interest to clinicians. METHODS: We systematically searched for relevant studies in four scientific databases. Furthermore, we screened the references of reviews and relevant studies. RESULTS: Our searches resulted in 45 original studies of bDMARD dose reduction in RA patients (15 RCTs and 30 observational studies). Current evidence shows that bDMARD dose reduction can be considered in all RA patients who achieve stable (e.g., ≥6 months) low disease activity or remission. The best strategies seem to be disease-activity-guided dose optimization and fixed dose reduction, since direct bDMARD discontinuation (without restarting) results in a high flare rate, worse physical functioning, and more joint damage. When tapering the bDMARD treatment of a patient, disease activity should be monitored closely, and if a flare occurs, the dose should be increased to the lowest effective dose. Current evidence shows that restarting bDMARD treatment is effective and safe. Unfortunately, no clear predictors of successful dose reduction have been identified so far. CONCLUSION: The current evidence and rising healthcare costs urge that dose reduction should be considered for eligible patients. However, the decision to start dose reduction should be made in shared decision-making. Future research should focus not only on a better understanding of the effects of dose reduction on clinical outcomes but also on the perspectives of patients and physicians as well as the implementation of this new treatment principle.