Cisplatin-based Chemoradiotherapy Research Articles

Therapeutic effects and prognostic factors of 125I brachytherapy for pelvic recurrence after early cervical cancer surgery

To investigate the efficacy of 125I seed implantation in the treatment regimen of pelvic recurrence after early cervical cancer surgery and to analyse prognostic factors. To evaluate efficacy and analyse prognostic factors of 125I seed implantation for pelvic recurrence after early cervical cancer surgery. A prospective study was conducted on 62 patients who experienced pelvic recurrence after early cervical cancer surgery between August 2005 and September 2015. The 62 patients were treated and assessed in 2 groups (n = 30). All 62 patients were randomized into two groups that received two different treatment regimens: the treatment group (n = 30), which received 125I particle implantation therapy, and the control group (n = 32), which received whole-pelvic irradiation using the anteroposterior/posteroanterior field and cisplatin-based concurrent chemoradiation therapy. The efficacy/efficiency of 125I seed implantation and prognostic factors were analysed by logistic regression. Overall survival was determined by Kaplan–Meier analysis. Multivariate analysis results were obtained by the Cox proportional hazards regression model. The effective control rates at 1, 3, 6 and 12 months were 76.7%, 80.0%, 83.3%, and 86.7% in the 125I particle implantation group. The total effective control rates at 1, 3, 6 and 12 months were 65.6%, 65.5%, 62.5%, and 71.9% in the chemoradiotherapy group. Significant differences were observed between the two groups. The overall survival rates at 1, 2, 3, 4, and 5 years and the median overall were 96.7%, 93.3%, 86.7%, 71.9%, 65.6% and 4.34 years, respectively, in the 125I seed implantation group and 81.3%, 71.9%, 62.5%, 56.3%, 53.1% and 3.59 years, respectively, in the control group. There were statistically significant differences in survival rates depending on the diameter of the largest recurrent pelvic tumour (χ2 = 6.611, P = 0.010). The multivariate analysis showed that the survival rates were related to the diameter of the largest recurrent pelvic tumour (χ2 = 4.538, P = 0.033). 125I implantation is an effective, safe, and promising method for the treatment of pelvic recurrence after early cervical cancer surgery. The diameter of the recurrent pelvic tumour was identified as a significant independent prognostic factor in patients who received 125I implantation.

Post hoc analysis of a randomized controlled trial comparing concurrent chemoradiation with cisplatin versus nimotuzumab-cisplatin, focusing on acute oral mucositis

BackgroundAcute oral mucositis has been infrequently studied in the patients with head and neck squamous cell carcinoma (HNSCC) receiving once-weekly cisplatin-based chemoradiotherapy (CRT). Hence, this analysis was conducted to explore the various aspects of the same.ResultsThe overall incidence of mucositis was 96.9% (n = 508) and of grade 3–5 mucositis was 61.3% (n = 321). The overall incidence of oral mucositis was similar in both the arms (CCRT and NCRT) (p value = 0.58) while grade 3–5 mucositis was more common in the NCRT arm (p value = 0.01). Out of all factors listed, the presence of nimotuzumab was the only significant risk factor for the development of grade 3 or more oral mucositis (p value = 0.01); (OR = 1.64, 95%CI 1.15–2.32). Delays in the treatment delivery were similar in both the arms.ConclusionAcute oral mucositis is a common occurrence in locally advanced-HNSCC patients receiving chemoradiotherapy. Nimotuzumab is a significant factor for development of grade 3 and above oral mucositis.

The association of skeletal muscle mass and cisplatin pharmacokinetics in head and neck cancer patients: The prospective PLATISMA study.

6021 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and toxicity has been described. This increased toxicity may be related to an altered cisplatin distribution and binding in the fat-free body mass, of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in HNSCC patients. Methods: We performed a prospective observational study in HNSCC patients treated with CRT with cisplatin. Patients received standard-of-care chemotherapy with three cycles of cisplatin, at a dose level of 100 mg/m2 per cycle. Quantitative data on body size descriptors including SMM, measured on computed tomography scans, and cisplatin pharmacokinetics (total and ultrafilterable plasma concentration) were collected, as well as data on toxicity. Results: 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and the body size descriptors SMM, weight, fat-free mass, and body surface area ( p< 0.005). In a simulation, patients with a low SMM were predicted to reach higher bound cisplatin concentrations. The higher concentration of bound cisplatin could be seen as a reflection of the smaller volume of distribution, and could thereby explain the increased toxicity in patients with a low SMM. Conclusions: We found an association between cisplatin pharmacokinetics and SMM. Patients with a low SMM were predicted to reach higher bound cisplatin concentrations, which could be an explanation for the increased toxicity in this patient group. Clinical trial information: Trial NL7469 (NTR7711).

De-intensified chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma based on plasma EBV DNA: A phase 2 randomized noninferiority trial.

110 Background: The cisplatin-based chemoradiotherapy (CCRT), given at a dose of 100 mg/m2 for 3 cycles during radiotherapy, is the major treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). As several retrospective studies showed that receiving a cumulative cisplatin dose of 200 mg/m2 can bring survival benefits to NPC patients, we sought to test the non-inferiority of 2-cycle concurrent cisplatin over 3-cycle in locoregionally advanced NPC with Epstein-barr virus (EBV) DNA levels < 4000 copies/ml. Methods: We did a non-inferiority, phase 2, randomised controlled trial. Patients were enrolled with stage III–IVB NPC, EBV DNA levels < 4000 copies/ml, aged 18–70 and adequate haematological, renal, and hepatic function. Eligible patients were randomly assigned (1:1) to receive 2 or 3 cycles of cisplatin-based CCRT. Patients in the 2-cycle group were scheduled to receive 100 mg/m2 cisplatin given every 3 weeks concurrently with radiotherapy, and patients in the 3-cycle group received 100 mg/m2 cisplatin given every 3 weeks for 3 cycles. Randomization was done by a computer-generated random number code with a block size of six, stratified by clinical stage III or IV. The primary endpoint was 3-year progression-free survival (PFS), with a non-inferiority margin of 10%. This study was registered with ClinicalTrials.gov, ID. NCT02871518. Results: Between September 2016 and October 2018, 342 patients were enrolled, of whom 332 were randomly assigned to receive 2 or 3 cycles of cisplatin. 314 (94.6%) patients completed protocol-defined cycles of chemotherapy. After median follow-up of 33.6 months, 20 (12.0%) patients in the 2-cycle group and 17 (10.2%) patients in the 3-cycle group had tumor progression, and the 3-year PFS rates were 88.0% and 90.4% respectively, with a difference of 2.4% (95%CI -4.3 to 9.1, Pnon-inferiority < 0.001). In the per-protocol analysis, 3-year PFS was 88.5% in the 2-cycle group and 90.6% in the 3-cycle group, with a difference of 2.1% (95% CI –4.7 to 8.9; Pnon-inferiority= 0.001). No significant difference was observed concerning OS, LRRFS and DMFS. The grade 3 or 4 acute adverse events were recorded in 113 (68.1%) patients in the 2-cycle group and 116 (69.9%) patients in the 3-cycle group. Patients in the 3-cycle group was observed to have significantly more hyponatremia. Besides, patients in the 3-cycle group presented with more grade 1 or 2 dry mouth, dysphagia, weight loss, fatigue, constipation, fever, mucositis and dermatitis. More grade 3 or 4 anorexia, mucositis and dermatitis were also recorded in the 3-cycle group. No patients died from treatment-related toxicities. Conclusions: IMRT plus 2 cycles of concurrent 100 mg/m2 cisplatin could be an alternative option for patients with low-risk locoregionally advanced NPC. Further phase III studies are needed to validate the findings of this study. Clinical trial information: NCT02871518.

Interim analysis of IMMUNEBOOST-HPV: A multicenter, randomized, open label, phase II study evaluating the feasibility, and tolerance of neoadjuvant nivolumab in high-risk HPV driven oropharynx cancer.

6037 Background: Among HPV-positive Oropharyngeal Cancer (OPC) patients (pts), some has a less favorable prognosis (T4, N2/N3, smokers >10 pack-year [p/y]). We assume that neoadjuvant immunotherapy might improve their oncological outcomes, so we tested nivolumab (N) prior to ChemoRadiaTion (CRT). Methods: The study population is restricted to HPV positive OPC pts (both p16+ & HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history >10 p/y. Pts were randomly allocated 1:2 to receive either cisplatin-based CRT (n=20) or 2 cycles of N 240 mg followed by CRT (n=41). The Primary Endpoint (PE) is the rate of pts who can receive Full Treatment in Due Time (FTDT), according to these criteria: a) 2 N infusions on day 1 and on day 14-16 b) CRT started between days 28-37 after the 1st N infusion c) No RT break ≥1 week d) RT dose received >95% of theoretical dose e) Cisplatin dose received ≥200 mg/m² To achieve FTDT, all criteria are required in the Experimental Arm (EA) while only criteria c), d), and e) are required in the Control Arm (CA). In the EA, the trial was designed in 2 steps, with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, a type I error of 0.10, and a type 2 error of 0.08. As per protocol, patient accrual was temporarily suspended after inclusion of 19 pts in the EA (1st step) and results were reviewed by an Independent Data Monitoring Committee (IDMC). To resume pts’ inclusion, FTDT had to be achieved in 18 pts in the EA. Results: From 07/2019 to 09/2020, 30 pts were enrolled including 11 in the CA (demographics are summarized in table). 2 pts in the EA did not reach the PE. For the 1st patient, the cisplatin dose was <200 mg/m2 due to grade 1 hearing loss and grade 2 tinnitus (1st cycle: 100 mg/m2, 2nd cycle: 80 mg/m2, no 3rd cycle). For the 2nd patient, CRT began at D38 due to logistical issues (maintenance of RT devices). As this delay was unrelated to N or to patient's condition, the IDMC considered that the inclusions could resume for the 2nd step. 7 N-related Adverse Events (AE) were reported in 4 pts including 3 serious AE (ankylosing spondylitis flare-up, colitis, diabetic ketoacidosis). Conclusions: Neoadjuvant N before CRT seems feasible for the treatment of OPC pts. The trial has reopened to inclusion as recommended by the IDMC. Clinical trial information: NCT03838263. [Table: see text]

A randomized phase II trial of diffusion-weighted MR imaging-guided radiotherapy plus chemotherapy versus standard chemoradiotherapy in locoregional advanced nasopharyngeal carcinoma.

6018 Background: We hypothesized that diffusion-weighted MR imaging (DWI) guided dose-painting radiotherapy (DP-RT) was associated with improved tumor control and survival compared with standard CT-based radiotherapy in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized phase II trial was to compare the efficacy and toxicity of DWI guided DP-RT plus chemotherapy versus standard CT-based radiotherapy plus chemotherapy in locoregionally advanced NPC. Methods: Two hundred and fifty-six patients with stage III-IVa (8th AJCC) NPC were randomly assigned to receive DWI-guided dose-painting radiotherapy plus chemotherapy (DP-RT group, n = 128) or standard CT-based radiotherapy plus chemotherapy (CT-based RT group, n = 128). Patients in both groups received 3 cycles of induction chemotherapy followed by cisplatin-based concurrent chemoradiotherapy. In DP-RT group, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean). The dose to GTVnx-DWI was escalated to DT 75.2 Gy/32 Fx in patients with T1-2 disease, and DT 77.55 Gy/33 Fx in those with T3-4 disease, in 2.35 Gy per fraction. In CT-based RT group (n = 128), PGTVnx was irradiated at DT 70.4-72.6 Gy/32-33 Fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn, number ChiCTR1800015779. Results: Compared with standard CT-based radiotherapy, DWI-guided DP-RT significantly improved 2-year local recurrence-free survival (LRFS, 100% vs. 95.4%; P = 0.024), distant metastasis-free survival (DMFS, 97.9% vs. 90.6%; P = 0.006), disease free survival (DFS, 93.2% vs. 86.8%; P = 0.021), and overall survival (OS, 100% vs. 95.2%; P = 0.038). No statistically significant differences in acute and late toxic effects were observed. Multivariate analysis showed that dose painting (DWI-guided DP-RT vs CT-based RT without DP) was a significant independent prognostic factor for DMFS and DFS (P = 0.021 and P = 0.020, respectively). Conclusions: Diffusion-weighted MR imaging guided dose-painting radiotherapy plus chemotherapy is associated with a considerable survival benefit, without increasing toxicity, as compared with standard CT-based radiotherapy plus chemotherapy, among patients with locoregionally advanced nasopharyngeal carcinoma. Clinical trial information: ChiCTR1800015779.

Matched pair analysis for comparison of survival outcome of alternative regimens to standard three-weekly cisplatin-based concurrent chemoradiation of head and neck cancer.

BackgroundTo compare head and neck cancer (HNC) patients treated with three-weekly versus weekly cisplatin-based or other chemotherapy-based concurrent chemoradiation (CRT) and CRT with versus without induction chemotherapy (ICT) to investigate differences in overall survival (OS) and cancer-specific survival (CSS).MethodsHNC patients treated with definitive or adjuvant CRT at Roswell Park Comprehensive Cancer Center between 2003 and 2017 were retrospectively reviewed. Propensity score matching was performed to obtain three sets of balanced matched pairs: three-weekly and weekly cisplatin CRT, three weekly and non-cisplatin CRT, CRT with and without ICT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate and compare survival outcomes.ResultsA total of 623 patients received either definitive (81%) or post-operative (19%) RT. Of these, 283 patients concurrently received three-weekly cisplatin (45%); 189 patients (30%) received weekly cisplatin; 151 patients (24%) received non-cisplatin regimen. Median follow-up was 55.4 months (interquartile range, 38.0–88.7). Patients who received CRT alone and those who received ICT and CRT had no difference in 5-year OS (51.5% and 41.0% respectively, P=0.53) and CSS (64.9% and 49.7% respectively, P=0.21). Compared to patients who received three-weekly cisplatin, patients who received weekly cisplatin had no difference in 5-year OS (59.3% vs. 54.1%, P=0.35) and CSS (70.3% vs. 62.4%, P=0.09); patients who received non-cisplatin CRT also had no difference in 5-year OS (54.5% vs. 58.3%, P=0.51) and CSS (67.5% vs. 64.7%, P=0.45).ConclusionsNo significant difference in OS and CSS was observed in any of the three pairs of CRT regimens. ICT prior to CRT did not improve survival of CRT alone. Non-cisplatin and weekly cisplatin regimens did not prove to be inferior to the standard three-weekly cisplatin.

Patterns, Predictors, and Prognostic Value of Skeletal Muscle Mass Loss in Patients with Locally Advanced Head and Neck Cancer Undergoing Cisplatin-Based Chemoradiotherapy.

Low skeletal muscle mass (SMM) is associated with toxicities and decreased survival in head and neck cancer (HNC). Chemoradiotherapy (CRT) may exaggerate loss of SMM. We investigated the changes in SMM, their predictors, and prognostic impact of SMM in patients treated with CRT between 2012 and 2018. Skeletal muscle area (SMA) segmentation was performed on pre- and post-CRT imaging. Observed changes in SMM were categorized into: (I) Stable, (II) moderate gain (III), moderate loss, (IV) large gain, and (V) large loss. In total, 235 HNC patients were included, of which 39% had stable SMM, 55% moderate loss, 13% moderate gain, 0.4% large loss, and 0.4% large gain of SMM. After CRT, SMA decreased compared to pre-CRT (31.6 cm2 versus 33.3 cm2, p < 0.01). The key predictor was a body mass index (BMI) of ≥30 kg/m2 (OR 3.6, 95% CI 1.4–9.3, p < 0.01). Low SMM at diagnosis (HR 2.1; 95% CI 1.1–4.1, p = 0.03) and an HPV-positive oropharyngeal tumor (HR 0.1; 95% CI 0.01–0.9, p = 0.04) were prognostic for overall survival. Changes in SMM were not prognostic for survival. Loss of SMM is highly prevalent after CRT and a high BMI before treatment may aid in identifying patients at risk.

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models.

PurposeThe side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy.Patients and MethodsThanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control.ResultsWhatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3.ConclusionThese data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.

BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair.

Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identified RAD51AP1 as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region of RAD51AP1 and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibiting RAD51AP1 transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.

Renal function impairment in cervical cancer patients treated with cisplatin-based chemoradiation: A review of medical records in a Zimbabwean outpatient department.

There is a potential increase in risk of renal function impairment among patients with invasive cervical cancer (ICC) who are HIV-positive and treated with cisplatin-based concurrent chemoradiation (CCRT). This concern is due to overlapping nephrotoxicity of the drugs, and nephropathy from the diseases themselves. There is limited literature available for the short-term renal outcomes for HIV-positive patients with ICC during routine clinical management. This study aimed to assess if HIV-infection increased the risk of renal impairment in ICC patients treated with CCRT, and explore the respective risk factors. This was a retrospective review of records of ICC patients treated with at least one cycle of weekly cisplatin during CCRT at the Parirenyatwa Radiotherapy Center from January 2017-December 2018. The RIFLE criteria were used to classify renal impairment. Analyses were performed with Fisher's Exact tests, Wilcoxon rank sum tests. Odds ratios (OR) were generated using logistic regression. All statistical tests were 2-sided at a 5% level of significance. Seventy-two eligible patients were identified, 32 (44.44%) were HIV-positive. HIV-positive patients were younger (p = 0.002), had lower albumin levels (p = 0.014) and received lower cisplatin doses (p = 0.044). The mean percent reduction in estimated glomerular filtration rate (eGFR) from baseline was -19% (95% CI: -25.9% to -13.2%) for all patients. Thirty-one (43.1%) patients experienced renal impairment, 50% and 37.5% of HIV-positive and -negative patients respectively (p = 0.287). HIV-infection was associated with an adjusted OR of 1.16 (95% CI 0.35-3.43, p = 0.769). Baseline eGFR< 60ml/min was the only independent predictor of renal impairment, OR 0.25 (95% CI: 0.07-0.85). Baseline eGFR<60ml/min was also associated with receipt of lower cisplatin doses (p = 0.044). HIV-infection was not associated with elevated risk of renal impairment. Patients with an eGFR<60ml/min appear to be managed more cautiously reducing their risk for renal impairment during cisplatin therapy. The high prevalence of renal impairment in this population suggests the need for optimization of pre-treatment protocols.

OROPHARYNGEAL SQUAMOUS CELL CARCINOMA TREATED CONCURRENTLY WITH CETUXIMAB: A CASE REPORT OF INTOLERANCE TO CISPLATIN IN YOUNG AGE

Squamous cell carcinoma of the oropharynx is a common case of head and neck cancer related to human papillomavirus. We present a case of moderately (G2) differentiated squamous cell carcinoma, which responded well to concurrent radiotherapy with cetuximab after intolerance of cisplatin. A 37-year-old woman referred to our hospital for a locally advanced cancer of the base of tongue. Physical examination revealed an ulcerative tumor with spread to the supraglottic structures, and swelling of the right side cervical lymph node at group IIA. The histological diagnosis from a biopsy specimen was moderately differentiated p16 positive squamous cell carcinoma. The patient underwent cisplatin-based concurrent chemoradiotherapy. Two – three weeks after receiving an intravenous cisplatin dose 100 mg/m 2 for the first day of chemorradiation, the patient presented with profound bilateral sensorineural hearing loss. The cisplatin-based chemotherapy had changed to alternative agent. The patient continuously underwent concurrently radiation with cetuximab without the break of radical radiotherapy course. The patient experienced partial recovery of hearing after radical treatment of cancer. Complete clinical and radiological response of oropharyngeal squamous carcinoma was achieved. Conclusions. Toxicity with only one standard dose of cisplatin can be profound also in young age. This risk should be addressed when counseling patient prior to initiation of treatment. In case of platinum ineligibility, replacing cisplatin with less toxic agent cetuximab may be taken into consideration for p16 positive carcinoma of the oropharynx.

Weekly versus triweekly cisplatin-based concurrent chemoradiotherapy for nasopharyngeal carcinoma: a systematic review and pooled analysis.

Background: Weekly and triweekly cisplatin-based concurrent chemoradiotherapy (CCRT) have been used in the treatment of nasopharyngeal carcinoma (NPC).Objective: This study aimed to compare the benefits and risks between the two treatments.Methods: We systematically searched electronic databases for prospective and retrospective clinical studies of NPC patients who received weekly compared with triweekly cisplatin-based CCRT. The primary endpoints comprised overall, failure-free, distant metastasis-free, and locoregional recurrence-free survivals (OS, FFS, DMFS, and LRFS). Secondary endpoints were toxicities.Results: Six studies were included in the systematic review, of which four with 1515 NPC patients were eligible for further pooled analysis. There were no significant differences between weekly and triweekly groups in terms of 5-year OS (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.51-1.79), FFS (OR 1.09, 95% CI 0.67-1.76), DMFS (OR 1.25, 95% CI 0.54-2.92), and LRFS (OR 0.83, 95% CI 0.55-1.25). For grade ≥ 3 toxicities, the weekly group had higher risks of anemia (risk ratio [RR] 2.96, 95% CI 1.12-7.81) and thrombocytopenia (RR 2.75, 95% CI 1.54-4.90), but a lower incidence of vomiting (RR 0.34, 95% CI 0.18-0.63) versus the triweekly group.Conclusion and Relevance: Both weekly and triweekly schedules could be recommended to NPC patients during CCRT. Additionally, hematologic adverse events in weekly strategy and non-hematologic adverse events in triweekly strategy are of higher concern.

Treatment algorithm and prognostic factors for patients with stage I–III carcinoma of the anal canal: a 20-year multicenter study

Despite a growing incidence in developed countries and a recent improved understanding of its pathogenesis, anal cancer management has not evolved over the past decades and drug combination used as first-line regimen still largely depends on clinician preferences. Aiming at paving the way for precision medicine, a large cohort of 372 HIV-negative patients diagnosed over a 20-year time period with locally advanced anal carcinoma was collected and carefully characterized at the clinical, demographic, histopathologic, immunologic, and virologic levels. Both the prognostic relevance of each clinicopathological parameter and the efficacy of different concurrent chemoradiation strategies were determined. Overall, the incidence of anal cancer peaked during the sixth decade (mean: 63.4) and females outnumbered males (ratio: 2.51). After completion of treatment, 95 (25.5%) patients experienced progression of persistent disease or local/distant recurrence and 102 (27.4%) died during the follow-up period (median: 53.8 months). Importantly, uni-multivariate analyses indicated that both negative HPV/p16ink4a status and aberrant p53 expression were far better predictors for reduced progression-free survival than traditional risk factors such as tumor size and nodal status. As for overall survival, the significant influences of age at diagnosis, p16ink4a status, cTNM classification as well as both CD3+ and CD4+ T-cell infiltrations within tumor microenvironment were highlighted. Cisplatin-based chemoradiotherapy was superior to both radiotherapy alone and other concurrent chemoradiation therapies in the treatment of HPV-positive tumors. Regarding their HPV-uninfected counterparts, frequent relapses were observed, whatever the treatment regimen administered. Taken together, our findings reveal that current anal cancer management and treatment have reached their limits. A dualistic classification according to HPV/p53 status should be considered with implications for therapy personalization and optimization.

Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers.

BackgroundCisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.MethodsThis phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.ResultsGiven significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41–65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.ConclusionsVPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).

Concomitant weekly cisplatin-based chemoradiotherapy in head and neck cancer: the value of a second measured glomerular filtration rate during treatment.

To assess the efficacy of the second measured glomerular filtration rate (GFR) during the course of weekly cisplatin-based chemoradiotherapy in head and neck cancer. Data was collected on consecutive 221 head and neck cancer patients who underwent cisplatin-based chemoradiotherapy. 68% patients managed to complete at least five out six proposed cycles of cisplatin, with a cumulative dose of ≥200 mg/m2. 181 patients underwent second measured GFR and it showed a mean fall in measured GFR by 12.0 ml/min/1.73 m2 (p < 0.0001). Out of these 181 patients, in 16 patients (9%), the decision to discontinue cisplatin was purely based on a low second measured GFR (below 50 ml/min/1.73 m2). Our study has shown that obtaining a second measured GFR is valuable in 9% of these patients. We propose that this should be considered as a standard procedure in these settings and also should be considered incorporating this additional safety measure, into future clinical trials as a mandatory procedure. To the best of author's knowledge, this is first study of its kind. The results of our study suggest that it should be a standard procedure of obtaining a second GFR in these settings.

280P Safety and efficacy of concurrent chemoradiotherapy for head and neck cancers in younger versus older patients: Post hoc analysis of a randomized control trial

Head and neck squamous cell carcinoma (HNSCC) is a well-known malignancy in the older population. However, there is scarcity of data on the effect of chemoradiation on them. We did a posthoc analysis of a randomized study conducted at our institution to understand this effect. We did a posthoc analysis of the study where the patients received chemoradiation. The database of this study was used for the present analysis. We evaluated the differences in demography, grade 3 or worse adverse events, compliance of treatment, loco-regional control (LRC), progression free survival (PFS) and overall survival (OS) between older (≥ 60 years) and the younger patients. Out of 300 patients, 283 (94.3%) comprised the younger cohort (age < 60 years) while the older cohort included 17 (5.7%) patients. There was no difference in the occurrence of severe (grade 3/4) toxicities in the older cohort when compared to the younger patients. At a median follow up period of 22 months (range, 3-51), the cumulative LRC at 2 years was 67.1% and 100% in younger and the older group respectively (P = 0.018). The estimated median PFS in younger patients was 24.4 months (95% CI, 12.5 to 36.3), while it was not reached in the older group (P = 0.53). The estimated median OS was 41.3 months in the younger and not reached in the older group (P = 0.613). Older patients with locally advanced HNSCC who received radical concurrent cisplatin-based chemoradiotherapy showed significantly better LRC. Older patients experienced similar adverse events as compared to the younger ones.

Radiotherapy With Weekly Cetuximab Versus Triweekly Carboplatin In The Definitive Treatment Of Cisplatin-Ineligible Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma: One Institution’s Retrospective Experience

Although Triweekly Cisplatin-based concurrent chemoradiation has recently been shown to be superior to Cetuximab-based concurrent therapy in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) in multiple randomized trials, the optimal concurrent agent in those who are poor candidates for Cisplatin is unknown. Here we report the cancer control and survival outcomes in this cohort of patients who underwent radiotherapy concurrent with either triweekly Carboplatin or weekly Cetuximab at our institution. A retrospective review was conducted from November 2006 through September 2016 of patients with non-metastatic p16-positive OPSCC who underwent definitive intensity modulated radiotherapy to a median dose of 70 Gy (range 66-70 Gy) concurrent with weekly Cetuximab (n = 40) per Bonner protocol or triweekly Carboplatin (AUC = 5) (n = 191). No patient received accelerated radiotherapy. Patients receiving induction chemotherapy or oncological surgery of any kind prior to concurrent therapy were excluded. All patients had stage conversion according to the AJCC 8th Edition Cancer Staging Manual. Three-year locoregional recurrence (LRR), distant metastasis (DM), overall recurrence rate (ORR), overall survival (OS), and cause-specific survival (CSS) are reported. Cetuximab and Carboplatin groups were compared accounting for age, sex, smoking history, T stage, and N stage. Patients who received Carboplatin were younger (median age 62 vs. 70, P<0.001). The Cetuximab group had a higher percentage of patients with >10 pack-years of smoking (57% vs. 37%, P<0.02). The two cohorts were otherwise well-balanced with respect to other baseline patient and disease characteristics including T and N stage. After a median follow up of 40 months for surviving patients, those receiving Carboplatin had lower 3-year rates of LRR (8% vs. 16%, p = 0.02), DM (11% vs. 21%, p = 0.01), and ORR (17% vs. 29%,p = 0.008), and superior OS (90% vs. 63%, p = 0.003) and CSS (93% vs. 77%, p = 0.01). Our study suggests that, if medically feasible, triweekly Carboplatin concurrent with radiotherapy should be preferred to that with cetuximab in patients with p16+ OPSCC who are not eligible to receive cisplatin as it results in superior cancer control and survival outcomes.

Treatment Outcome of Cervical Cancer Patients Treated with Low-Versus High Dose Rate Brachytherapy after Concurrent Chemo-Radiation

Cervical cancer (CC) is the commonest gynecological cancer seen in the Ghanaian woman. Majority of patients here present with locally advanced diseases due poor screening practices aimed at detecting and treating precancerous conditions. The current standard curative treatment for locally advanced CC is concurrent cisplatin-based chemo-radiation plus intracavitary brachytherapy. The brachytherapy (BT) component has been Low-Dose Rate (LDR) BT for almost a century now until a few decades ago when High-Dose Rate (HDR) BT was developed to overcome disadvantages of LDR BT such as long treatment duration. In October 2014, HDR BT was introduced as the BT technique for the management of CC patients at this Centre, after several years of using LDR BT. The hypothesis for this study was that there was no difference in the treatment outcomes of CC patients treated with HDR BT compared with those who received LDR BT at this center. The aim of this study was to compare the treatment outcomes and toxicity of CC patients treated with LDR BT versus HDR BT treated at this Centre. Patients with histologically confirmed CC treated from January 2008 to December 2017 were enrolled after applying the inclusion and exclusion criteria. Information regarding patient demographics, stage of disease, type of BT received, total radiation dose received, response to treatment and treatment related toxicities experienced were extracted from the medical records of the patients. The primary end points of the study included local control (LC), disease free survival (DFS) and overall survival (OS) all at 2 years. Toxicities were also assessed. Primary endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. Over the 10-year period, 284 LDR (2008 –mid-2014) and 136 HDR (mid-2014-2017) patients fit the inclusion criteria. The median follow-up was 22 months (1-132months) vs. 11 months (1-41months) in LDR vs. HDR group respectively. For stages IB, IIA, IIB, IIIA and IIIB disease, the 2-year LC rates for LDR vs. HDR were 63 % vs. 61% p = 0.348, 86% vs. 90% p = 0.680, 86% vs. 88% p = 0.829, 66% vs. 60% p = 0.556 and 77% vs. 40% p = 0.005 respectively. The 2-year DFS for LDR vs. HDR BT were 64% vs. 61% p = 0.495, 81% vs. 69% p = 0.179, 81% vs. 80% p = 0.540, 62% vs. 33%, p = 0.818, and 71% vs.30%, p = 0.001 for stages IB, IIA, IIB, IIIA and IIIB respectively. The OS were comparable in both treatment groups stage for stage. Frequencies of acute and chronic toxicities for LDR vs. HDR were 22.6 % vs. 23.5%, and 3.9% vs. 6.9%, respectively. Comparable LC, DFS and OS were observed for IB, IIA, IIB and IIIA patients treated with LDR vs. HDR BT. HDR BT for the treatment of CC is therefore an acceptable alternative to LDR BT. However, the poorer LC and DFS rates observed for IIIB patients, and the higher frequencies of toxicities in the HDR BT cohort highlights the need for refining the HDR BT techniques at the Centre.

Feasibility of Portable Audiometry for Ototoxicity Monitoring in a Radiation Oncology Clinic for Head and Neck Cancer Patients Receiving Cisplatin-Based Chemoradiotherapy

Feasibility of Portable Audiometry for Ototoxicity Monitoring in a Radiation Oncology Clinic for Head and Neck Cancer Patients Receiving Cisplatin-Based Chemoradiotherapy