Definitive Chemo-Radiotherapy for Regionally Advanced Head and Neck Cancer With or Without Up-front Neck Dissection
- Conditions
- Head and Neck Neoplasms
- Interventions
- Procedure: up-front neck dissectionRadiation: radiotherapyDrug: Chemotherapy (Cisplatin)Procedure: Early Salvage Neck Dissection in case of less than cCR (Arm A only)
- Registration Number
- NCT02918955
- Lead Sponsor
- Insel Gruppe AG, University Hospital Bern
- Brief Summary
Treatment of regionally-advanced head and neck squamous cell carcinoma (HNSCC) requires a multidisciplinary approach with a combination of surgery, radiotherapy (RT) and chemotherapy. Due to these aggressive combined modalities, patients undergoing treatment and many survivors develop toxicities which impact quality of life (QoL) and sometimes lead to mortality.
Lymph node metastases of HNSCC are frequent and considered one of the most important prognostic factors, resulting in decreased survival by 50%. More than three decades, the optimal management strategy of node positive HNSCC was a key subject of debate. In summary, the current literature provides us two important findings: First, with the contemporary imaging and treatment modalities, there is no role of a planned neck dissection (ND) added to (chemo)radiotherapy ((C)RT) in terms of oncological outcome and survival. Second, with modern RT techniques, a tailored treatment followed after an up-front neck dissection (UFND) allows a significant reduction of treatment volumes and de-escalation of the dose to the neck, leading to reduction of treatment related toxicities.
In this study strategies with and without up-front neck dissection prior to chemo-radiotherapy will be compared.
- Detailed Description
The main objective of this project is to test the hypothesis that the addition of UFND prior to (C)RT results in a significant reduction of treatment toxicities and improvement of QoL in regionally advanced (cN2-3) HNSCC through dose de-escalation and volume reduction of RT.
The primary endpoint of this trial is to evaluate the toxicity from the beginning of radiotherapy until 90 days after the end of the treatment. The incidence of acute and subacute toxicities higher than grade ≥3 (CTCAE v.4, except for Xerostomia, for which RTOG/EORTC scale will be used) will be compared between study arms. Secondary endpoints include the survival endpoints for both treatment modalities; i.e. loco-regional control, progression-free and overall survival. Assessment of QoL (EORTC QLQ-C30 + H\&N43), late toxicity, surgical complications, cost-effectiveness and the need of feeding-tube will be a part of the final analysis of this trial.
Trial design: randomized multi-center open-label comparative one-staged phase III trial with a superiority design and the primary endpoint of highest grade radiation toxicity during and until 90 days after the completion of the treatment. Interventions in both arms of the trial are considered as standard treatments. No experimental diagnostic tools will be used during the trial. In addition to the randomized arms, two identical observational arms will be opened for the patients who are diagnosed before the activation of the randomized arms, and subsequently for those who refuse to be randomized. Their aim is to prospectively acquire high quality data for patients who refuse randomization. The observational and randomized cohorts will be analyzed separately for the pre-defined endpoints.
For the calculation of the sample size, grade ≥3 acute radiation toxicity in the CRT alone (Arm A) was assumed as 70% based on literature. For the primary endpoint, a follow-up period of 90 days after the last day of (C)RT is needed after the accrual of the last patient. However, 2 years of follow-up after (C)RT is needed for the secondary endpoints (exception: oncological outcome and survival will be calculated from the day of randomization in order to avoid immortal time bias). On this basis, sample size was calculated based on the Pearson chi-squared test and performed in Stata. Assuming a toxicity fraction of 70% for any grade 3 or higher toxicity in Arm A, a relative risk of 0.5 (35% in Arm B), a two-sided alpha of 0.05, a power of 80%, a drop-out rate of 5%, and an allocation ratio of 1 we calculated an overall sample size of 65. Expected accrual time is 3 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 65
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm rB (randomized) up-front neck dissection Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm rA (randomized) radiotherapy Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response Arm rA (randomized) Chemotherapy (Cisplatin) Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response Arm rA (randomized) Early Salvage Neck Dissection in case of less than cCR (Arm A only) Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response Arm oB (non-randomized) up-front neck dissection Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm oB (non-randomized) radiotherapy Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm oB (non-randomized) Chemotherapy (Cisplatin) Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm rB (randomized) radiotherapy Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm rB (randomized) Chemotherapy (Cisplatin) Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery Arm oA (non-randomized) radiotherapy Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response Arm oA (non-randomized) Chemotherapy (Cisplatin) Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response Arm oA (non-randomized) Early Salvage Neck Dissection in case of less than cCR (Arm A only) Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response
- Primary Outcome Measures
Name Time Method Number of patients with acute & subacute toxicity based on CTCAE scoring system v4.03 from the beginning of radiotherapy until 90 days after the end of the treatment
- Secondary Outcome Measures
Name Time Method Loco-regional control 2 years from the randomization Progression-free survival 2 years from the randomization Overall survival 2 years from the randomization Distant metastasis-free survival 2 years from the randomization Disease-specific survival 2 years from the randomization Number of patients with late Toxicity based on CTCAE scoring system v4.03 beginning from 91 days after the end of radiotherapy until the end of the 2 years follow up Change from baseline quality of life(QoL)using EORTC QLQ-C30 v3&EORTC QLQ-H&N43 modules(Health related QoL specific for Head&Neck ca.)scores at end of RT, 3,12&24 months after RT.Swallowing (H&N43:4-item scale)3 months after RT is the primary QoL domain up to 24-28 months depending on the treatment duration. EORTC QLQ-C30 and H\&N43 will be used
QoL comparison between the patients who accepted to be randomized (into rA and rB) and not (into oA and oB: in other words, patients who chose their own treatment strategy) Baseline QoL and until the end of 2 years follow-up Surgical complication rates 2 years from the randomization Rate of Isolated nodal control 2 years from the randomization The absence of metastatic lymph node metastases in the neck without any synchronous or preceding local recurrence or distant metastases
Radiation dose and volumes until the end of radiotherapy, expected to be on average 7 weeks The dose-volume histograms of all organs-at-risk (defined per protocol) will be compared between patients with and without up-front neck dissection. The doses will be reported in Gy and the volumes in cc.
Comparison of applied RT plan and the virtual RT plan done on the pre-UFND diagnostic CT images until the end of radiotherapy, expected to be on average 7 weeks The dose-volume histograms of all organs-at-risk (defined per protocol) will be compared between the plans generated based on the pre- and post-UFND CT-scans of patients allocated the UFND arm. The doses will be reported in Gy and the volumes in cc.
Comparison between clinical and pathological stages of patients allocated to the UFND arm. according to the AJCC/UICC TNM staging system (7th edition). until the generation of the definitive pathology report after the up-front neck dissection, expected to be within 3 weeks after patients' study enrollment
Trial Locations
- Locations (2)
University Hospital of Geneva
🇨🇭Geneva, Switzerland
Inselspital Bern
🇨🇭Bern, Switzerland