A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Phase III Randomized Study of Induction Chemotherapy Followed by Definitive Radiotherapy + Cetuximab Versus Chemoradiotherapy in Squamous Cell Carcinoma of Head and Neck: The INTERCEPTOR-GONO Study (NCT00999700).

OBJECTIVES: Induction chemotherapy followed by cetuximab and RT (IBRT) (Arm A) was compared to cisplatin/RT (CRT) (Arm B) in a randomized phase III study. PATIENTS AND METHODS: Naïve patients with stage III-IVa, histologically proven locally advanced head and neck cancer (LASCCHN) were eligible. Arm A (IBRT): 3 TPF induction followed by cetuximab-RT (equivalent daily dose 2 Gy up to 70 Gy); Arm B: 3 cisplatin concurrent with the same RT scheduling. Due to slow accrual and incomplete data collection a futility analysis was performed. RESULTS: 236/282 patients were evaluable. Therefore, no formal analyses can be made between the two arms. OS was 45.2/53.6 months in Arm A/B. Complete responses were achieved in 64% of patients in both arms. Neutropenia and skin toxicity were significantly worse in Arm A and body weight loss was significantly worse in Arm B. Compliance with the planned drug administration was higher in Arm B (p = 0.0008). CONCLUSION: The study suggests that IBRT and CRT have similar efficacy, activity and toxicity.

Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m2) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m2 cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m2 cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m2 (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m2 cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

Randomized phase 3 noninferiority trial of radiotherapy and cisplatin vs radiotherapy and cetuximab after docetaxel-cisplatin-fluorouracil induction chemotherapy in patients with locally advanced unresectable head and neck cancer.

OBJECTIVES: Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT. MATERIALS AND METHODS: This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of < 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL). RESULTS: Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153). CONCLUSION: Noninferiority of cet+RT over cis+RT was not demonstrated.

Evolving multidisciplinary treatment of squamous cell carcinoma of the head and neck in India✰.

In this article, we highlight the evolution of a multimodal approach in the overall management of squamous cell carcinoma of the head and neck (SCCHN) in India; present advances in technology (newer surgical techniques), novel medical and radiotherapy (RT) approaches; review their roles for an integrated approach for treating SCCHN and discuss the current role of immunotherapy in SCCHN. For locally advanced (LA) SCCHN, the multidisciplinary approach includes surgery followed by RT, with or without chemotherapy (CT) or concurrent chemoradiotherapy. Improved surgical techniques of reconstruction and voice-preservation are being implemented. Advanced forms of high-precision conformal techniques like intensity-modulated radiotherapy are used to deliver highly conformal doses to tumors, sparing the surrounding normal tissue. Compared with RT alone, novel CT regimens and targeted therapeutic agents have the potential to improve locoregional control and survival and reduce treatment-induced toxicities. Several clinical trials have demonstrated efficacy, safety, and quality of life benefits of adding cetuximab to RT regimens in LASCCHN. Studies have also suggested a cetuximab-related laryngeal preservation benefit. At progression, platinum-based CT combined with cetuximab (a monoclonal anti-epidermal growth factor receptor antibody) is the only validated option available as the first-line therapy. Thus, an integrated multidisciplinary approach plays a key role in maximizing patient outcomes, reduction in treatment related morbidities that consequently impact quality of life of survivors.

Docetaxel, cisplatin and 5-FU compared with docetaxel, cisplatin and cetuximab as induction chemotherapy in advanced squamous cell carcinoma of the head and neck: Results of a randomised phase II AGMT trial.

PURPOSE: Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C). PATIENTS AND METHODS: In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. RESULTS: On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0-93.1%] in the TPC arm and 78.5% [95% CI, 63.7-87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification. CONCLUSION: TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted.

Radiochemotherapy for locally advanced squamous cell carcinoma of the head and neck: Higher-dose cisplatin every 3 weeks versus cisplatin/5-fluorouracil every 4 weeks.

Many patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive cisplatin-based radiochemotherapy. The optimal regimen is still unclear when considering both efficacy and feasibility. This study compared two regimens for locoregional control (LRC), overall survival (OS), and adverse events. Data of 329 patients with LASCCHN receiving definitive or postoperative radiochemotherapy were retrospectively analyzed. A total of 131 patients received 100 mg/m(2) cisplatin on days 1, 22, and 43 (group A), and 198 patients received 20 mg/m(2) cisplatin plus 600/1000 mg/m(2) 5-FU on days 1-5 and days 29-33 (group B). Radiochemotherapy regimens plus nine factors were compared for LRC and OS, and radiochemotherapy regimens additionally for adverse events. On univariate analysis, chemotherapy type was not associated with LRC (p = 0.36). On multivariate analysis, performance score (p = 0.039), N-category (p = 0.007), histologic grade (p = 0.007), upfront surgery (p = 0.030), and pre-radiochemotherapy hemoglobin levels (p < 0.001) were associated with LRC. On univariate analysis, chemotherapy type had no impact on OS (p = 0.64). On multivariate analysis, performance score (p < 0.001), T-category (p = 0.025), N-category (p < 0.001), histologic grade, and hemoglobin levels (p < 0.001) were associated with OS. Renal failure occurred significantly more often in group A (p = 0.008). Otherwise, adverse events were not significantly different. Thus, both radiochemotherapy regimens appeared similarly effective for LASCCHN. Patients receiving 100 mg/m(2) of cisplatin require close monitoring of their renal function.

Chemoradiation of locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN): Is 20mg/m(2) cisplatin on five days every four weeks an alternative to 100mg/m(2) cisplatin every three weeks?

OBJECTIVES: To compare chemoradiation with 100mg/m(2) cisplatin every three weeks to 20mg/m(2) on five days every four weeks for locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN). MATERIALS AND METHODS: In 230 patients receiving chemoradiation for LASCCHN, 100mg/m(2) cisplatin every three weeks (N=126) and 20mg/m(2) cisplatin on five days every four weeks (N=104) were retrospectively compared. Chemoradiation plus eleven characteristics (T-/N-classification, performance score, gender, age, tumor site, grading, surgery, radiation technique, pre-chemoradiation hemoglobin, cumulative cisplatin dose) were analyzed for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Chemoradiation groups were compared for adverse events. RESULTS: On univariate analyses, chemoradiation had no impact on LRC (p=0.53), MFS (p=0.67) and OS (p=0.14). On multivariate analysis of LRC, T-classification (p=0.045) and hemoglobin (p<0.001) were significant. On multivariate analysis of MFS, performance score (p=0.028) was significant. On multivariate analysis of OS, performance score (p=0.009) and hemoglobin levels (p=0.002) achieved significance. Chemoradiation with 100mg/m(2) cisplatin was associated with more pneumonia/sepsis (p=0.003), grade ⩾2nausea/vomiting (p<0.001), grade ⩾2 nephrotoxicity (p=0.005), grade ⩾2 xerostomia (p=0.002), grade ⩾3 hematotoxicity (p=0.052) and grade ⩾2 ototoxicity (p=0.048). CONCLUDING STATEMENT: 20mg/m(2) cisplatin on five days every four weeks was associated with fewer adverse events than 100mg/m(2) cisplatin every three weeks. 100mg/m(2) cisplatin was not significantly superior to 20mg/m(2) cisplatin regarding LRC, MFS and OS. Given the limitations of a retrospective study, 20mg/m(2) cisplatin appeared preferable. The results should be confirmed in a randomized trial.