UPDATES in radiotherapy head and neck cancer
- 1. Radiotherapy in head and neck cancer updates Dr.srinivas reddy
- 2. Oral Cavity • stage I and II- primary surgery or definitive RT, while stage III and IV, surgery followed by adjuvant RT with or without CRT. • Radiation doses for OCC -ranges from 70 Gy for gross disease, 60–66 Gy for high-risk regions, and 50–54 Gy to cover low-risk areas subject to microscopic spread. • In the definitive setting, doses of 66–70 Gy are typically used with chemotherapy • or alternative fractionation schemas including hypofractionation or hyperfractionation for patients receiving radiation alone.
- 3. Oral Cavity • Rosenthal et al. conducted a phase III RCT on 264 pts • Low-risk regions were treated with RT at doses of 57.6 Gy or 63 Gy, while high-risk regions were randomized to receive 63 or 68.4 Gy, over 1.8 Gy per fraction. • (OS rates for 5- and 10-year marks were found to be 32% and 20%, respectively. • The study has found that increasing the dose from 57.5 to 68.4 Gy without chemotherapy does not improve tumor control. • However, treatment time shorter than 85 days demonstrates better locoregional control compared to >85 days for dose levels >60 Gy. • Shortening time in the study improved cancer specific survival (CSS), locoregional control (LRC) and OS for HNSCC, independently ofthe total RT dose delivered.
- 5. Oropharynx • HPV is a prognostic marker in OPSCC • tumor HPV positivity is associated with substantially higher cure rates and improved survival • Three prospective trials, the De- ESCALaTE HPV trial, RTOG1016 and TROG12.01 have evaluated the impact of deascalation using cetuximab • In these trials non-inferiority of cetuximab was not achieved and cisplatin-based chemoradiotherapy (CRT) remained the standard of care in HPV-driven OPSCC • As of now, the standard remains cisplatin-based chemotherapy as two randomized trials showed inferior outcomes with cetuximab • Ongoing NRG HN005 study is a three-armed study is comparing the current standard of care (70 Gy with cisplatin) to either lower dose RT with cisplatin or RT with nivolumab
- 6. Reduction of radiotherapy dose/volume • NCT01530997 and NCT02281955 trials in patients with HPV-positive OPSCC tumours with stages T0- T3, N0- N2c, M0 : encouraging results when reducing the radiation dose from 70 to 60Gy, and decreasing the cisplatin dose by 20–40% • NRG-HN002 studied the possible omission of simultaneous chemotherapy in HPV-positive patients. • In this trial 316 patients were randomized to either 60Gy IMRT in 6 weeks with concomitant weekly cisplatin 40mg/m2 or accelerated stand-alone IMRT 60Gy in 5 weeks • Because of lower PFS in the IMRT alone arm at 5 years (87.6% vs. 90.5% in the combined arm), this study failed to meet acceptability criterion of noninferiority
- 7. De-intensification using immunotherapy • The ongoing study NCT03799445 is evaluating the impact of dual treatment with nivolumab and ipilimumab followed by IMRT up to 50–66Gy on disease outcome in advanced HPV-associated SCC. • NRG-HN005 (NCT03952585) is a prospective trial aiming to randomize 711 patients with p16-HPV- positive OPSCC to either reduced dose of RT (60Gy in 6 weeks) with cisplatin, reduced dose of RT (60Gy in 5 weeks) with nivolumab or standard of care RT of 70Gy in 5 weeks with cisplatin. • The results of these studies are highly awaited
- 8. Reducing toxicity using adaptive radiotherapy • Together with improved target definition using advanced imaging MRI, PET/CT), improved accuracy of radiation delivery using IGRT) and reacting to tumour volume changes during the treatment course through image-guided adaptive radiotherapy (IGART), • the overall toxicity can be reduced without treatment de- intensification to the tumour site MRI-guided adaptive radiotherapy is a novel strategy • using a MR-Linac in order to track volume changes in the tumour in real time throughout the treatment course and adapt the RT volumes accordingly. • This newest development in the treatment of head and neck cancers • is being adopted in clinical practice
- 11. MARCH METAANALYSIS • Altered fractionation radiotherapy was associated with a significant benefit on overall survival, with an absolute difference at 5 years of 3·1% and at 10 years of 1·2% • the overall survival benefit being restricted to the hyperfractionated group with absolute differences at 5 years of 8·1% and at 10 years of 3·9% • Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy , with absolute differences at 5 years of –5·8% and at 10 years of –5·1% .
- 13. Mach-nc metaanalysis • comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) • benefit being limited to concomitant CT , 10- year absolute benefit of 6.5%
- 14. RESULTS-MACH-NC • Efficacy decreased as patients age increased • OS was not increased by the addition of induction or adjuvant CT • Efficacy of induction CT decreased with poorer performance status • For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS
- 15. RESULTS-MACH-NC • A regimen of fluorouracil plus carboplatin combined to conconcomitant RT can also be used, as its benefit was much the same as that which was noted for concomitant high-dose single-agent cisplatin in the MACH-NC meta- analysis
- 16. Systemic Therapy: Concomitant Chemo • JCOG1008 phase II/III trial—which randomized patients with postoperative high-risk HNSCC cancer to receive either CRT with 3-weekly cisplatin (100 mg/mq) or with weekly cisplatin (40 mg/mq)— • demonstrated that CRT with weekly cisplatin was non-inferior to 3-weekly cisplatin in terms of overall survival (HR 0.69,), with a favorable toxicity profile
- 17. Neoadjuvant Chemotherapy • second update of the MACH-NC provided a analysis of the role of induction chemotherapy in non- nasopharyngeal HNSCC management . • The effect of induction chemotherapy was evaluated in 45 trials (7054 patients) with a median follow-up of 5.7 years • The OS benefit was 0.96 with an absolute benefit of 2.2% at 5 years and 1.3% at 10 years compared to CRT alone • All survival endpoints demonstrated results in favor of CRT, with an absolute OS benefit of 6.2% at 5 years, an absolute event-free survival benefit of 3.7% at 5 years and an absolute locoregional failure benefit of 5.8% at 5 years
- 18. NACT: Nasopharynx • In a multicenter phase III RCT in 480 evaluable adults with previously untreated, stage III–IVB NPC, Sun et al. compared the outcomes of IC before CRT with CRT alone. • CRT consisted of three cycles of 100 mg/m2 cisplatin every 3 weeks and RT using IMRT. • Both groups received RT at a median dose of 70 Gy. • Three-year PFS, OS and DFS were significantly higher in the group who received chemotherapy before CCRT (80% vs. 72%,; • 95% vs. 86%, and 90% vs. 83%, respectively). • However, locoregional failure-free survival was not significantly different between the groups (95% vs. 89%,. • As expected, chemotherapy-related Grade 3 and 4 adverse events were higher in those who received IC;
- 19. Systemic Therapy: Recurrent/Metastatic/Locally Advance • Combination of chemotherapy (cisplatin or carboplatin plus 5-fluoruracil) plus pembrolizumab and pembrolizumab monotherapy is the standard-ofcare first-line therapy for recurrent/metastatic HNSCC with a CPS 1 . • EXTREME regimen (cisplatin or carboplatin plus 5- fluoruracil plus cetuximab) remains the standard of care for patients with HNSCC not expressing PD-L1 and patients with contraindications to anti- programmed death-1 (PD-1) inhibitors
- 20. Combination of chemotherapy and immunotherapy • JAVELIN Head and Neck 100 trial was aiming at improvement of outcomes in patients with locally advanced head and neck cancers by combination of avelumab with chemoradiotherapy • the trial was stopped at the time of preplanned interim analysis, because the study was unlikely to meet the primary objective of prolonging PFS
- 21. Combination of chemotherapy and immunotherapy • The Keynote 412 study is a randomized phase III study evaluating the efficacy and safety of pembrolizumab or placebo given concomitantly with CRT followed by maintenance therapy in patients with locally advanced (LA) HNSCC. • The addition of pembrolizumab was associated with a favourable trend toward improved eventfree survival (EFS),
- 23. Take home • These data confirmed the cisplatin-based CRT as the standard of care, as well as the importance of reaching a cumulative dose of cisplatin 200 mg/mq in locally advanced HNSCC, • There is currently insufficient evidence regarding treatment de- escalation in patients with p16-positive oropharyngeal cancer. • Omitting concomitant chemotherapy or replacing chemotherapy with cetuximab is not recommended . • Cetuximab should be reserved for those patients considered unfit for cisplatin adequate definition of unfit patient for cisplatin-based concomitant therapy is crucial • hyperfractionated RT alone represents another valid option for the treatment of locally advanced HNSCC. a direct comparison between hyperfractionated RT and concomitant CRT remains to be specifically tested