For long, the treatment of locoregionally laryngeal and hypopharyngeal squamous cell cancer (SC) consisted of either total laryngectomy (TL) or radical radiotherapy (RT). The appearance of induction cisplatin/5-fluorouracil (PF) and the correlation between chemo and radiosensitivity opened a new era of treatment aiming at larynx preservation (LP).
The first two trials (VALGSG for larynx SCC and EORTC 24891 for hypopharynx SCC) had survival as primary endpoint in order to check the safety of induction PF followed by RT in good responders to PF when compared to TL. As survival was not found compromised, and as the larynx was preserved in nearly 60% of cases, in the induction arm, this concept was validated. The trials performed thereafter had LP as primary endpoint but unfortunately with different definitions of LP, making their comparisons quite difficult.
The EORTC 24954 trial compared 4 cycles of induction PF followed by RT in good responders vs alternating PF-RT in larynx and hypopharynx SCC. There was no significant difference in 5-year overall survival with a functional larynx between both arms (31% vs 35%). Of note the total dose of PF and RT was lower in the alternating arm, which resulted in a slightly better tolerance. However in daily practice this protocol is quite difficult to organize.
The RTOG 91-11 trial compared induction PF + RT in good responders vs concurrent chemoradiotherapy (chemo-RT) versus RT alone in larynx SCC. There was no significant difference in 5-year laryngectomy-free survival between the patients treated with induction chemotherapy (44%) versus those treated with chemo-RT (47%), both being superior to RT alone (34%). At 5 years, LP was superior with chemo-RT: 84% versus 71% with induction PF. However there were twice as many non-cancer related deaths in the concurrent arm.
The appearance of docetaxel (T) added to PF for induction chemotherapy had demonstrated its superiority over PF and was considered as the new induction chemotherapy standard (TPF). The GORTEC 2000-01 trial compared induction PF to induction TPF both followed by RT in good responders in larynx and hypopharynx SCC. The 5-year LP was significantly higher in the TPF arm (60% vs 39%) but without any difference in survival. Induction TPF became the standard for induction chemo also for LP.
Two trials explored the role of cetuximab (E) in LP in larynx and hypopharynx SCC. The TREMPLIN trial compared RT + E or chemo-RT (RT + P) after TPF. The Delos II trial compared TPE followed by RT + E vs TP followed by RT. Their results showed some interesting data: feasibility of salvage surgery in the E arm of the TREMPLIN study, response to induction TPE in the Delos trial. But they failed to show an advantage over the above-mentioned results.
To date, 2 approaches have been validated: induction TPF + RT for larynx and hypopharynx SCC and concurrent chemo-RT for larynx SCC in patients for whom TL is required (i.e. excluding patients eligible for partial laryngectomy), as well as T4 diseases (better controlled by TL if resectable). An on-going trial (SALTORL) is comparing induction TPF and chemo-RT.
Larynx preservation Surgery Radiotherapy Chemotherapy Biotherapy
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