Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC): Throughout the 1970s, 1980s, and 1990s, cytotoxic chemotherapy (CT) was the only available systemic therapy for patients (pts) with R/M-HNSCC, with cisplatin being the most active single agent. Median overall survival (mOS) in first line varied from 5.0 to 8.7 months, which was possibly better than what could be obtained with supportive care only (0.8–2.1 months). Pts with platinum-resistant disease did poorly (median progression-free survival 1.5–1.7 months, mOS 3.7–6.0 months). Grade ≥ 3 toxicity occurred in about 30% of these pts, which had a negative effect on their quality of life (QoL). Among the many targeted therapies tested, only cetuximab is FDA approved for treatment of pts with HNSCC) (2006) and showed a 13% response rate and a nearly 50% disease control rate in pts with platinum-refractory disease. Improved survival (mOS 10.4 months), without compromised QoL, was observed when cetuximab was combined with platinum/5-fluorouracil (PF)-based CT in biomarker unselected pts (EXTREME trial) and became the new standard-of-care treatment for the next 10 years. The benefit was present in both p16-positive and -negative cases. The next and latest improvement (2016 and 2019) concerns immune checkpoint inhibitors (ICIs), showing significant survival benefit in second line after platinum-based CT when compared with physician’s choice. In first line, significant improvement in mOS was observed when ICIs were used as a single agent in programmed cell death ligand-1 (PD-L1) positive tumors and also when ICIs were combined with platinum-based CT in all comers. Both ICI regimens were compared with EXTREME resulting in mOS of 12.3 months vs. 10.3 months and 13.0 months vs. 10.7 months, respectively). Single agent ICI is better tolerated than cytotoxic CT, has a favorable impact on QoL, and is similarly active in elderly pts as in their younger counterparts. The introduction of ICIs has definitively improved the outcome of a small proportion of patients with R/M-HNSCC), stimulating further research of biomarker-based approaches. Locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC): High response rates, including complete response rates, were noticed already in the 1980s when platinum-based CT regimens were used in the neoadjuvant setting (induction chemotherapy [ICT]). This concept later developed in larynx preservation strategies in pts who were candidates for a radical surgical approach (ICT → radiotherapy [RT] in pts responding to ICT and salvage surgery in those who failed to respond vs. total laryngectomy). Since the early 2000s, concurrent CT and RT (CCRT) has become the standard approach for most high-risk pts who otherwise would have been treated in the past with RT alone either in the definitive or postoperative settings. CCRT led to an OS gain of 6% at 5 years at the cost of substantial toxicity and late complications, which is particularly worrisome in pts with human papillomavirus (HPV)/p16 positive oropharyngeal carcinoma who are generally younger than other HNSCC) pts and fare anyhow better, irrespectively of the treatment used. Despite a decrease in distant metastasis rate in those receiving ICT, no survival benefit was observed with either the PF or TPF (PF + docetaxel) regimen. The latter has been considered a standard of care since 2007. Cisplatin is the crucial drug to enhance the RT effect; alternatives for those ineligible for cisplatin are carboplatin/5-fluorouracil/RT and cetuximab/RT, the latter being superior to RT alone but inferior to CCRT. Cetuximab added to CCRT only leads to more toxicity and no survival benefit. De-escalation studies in p16/HPV-positive pts and treatment intensification in p16/HPV-negative pts have not changed practice concerning the use of systemic agents. Contrary to the results in pts with R/M-HNSCC), the role of immunotherapy in LA-HNSCC is unclear and has not changed practice so far. Period analyses have shown substantial survival improvement over time in the Western world. However, due to lack of data on systemic therapies it is not possible to directly examine the effects of systemic therapies on survival over time.

50 Years of Systemic Therapy: What Have We Gained?

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2025年

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Petr Szturz,
Jan B. Vermorken

摘要

Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC): Throughout the 1970s, 1980s, and 1990s, cytotoxic chemotherapy (CT) was the only available systemic therapy for patients (pts) with R/M-HNSCC, with cisplatin being the most active single agent. Median overall survival (mOS) in first line varied from 5.0 to 8.7 months, which was possibly better than what could be obtained with supportive care only (0.8–2.1 months). Pts with platinum-resistant disease did poorly (median progression-free survival 1.5–1.7 months, mOS 3.7–6.0 months). Grade ≥ 3 toxicity occurred in about 30% of these pts, which had a negative effect on their quality of life (QoL). Among the many targeted therapies tested, only cetuximab is FDA approved for treatment of pts with HNSCC) (2006) and showed a 13% response rate and a nearly 50% disease control rate in pts with platinum-refractory disease. Improved survival (mOS 10.4 months), without compromised QoL, was observed when cetuximab was combined with platinum/5-fluorouracil (PF)-based CT in biomarker unselected pts (EXTREME trial) and became the new standard-of-care treatment for the next 10 years. The benefit was present in both p16-positive and -negative cases. The next and latest improvement (2016 and 2019) concerns immune checkpoint inhibitors (ICIs), showing significant survival benefit in second line after platinum-based CT when compared with physician’s choice. In first line, significant improvement in mOS was observed when ICIs were used as a single agent in programmed cell death ligand-1 (PD-L1) positive tumors and also when ICIs were combined with platinum-based CT in all comers. Both ICI regimens were compared with EXTREME resulting in mOS of 12.3 months vs. 10.3 months and 13.0 months vs. 10.7 months, respectively). Single agent ICI is better tolerated than cytotoxic CT, has a favorable impact on QoL, and is similarly active in elderly pts as in their younger counterparts. The introduction of ICIs has definitively improved the outcome of a small proportion of patients with R/M-HNSCC), stimulating further research of biomarker-based approaches. Locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC): High response rates, including complete response rates, were noticed already in the 1980s when platinum-based CT regimens were used in the neoadjuvant setting (induction chemotherapy [ICT]). This concept later developed in larynx preservation strategies in pts who were candidates for a radical surgical approach (ICT → radiotherapy [RT] in pts responding to ICT and salvage surgery in those who failed to respond vs. total laryngectomy). Since the early 2000s, concurrent CT and RT (CCRT) has become the standard approach for most high-risk pts who otherwise would have been treated in the past with RT alone either in the definitive or postoperative settings. CCRT led to an OS gain of 6% at 5 years at the cost of substantial toxicity and late complications, which is particularly worrisome in pts with human papillomavirus (HPV)/p16 positive oropharyngeal carcinoma who are generally younger than other HNSCC) pts and fare anyhow better, irrespectively of the treatment used. Despite a decrease in distant metastasis rate in those receiving ICT, no survival benefit was observed with either the PF or TPF (PF + docetaxel) regimen. The latter has been considered a standard of care since 2007. Cisplatin is the crucial drug to enhance the RT effect; alternatives for those ineligible for cisplatin are carboplatin/5-fluorouracil/RT and cetuximab/RT, the latter being superior to RT alone but inferior to CCRT. Cetuximab added to CCRT only leads to more toxicity and no survival benefit. De-escalation studies in p16/HPV-positive pts and treatment intensification in p16/HPV-negative pts have not changed practice concerning the use of systemic agents. Contrary to the results in pts with R/M-HNSCC), the role of immunotherapy in LA-HNSCC is unclear and has not changed practice so far. Period analyses have shown substantial survival improvement over time in the Western world. However, due to lack of data on systemic therapies it is not possible to directly examine the effects of systemic therapies on survival over time.