The incidence of HPV(+) OPC has rapidly increased in recent years [20, 21]. Several investigators recognized and actually reported that more favorable locoregional control and OS outcomes were achievable among patients with HPV(+) OPC treated with contemporary standard treatment approaches than among patients with HPV(-) OPC [9, 21]. This has led to controversy among many head and neck oncologists as to whether the intensity of the traditional standard treatment is optimal for HPV(+) patients, which has introduced the concept of “treatment de-escalation.” Several attempts have been made to de-escalate treatment for HPV(+) OPC to preserve normal functional status and to maintain quality of life without compromising clinical outcomes .
The eighth edition of the American Joint Committee on Cancer staging system for HPV(+) OPC has designated lower stages than the same stage for HPV(-) OPC, unlike previous editions. These changes were due to the perception that the prognosis of patients with HPV(+) OPC was more favorable, although it appears to have had little effect on changing the treatment modality and/or its intensity. The treatment guideline by the National Comprehensive Cancer Network, however, still recommends high-dose CCRT for HPV(+) OPC patients with locoregionally advanced disease extent .
This questionnaire study showed interesting results regarding changes in radiotherapy protocols for HPV(+) OPC. Various studies have attempted to reduce the RT dose depending on the response, to omit chemotherapy or to replace it with immunotherapy or targeted therapy, and to sequentially administer chemoradiation instead of concurrently [23, 24]. However, a treatment policy for radiation therapy in HPV(+) OPC has not yet been established. The most recently published European guidelines recommend the same treatment as that for HPV(-) OPC .
This study aimed to investigate current opinions regarding RT in a definitive and adjuvant setting and to assess the practical considerations of de-escalation in HPV(+) OPC. This is because many head and neck oncologists were asked questions regarding whether the intensity of the traditional standard treatment had been either optimal or stronger than necessary for patients with HPV(+) OPC. This questionnaire will help develop the framework of a consensus for suitable radiotherapy. It is important to examine current clinical practice before the results of ongoing prospective trials provide clear evidence. We demonstrated reported and ongoing trials associated with the radiation field and dose in four paradigms: 1) de-escalation of chemotherapy in definitive CCRT; 2) de-escalation of the RT field and dose in definitive CCRT; 3) de-escalation of the RT field and dose in adjuvant RT after transoral surgery (TORS); and 4) omission or de-escalation of RT in complete remission after induction chemotherapy for locally advanced stage.
In the current questionnaire regarding definitive CCRT, approximately 20% of respondents prescribed radiation dose reduction in the primary tonsillar fossa and high-risk cervical LN chains in HPV(+) OPC; however, there was no tendency to reduce the radiation field. De-escalation in the treatment of gross tumors would be risk for tumor control and survival. For this reason, there have been few studies on de-escalation of the radiation field and dose in a definitive setting. Instead of radiotherapy, there have been completed and ongoing trials on de-escalation of chemotherapy in definitive CCRT according to risk stratification. These studies can be divided into two research designs: those that do not use chemotherapy and treat with radiotherapy alone, and those that replace chemotherapeutic agents with immunotherapy. In a phase II randomized clinical study (NRG-HN002) of the omission of chemotherapy, it was reported that the 2-year progression-free survival (PFS) rate was 87.6% (p = 0.2284) in the radiotherapy alone group, which did not meet the 2-year PFS acceptability criteria . In a phase III study of immunotherapy instead of chemotherapeutic drugs in definitive CCRT (RTOG 1016, De-ESCALaTE), cetuximab as immunotherapy led to inferior OS and PFS compared with those with cisplatin [23, 24]. The TROG 12.01 (NCT01855451) phase III randomized trial has been conducted using a similar study design to the above mentioned RTOG 1016 and De-ESCALaTE studies, and the results will be released soon.
Rather than omitting chemotherapy or replacing it with immunotherapy, there are ongoing phase II trials to reduce the radiation dose from 70 Gy to 60 Gy according to risk stratification in CCRT (NCT03077243) or reduction of the irradiated volume of the elective nodal chain (EVADER, NCT03822897). More studies are needed to determine suitable changes in the treatment for definitive CCRT.
De-escalation of adjuvant treatment after surgery is being discussed more frequently, and many studies are being conducted to evaluate the association between survival and de-escalation. In the AVOID phase II study, radiotherapy was performed only on the neck, excluding the primary lesion, in patients with no pathological adverse factors after TORS and neck dissection, and the results showed that the 2-year local control rate was 98.3% and the PFS rate was 96.2% . During the median follow-up period of 2.4 years, none of the patients required a feeding tube associated with RT. A similar phase II study (NCT03729518) is in progress where radiotherapy avoiding the primary site was provided after TORS primary site resection and ipsilateral neck dissection for locally advanced HPV(+) OPC.
There are clinical studies of radiation dose reduction for adjuvant treatment after surgery in which results have been reported or ongoing. In MC1273 phase II study, radiation doses of 30 Gy and 36 Gy were prescribed according to risk stratification, and survival analysis after adjuvant CCRT was performed . The 2-year OS and PFS were 98.7% and 91.1%, respectively, and a low risk of toxicity was reported. In an ongoing phase III clinical study (DART-HPV, NCT02908477), RT (30 Gy) with docetaxel and radiotherapy alone (60 Gy) were randomly assigned to patients with intermediate risk according to risk stratification.
Although relatively good local control rates were reported in the AVOID phase II study, there were no respondents who performed radiotherapy alone in the neck except at the primary site in the current survey . In this survey, two respondents excluded the primary site from the radiation field. Most respondents did not prescribe a very low dose of 30–36 Gy, as in the MC1273 study . However, attempts to slightly reduce the dose from 60 Gy to 50 Gy in patients at intermediate risk according to risk stratification, such as in the ongoing ECOG 3311 and PATHOS trials, were observed in approximately 20% of respondents .
The role of IC in locally advanced HNC is not recommended, and previous studies have reported relatively low evidence of improved survival [29–33]. However, the benefit of IC has been expected to reduce distant metastasis and organ preservation in real-world practice. There have been several studies on the de-escalation of radiotherapy after IC, and PFS and toxicity were evaluated for 2-years after lowering the radiation dose according to the degree of response or risk stratification. In the phase II single-arm E1308 trial, IC (cisplatin, paclitaxel, and cetuximab) followed by RT (54 Gy) with cetuximab in ycCR was performed, and a 2-year PFS of 80% and OS of 94% were reported . In patients treated with reduced doses, it was found that swallowing and feeding-related toxicity were relatively low. In the Quarterback phase II study, CCRT was performed by reducing the dose of 56 Gy by 2:1 randomization after IC with docetaxel, cisplatin, and 5-fluorouracil, and the 3-year PFS and OS results were similar to those of the standard dose group . Currently, the Quarterback 2b study, a study in which CCRT was performed with RT at a dose of 56 Gy versus a standard dose according to the response to IC, is ongoing.
In the OPTIMA phase II study, CCRT of 45, 50, or 75 Gy of radiation with paclitaxel, 5-fluorouracil, and hydroxyurea was provided according to risk stratification after nab-paclitaxel and carboplatin chemotherapy; the 2-year PFS rates were 95% and 94% in low-risk and high-risk patients, respectively . The incidence of mucositis and need for a gastrostomy tube were significantly lower in the low-dose group than in the high-dose group. The OPTIMA-II phase II study is now in progress, adding nivolumab as an induction chemotherapeutic agent and administering cisplatin as the CCRT regimen. In the current study, 18% of respondents prescribed a radiation dose of ≤ 54 Gy to the high-risk neck chain. Although a large-volume phase III study remains necessary, the reduction of radiation dose to 54–56 Gy has shown reduced toxicity with no reduction in 2-year PFS in phase II studies.
In conclusion, in a survey of radiation oncologists for head and neck tumors in Korea, most of HPV(+) OPC treatments were performed according to the guidelines for HPV(-) OPC treatments with respect to the radiation field and dose. However, the tendency to de-escalate treatment was found in approximately 18–20% of the respondents. It is necessary to establish a consensus on the radiation field and dose through multidisciplinary conferences. When de-escalation is attempted in specific patients, clinical trial enrollment is actively recommended before the evidence-based results of the abovementioned ongoing clinical studies become available.