**8. De-escalating treatment intensity**

The treatment options for early-stage OPSCC includes radical radiotherapy versus surgery (resection of the primary+/\_ ipsilateral or bilateral neck dissection). For locally advanced oropharyngeal carcinoma primary treatment is radical chemoradiation or induction chemotherapy followed by radical chemoradiation with or without salvage surgery. The primary lesion and involved node with a margin are treated to a dose of 66-70Gy in 33–35 fractions and prophylactic nodal stations will receive 54 Gy in 30 fractions. With the introduction of intensity-modulated radiotherapy (IMRT) dose to dysphagia aspiration, related structures can be minimized. Cisplatin 80–100 mg/m2 once in 3 weeks is the standard concurrent chemotherapy schedule. For primary lesions of the oropharynx, surgical clearance is an issue, considering the complex anatomy and proximity to critical structures. Reconstruction is difficult and retropharyngeal nodes cannot be surgically removed. Bilateral neck dissection should be considered for lesions over the base of the tongue, soft palate, posterior pharyngeal wall, or tonsillar lesion invading the base of the tongue. Functional outcome is better with radiotherapy. In advanced-stage disease, surgery is often followed by adjuvant therapy which will lead to increased morbidity and decreased quality of life. Major factors deciding the treatment modality include performance status of the patient, location of the primary lesion, expertise available, morbidities associated with each treatment option, and patient preference. Since HPV-positive oropharyngeal carcinoma patients tend to be younger and have prolonged survival, there is a potential to improve the quality of life through reducing the treatment-related toxicities. Application of this knowledge has led to multiple de-escalating strategies.

#### **8.1 Minimally invasive surgery**

The development of minimally invasive surgical techniques like transoral laser microsurgery (TLM) and transoral robotic surgery (TORS) has changed the surgical management for early oropharyngeal carcinoma. No prospective randomized studies are supporting the use of TORS over conventional surgery for oropharyngeal carcinoma. Small series report better swallowing outcomes in selected oropharyngeal carcinoma patients treated with less invasive surgery with or without neck dissection, followed by adjuvant therapy [24]. Complications include postoperative haemorrhage and the need for temporary tracheostomy.

*Human Papillomavirus Associated Oropharyngeal Carcinoma-Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.96234*

ORATOR trial is the first phase 2 randomized trial comparing radiotherapy with transoral robotic surgery and neck dissection for early stage oropharyngeal squamous cell carcinoma [25]. Patients with T1–T2, N0–2 (≤4 cm) OPSCC tumor types were randomized to radiotherapy arm (70 Gy, with chemotherapy, if N1–2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). In the surgery arm, 24% of patients received postoperative chemoradiotherapy. The initial report showed swallowing related quality of life score was better in the radiotherapy group after one year follow up. The ongoing ORATOR II trial is testing the overall survival between radiotherapy arm versus surgery [26].

Few other trials are assessing whether the swallowing function can be improved following minimally invasive surgery like Trans Oral Robotic Surgery (TORS) and to prove non-inferiority of reducing the intensity of adjuvant treatment in terms of overall survival. **Table 5** shows de-intensification trials after surgical intervention. The aim of the ECOG 3311 study was to find out whether the dose of adjuvant radiotherapy can be reduced in the intermediate risk patients [27]. 2-year Progression free survival was not affected by observation alone in the low risk group and reduced dose radiotherapy in the intermediate risk group. Pathos trial examines whether swallowing function is better in patients undergoing transoral resection of HPV-positive OPSCC with reduced adjuvant treatment and results are awaited [28]. The rationale behind ADEPT trial is to find out is it safe to avoid concurrent chemotherapy in patients with extracapsular extension following minimally invasive surgery [29].

In the ECOG 3311 trial, the negative margin was defined as 3 mm or greater and adjuvant radiotherapy was offered to those with, <3 mm margin [27]. For transoral resection, the chance of positive margin is likely for the base of tongue tumors than Tonsillar tumors. In transoral laser microsurgery, the tumor may be removed in multiple pieces and it may be difficult to commend on the margin status. In many recent studies, the margin is generally considered clear unless involved [24].


#### **Table 5.**

*Trials addressing the role of minimal invasive surgery and reduced dose radiotherapy.*

Currently, it is proven that the number of involved nodes is more prognostic than extranodal extension in resected oropharyngeal carcinoma and has been incorporated in the pathological staging of AJCC 8th edition [30]. Some authors have tried omitting chemotherapy in high-risk patients with extranodal extension, to reduce the toxicity associated with triple modality treatment [31]. In the absence of evidence, this practice is not recommended. Routman has reported resected oropharyngeal cancer patients without high-risk features have an 11% risk of failure, whereas those with ECE had a 53% risk of recurrence [32]. This implicates the role of adjuvant radiotherapy in this setting. The role of adjuvant radiotherapy in resected HPV positive oropharyngeal cancer with intermediate-risk patients (PNI, LVI, T3 to T4, or N2 diseases) needs further clarification. The basic principle of oncology is to limit the number of modalities used for treatment to reduce long term morbidities. Long-term data are needed for further refinement of the best management strategy.

## **8.2 Non-surgical de-intensification strategies**

De-intensification strategies employing reducing the dose or volume of radiation therapy have the potential to reduce gastric tube dependence, osteoradionecrosis, dysphagia, xerostomia, dental decay, hypothyroidism, carotid stenosis, etc. which include the following


#### *8.2.1 Replace cisplatin with cetuximab*

In the subset analysis of Bonners trial, the benefit of Cetuximab plus RT was restricted to the oropharyngeal subsite [33]. It was later hypothesized to replace Cisplatin with Cetuximab in this favorable group. The three major trials which looked into this aspect were RTOG1016, De-Escalate HPV, and the TROG study (Summarized in **Table 6**).

Results from both RTOG 1016 trial and De-Escalate HPV trial show that HPV positive disease has a good prognosis, there was no difference of toxicity between the two arms, better overall survival and less recurrence with Cisplatin plus RT arm and Cisplatin plus RT remains the standard of care in low-risk HPV positive disease. The result of the TROG 12.01 study is awaiting [36].

#### *8.2.2 Neoadjuvant chemotherapy followed by decreased radiotherapy dose/volume*

E1308 was a phase II trial, in which patients were selected to reduced RT dose based on complete clinical response to neoadjuvant chemotherapy with Cisplatin + Paclitaxel + Cetuximab [37]. Those who achieved complete clinical response was treated to an RT dose of 54Gy in 27 fractions, 5 days a week with concurrent cetuximab for 6 weeks, and those patients who achieved a partial response or stable disease was treated to a


T1N1 –T4N3 excludes > N2b, >10 PY

(excluding T1–2, N1) or IV (excluding T4, N3, or M1) if ≤10 PY. If >10 PY, only N0 − 2A

Conventional RT+ Cetuximab vs. RT + weekly Cisplatin

RT+cetuximab vs. RT+ weekly Cisplatin

2-year survival 89·4% vs. 97·5% (p = 0.001)

Awaited

III 334 T3N0–T4N0,

TROG 12.01 [36] III 200 Stage III

*Human Papillomavirus Associated Oropharyngeal Carcinoma-Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.96234*

#### **Table 6.**

*PY: pack years.*

De-ESCALaTE HPV [35]

*Trials replacing Cisplatin with Cetuximab.*

dose of 69.3 Gy in 33 fractions, 5 days a week with concurrent Cetuximab for 7 weeks. After a median follows up of 35.4 months, the 2-year progression-free survival was 80% in the reduced RT group with improved swallowing and nutritional status.

The Quarterback trial is another trial that is looking into this aspect. It is a phase III randomized trial comparing reduced dose (IMRT,56Gy in 28 fractions with concurrent Carboplatin weekly) and standard-dose radiotherapy (IMRT,70Gy in 35 fractions with concurrent Carboplatin weekly) for locally advanced HPV oropharyngeal carcinoma after neoadjuvant chemotherapy with TPF (Cisplatin, Docetaxel, and 5-Fluorouracil) regimen [38]. The primary endpoint is progressionfree survival and results are awaited.

Another study has tried reducing the radiation therapy volume, keeping the radiation dose unchanged [39]. Following induction chemotherapy (Cisplatin, Paclitaxel, Cetuximab ± Everolimus), patients with >50% reduction received radiotherapy to gross disease only. Whereas patients with <50% reduction received radiotherapy to gross disease and next elective nodal station. Two -year PFS was 93.1% in the responders versus 74% in the non-responders.

In the OPTIMA trial, both dose reduction and volume de-escalation were tried where radiation was limited to the first echelon of uninvolved nodes [40]. After 3 cycles of neoadjuvant chemotherapy (Carboplatin+ nab-Paclitaxel), low-risk patients with ≥50% response received 50 Gy RT, low-risk patients with 30%–50% response, and high-risk patients with ≥50% response received 45 Gy RT + concurrent chemotherapy and patients with the lesser response received 75Gy + concurrent chemotherapy. Two-year progression survival was not compromised compared to historical control.

#### *8.2.3 Chemoradiation with decreased radiotherapy and chemotherapy doses*

In a phase II trial, favourable risk HPV associated oropharyngeal carcinoma patients were randomized to receive 60Gy intensity-modulated radiation therapy with concurrent weekly Cisplatin (30 mg/m<sup>2</sup> ) followed by biopsy from the primary site and planned neck dissection of the initially involved site [41]. The primary endpoint of the study, pathological complete response was 86% and was associated with less toxicity. Few drawbacks of this study are that they included early-stage cases, short follow-up (14 months), and planned neck dissection which was unnecessary in some patients. In the follow up study, with the same IMRT dose 60 Gy in 30 fractions, multiple chemotherapy options were there (weekly regimens with Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250 mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 ) and chemotherapy was omitted for patients with T0-2 N0-1 disease, ≤ 10 pack-years smoking history [42]. The neck dissection was advised based on positive PET/CT done after 10–16 weeks. The results are awaited.

### *8.2.4 Omitting chemotherapy*

In the HN 002 trial, patients with stage T1- T2, N1-N2b or T3, N0-N2b, p16 positive oropharyngeal carcinoma patients were randomized to receive either IMRT 60 Gy/30 fractions over 6 weeks, or IMRT with concurrent weekly Cisplatin 40 mg/m2 [43]. Estimated 2-year survival and late toxicity were similar and acute toxicity were more in the chemotherapy arm.

### *8.2.5 Protons instead of photons*

The goal of the trial was to compare the side effects of 2 radiation treatments; intensity-modulated photon beam therapy 70Gy(RBE) in 33 fractions, with intensity-modulated proton beam therapy, 70Gy(RBE) in 33 fractions. The estimated study completion date is 2024 [44].
