# Radiation Oncology/Head & Neck/Oropharynx

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## Anatomy

* Superior edge - plane of superior surface of the soft palate
* Inferior edge - superior surface of hyoid bone / floor of the vallecula
* Includes base of tongue, inferior (anterior) surface of the soft palate, uvula, anterior and posterior tonsillar pillars, glossotonsillar sulci, pharyngeal tonsils, and lateral and posterior pharyngeal walls

## Risk Factors

* Smoking
* Alcohol
* EGFR amplification
* HPV 16
* chronic irritation

### HPV infection as a risk factor

* RTOG 0129; 2010 PMID 20530316 -- "Human Papilloma Virus and Survival of Patients with Oropharyngeal Cancer." Ang KK, N Engl J Med. 2010; 363, 24-35
** Post-hoc analysis. Randomized trial of standard fractionation vs accelerated fractionation and concurrent cisplatin. 317 of 433 patients with oropharyngeal CA, who had HPV status. HPV positive 83%. Median F/U 4.4 years
** Outcome:
** Risk Stratification:
** Conclusion: HPV status strongly associated with survival. Smoking increases risk of death, even in HPV+ population. Risk stratification possible (High/Intermediate/Low)
* RTOG 0129; 2009 ASCO Abstract -- "Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129." (Gillison ML, J Clin Oncol 27:15s, 2009 (suppl; abstr 6003))
** Post-hoc analysis. Randomized trial of standard fractionation vs accelerated fractionation and concurrent cisplatin. 317 of 433 patients with oropharyngeal CA, who had HPV status. HPV positive 83%. Median F/U 4.4 years
** Outcome: 2-year OS HPV+ 87% vs. HPV- 67% (HR 0.54, SS); PFS 72% vs. 51% (SS). Hazard rate for death if HPV-/tobacco+ 4.3 vs. HPV-/tobacco- 2.4 vs HPV+/tobacco+ 1.8 vs HPV+/tobacco- 1.0
** Conclusion: HPV status strongly associated with survival
* Johns Hopkins, 2007 PMID 17494927 -- "Case-control study of human papillomavirus and oropharyngeal cancer." D'Souza G et al. N Engl J Med. 2007; 356(19):1944-56
** Case control study of 100 pts w/ newly diagnosed oropharyngeal CA and 200 control pts.
** Oropharyngeal CA significantly associated w/ HPV type 16 and high lifetime number of oral sex partners (>6) and high lifetime number of vaginal sex partners (>26).
** Smoking/alcohol w/ increased association with oropharyngeal CA among subjects w/o HPV-16 exposure.

### HPV and EGFR Interaction

* Sydney Cancer Centre; 2010 (1987-2006) PMID 20537890 -- "Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer." (Hong A, Eur J Cancer. 2010 May 25. [Epub ahead of print])
** Retrospective. 270 oropharynx SCC reviewed, HPV E6 by PCR and increased p16 by IHC, EGFR by IHC. HPV+ 37%; EGFR+ 87%. Significant inverse relationship between HPV and EGFR (if HPV- then EGFR+ 93%, if HPV+ then EGFR+ 78% (SS)). Median F/U 2.5 years
** Outcome: Adjusted hazard rate for LRF and OS 0.3 if HPV+ compared with HPV-. Adjusted hazard rate for LRF 5.1 and OS 2.5 if EGFR+ compared with EGFR-. If both HPV- and EGFR+, adjusted HR 13x risk for LRF and 4x risk for OS compared with HPV+/EGFR-
** Conclusion: HPV and EGFR are independent prognostic markers; combination of HPV- and EGFR+ significantly worse prognosis

## Staging

AJCC 7th Edition (2009) Tumor
* T1 - <= 2 cm
* T2 - >2 and <=4 cm
* T3 - >4 cm or extension to lingual surface of epiglottis
* T4a - invades larynx, deep/extrinsic muscles of the tongue, medial pterygoid, hard palate, or mandible
    Note: extrinsic muscles of the tongue are: genioglossus, hyoglossus, styloglossus, and palatoglossus
* T4b - invades lateral pterygoid, pterygoid plates, lateral nasopharynx, skull base, or encases carotid
Nodes (same as for most H&N sites)
* NX - Cannot be assessed
* N0 - No regional lymph nodes metastasis
* N1 - Single ipsilateral lymph node, <= 3cm in greatest dimension
* N2
** N2a - Single ipsilateral lymph node, 3-6 cm in greatest dimension
** N2b - Multiple ipsilateral lymph nodes, <= 6cm in greatest dimension
** N2c - Bilateral or contralateral lymph nodes, <= 6cm in greatest dimension
* N3 - Lymph node(s) >6 cm in greatest dimension
Metastasis
* M0 - none
* M1 - yes
Stage Grouping
* I - T1 N0
* II - T2 N0
* III - T3 N0, T1-3 N1
* IVA - T4a, N2
* IVB - T4b, N3
* IVC - M1
Changes from 6th edition: Added invasion of lingual surface of epiglottis (T3)

### Older staging systems

AJCC 6th Edition (2002) Tumor
* T1 - <= 2 cm
* T2 - >2 and <=4 cm
* T3 - >4 cm
* T4a - invades larynx, deep/extrinsic muscles of the tongue, medial pterygoid, hard palate, or mandible
* T4b - invades lateral pterygoid, pterygoid plates, lateral nasopharynx, skull base, or encases carotid
Nodes (same as for most H&N sites)
* NX - Cannot be assessed
* N0 - No regional lymph nodes metastasis
* N1 - Single ipsilateral lymph node, <= 3cm in greatest dimension
* N2
** N2a - Single ipsilateral lymph node, 3-6 cm in greatest dimension
** N2b - Multiple ipsilateral lymph nodes, <= 6cm in greatest dimension
** N2c - Bilateral or contralateral lymph nodes, <= 6cm in greatest dimension
* N3 - Lymph node(s) >6 cm in greatest dimension
Metastasis
* M0 - none
* M1 - yes
Stage Grouping
* Stage I - T1N0
* Stage II - T2N0
* Stage III - T3N0, T1-3N1
* Stage IVA - T4a or N2
* Stage IVB - T4b or N3
* Stage IVC - M1

## Risk of LN Involvement

* Johns Hopkins; 2009 (1998-2007) PMID 19131181 -- "Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma." (Sanguineti G, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1356-64. Epub 2009 Jan 7.)
** Retrospective. 103 patients with T1-T2 clinically N+ oropharyngeal CA, who underwent neck dissection (radical LND 15%, modified radical LND 71%, selective LND 14%).
** Outcome: Positive Level IB 9%, Level II 91%, Level III 41%, Level IV 18%, and Level V 3%. If CT (-), then positive Level IB 3%, Level II 76%, Level III 17%, Level IV 6%, and Level V 1%. Can contour Level IB only posterior half
** Conclusion: Levels II and III should be included in high risk volumes regardless of imaging, Level IV should be low risk; Levels IB and V at very low risk and could be excluded from RT

## Early Stage

* RTOG 00-22 (2001-2005) Protocol (PDF)
** Prospective. 69 patients. Stage I-III (T1-2 N0-1) oropharynx (tonsil, base of tongue, or palate). Neck staging is based on palpation, not CT, but patients who are "upstaged" by CT are eligible. RT 66 Gy / 30 fractions (2.2 Gy/fx) to primary target PTV and 54-60 Gy / 30 fractions (1.8-2.0 Gy/fx) to secondary target PTV. No chemotherapy. Objectives: 1) assess feasibility of target coverage and parotid sparing. 2) Determine patterns of failure. 3) Acute and late effects. Median F/U 2.8 years.
** 2009 PMID 19540060 -- "Multi-Institutional Trial of Accelerated Hypofractionated Intensity-Modulated Radiation Therapy for Early-Stage Oropharyngeal Cancer (RTOG 00-22)." (Eisbruch A, Int J Radiat Oncol Biol Phys. 2010 Apr;76(5):1333-8. Epub on 2009 Jun 17.)
*** Outcome: 2-year LRF 9% (if major deviations 50%, else 6%, SS)
*** Toxicity: Grade 2+ skin 12%, mucosa 24%, salivary 67%, esophagus 19%, ORN 6%. Xerostomia 6 months 55%, 1 years 25%, 2 years 16%; salivary output didn't recover over time
*** Conclusion: Moderately AHFX IMRT alone feasible

## Surgery vs RT

* ORATOR Trial (2012-2019)
** Randomized. 68 patients, T1-T2 N0-N2 (<4 cm). OPSCC. Arm 1) RT 70/35 +/- cisplatin or cetuximab if N+ vs Arm 2) transoral robotic surgery (TORS) + nodal dissection (29%), with adjuvant RT 60/30 (47%) or adjuvant chemo-RT 64/32 (24%) based on risk. Primary end-point swallowing QOL at 1 year
** 4 years; 2022 -- "Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial" (Nichols AC, J Clin Oncol. 2022 Mar 10;40(8):866-875.doi: 10.1200/JCO.21.01961. Epub 2022 Jan 7.). Median F/U 3.7 years
*** Outcome: 3-year dysphagia QOL RT 89 vs TORS 83 (NS). However, on linear mixed-effects analysis, RT superior (p=0.049). 3-year OS 87% vs 88% (NS). 3-year PFS 87% vs 85% (NS)
*** Toxicity: Grade 2+ RT 91% vs TORS 97% (NS)
*** Conclusion: Swallowing QOL RT slightly superior, but difference decreases over time. Oncologic outcomes same. Should counsel about pros and cons

## Pre-op RT vs. Post-op RT

* RTOG 73-03 (1973-1979)
** Randomized. 320 patients. Operable stage T2-T4 any N (but not fixed); oral cavity, oropharynx, supraglottic larynx, hypopharynx, or maxillary sinus. Arm 1) Pre-op RT 50 Gy vs. Arm 2) Post-op RT 60 Gy. In addition, OC and OP lesions may be randomized Arm 3) definitive RT 65-70 Gy, with surgery reserved for salvage (n=43).
** 10-years; 1999 PMID 1993628 — "Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03." (Tupchong L et al. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8.)
*** Only pre-op vs. post-op subset (n=277). Oral cavity (14%), oropharynx (17%), hypopharynx (43%), supraglottic larynx (26%)
*** Outcome: LRC pre-op 58% vs. post-op 70% (SS), <2 years no difference (failures 59% vs. 58%), but marked >2 years (failures 27% vs 8%); OS no difference due to late (>2 years) deaths from DM and from second primaries
*** Supraglottic larynx: LRC pre-op 53% vs. post-op 77% (SS); 78% failures <2 years
*** Toxicity: no difference
*** Conclusion: Post-op RT better for LRC (especially in SGL), but no impact on OS due to distant failure and second primaries
** Comment: some argument for definitive chemoRT instead of surgery and post-op RT since after 2 yrs, distant mets are primary cause of failure resulting in similar 10 OS in this trial. LRC still better for post-op vs definitive RT alone. Also, different doses used, at the time believed equivalent given the setting

## Surgery + RT vs. Chemo-RT

* Singapore (1996-2000)
** Randomized. Stopped early due to slow accrual. 199 patients, resectable Stage III/IV SCHNC excluding NPC and salivary glands (larynx 32% (supraglottis 23%), oral cavity 27%, oropharynx 21%, hypopharynx 12%). T4 56%. Arm 1) surgery + adjuvant RT 60/30 vs. Arm 2) RT 66/33 + concurrent cisplatin 20 mg/m2/d + 5-FU 1000 mg/m2/d both given as continuous IV over 96 hours x2 cycles. 90% received at least 1 cycle of chemo
** 2005 PMID 16012523 -- "Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison." (Soo KC, Br J Cancer. 2005 Aug 8;93(3):279-86.) Median F/U 6 years
*** Outcome: 3-year DFS: S+RT 50% vs. chemo-RT 40% (NS). Organ preservation (larynx/hypopharynx 68%, oropharynx 55%, oral cavity 21%). Chemo-RT group had poor surgical salvage of 47%, with no long-term survivors (possibly due to larger proportion of T4 and oral cavity cancers)
*** Conclusion: Chemo-RT not superior to surgery+RT, but can be attempted for organ preservation in larynx, hypopharynx, and oropharynx; organ preservation in oral cavity poor

## Induction Chemo-RT vs. Primary RT alone

* RTOG 68-01 -- methotrexate
** Randomized. 638 patients, Stage III-IV oral cavity (23%), oropharynx (55%), supraglottic larynx (12%), hypopharynx (10%). Arm 1) RT alone vs. Arm 2) IV MTX 25 mg q3d x5 followed by RT. RT 55-80 Gy
** 1980 PMID 7410127 -- "Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx." (Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 May;6(5):533-41.)
*** Outcome: median OS RT vs. MTX-RT: oral cavity 11.8 mo vs. 12.4 mo, oropharynx 13.6 mo vs. 13.1 mo, SGL 17.2 mo vs. 19.2 mo, hypopharynx 9.7 mo vs. 13.4 mo
*** Conclusion: Minimal gain, induction methotrexate should not be used

## Altered Fractionation

* RTOG 90-03 (1991-1997) -- SF vs HF vs Split course AFX vs AFX-CB
** Randomized, 4 arms. 1073 patients. Stage III-IV (oral cavity, oropharynx, or supraglottic larynx) or Stage II-IV (base of tongue, hypopharynx). Arm 1) SF standard fractionation 70/35 @ 2 Gy/fx vs. Arm 2) HF hyperfractionated 81.6/68 @ 1.2 Gy BID vs. Arm 3) AFX-S split course accelerated fractionation 67.2/42 @ 1.6 Gy BID with 2 week break after 38.4 Gy vs. Arm 4) AFX-CB concomitant boost 72 Gy given 54/30 @ 1.8 Gy + 18/12 @ 1.5 Gy concurrent BID boost
** 2-years; 2000 PMID 10924966 -- "A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003." (Fu KK, Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):7-16.). Median F/U 2 years, 3.4 for alive patients
*** Outcome: 2-year LRC SF 46% vs. HF 54% (SS) vs. AFX-S 47% (NS) vs. AFX-CB 54% (SS); DFS 32% vs. 38% (NS) vs. 33% (NS) vs. 39% (NS); OS 46% vs. 54% (NS) vs. 46% (NS) vs. 51% (NS)
*** Sites of failure: LF 44% vs. 38% vs. 43% vs. 37%; RF 32% vs. 27% vs. 31% vs. 33%
*** Toxicity: Increased acute effects but no increase in late effects
*** Conclusion: HF or CB improve LRC compared to SF, no impact on DFS and OS. Split course comparable to SF
* RTOG 71-01 (1971-1976) -- continuous vs. split-course
** 1993 PMID 8213620 -- ""Compensated" split-course versus continuous radiation therapy of carcinoma of the tonsillar fossa. Final results of a prospective randomized clinical trial of the Radiation Therapy Oncology Group." (Marcial VA, Am J Clin Oncol. 1993 Oct;16(5):389-96.)
*** Randomized. 137 patients. All stages, no adenoCA. Arm 1) split course RT 30/10 + 30/10 vs. Arm 2) continuous RT 60/30-66/33
*** Outcome: 5-year LRC split course 25% vs. continuous 28% (NS); 5-year OS 19% vs. 29% (NS)
*** Late toxicity: split course 17% vs. continuous 24% (NS)
*** Conclusion: No difference
* EORTC 22791
** See Radiation Oncology:H&N
** Improved LC for T3 but not T2 tumors. Trend to improved OS.

## Radiation + Concurrent Chemo Options

* RTOG 1016 (2011 - 2014) - RT 70 Gy + cisplatin vs cetuximab
** Randomized. Multicenter, non-inferiority. 849 patients. HPV+ oropharyngeal carcinoma. Arm 1) RT + cetuximab (400 mg/m2 loading + 250 mg/m2 weekly) vs Arm 2) RT + cisplatin (100 mg/m2 Q3 weeks x2). RT given 70/35 accelerated over 6 weeks at 6 fractions per week.
** 5 years PMID 30449625 -- "Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial." Gillison ML, Lancet. 2019 Jan 5;393(10166):40-50. doi: 10.1016/S0140-6736(18)32779-X. Epub 2018 Nov 15.) Median F/U 4.5 years
*** Outcome: 5-year OS cetuximab 78% vs cisplatin 85% (SS). PFS 67% vs 78% (SS). LR failure 17% vs 10% (SS).
*** Toxicity: Moderate/severe toxicity similar, though events per patient lower in cetuximab arm
*** Conclusion: For HPV+ patients, RT + cetuximab is worse in terms of survival, PFS, and local control. RT + cisplatin is the standard
* De-ESCALaTE HPV (2012 - 2016) - RT 70 Gy + cisplatin vs cetuximab
** Randomized. Multiinstitutional. 334 patients. HPV+ oropharyngeal cancer, nonsmoker or <10 pack years. Arm 1) RT + cetuximab (400 mg/m2 loading, 250 mg/m2 weekly) vs Arm 2) RT + cisplatin (100 mg/m2 Q3 weeks x3) vs RT given as 70/35 in 7 weeks. Primary outcome lower toxicity with cetuximab
** 5 years PMID 30449623 -- "Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial." (Mehanna H, Lancet. 2019 Jan 5;393(10166):51-60. doi: 10.1016/S0140-6736(18)32752-1. Epub 2018 Nov 15.)
*** Outcome: 2-year OS cetuximab 89% vs cisplatin 97% (SS); LR 16% vs 6% (SS)
*** Toxicity: No difference
*** Conclusion: Cetuximab showed no reduction in toxicity, but worse tumor control. RT + cisplatin should be standard of care

## Base of Tongue

* Clinical presentation
** Mild sore throat
** Many clinically silent locally, and present with neck mass
** With further enlargement, difficulty swallowing, nasal or "hot potato" voice quality, and ear pain
* Spread
** BOT proper: tend to stay confined to tongue for long time. Advanced lesions spread toward larynx, oral tongue, and parapharyngeal space
** Valecula: spread along mucosal surface to epiglottis and lateral pharyngeal wall. Can penetrate hyoepiglottic ligament into pre-epiglottic space
** Lateral BOT: spread into glossotonsillar sulcus, and then into neck
* LN drainage
** LN+ in 50-80%
** Bilateral LN+ in 35-55%
** If clinical ipsilateral N0, pN+ 20-30%
* Treatment overview
** Surgery and RT produce comparable outcomes; however, BOT excision generally causes greater disability
** Surgical approaches
*** Small volume T1-T2 can consider transoral laser excision with neck dissection
*** Approaches through the mandible can be via midline split or via horizontal split
*** Suprahyoid, transhyoid, and infrahyoid approaches can also be used
*** Removal of large tumors may require laryngectomy
** If N0, consider treating bilateral neck to Levels II-IV. If N+, consider treating bilateral neck to Levels I-V
* Outcome: local control for RT varies with stage, from >95% for T1 to ~50% for T4 (see PMID 16462500)

### Definitive RT

* University of Florida; 2006 (1964-2003) PMID 16462500 -- "Definitive radiotherapy for squamous cell carcinoma of the base of tongue." (Mendenhall WM, Am J Clin Oncol. 2006 Feb;29(1):32-9.)
** Retrospective. 333 patients with BOT, treated with definitive RT. Daily (25%, median dose 70 Gy) or twice daily (75%, median dose 76.8 Gy or concomitant boost 72 Gy) fractionation. IMRT for last 3 year in N0 or ipsilateral N+. Adjuvant chemo (more recently) in 18%. Median F/U 6.6 years
** Outcome: 5-year LC T1 98%, T2 92%, T3 82%, T4 53%. 5-year LRC Stage I-II 100%, III 82%, IVa 87%, IVb 58%. 5-year CSS by Stage 91%, 77%, 84%, 45%. 5-year OS by Stage 67%, 66%, 67%, 33%
** Toxicity: Severe complications 16%
** Conclusion: LRC and survival after RT comparable to surgery; morbidity less

### Concurrent Chemotherapy

* MD Anderson; 2004 - PMID 15022283 (1975-98) — "Is concurrent chemoradiation the treatment of choice for all patients with Stage III or IV head and neck carcinoma?" Garden AS et al. Cancer. 2004 Mar 15;100(6):1171-8.
** Retrospective. 299 pts with small tumors (T1-T2) of oropharynx that are Stage III-IV based on N-stage. Treated with RT alone.
** Median f/u 82 mo. 5-yr LRF, DM, OS were 15%, 19%, and 64%. LRC was 95% for T1 vs 79% for T2.
** Conclusion: Excellent local control for small T-stage tumors of the oropharynx. Chemoradiotherapy would not significantly benefit these pts.

### Interstitial Brachytherapy

* Mass General Hospital, 2005 - PMID 15726587 (1983-00) -- "Definitive radiotherapy with interstitial implant boost for squamous cell carcinoma of the tongue base." Karakoyun-Celik O et al. Head Neck. 2005 May;27(5):353-61.
** 40 pts w/ primary or recurrent SCC of BOT who received interstitial brachy as part of initial management. 54% had T3/T4 dz.
** Oropharynx, b/l necks, SC comprehensively irradiated w/ BOT receiving median of 61 Gy via EBRT. Median implant dose 17.4 Gy (adjusted to reach dose to tumor of 80 Gy).
** 5 yr OS 62%, 10 yr OS 27%.
** Local control 78% at 5 yrs, 70% at 10 yrs. 78% organ preservation rate.
** 2 pts w/ grade 3 osteonecrosis (5%)
* William Beaumont, 1996 - PMID 8780531 (1986-1995) -- "Excellent functional outcome in patients with squamous cell carcinoma of the base of tongue treated with external irradiation and interstitial iodine 125 boost." Horwitz EM et al. Cancer. 1996 Sep 1;78(5):948-57.
** 20 pts w/ carcinoma of BOT w/ I-125 seed brachytherapy as component of tx.
** Pts received 50-66.6 Gy via EBRT followed by interstitial implant 2-3 wks later. Median implant dose of 27 Gy. Implant volume included tumor, glossotonsillar sulcus, and pharyngeal wall/tonsil in select cases.
** 5 yr actuarial local control rate of 88%. After salvage, overall 5 yr actuarial local control was 93%
** Speech and swallow preserved in 18/20 patients.
* Gainesville, 1990 - PMID 2370179 (1964-1986) -- "Is interstitial implantation essential for successful radiotherapeutic treatment of base of tongue carcinoma?" Foote RL et al. Int J Radiat Oncol Biol Phys 1990 Jun;18(6):1293-8.
** 84 pts w/ SCC of BOT tx'd w/o interstitial implantation. (qD in 59 pts, BID in 25 pts)
** Local control rate for T2 (88%), T3 (77%), T4 (36%). Improved local control seen for T4 pts if BID fractionation.
** Incidence of bone exposure 6%, soft tissue necrosis 19%

### Management of Neck

* MSKCC, 1997 - PMID 9276364 (1981-1996) -- "Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma." Lee HJ et al. Int J Radiat Oncol Biol Phys. 1997 Jul 15;38(5):995-1000.
** 68 pts w/ SCC of BOT tx'd w/ primary RT.
** 54 Gy to tumor via EBRT + 20-30 Gy interstitial implant. 50 Gy to neck (boosted to 60 Gy for if clinically positive. Neck dissection done if clinically palpable neck nodes (even if complete response to RT)
** Actuarial 5 yr neck control 95%, 10 yr neck control 86%
** No cases of grade 3 fibrosis.
** Neck dissection suggested at time of implant for BOT SCC.

## Tonsil

* RT alone: >80% LC for stages I-III; surgery can be reserved for salvage
* Concurrent chemotherapy used for advanced stage; planned neck dissection can be considered for bulky disease. Conversely, primary surgery with adjuvant RT may be used
* Contralateral neck treatment: Overall failure rate <5% in select patients (mostly T1-2N0-1; see below). Consider contralateral RT for CTV crossing midline, infiltration of base of tongue or glossopalatine sulcus, or N2c/N3 disease (Perez 5th)

### Primary Outcomes

* University of Florida
** 2006 (1964-2003) PMID 16755183 -- "Definitive radiotherapy for tonsillar squamous cell carcinoma." (Mendenhall WM, Am J Clin Oncol. 2006 Jun;29(3):290-7.)
*** Retrospective. 503 patients; 198 planned neck dissection, 57 chemo. Minimum 2-year F/U
*** 5-year outcome: LC: T1 88%, T2 84%, T3 78%, T4 61%. Neck control: N0 95%, N1 93%, N2a 89%, N2b 84%, N2c 77%, N3 66%. LRC: Stage I 92%, II 88%, III 88%, IVA 84%, IVB 66%. High failure rates for anterior pillar lesions compared with fossa/posterior pillar
*** Contralateral neck: 2/58 (3%) patients treated with ipsilateral primary & neck RT developed recurrence in contralateral neck
*** Severe late toxicity: 9%
*** Conclusion: Definitive RT provides comparable cure rates as surgery, with lower complications
** 2000 PMID 10829041, 2000 (1964-1997) — "Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery?" Mendenhall WM et al. J Clin Oncol. 2000 Jun;18(11):2219-25.
*** Retrospective. 400 pts. with T1-T4, N0-N3, tonsil cancers. Treated with radiation therapy alone. Minimum 2 year follow-up.
*** Outcome: 5-yr LC by stage: T1, 83%; T2, 81%; T3, 74%; and T4, 60%.
*** Recurrence: 83 patients had LR, 36 underwent a salvage procedure, and 17 pts were successfully salvaged. (About 1/2 of LR can be successfully salvaged)
*** Toxicity: No patients had severe acute complications from RT.
*** Conclusion: Local-regional control similar after surgery or RT for tonsillar cancer, with the risks of a severe or fatal complication higher for those patients treated surgically.

### Contralateral Neck

* Colorado; 2009 PMID 19168295 --"Freedom from local and regional failure of contralateral neck with ipsilateral neck radiotherapy for node-positive tonsil cancer: results of a prospective management approach." (Rusthoven KE, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1365-70.)
** Retrospective. 20 patients with well lateralized, ipsilateral node positive tonsil cancer. Lesions not involving midline structures (BOT, soft palate or glossotonsillar sulcus)
** 80% stage IV; N1 20%; N2a 15%; N2b 65%
** No contralateral failures observed at median FU of 19 months
** Conclusion: Ipsilateral-only RT may be reasonable in well selected patients with ipsilateral node-positive tonsil cancer. More patients and longer follow-up are required to validate these results
* University of Florida; 2006 (1964-2003) PMID 16755183 -- "Definitive radiotherapy for tonsillar squamous cell carcinoma." (Mendenhall WM, Am J Clin Oncol. 2006 Jun;29(3):290-7.)
** See full study above. Retrospective, 503 patients
** Contralateral neck: 2/58 (3%) patients treated with ipsilateral primary & neck RT developed recurrence in contralateral neck
** Conclusion: Ipsilateral fields can be used for patients with well-lateralized tumors
* Erasmus Medical Center; 2004 (1986-2001) PMID 15183475 -- "Brachytherapy versus surgery in carcinoma of tonsillar fossa and/or soft palate: late adverse sequelae and performance status: can we be more selective and obtain better tissue sparing?" (Levendag P, Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):713-24.)
** Retrospective. 190 patients with T1-3N0-3. For full details, please see PMID abstract
** Contralateral neck: 0/29 patients T1-3N0 disease and no contralateral treatment had recurrence. 6/149 (4%) patients T1-3 ipsilateral N0/+ contralateral N0, with electively treated contralateral necks developed recurrence. Substantial relapse (>10%) if base of tongue infiltration
** Conclusion: One can be more selective in treating contralateral neck; don't need to treat unless the tumor extends beyond the midline of the soft palate (uvula) or beyond the lateral one-third of the ipsilateral base of the tongue.
* Princess Margaret; 2001 (1970-91) - PMID 11567806 — "The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region." O'Sullivan B et al. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):332-43.
** Retrospective. 228 pts were treated with ipsilateral nodal irradiation. 84% had T1-2, 58% N0 tumors. Median F/U 5.7 years
** Contralateral failure: Crude rate 3.5%. T1 0%, T2 1.5%, T3 10%, T4 0%. N0 0%, N1 9%, N2/3 0%. All T1 or N0 patients had no contralateral failures. Significant risk (>10%) if involving medial one third of palate, base of tongue
** Conclusion: Selected cases of tonsilar carcinoma show low risk of contralateral neck failure with ipsilateral technique.
* Hokkaido; 2000 (1989-1996) PMID 10699473 -- "Ipsilateral irradiation for carcinomas of tonsillar region and soft palate based on computed tomographic simulation." (Kagei K, Radiother Oncol. 2000 Feb;54(2):117-21.)
** Retrospective. 32 patients, tonsil/soft palate. Tumor didn't cross midline, no contralateral LNs. Ipsilateral technique 65/26 +/- 5-15 Gy boost. Median F/U 3.7 years
** Contralateral failure: 0%
** Conclusion: Ipsilateral technique for tumors that don't cross midline and have no contralateral LNs
* British Columbia; 1999 (1975-1993) PMID 10435802 -- "Cancer of the tonsil: the results of ipsilateral radiation treatment." (Jackson SM, Radiother Oncol. 1999 May;51(2):123-8.)
** Retrospective. 178 patients ipsilateral RT, compared with 72 bilateral RT. Dose 60/25. T1-2 66%, T3 29%; N0 57%, N1 30%; Stage III-IV 63%
** Contralateral failure: crude rate 2.6%. Stage I 0%, II 2%, III 4%, IV 0%; N0 0%, N1 4%, N2-3 0% (but 52% ipsilateral failure, ? first)
** Conclusion: Ipsilateral RT only has results comparable to bilateral RT, with fewer side effects, and low risk of contralateral failure. Vast majority of failures inside original fields

## Proton Therapy

* Loma Linda; 2005 (1991-2002) PMID 15890592 -- "Proton radiation for treatment of cancer of the oropharynx: early experience at Loma Linda University Medical Center using a concomitant boost technique." (Slater JD, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):494-500.)
** Prospective. 29 patients, localized Stage II-IV oropharyngeal cancer. Accelerated mixed photon and proton RT 75.9 GyE in 45 fractions to primary disease, involved LNs and subclinical areas. Photons lateral opposed beam and anterior field for lower to 50.4/28. PT used as concomitant boost 25.5 GyE/17 starting Day 12, typically single posterior oblique field. No chemotherapy mentioned
** Outcome: 5-year LC 88%, LN control 96%, LRC 84%; 2-year DFS 81%, 5-year DFS 65%
** Toxicity: Late Grade 3 in 10%
** Conclusion: Preliminary results reveal increased LRC without increased toxicity

## Neoadjuvant Chemo

* ECOG E2399 PMID 17761982 -- "Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399." (Cmelak AJ, J Clin Oncol. 2007 Sep 1;25(25):3971-7.)
** Phase II. 105 patients. Resectable T2N+ or T3-4N0-3, larynx (34%) or oropharynx (66%) squamous cell. Induction paclitaxel 175 mg/m2 and carboplatin AUC 6 x2 cycles, then concurrent paclitaxel 30 mg/m2 + RT 70 Gy. Primary endpoint organ preservation. 94% full dose RT. Median F/U 3 years
** Outcome: No progression on chemo. Organ preservation larynx 74%, OP 84%. Primary site salvage surgery larynx 19%, OP 9%. 2-year OS larynx 63%, OP 83%
** Conclusion: High organ preservation in oropharynx but not larynx