# Radiation Oncology/Head & Neck/Oral cavity

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Includes lip and oral cavity.

## Anatomy

Divided into specific areas:
* Mucosal lip - vermillion surface only
* Buccal mucosa - membrane lining inner surface of the lip and cheeks to the attachment of mucosa to alveolar ridges and pterygomandibular raphe
* Lower alveolar ridge - mucosa overlying the alveolar ridge of the mandible. Extends from lower buccal gutter to free mucosa of the floor of the mouth. Posteriorly goes to ascending ramus of the mandible
* Upper alveolar ridge - mucosa overlying the alveolar ridge of the maxilla. Extends from upper buccal gutter to junction of hard palate. Posteriorly goes to upper end of pterygopalatine arch
* Retromolar trigone - mucosa overlying ascending ramus of mandible from posterior surface of last molar tooth to apex, adjacent to tuberosity of maxilla
* Floor of mouth - semilunar space over mylohyoid and hyoglossus muscles. Extends from inner surface of lower alveolar ridge to undersurface of tongue, and posteriorly to base of anterior pillar of the tonsil. Contains ostia of submaxillary and sublingual salivary glands
* Hard palate - semilunar area between upper alveolar ridge and mucous membrane covering the palatine process of maxillary palatine bones. Extends from inner surface of superior alveolar ridge to posterior edge of the palatine bone
* Oral tongue - extends anteriorly from circumvallate papillae to undersurface of the tongue at the junction of the floor of mouth. It consists of tip, lateral borders, dorsum, and undersurface

## Staging

AJCC 8th edition (2018) Tumor
* T1 - 2 cm or less, <= 5mm DOI
* T2 - > 2 cm but <= 4 cm with <= 10mm DOI or 2cm or less with 5-10mm DOI
* T3 - >4 cm or DOI > 10mm
* T4 (Lip) - Invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face (i.e. chin or nose)
* T4a (Oral cavity) - Invades through cortical bone, maxillary sinus, or skin of face
    Note: extrinsic muscles of the tongue are: genioglossus, hyoglossus, styloglossus, and palatoglossus (NO LONGER T4 for 8th Edition)
* T4b - Involves masticator space, pterygoid plates, or skull base, or encases internal carotid artery
Node Clinical
* cN1 - Single ipsilateral <= 3cm
* cN2a - Single ipsilateral 3-6cm
* cN2b - Multiple ipsilateral <= 6cm
* cN2c - Bilateral or contralateral <= 6cm
* cN3a - > 6cm bulky
* cN3b - clinically or radiographically +ECE
Pathologic
* pN1 - Single ipsilateral <= 3cm (ECE-)
* pN2a - Single ipsilateral 3-6cm (ECE-) or Single ipsilateral <=3cm (ECE+)
* pN2b - Multiple ipsilateral <= 6cm (ECE-)
* pN2c - Bilateral or contralateral <= 6cm (ECE-)
* pN3a - > 6cm bulky (ECE-)
* pN3b - >= pN2 disease with ECE+
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
AJCC 7th edition (2009) Tumor
* T1 - 2 cm or less
* T2 - > 2 cm but <= 4 cm
* T3 - >4 cm
* T4 (Lip) - Invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face (i.e. chin or nose)
* T4a (Oral cavity) - Invades through cortical bone, into deep (extrinsic) muscle of tongue, maxillary sinus, or skin of face
    Note: extrinsic muscles of the tongue are: genioglossus, hyoglossus, styloglossus, and palatoglossus
* T4b - Involves masticator space, pterygoid plates, or skull base, or encases internal carotid artery
Node
* 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

### Older staging systems

AJCC 6th edition (2002) no changes compared to 7th edition

## Postop Recurrence Nomogram

* Memorial Sloan Kettering; 2008 PMID 18720518 -- "Nomogram for deciding adjuvant treatment after surgery for oral cavity squamous cell carcinoma." (Gross ND, Head Neck. 2008 Oct;30(10):1352-60.)
** Nomogram link
** Nomogram. 590 patients with oral cavity SCC at MSKCC, validated using 417 patients from HACC Sao Paulo. Concordance index 0.693

## Induction chemo-RT + Surgery vs Surgery Alone

* DOSAK -- induction chemo-RT vs surgery alone
** Randomized. 268 patients, oral cavity/oropharynx T2-T4 N0-N3. Arm 1) Induction RT 36/18 with cisplatin 12.5 mg/m2 vs Arm 2) Surgery
** 1994 PMID 7930766 -- "Preoperative radiochemotherapy and radical surgery in comparison with radical surgery alone. A prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up)." (Mohr C, Int J Oral Maxillofac Surg. 1994 Jun;23(3):140-8.)
*** Outcome: Locoregional recurrence induction 16% vs surgery alone 31%; OS 72% vs 81% (SS); 1-year OS benefit 4.5% and 2-year OS benefit 8.3%
Retrospective
* Cologne; 2008 PMID 18188519 -- "Neoadjuvant radiochemotherapy and radical resection for advanced squamous cell carcinoma of the oral cavity. Outcome of 134 patients." (Eich HT, Strahlenther Onkol. 2008 Jan;184(1):23-9.)
** Retrospective. 134 patients, resectable SCC of oral cavity, Stage II-IV (Stage IV in 70%). Neoadjuvant chemo-RT 39.6/22 + carboplatin 70 mg/m2. Radical resection + neck dissection (R0 88%, R1 5%, R2 2%). Post-op RT in 18%. Median F/U 6.1 years
** Outcome: pCR 14%. Local recurrence 29%, regional recurrence 10%, DM 12%. 2-year OS 65%, 5-year OS 45%
** Toxicity: Grade 3-4 in 5%
** Conclusion: Neoadjuvant chemo-RT with radical surgery is safe and effective

## 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; 1991 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
*** 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 Primary RT

* Scottland (1991-1993) -- Surgery + post-op RT vs radical RT
** Randomized. Trial closed prematurely after significant survival benefit for combined arm. 35 of expected 350 patients, 4 institutions, oral cavity/oropharynx, excluded T1N0. Arm 1) Surgery + postop RT 60/30 vs Arm 2) radical RT 66/33 alone. Only 50% and 41% of patients respectively received XRT as planned, mainly due to machine breakdown
** 1998 PMID 9704176 -- "Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours." (Robertson AG, Clin Oncol (R Coll Radiol). 1998;10(3):155-60.) Median F/U 1.9 years
*** Outcome: OS combined arm 53% vs. RT 11% (HR 0.24, SS); DSS 65% vs 33% (SS). Residual local disease 0% vs. 53% (SS)
*** Conclusion: Surgery with postop RT superior to radical RT alone

## 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 + 5-FU 1000 mg/m2 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. Poor organ preservation in oral cavity

## Induction chemo + RT vs Primary RT

* RTOG 68-01 (1968-1972) -- induction MTX + RT vs RT alone
** 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

## Oral Tongue

* Colorado-SEER, 2008 - PMID 18041071 -- "Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma." Rusthoven K et al. Cancer 2008: Jan 15;112(2):345-51.
** Retrospective analysis of 6791 patients entered into SEER database with T1-2N0 oral cavity SCC
** 40% had Oral tongue cancer and 60% had other oral cavity cancers
** OS and CSS were significantly worse for patients with oral tongue SCC
*** 5yr OS: 60.9% (oral tongue) vs 64.9% (other OC) HR: 1.24
*** 5yr CSS: 83.5% (oral tongue) vs 94.1% (other OC) HR 3.04
** CSS for stage II oral tongue cancer was significantly worse than CSS in patients with stage III and stage IV oropharyngeal cancer. OS was similar for stage II oral tongue and stage III/IV oropharyngeal cancer
* Kobe University, Japan, 2005 PMID 15921890 -- "A comparison of brachytherapy and surgery for the treatment of stage I-II squamous cell carcinoma of the tongue." Umeda M et al. Int J Oral Maxillofac Surg. 2005 Oct;34(7):739-44.
** 180 pts w/ stage I-II oral tongue CA tx'd w/ LDR (78), HDR (26), or surgery (71)
** Local recurrence seen in 17% LDR, 35% HDR, and 6% surgery groups
** After salvage, local control was 91% in LDR, 85% in HDR and 100% in surgery groups
** 5yr OS 84% in LDR, 73% in HDR, and 95.4% in surgery groups for stage I, 72%, 51.5% and 93.8% in stage II
* Osaka University, Japan Randomized Trial, 1996 (1992-93) - PMID 8985043 -- "Phase III trial of high and low dose rate interstitial radiotherapy for early oral tongue cancer." Inoue T et al. Int J Radiat Oncol Biol Phys 1996 Dec 1;36(5):1201-4.
** Inclusion criteria: T1-2N0 that could be tx'd w/ single plane implant, localized at lateral tongue border, <1cm, absence of severe concurrent dz
** Pts randomized to LDR (70 Gy over 4-9 days) vs HDR 60 Gy in 10 fx over 6 days; 15 pts in LDR arm, 14 in HDR arm
** 86% local control at 2yrs for LDR, 100% for HDR
** UPDATE PMID 11516867 -- 51 pts evaluable in update. 5yr local control 77% (LDR) and 76% (HDR)
* MDACC, 1990 (1963-79) - PMID 2370178 -- "Primary radiotherapy in the treatment of stage I and II oral tongue cancers: importance of the proportion of therapy delivered with interstitial therapy." Wendt CD et al. Int J Radiat Oncol Biol Phys 1990 Jun;18(6):1287-92.
** 103 pts w/ T1-2N0 SCC of oral tongue (18 T1, 85 T2). Tx regimens included interstital brachy alone, hypofractionated EBRT + interstitial brachy, conventional fractionation EBRT + interstitial brachy, EBRT alone.
** 5/8 pts w/ EBRT alone failed locally. 6/18 w/ interstitial alone failed locally.
** 2 yr local control 92% if EBRT doses <40 Gy w/ hi proportion of RT given by interstitial brachy. 2yr local control 65% if EBRT >40 Gy w/ lower brachy doses.
** 44% neck recurrences if no therapy to neck.
** 13% severe complication rate

## Buccal Mucosa

* Orissa, India Randomized Trial, 1996 - PMID 8903493 -- "Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective randomized trial." Mishra RC et al. Eur J Surg Oncol. 1996 Oct;22(5):502-4.
** Pts w/ stage III and IV SCC of buccal mucosa. Randomized to surgery alone vs surg + postop RT.
** DFS 38% (surgery alone) vs 68% (postop RT)
* Centre Alexis Vautrin, France, 1995 (1973-91) - PMID 7673032 -- "An original technique of brachytherapy in the treatment of epidermoid carcinomas of the buccal mucosa." Lapeyre M et al. Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):447-54.
** 42 pts (36 T1, 35 N0) SCC of buccal mucosa tx'd w/ brachytherapy.
** Either parallel wires technique or loop technique used. 23 pts w/o elective nodal tx, 8 w/ EBRT, 4 w/ neck dissection
** 63% OS at 2 yrs, 47.5% OS at 5 yrs; >80% recurrences w/i 1 yr
** 91% local control w/ loop technique, 58% local control w/ parallel wire technique.
** Elective nodal tx appeared to be necessary if lesion >1cm

## Floor of mouth

* Gustave-Roussy Institute, France, 2002 (1970-85) - PMID 11955737 -- "Brachytherapy for T1-T2 floor-of-the-mouth cancers: the Gustave-Roussy Institute experience." Marsiglia H et al. Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1257-63.
** 160 pts with carcinoma of FOM tx'd definitively with interstitial brachy. (49% had T1, 51% had T2, 21% had N1).
** 89% actuarial survival at 2 yrs, 75% actuarial survival at 5 yrs.
** <10% rate of severe necrosis. 18% rate of bone necrosis in total.
* Roswell Park, 1997 (1971-91) - PMID 9243267 -- "Squamous cell carcinoma of the floor of mouth: a 20-year review." Hicks WL Jr et al. Head Neck. 1997 Aug;19(5):400-5.
** 99 pts with carcinoma of FOM (43 w/ stage I or II).
** 21% likelihood of occult nodal metastatic disease in T1 pts.
** Local control for surgery alone for 81% and regional control was 71%
** RT improved regional control rate for stage IV.
** Conclusion: Elective treatment of regional lymphatics is warranted in carcinoma of FOM.
* Centre Alexis Vautrin, France, 1995 (1976-1992) - PMID 7480819 -- "Epidermoid carcinomas of the floor of mouth treated by exclusive irradiation: statistical study of a series of 207 cases." Pernot M et al. Radiother Oncol. 1995 Jun;35(3):177-85.
** 207 pts w/ carcinoma of the FOM tx'd w/ definitive RT. 105 received EBRT + brachy, 102 received brachy alone. 83% pts were N0.
** Local control at 5 yrs was 97% for T1, 72% for T2, 51% for T3.
** Exclusive brachy for T1-2 appeared to be preferable to a combination of EBRT + brachy in T1-2N0 pts.
* Gainesville, 1993 (1964-87) - PMID 8416850 — "Management of squamous cell carcinoma of the floor of mouth." Rodgers LW Jr et al. Head Neck. 1993 Jan-Feb;15(1):16-9.
** 194 pts. Similar LC for RT alone or surgery alone. Recommend combination therapy for advanced lesions because of poor local control for a single modality.

## Retromolar Trigone

* Gainesville, 2005 (1966-2003) - PMID 15825160 -- "Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery." Mendenhall WM et al. Cancer. 2005 Jun 1;103(11):2320-5.
** 99 pts w/ SCC of RMT tx'd w/ RT alone (35) or RT + surg (64).
** 5yr locoregional control for RT alone for stage I-III was 51%, for RT + surg was 87%; 5yr LR control for stage IV was 42% for RT alone, 62% for RT + surg
** Multi-variate analysis suggested surgery + RT was better modality than RT alone.
* Mallinckrodt, 2001 (1971-94) - PMID 11505486 -- "Cancer of retromolar trigone: long-term radiation therapy outcome." Huang CJ et al. Head Neck. 2001 Sep;23(9):758-63.
** 65 pts w/ SCC of RMT tx'd w/ RT (10 pts preop, 39 pts postop, 15 tx'd w/ RT alone).
** 5yr DFS 76% w/ T1, 50% w/ T2, 72% w/ T3, 54% w/ T4
* MDACC, 1987 (1966-81) - PMID 3597160 -- "Results of irradiation in the squamous cell carcinomas of the anterior faucial pillar-retromolar trigone." Lo K et al. Int J Radiat Oncol Biol Phys 1987 Jul;13(7):969-74.
** 159 pts w/ SCC of ant faucial pillar or RMT tx'd w/ definitive RT.
** Doses ranged from 60 to 75 Gy. If N0, only ipsi JD nodes treated.
** 92% of recurrences occurred within 2 yrs.
** Local failure rates were 29% for T1, 30% for T2, 24% for T3, 40% for T4. After salvage surgery, ultimate failure rate was 0% for T1, 6% for T2, 8% for T3, 20% for T4. 10% experienced neck failure.
** 30% developed some degree of bone exposure, 5.6% requiring segmental mandibular resection.

## Patterns of failure

After IMRT:
* U. of Iowa; 2007 (2001-5) - PMID 17276613 -- "The failure patterns of oral cavity squamous cell carcinoma after intensity-modulated radiotherapy-the university of iowa experience." (Yao M, Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1332-41.)
** 55 pts treated with IMRT (49 post-op, 1 neoadj, 5 definitive). Chemo in 6 pts (3 receiving definite RT, 2 postop, 1 neoadj).
** Median f/u 17 months. 9 pts with LRF. Median time to LRF 4 months. All but 1 of the failures was in the high risk region (CTV1 or CTV2).
** Areas at high risk for recurrence include:
*** Primary tumor bed
*** Infratemporal fossa (via inferior alveolar N and mental N). "The infratemporal fossa should also be included in the radiation field for tumor adjacent to these nerves with extensive perineural invasion and for tumor invading the pterygoid muscle, which is most commonly seen in patients with retromolar trigone cancer or tonsil cancer."
*** Area between primary oral tongue cancer and regional lymph nodes. Should be included in the high risk region for post-op RT.
*** Contralateral neck. Contralateral neck should be included for post-op RT of the oral tongue.
** Conclusion: "Intensity-modulated RT is effective for oral cavity SCC. Most failures are in-field failures. Further clinical studies are necessary to improve the outcomes of patients with high-risk features, particularly for those with extracapsular extension."