# Radiation Oncology/Head & Neck/Hypopharynx

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Hypopharynx Cancer

## Epidemiology

* 2,500-3,000 annual cases in US
* Pyriform sinus most common (65-75%), posterior pharyngeal wall 10-20%, postcricoid region 5-15%
* Majority (>80%) present with Stage III-IV disease
* Highly associated with tobacco use; EtOH impact not as clear (per Perez, 5th ed). Also occupational exposure to dust, iron compounds, fumes
* HPV associated in 20-25%, clinical implications not yet clear
* May arise in the setting of Plummer-Vinson syndrome, characterized by iron deficiency anemia, hypopharyngeal webs, weight loss, and dysphagia

## Anatomy

* Extent
** Superior extent - level of superior border of hyoid bone / floor of valecula
** Inferior extent - level of lower border of cricoid cartilage
** Anterior extent - connection of the two pyriform sinuses at post cricoid region.
** Posterior extent - posterior pharyngeal wall
* Subsites
** Bilateral pyriform sinuses
*** Extends from pharyngoepiglottic fold to upper end of esophagus, at the lower border of cricoid cartilages
*** Superiorly are surrounded by thyrohyoid membrane, through which passes the internal branch of superior laryngeal nerves. Tumor involvement can result in referred otalgia
** Postcricoid region
*** Mucosa overlying cricoid cartilage. Arytenoids and AE folds form the superior border. Esophageal mucosa forms the inferior border
** Posterior pharyngeal wall
*** Squamous mucosa covering middle/inferior pharyngeal constrictor muscles, typically <1 cm thinck

## Nodal Drainage

* Rich lymphatic network draining through thyrohyoid membrane into jugulodigastric LNs; there may also be direct drainage to spinal accessory LNs
* Typical primary drainage for posterior pharyngeal wall: Level II and III, typically below jugulodigastric LN
* Surgical reports show direct drainage to lateral retropharyngeal LNs, bypassing jugulodigastric LNs
* Case report from Dana Farber shows involvement of retropharyngeal LNs at base of skull
* >50% present with clinically positive LNs
* Dana Farber, 2007 PMID 17290070 -- "Retropharyngeal nodes in hypopharynx cancer on positron emission tomography." (Allen AM, J Clin Oncol. 2007 Feb 10;25(5):599-601.)
** Case report. Hypopharynx T2N1 (2.5cm right jugulodigastric LN)
** PET/CT: Additionally bilateral lateral retropharyngeal nodes (nodes of Rouviere) positive. Patient upstaged to Stage IV (T2N2c)
** Conclusion: recommend including lateral retropharyngeal LNs to base of skull in IMRT volumes

## Staging

AJCC 7th Edition (2009) Primary Tumor
* T1 - one subsite of hypopharynx and <= 2 cm
    AJCC Subsites: left/right pyriform sinus, left/right lateral hypopharyngeal wall, posterior hypopharyngeal wall, postcricoid region
* T2 - more than one subsite of hypopharynx or adjacent site, or >2 but <=4 cm
* T3 - >4 cm, or fixation of hemilarynx or extension to esophagus
* T4a - invades thyroid or cricoid cartilage, hyoid, thyroid gland, central compartment soft tissue (e.g, strap muscles, subcutaneous fat)
* T4b - invades prevertebral fascia, encases carotid, involves mediastinum
Note: T4a and T4b are the same as for larynx (glottic, subglottic, and supraglottic)
Regional Lymph Nodes
* 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
Distant Metastasis
* MX - Cannot be assessed
* M0 - No distant metastasis
* M1 - Distant metastasis
Clinical Stage
* Stage 0 - Tis N0 M0
* Stage I - T1 N0
* Stage II - T2 N0
* Stage III - T3 or N1
* Stage IVA - T4a or N2
* Stage IVB - T4b or N3
* Stage IVC - M1
Changes from 6th edition: Extension to esophagus is now T3 instead of T4a.

### Older staging systems

AJCC 6th Edition (2002) Primary Tumor
* T1 - one subsite of hypopharynx and <= 2 cm
    AJCC Subsites: left/right pyriform sinus, left/right lateral hypopharyngeal wall, posterior hypopharyngeal wall, postcricoid region
* T2 - more than one subsite of hypopharynx or adjacent site, or >2 but <=4 cm
* T3 - >4 cm, or fixation of hemilarynx
* T4a - invades thyroid or cricoid cartilage, hyoid, thyroid gland, esophagus, central compartment soft tissue (e.g, strap muscles, subcutaneous fat)
* T4b - invades prevertebral fascia, encases carotid, involves mediastinum
Note: T4a and T4b are the same as for larynx (glottic, subglottic, and supraglottic)
Regional Lymph Nodes
* 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
Distant Metastasis
* MX - Cannot be assessed
* M0 - No distant metastasis
* M1 - Distant metastasis
Clinical Stage
* Stage 0 - Tis N0 M0
* Stage I - T1 N0
* Stage II - T2 N0
* Stage III - T3 or N1
* Stage IVA - T4a or N2
* Stage IVB - T4b or N3
* Stage IVC - M1

## Treatment

* Memorial Sloan Kettering; 2007 PMID 17493769 -- "Concurrent chemotherapy and intensity-modulated radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers." (Lee NY, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):459-68. Epub 2007 May 9.)
** Retrospective. 20 larynx and 11 hypopharynx patients, treated with IMRT and concurrent platinum-based chemo. Most Stage IV disease. RT dose painting GTV 70 Gy (@2.12 Gy/fx), high-risk CTV 59.4 Gy (@1.8 Gy/fx, typically Levels II-IV; Levels I or V not routinely contoured unless judged high risk eg positive Level II), low-risk CTV 54 Gy (@1.64 Gy/fx, uninvolved contralateral neck and base of skull). Chemo cisplatin 100 mg/m2 Q3W or carbo 60-70 mg/m2 + 5-FU 600 mg/m2. Median F/U 2.2 years
** Outcome: 2-year LC 86%, RC 94%, laryngectomy-free 89%, DM-free 92%, OS 63%.
** Toxicity: No late G2+ xerostomia. PEG-dependent hypopharynx 31% vs. larynx 15%
** Conclusion: IMRT + chemo encouraging LR control in advanced larynx/hypopharynx. However, high rate of PEG dependency
* Kyushu, 2005 (Japan) PMID 15936545 -- "Chemoradiation therapy with or without salvage surgery for early squamous cell carcinoma of the hypopharynx." (Nakamura K, Int J Radiat Oncol Biol Phys. 2005)
** 43 patients with Stage I/II: 30-40 Gy +/- chemo, if complete response (75%), RT to 61.2 Gy
** 5-year OS 70.4%, DSS 89.5%
** Conclusion: Majority of patients with early hypopharyngeal cancer was curable. However, second malignancies influenced the overall outcome of patients with early hypopharyngeal cancer.

## 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
*** 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

## Induction Chemo-RT vs. Primary RT alone

* RTOG 68-01
** 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

## Laryngectomy + RT vs. Chemo-RT

* EORTC 24891 (1990-1993) - Surgery + post-op RT vs Induction cisplatin/5-FU + RT
** Randomized. 194/202 patients. Operable SCC of the pyriform sinus or AE fold, Stage T2-T4 N0-N2b, N3 (N2c initially allowed, stopped in 1992). Arm 1) Immediate surgery + post-op RT 50-70 Gy vs. Arm 2) Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x2 cycles. If CR, then RT 70 Gy. If PR, then cisplatin/5-FU x another cycle. If CR, then RT 70 Gy. If PR, or PD anytime, then surgery. RT given 50 Gy bilateral neck + 20 Gy boost to tumor/palpable LNs. Surgery was total laryngectomy with partial pharyngectomy to allow primary closure
** 4-years; 1996 PMID 8656441 — "Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group." Lefebvre JL et al. J Natl Cancer Inst. 1996 Jul 3;88(13):890-9.) Median F/U 4.25 years
*** Outcome: median OS surgery 2.1 years vs. chemo-RT 3.7 years (equivalent). Larynx preservation 3-years 42%, 5-years 35%. LF 12% vs. 17%, RF 19% vs. 23%
*** Conclusion: Larynx-preserving strategy is feasible, induction chemo followed by RT is new standard treatment for EORTC.
** 10-years; 2004 ASCO Abstract -- "Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe in the treatment of hypopharyngeal SCC? Final results of the phase III EORTC 24891 trial." (Lefebvre JL, Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 5531) Median F/U 10 years
*** Outcome: 5-year OS surgery 33% vs. chemo-RT 38%; 10-year OS 14% vs. 13%. 5-year PFS 26% vs. 32%. Larynx preservation 5-years 22% (58% survivors), 10-years 9% (69% survivors)
*** Conclusion: Similar survival curves with larynx preservation as with conventional total laryngectomy, with 2/3 survivors retaining their larynx

## Primary Chemo-RT Timing Strategies

* France (2001-2005) -- Induction chemo-RT vs. concurrent chemo-RT
** Randomized. 75 patients, T3 pyriform sinus (N0-N3). 4 centers. Arm 1) concurrent chemo-RT. Chemo cisplatin 100 mg/m2 Q3W, RT 70 Gy vs. Arm 2) induction chemo cisplatin 100 mg/m2 + 5-FU 100 mg/m2 x2 courses. If CR/PR >80%, RT 70 Gy, else total laryngectomy
** 2009 PMID 19449227 -- "Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus carcinoma." (Prades JM, Acta Otolaryngol. 2009 May 15:1-6.) Median F/U 2 years
*** Outcome: 2-year laryngeal preservation concurrent 92% vs induction 68% (SS). Local control 81% vs. 62%. Distant mets 19% vs 38%. EFS 36% vs. 41% (NS). 2-year OS 47% vs. 51% (NS)
*** Toxicity: any toxicity 76% vs 71%
*** Conclusion: Concurrent chemo-RT superior to sequential chemo-RT
* EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
** Randomized. 450 patients. Larynx T2-T4 N0-N2 (21% by AJCC staging) or Hypopharynx T2-T4 N0-N2 (79% by AJCC staging), surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week (based on prior Italian randomized data)
** 6-years; 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead of print]) Median F/U 6.5 years
*** Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs. 36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years (NS). DSS ~50%. Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
*** Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
*** Conclusion: Both strategies valid for larynx preservation
*** Editorial (PMID 19176460): larynx preservation defined as survival with larynx without tumor, tracheotomy or use of feeding tube, which gives these states equal utility as death; other issues with endpoints used for larynx preservation. Need a common standardized endpoint