# Radiation Oncology/Head & Neck/General

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
General Information About H&N Cancers

## HPV Status

* Please also see the Oropharynx page
* DAHANCA 5 (1986-1990)
** Randomized. 414 pts w/ pharynx or supraglottic larynx ca. RT median 66 Gy. Randomized: 1) +/- Nimorazole. Pts with low hgb level underwent 2nd randomization: 2) +/- transfusion.
** HPV Response; 2009 PMID 19289615 -- "Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck." (Lassen P, J Clin Oncol. 2009 Apr 20;27(12):1992-8. Epub 2009 Mar 16.)
*** Subset analysis. p16/HPV+ in 22%
*** Outcome: 5-year LRC p16+ 58% vs p16- 28% (SS), DSS 72% vs 34% (SS), OS 62% vs 26% (SS). p16 remained strong predictor on MVA
*** Conclusion: Expression of p16 has a major impact on treatment response and survival
** HPV & Hypoxia; 2010 PMID 19910068 -- "HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer." (Lassen P, Radiother Oncol. 2010 Jan;94(1):30-5. Epub 2009 Nov 10.)
*** Subset analysis. 331 patients with pretreatment tumor blocks, stained for p16. p16+ in 25% (oropharynx 37%, SGL 21%, others 10%)
*** Outcome: Nimorazole improved LRC overall (HR 0.7, SS). p16- improved LRC overall (HR 0.4, SS). If p16-, nimorazole improved LRC (HR 0.7, SS), but if p16+, nimorazole did not improved LRC (HR 0.9, NS)
*** Conclusion: Hypoxic modification improved outcome in HPV/p16 negative patients, but had no impact in HPV/p16 positive patients

## Lymphatic Risk

* MD Anderson; 1972 (1948-1965) PMID 5031238 -- "Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts." (Lindberg R, Cancer. 1972 Jun;29(6):1446-9.)
** Retrospective. 2044 patients, previously untreated. Incidence and topographic distribution of neck LNs
Incidence of clinical nodal metastases :
| Site | Overall | Overall | T1 | T1 | T2 | T2 | T3 | T3 | T4 | T4 |
| | N0 | N+ | N0 | N+ | N0 | N+ | N0 | N+ | N0 | N+ |
| Oral tongue | 65 | 35 | 86 | 14 | 70 | 30 | 52 | 48 | 23 | 77 |
| Floor of mouth | 70 | 30 | 89 | 11 | 71 | 29 | 56 | 44 | 46 | 54 |
| Retromolar Trigone | 55 | 45 | 88 | 12 | 62 | 38 | 46 | 54 | 32 | 78 |
| Soft Palate | 56 | 44 | 92 | 8 | 63 | 37 | 35 | 65 | 33 | 67 |
| Tonsil | 24 | 76 | 29 | 71 | 32 | 68 | 30 | 70 | 10 | 90 |
| Base of tongue | 22 | 78 | 30 | 70 | 29 | 71 | 25 | 75 | 15 | 85 |
| Nasopharynx | 13 | 87 | 7 | 93 | 15 | 85 | 11 | 89 | 17 | 83 |
| Pharyngeal wall | 41 | 59 | 75 | 25 | 70 | 30 | 33 | 67 | 24 | 76 |
| Supraglottic larynx | 45 | 55 | 61 | 39 | 58 | 42 | 35 | 65 | 41 | 59 |
| Hypopharynx | 25 | 75 | 37 | 63 | 30 | 70 | 21 | 79 | 26 | 74 |
* University of Florida; 1995 PMID 7782203 -- "Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck." (McLaughlin MP, Head Neck. 1995 May-Jun;17(3):190-8.)
** Retrospective. 619 patients. Review of pretreatment CT and/or MRI to determine presence of retropharyngeal LNs
** Outcome: Highest incidence in NPC (74%) and pharyngeal wall (19%). Neck relapse and DM significantly higher, RFS and OS significantly worse if present
** Conclusion: Retropharyngeal adenopathy predictor of poor outcome
Incidence of CT/MRI retropharyngeal nodal metastases :
| Site | Clinical Neck | Clinical Neck | Clinical Neck |
| | Overall | cN0 | cN+ |
| Nasopharynx | 74 | 40 | 86 |
| Pharyngeal wall | 19 | 16 | 21 |
| Soft palate | 13 | 5 | 19 |
| Tonsil | 9 | 4 | 12 |
| Pyriform sinus | 5 | 0 | 9 |
| Base of tongue | 4 | 0 | 6 |
| Supraglottic larynx | 2 | 0 | 4 |
* Washington University; 2002 (1997-2000) PMID 12128118 -- "Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT." (Chao KS, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1174-84.)
** Retrospective. 126 patients treated with IMRT. System for nodal target volumes used. Median F/U 2.2 years. Patterns of failure analyzed.
** Outcome: persistent/recurrent nodal disease in 12% of definitive IMRT patients and 9% of postop IMRT patients
** Conclusion: Development of guidelines for nodal target volumes
Incidence of pathologic nodal metastases :
| Site | Level I | Level I | Level II | Level II | Level III | Level III | Level IV | Level IV | Level V | Level V | Retropharngeal$^*$ | Retropharngeal$^*$ |
| | N- | N+ | N- | N+ | N- | N+ | N- | N+ | N- | N+ | N- | N+ |
| Nasopharynx | - | - | - | - | - | - | - | - | - | - | 40 | 86 |
| Oral tongue | 14 | 39 | 19 | 73 | 16 | 27 | 3 | 11 | 0 | 0 | - | - |
| FOM | 16 | 72 | 12 | 51 | 7 | 29 | 2 | 11 | 0 | 5 | - | - |
| Alveolar ridge RMT | 25 | 38 | 19 | 84 | 6 | 25 | 5 | 10 | 1 | 4 | - | - |
| Base of tongue | 4 | 19 | 30 | 89 | 22 | 22 | 7 | 10 | 0 | 18 | 0 | 6 |
| Tonsil | 0 | 8 | 19 | 74 | 14 | 31 | 9 | 14 | 5 | 12 | 4 | 12 |
| Pharyngeal wall | 0 | 11 | 9 | 84 | 18 | 72 | 0 | 40 | 0 | 20 | 16 | 21 |
| Pyriform sinus | 0 | 2 | 15 | 77 | 8 | 57 | 0 | 23 | 0 | 22 | 0 | 9 |
| Supraglottic larynx | 6 | 2 | 18 | 70 | 18 | 48 | 9 | 17 | 2 | 16 | 0 | 4 |
| Glottic larynx | 0 | 9 | 21 | 42 | 29 | 71 | 7 | 24 | 7 | 2 | - | - |
| $^*$Radiologically enlarged retropharyngeal nodes. Table adapted from Chao 2002 (PMID 12128118) |||||||||||||
Incidence of contralateral and bilateral lymph nodes:
* >30% cN+ bilateral - pharyngeal wall (50%), pyriform sinus (49%), supraglottis (39%)
* cN- but pN+ bilateral - pyriform sinus (59%), BOT (55%), phar. wall (37%), oral tongue (33%), supraglottis (26%), FOM (21%), glottic larynx (15%)
    Adopted from Chao 2002 (PMID 12128118)

## Effect of surgery to radiotherapy interval (SRI)
### Higher dose may "make up for" prolonged treatment time

* MSKCC, 1990 - PMID 2325418 — "Impact of the time interval between surgery and postoperative radiation therapy on locoregional control in advanced head and neck cancer." Schiff PB et al. J Surg Oncol. 1990 Apr;43(4):203-8.
** Patients receiving < 60 Gy had locoregional recurrence rate of 7% when SRI < 6 weeks vs 27% when greater than 6 weeks. However when doses > 60 Gy were given, failure rates were 15% and 12%, respectively.

## Recursive Partitioning Analysis

* RTOG RPA, 1996 - PMID 8646692 — "Recursive partitioning analysis of 2105 patients treated in Radiation Therapy Oncology Group studies of head and neck cancer." Cooper JS et al. Cancer. 1996 May 1;77(9):1905-11.
** 2105 pts. For survival, most predictive factor was T stage. For T1-T2, next most important was tumor location, whereas for T3-T4, it was KPS. For LRC, N stage was most important; for N0, T stage was next most important, whereas for N+ number of treatment fractions was.
** Survival: Group 1) T2 or less, glottic, age < 75; 2) Group 1 but age >= 75; 3) T2 or less, not glottic, N0-2, KPS >= 80, age < 75; or T3-4 N0-2 site:NP,OP,SGL,sinus KPS 90-100; 4) T2 or less, not glottic, N3, KPS >=80; or T3-4, N0-2, KPS 90-100, oral cavity, hypopharynx, or glottis; or T3-4 N3 or Nx KPS < 90; 5) T2 or less, not glottic, KPS <80; or N3, T3-4, KPS 90-100, N3; or T3-4, N1-3, KPS < 90.
** Local control:
* PMID 11443750 - "Validation of the RTOG recursive partitioning classification for head and neck tumors." Cooper et al. - Tested validity using a separate database from RTOG 85-27.
* PMID 15672358, 2005 - "Comparison of the Radiation Therapy Oncology Group recursive partitioning classification and Union Internationale Contre le Cancer TNM classification for patients with head and neck carcinoma."
** 2166 pts classified both by RPA and TNM stage and compared overall survival and loco-regional DFS. No differences between the systems in terms of survival, but for locoregional control, RPA system depended on treatment and was not generalizable.

## 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 (and salvage) in oral cavity

## Reviews

* PMID 3278390, 1988 - "Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer."

## Prediction of Response

* MSKCC, 2007 PMID 17416856 -- "Identification of angiogenesis/metastases genes predicting chemoradiotherapy response in patients with laryngopharyngeal carcinoma." (Ganly I, J Clin Oncol. 2007 Apr 10;25(11):1369-76.)
** Gene arrays. Correlation of 277 genes (angiogenesis and/or mets) to locoregional control
** MDM2 and erbB2 are predictors of locoregional failure in patients treated with chemo-RT

## Patterns of failure

* M.D.Anderson, Hong, 1985 - PMID 4027864 — "Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy." Hong WK et al. Cancer. 1985 Sep 15;56(6):1242-5.
** 103 pts treated with induction chemotherapy followed by surgery and/or RT. 71 pts were free of disease. 5-year recurrence rate was 51% (39% local and 26% distant failure). Relapse patterns were affected by: site (oral cavity more likely to fail locally, hypopharynx more likely to have DM); type of treatment (surgery + RT had lower local failure); TN stage (T3-4N3 had higher risk of local and distant failure); oropharynx (higher local + distant failure).

## Planned Neck Dissection

* General consensus suggests that adjuvant neck dissection is not necessary for patients with N1 neck and CR after chemo-RT
* Historically, ipsilateral neck recurrence was lower for N2/N3 disease after primary RT + adjuvant neck dissection than either modality alone
* The necessity of adjuvant neck dissection after chemo-RT is controversial
** ~25% of patients with clinical/radiographic CR who undergo neck dissection have residual disease
** 30-40% of patients with clinical/radiographic detectable disease who undergo neck dissection have no residual disease
** Thus, overall accuracy of neck response by clinical/radiographic evaluation is ~60%
** PET shows promise, and appears more accurate than clinical, CT, or MRI neck evaluation
** It may be reasonable to observe patients with clinical/radiographic CR, and negative PET 12 weeks after completing chemo-RT
** It is not clear what negative PET means in setting of clinical/radiographic detectable disease
* TROG 98.02 subset analysis suggests that after chemo-RT, ipsilateral failure is low in patients with clinical/radiographic CR
* RTOG 98.02
** Subset analysis. TROG 98.02 is Phase II randomized trial of RT 70/35 with Arm 1) concurrent cisplatin/tirapazamine vs. Arm 2) concurrent cisplatin/5-FU. Subset patients with initial N2-3 disease, who achieved complete clinical/radiological CR at 12 weeks (N2 63%, N3 40%) and no planned neck dissection was performed
** 2008 PMID 18286488 -- "N2-N3 neck nodal control without planned neck dissection for clinical/radiologic complete responders-Results of Trans Tasman Radiation Oncology Group Study 98.02." (Corry J, Head Neck. 2008 Feb 19 [Epub ahead of print]). Median F/U 4.3 years
*** Outcome: First failure: local 4%, locoregional 2%, distant 28%, locoregional + distant 6%. No patients with neck-only failure
*** Conclusion: Patients with CR do not need planned neck disection

## Radiation Injury

Please see Radiation Oncology/Toxicity/Head & Neck

## Other histologic types

Sarcomatoid carcinoma - also called spindle cell carcinoma
* MDACC; 1998 PMID 9591559 -- "Radiation therapy for early stage (T1-T2) sarcomatoid carcinoma of true vocal cords: outcomes and patterns of failure." (Ballo MT, Laryngoscope. 1998 May;108(5):760-3.)
** 5-yr LC 94% for T1 and 54% for T2. 10-year DSS 92%, OS 63%
** Conclusion: similar control rates to typical squamous cell carcinoma. The histologic diagnosis of sarcomatoid carcinoma by itself should not influence the decision to treat a patient with early stage glottic disease with irradiation.

## Other Resources

* eContouring Webinar - Head and Neck with Kenneth Hu, M.D.
* ASTRO/ARRO Journal Club Webinar 2012 - "RT + Cetuximab for Locoregionally Advanced Head and Neck Cancer: 5 Year Update" with Alexander Lin, M.D.

## To Add

add: hypopharynx - randomized surgery vs chemo/rt