Radiation Oncology/Head & Neck/General

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		T1		T2		T3		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
	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 II		Level III		Level IV		Level V		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