Clinical and scientific impact of human papillomavirus on head and neck cancer

Table 2 Selected references for association of tumor human papillomavirus status with prognosis

Ref.	Country	N	Site	Detection (PCR, p16,ISH)a	Prevalence of HPV-positive diseaseb	Follow-up timec (1median, 2mean, 3range)	Significantly improved prognosis for HPV-positive tumor status? (Yes/No)	Prognosis for HPV-positivevs HPV-negative diseased	Factors adjusted for
Andl et al[31], 1998	Germany	31	Tonsil	PCR, p16	48%	28 mo2	Yes	OS: improved (P = 0.0071) DFS: median 61.1 mo vs 25.8 mo (P = 0.028)	Overall stage
Gillison et al[47], 2000	United States	259	HNSCC	PCR, ISH	25% overall; 57% OP	31 mo2	Yes	OS: 91 mo vs 76 mo, HR 0.6 (0.35-1.0, P = 0.07); DSS: HR 0.41 (0.20-0.88, P = 0.02)	Age, LN disease, alcohol
Mellin et al[32], 2000	Sweden	60	Tonsil	PCR	43%	59 mo1	Yes	OS: 5-yr 53.5% vs 31.5%; RFS: OR 19.6 (P = 0.014); DSS: improved (P = 0.047)	RFS: Overall stage DSS: Overall stage, LN metastases, age, gender
Lindel et al[33], 2001	Switzerland	99	OP	PCR	14%		Yes	LFFS: RR 0.31 (0.09-0.99, P = 0.048)	T, alcohol, intratumoral microvessel density
Weinberger et al[78], 2006	United States	123	OP	p16	13%	33 mo2	Yes	OS: 5-yr 60% vs 21%, HR 0.422 (0.2-0.9, P = 0.021) DFS: 5-yr 62% vs 19%, HR 0.359 (0.2-0.7, P = 0.006)	tumor type (primary vs recurrent), overall stage, grade, treatment
Weinberger et al[78], 2006	United States	79	OP	PCR, p16	61%	22 mo2	Yes	OS: 5-yr 79% vs 18%-20%, HR 0.19 (0.1-0.7, P = 0.13) DFS: 5-yr 75% vs 13%-15%, HR 0.20 (0.1-0.6), P = 0.005)	primary vs recurrence, treatment, overall stage, grade
Licitra et al[82], 2006	Italy	90	OP	PCR, p16	19%	5.8 yr1	Yes	OS: 5-yr 79% vs 46% (P = 0.0018), improved when adjusted for stage	Overall stage
Reimers et al[72], 2007	Germany	106	OP	PCR, p16	30%		Yes	DFS: 85% vs 49% (P = 0.009), HR for HPV-negative tumors 7.5 (1.22-46.19), P = 0.030	EGFR expression status, overall stage
Kumar et al[73], 2008	United States	66	OP	PCR, p16			Yes	OS: improved (P = 0.006) DSS: improved (P = 0.02)	Smoking, gender
Fakhry et al[6], 2008	United States	96	OP, larynx	PCR, ISH	63% OP, 0% larynx	39.1 mo1	Yes	OS: 2-yr 95% vs 62% (P = 0.005), HR 0.36, (0.15-0.85) PFS: HR 0.27 (0.10-0.75)	age, overall stage, ECOG performance status
Hafkamp et al[71], 2008	Netherlands	81	Tonsil	ISH, p16	41%	30 mo2	Yes	DSS: 5-yr 55% vs 29%, unadjusted HR 2.3 (1.1-4.5)
Worden et al[37], 2008	United States	66	OP	PCR	64%	64 mo1	Yes	OS: improved (P = 0.008) DSS: improved (P = 0.004)	gender, smoking, T, N, age, site
Smith et al[28], 2009	Germany	60	OP	PCR, ISH, p16	47%	27.5 mo1	Yes	DFS: 5-yr 71% vs 46%(P = 0.02)
Lassen et al[36], 2009	Denmark	156	Supragl- ottic larynx, pharynx	p16	22%	> 5 yr	Yes	OS: 5-yr 62% vs 26% (P = 0.0003), HR 0.44 (0.28-0.68) DSS: 5-yr 72% vs 34% (P = 0.0006), HR 0.36 (0.20-0.64)	T, N
Ang et al[7], 2010	United States	323	OP	ISH, p16	63.80%	4.8 yr1	Yes	OS: 3-yr 82.4% vs 57.1% (P < 0.001), HR 0.42 (0.27-0.66) PFS: 3-yr 73.7% vs 43.4% (P < 0.001), HR 0.49 (0.33-0.74)	age, race, T, N, tobacco exposure, treatment assignment
Rischin et al[44], 2010	United States, Canada, Australia, New Zealand, Europe	184	OP	PCR, ISH, p16	57%	29 mo2	Yes	OS: 2-yr 91% vs 74% (P = 0.004), HR 0.43 (0.20-0.93), P = 0.031	ECOG performance status, hemoglobin, T, N
Chaturvedi et al[14], 2011	United States	271	OP	PCR , ISH	44%	112 mo1	Yes	OS: median 131 vs 20 mo (P < 0.001), HR 0.31 (0.21-0.46)	age, calendar period of diagnosis, overall stage, treatment
Posner et al[35], 2011	United States	111	OP	PCR	50%	82-83 mo1	Yes	OS: improved, unadjusted HR 0.2 (0.10-0.38, P < 0.0001) PFS: 73% vs 29% (P < 0.0001) LRF: 13% vs 42% (P = 0.0006)
Liang[36], 2012	United States	488	HNSCC	PCR, p16	62%		No	DSS (OP): HR 0.1 (0.02-0.4)

^aPCR is polymerase chain reaction to assess for HPV-related DNA; p16 refers to immunohistochemistry for HPV oncoprotein p16; ISH is in-site hybridization for HPV;

^bHPV tumor status as defined by individual study;

^cFollow-up time included when reported (¹Median,

²Mean,

³Range);

^dIncludes prognos tic data when available and as reported. HR are adjusted and for HPV-positive tumors unless indicated otherwise. 95% confidence intervals are included in parentheses. PCR: Polymerase chain reaction to assess for HPV-related DNA; ISH: In-situ hybridization; P16: Immunohistochemical assay for p16 expression; OS: Overall survival; DSS: Disease-specific survival; RFS: Recurrence-free survival; EFS: Event-free survival; LR: Local recurrence; LFFS: Local failure free survival; FFS: Failure-free survival; LRC: Locoregional control; LRR: Locoregional recurrence; HR: Hazard ratio; OR: Odds ratio; RR: Relative risk; LN: Lymph node; OC: Oral cavity; OP: Oropharynx; BOT: Base of tongue; DSS: Disease-specific survival; FOM: Floor of mouth; T: Tumor stage; N: Nodal stage.