Abstract

Objective

Prognosis in patients with recurrent or metastatic squamous cell carcinoma of the head and neck is poor, and systemic chemotherapy has an only modest impact on the outcome. Chemotherapy with cisplatin plus 5-FU (PF) is widely used, but the standard dosage, PF (100/1000; cisplatin 100 mg/m2 day 1 and 5-FU 1000 mg/m2/24 h by continuous intravenous infusion on days 1 through 4), is relatively toxic for palliative use, and PF (80/800; cisplatin 80 mg/m2 day 1 and 5-FU 800 mg/m2/24 h by continuous intravenous infusion on days 1 through 5) is more commonly used in Japan, albeit without clear comparative data. We retrospectively analyzed the efficacy and safety of this regimen in our institution.

Methods

Thirty of 43 patients with recurrent or metastatic head and neck cancer treated with PF in our institution between 2001 and 2006 were analyzed. Entry criteria included histologically proven squamous cell carcinoma and recurrent or metastatic disease.

Results

The most common chemotherapy-related Grade 3 or 4 toxicities were nausea (16.6%), anorexia (40%), stomatitis (6.6%) and leukopenia (10%), all of which were manageable. Complete response was achieved in one patient and partial response in eight, giving an overall response rate of 30%. Median progression-free survival was 3.0 months. Estimated 2-year survival rate was 16.7% and median overall survival was 9.8 months. Of the 30 patients, 5 (16.7%) survived more than 2 years, all of whom had primary oropharyngeal cancer.

Conclusions

In this retrospective analysis, chemotherapy with PF (80/800) for recurrent or metastatic head and neck cancer appeared to have equal efficacy and better safety than PF (100/1000).

INTRODUCTION

Head and neck cancer is the 10th most frequent cause of cancer in Japan and accounts for approximately 2.1% of cancer-related deaths (1). Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis, and the goals of treatment are limited, but include the prolongation of survival, palliation of existing symptoms and prevention of new cancer-related symptoms. Systemic chemotherapy has only a modest impact on the outcome in these patients (2), and median survival in reported Phase III randomized trials has ranged from 6 to 9 months (3–9). Platinum-based chemotherapy remains the standard, and although combination therapy has shown higher response rates, no other regimen has demonstrated a survival advantage over cisplatin monotherapy (4,5,8,9). In their randomized Phase III trial of cisplatin plus 5-FU (PF) with or without cetuximab against PF for R/M SCCHN (EXTREME study), Vermorken et al. (10) recently reported that the hazard ratio for overall survival of PF plus cetuximab to PF alone was 0.797 (95% confidence interval, 0.644–0.986), and median overall survival was 10.1 months for PF plus cetuximab versus 7.4 months for PF alone (P = 0.0362). This study was the first to demonstrate an improvement in survival for systemic treatment over platinum-based chemotherapy in this patient population.

Since the first report by Kish et al. (11) in 1982, PF has remained a standard treatment for R/M SCCHN. Although PF (100/1000; cisplatin 100 mg/m2 day 1 and 5-FU 1000 mg/m2/24 h by continuous intravenous infusion on days 1 through 4) is the most widely used dose in western countries, toxicity is relatively high, with a number of randomized trials reporting a percentage of Grade 3 or more leukopenia and stomatitis of 31–63% and 14–31%, respectively, a percentage of renal insufficiency requiring treatment discontinuation of 9–10% and a percentage of treatment-related deaths of approximately 5% (4,5,7,10). PF is a standard treatment for R/M SCCHN in Japan also, albeit usually at lower doses than in western countries, with PF (80/800; cisplatin 80 mg/m2 day 1 and 5-FU 800 mg/m2/24 h by continuous intravenous infusion days 1 through 5) the most common regimen. Of interest, a similar PF regimen (cisplatin 70–80 mg/m2 per course and 5-FU 3500–4000 mg/m2 per course) has been recommended in Japan for recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) (12,13). Since these PF regimens, with a slight dose decrease in cisplatin and 5-FU for R/M ESCC, were less toxic than PF (100/1000) but had approximately equal efficacy, we selected PF (80/800) as a standard regimen in patients with R/M SCCHN treated at our institution. Nevertheless, the efficacy and safety of PF in these regimens has not been compared.

Here, given the paucity of data on the efficacy and safety of PF in Japanese patients with R/M SCCHN, we conducted a retrospective analysis to evaluate the efficacy and safety of systemic chemotherapy with PF (80/800) for patients with R/M SCCHN treated at our institution between 2001 and 2006.

PATIENTS AND METHOD

We reviewed the clinical records of 43 consecutive patients with recurrent or metastatic head and neck cancer who were treated with PF at the National Cancer Center Hospital East between 2001 and 2006. From these, we selected 30 patients who met the following criteria from our database: (i) histologically proven squamous cell carcinoma; (ii) recurrent or metastatic disease; (iii) primary site in the oral cavity, oropharynx, hypopharynx, larynx or maxillary sinus; (iv) age 20–75 years; (v) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2; (vi) adequate organ function; (vii) no prior chemotherapy for recurrent or metastatic disease; (viii) no severe comorbidity and (ix) no prior malignancy. Of the 13 patients excluded from this retrospective analysis, 5 had primary nasopharyngeal disease, 2 had a parotid primary, 2 had adenocarcinoma, 1 had adenoid cystic carcinoma and 3 had received prior chemotherapy within the previous 6 months.

Treatment with PF (80/800; cisplatin 80 mg/m2 day 1 and 5-FU 800 mg/m2/24 h by continuous intravenous infusion on days 1 through 5) was given every 4 weeks, and continued until disease progression or unacceptable toxicity was observed. The maximum number of treatment cycles was 6 cycles.

Tumor evaluations were performed with either or both computed tomography scanning and magnetic resonance imaging using World Health Organization standard response criteria (14). Chemotherapy-related toxicities were graded in accordance with the National Cancer Center Institute Common Toxicity Criteria version 2.

Overall survival time was calculated from the initiation of chemotherapy with PF (80/800) to the date of death or last confirmed day of survival, whichever occurred first. Progression-free survival time was calculated from the initiation of chemotherapy with PF (80/800) to the documentation of progression or death from any cause, whichever occurred first. Actuarial survival was estimated by the Kaplan–Meier method (15). Patient characteristics of 2-year survivors were analyzed. Using the log-rank test to assess the significance of univariate associations, the following variables were analyzed: age, gender, ECOG PS, site of the primary tumor, residual tumor in the primary site, the presence of distant metastasis, prior radiation therapy, tumor cell differentiation and response to chemotherapy. Differences were considered statistically significant at a P value of <0.05. All analyses were conducted using the statistical analysis software Stat View-J Ver. 5.0, Windows (SAS Institute Inc., NC, USA).

RESULTS

Patient characteristics

Patient characteristics are summarized in Table 1. By age, the 26 males and 4 females ranged from 43 to 75 years, with a median of 64 years. Most patients were ECOG PS 0 or 1. Twenty-one patients had recurrent disease and nine had newly diagnosed metastatic disease. Prior treatment for recurrent disease is also summarized in Table 1. Of the 21 patients with recurrent disease, 10 recurred after surgery alone, 8 after surgery and adjuvant radiation therapy, 2 after platinum-based chemoradiotherapy and 1 after definitive radiation therapy.

Table 1.

Patient characteristics (n = 30)

Age: median (range) 64 (43–75) 
Gender: male/female 26/4 
PS: 0/1/2 9/19/2 
Primary site  
 Oral cavity 
 Oropharynx 11 
 Hypopharynx 
 Larynx 
 Maxillary sinus 
Distant metastases: present/absent 18/12 
Site of disease  
 Local 16 
 Lymph node 19 
 Lung 16 
 Skin 
 Liver 
Recurrent/newly diagnosed 21/9 
Prior treatment: present/absent 21/9 
 Surgery alone 10 
 Surgery + adjuvant radiation 
 Chemoradiation 
 Radiation alone 
Histology: squamous cell carcinoma 30 
 Well differentiated 
 Moderately differentiated 15 
 Poorly differentiated 11 
 Unclassified 
Age: median (range) 64 (43–75) 
Gender: male/female 26/4 
PS: 0/1/2 9/19/2 
Primary site  
 Oral cavity 
 Oropharynx 11 
 Hypopharynx 
 Larynx 
 Maxillary sinus 
Distant metastases: present/absent 18/12 
Site of disease  
 Local 16 
 Lymph node 19 
 Lung 16 
 Skin 
 Liver 
Recurrent/newly diagnosed 21/9 
Prior treatment: present/absent 21/9 
 Surgery alone 10 
 Surgery + adjuvant radiation 
 Chemoradiation 
 Radiation alone 
Histology: squamous cell carcinoma 30 
 Well differentiated 
 Moderately differentiated 15 
 Poorly differentiated 11 
 Unclassified 

PS, performance status.

Treatment results

All 30 patients received chemotherapy with PF (80/800), with a median of two cycles and a range of one to six. All 30 patients had an assessable response to PF (80/800). Complete response (CR) was obtained in one patient and partial response (PR) in eight, giving an overall response rate of 30%. All 30 patients had died by the time of last follow-up. Median progression-free survival was 3.0 months (Fig. 1). Estimated 2-year survival rate was 16.7% and median overall survival was 9.8 months (Fig. 2).

Figure 1.

Kaplan–Meier estimates of progression-free survival (n = 30).

Figure 1.

Kaplan–Meier estimates of progression-free survival (n = 30).

Figure 2.

Kaplan–Meier estimates of overall survival (n = 30).

Figure 2.

Kaplan–Meier estimates of overall survival (n = 30).

After the failure of PF (80/800), 20 of 30 patients received second-line chemotherapy. Eleven of the 20 patients received docetaxel (60 mg/m2, tri-weekly) and 5 received S-1 (80 mg/m2, 4 weeks on followed by 2 weeks off). The other four patients received investigational drugs. Four of the 11 patients receiving docetaxel achieved an objective response, as did two of the five receiving S-1, meaning 6 of 20 patients who received second-line chemotherapy achieved an objective response.

Chemotherapy-related toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 2 and are listed in Table 2. The major chemotherapy-related Grade 3 or 4 toxicities were nausea (16.6%), anorexia (40%), stomatitis (6.6%) and leukopenia (10%), all of which were manageable. Renal toxicity is common with cisplatin therapy. In this analysis, no Grade 3 or 4 renal toxicity or treatment discontinuation related to cisplatin-induced renal insufficiency occurred. Three patients discontinued PF treatment due to toxicity, two owing to prolonged Grade 3 anorexia. In one of the three patients, Grade 3 encephalopathy was observed, which resolved after the discontinuation of 5-FU infusion. No treatment-related death within 30 days was observed.

Table 2.

Adverse events during chemotherapy with cisplatin plus 5-FU

Adverse event Grade 3 Grade 4 % Grade 3/4 
Leukopenia 10.0 
Neutropenia 
Anemia 3.3 
Thrombocytopenia 
Nausea 16.6 
Anorexia 12 40.0 
Stomatitis 6.6 
Diarrhea 3.3 
Renal toxicity 
Encephalopathy 3.3 
Adverse event Grade 3 Grade 4 % Grade 3/4 
Leukopenia 10.0 
Neutropenia 
Anemia 3.3 
Thrombocytopenia 
Nausea 16.6 
Anorexia 12 40.0 
Stomatitis 6.6 
Diarrhea 3.3 
Renal toxicity 
Encephalopathy 3.3 

Characteristics of 2-year survivors

Characteristics of long-term survivors are summarized in Table 3. Of the 30 patients, 5 (16.7%) survived more than 2 years, all of whom had primary oropharyngeal disease.

Table 3.

Patient characteristics of 2-year survivors

 Age Gender Tumor differentiation Primary Site of disease Response Survival (months) Status 
56 Male Poorly ORP LN, Loc NC 25.2 Dead 
60 Male Moderately ORP PR 27.1 Dead 
57 Male Poorly ORP NC 28.3 Dead 
75 Male Unclassified ORP LN, Loc NC 30.8 Dead 
68 Male Poorly ORP LN, L, Loc CR 51.3 Dead 
 Age Gender Tumor differentiation Primary Site of disease Response Survival (months) Status 
56 Male Poorly ORP LN, Loc NC 25.2 Dead 
60 Male Moderately ORP PR 27.1 Dead 
57 Male Poorly ORP NC 28.3 Dead 
75 Male Unclassified ORP LN, Loc NC 30.8 Dead 
68 Male Poorly ORP LN, L, Loc CR 51.3 Dead 

ORP, oropharynx; LN, lymph node; L, lung; Loc, local; CR, complete response; PR, partial response; NC, no change.

Univariate analysis

Univariate analysis for survival was conducted using the following variables: age, gender, ECOG PS, site of the primary tumor, residual tumor in the primary site, the presence of distant metastasis, prior radiation therapy, tumor cell differentiation and response to chemotherapy (Table 4). Allowing for the small sample size of this retrospective analysis, significantly poorer survival was seen for female sex and ECOG PS 1–2, and significantly better survival was seen for primary disease in the oropharynx.

Table 4.

Univariate analysis of survival (n = 30)

 No. of patients Median survival (months) 2-year survival (%) P value 
Age (years)     
 <70 20 9.6 15 0.91 
 ≥70 10 10.6 10 
Gender     
 Male 26 11.1 19.2 0.0096 
 Female 4.6 
ECOG PS     
 0 21.2 33.3 0.041 
 1–2 21 9.6 9.5 
Site of primary tumor     
 Oropharynx 11 18.4 45.5 0.0053 
 Other 19 8.7 
Residual tumor at the primary site     
 Yes 16 8.1 18.8 0.92 
 No 14 11.1 14.3 
Distant metastatic disease     
 Yes 18 11.4 16.7 0.31 
 No 12 8.1 16.7 
Prior radiation therapy     
 Yes 11 11.1 18.2 0.84 
 No 19 9.6 15.8 
Response to chemotherapy     
 Objective response (CR + PR) 21 22.2 0.16 
 No response 21 9.6 14.3 
Tumor differentiation 27    
 Poor 11 11.1 27.3 0.23 
 Other 16 9.8 6.9 
 No. of patients Median survival (months) 2-year survival (%) P value 
Age (years)     
 <70 20 9.6 15 0.91 
 ≥70 10 10.6 10 
Gender     
 Male 26 11.1 19.2 0.0096 
 Female 4.6 
ECOG PS     
 0 21.2 33.3 0.041 
 1–2 21 9.6 9.5 
Site of primary tumor     
 Oropharynx 11 18.4 45.5 0.0053 
 Other 19 8.7 
Residual tumor at the primary site     
 Yes 16 8.1 18.8 0.92 
 No 14 11.1 14.3 
Distant metastatic disease     
 Yes 18 11.4 16.7 0.31 
 No 12 8.1 16.7 
Prior radiation therapy     
 Yes 11 11.1 18.2 0.84 
 No 19 9.6 15.8 
Response to chemotherapy     
 Objective response (CR + PR) 21 22.2 0.16 
 No response 21 9.6 14.3 
Tumor differentiation 27    
 Poor 11 11.1 27.3 0.23 
 Other 16 9.8 6.9 

ECOG PS, Eastern Cooperative Oncology Group performance status.

DISCUSSION

In this retrospective analysis of 30 patients receiving treatment for R/M SCCHN at a single institution in Japan, chemotherapy with PF (80/800) appeared as effective as and more feasible than PF (100/1000). These findings may suggest that PF (80/800) is an appropriate chemotherapy regimen for R/M SCCHN.

In 1982, Kish et al. (11) reported an overall response rate of 70% and CR rate of 27% in 30 patients with recurrent and disseminated SCCHN treated with cisplatin and infusional 5-FU, and cisplatin plus 5-FU is now one of the most widely used regimens for R/M SCCHN (4,5,7,9). Randomized trials of platinum-based chemotherapy for R/M SCCHN have reported response rates and median survival times of approximately 30% and 6–9 months, respectively (4,5,7–9). Although our present study was a retrospective analysis in a single institution and sample size was small (n = 30), respective values for PF (80/800) were 30% and 9.8 months, and thus closely similar to these previous reports. On the other hand, the toxicity of PF (100/1000) is relatively high, with a number of randomized trials reporting a percentage of Grade 3 or more leukopenia and of renal insufficiency requiring the discontinuation of treatment of 31–63% and 9–10%, respectively, whereas the percentage of treatment-related deaths was approximately 5% (4,5,7,10). By comparison, however, the toxicity profile of PF (80/800) was relatively mild, and no irreversible renal insufficiency or treatment-related death within 30 days was observed. Thus, although cisplatin dose in the PF (80/800) regimen is 20% lower than in the PF (100/1000) regimen and that of 5-FU (4000 mg/m2) is the same, our results suggest that PF (80/800) may be as effective as PF (100/1000) and more feasible than it.

The prognosis of oropharyngeal cancer is generally better than that of other head and neck cancers. In our present analysis, we experienced five (16.7%) 2-year survivors, all of whom had primary oropharyngeal cancer and, allowing for the small sample size of this retrospective analysis, significantly favorable survival was seen for oropharyngeal cancer in univariate analysis. Recently, several reports have suggested an association between the occurrence of oropharyngeal cancer and human papilloma virus (HPV) infection (16–18). Of interest, HPV-associated oropharyngeal cancer has been associated with a better prognosis than HPV-negative tumors (18). Although we did not analyze HPV infection status in our patients, it is intriguing to speculate that this result might reflect an association between good prognosis of oropharyngeal cancer in our analysis and HPV infection.

A number of previous studies have reported prognostic factors in patients with R/M SCCHN (2,4,5,9,19,20). Among these studies, the largest combined analysis of studies using contemporary platinum-based regimens identified one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG PS, weight loss, prior radiation therapy (RT) and location of the primary tumor) as independent predictors of overall survival (OS) (19). According to our present univariate analysis for survival, ECOG PS 1–2 was associated with poorer outcomes and primary tumors of the oropharynx with better outcomes. Although recurrence after radiation treatment is recognized as one of the most unfavorable prognostic factors, we saw no significant relationship between prior RT and survival outcome, likely owing to our small sample size.

Platinum-based chemotherapy remains the standard treatment for R/M SCCHN, and although higher response rates have been observed with combinations, no survival advantage over cisplatin monotherapy has been demonstrated for any regimen (3–5). In patients with recurrent or metastatic disease and an ECOG PS of 0–2, however, reported median progression-free survival is only 2 months (4), highlighting the urgent need for novel systemic treatments for these patients. One promising strategy involves the epidermal growth factor receptor (EGFR), which is commonly expressed in SCCHN. Expression is often higher in the tumor than in the adjacent normal tissue, a situation associated with poor prognosis (21,22). Cetuximab (C225, Erbitux; Imclone Systems Inc., Branchburg, NJ, USA) is a monoclonal antibody that binds the extracellular portion of the EGFR with high affinity and interferes with binding and receptor activation by the natural ligands of EGFR (23). Recently, Vermorken et al. (10) reported that PF (100/1000) plus cetuximab showed a significant survival benefit over PF (100/1000) alone for R/M SCCHN, and this regimen has now become the new standard regimen for these patients. Approval of cetuximab in Japan would allow a similar improvement in survival outcomes in Japanese patients, and an important rationale for the present study was in fact to provide data validating the lower PF (80/800) dosage used in Japan in preparation for this eventuality.

In conclusion, the present study is the first analysis of the efficacy and safety of PF for R/M HNSCC in Japan. Results showed the PF (80/800) in our institution might be as effective as and more feasible than PF (100/1000) in these patients.

Conflict of interest statement

None declared.

References

1
Cancer Mortality
 , 
2005
Japan
Center for Cancer Control and Information Services, National Cancer Center
2
Morton
RP
Rugman
F
Dorman
EB
Stoney
PJ
Wilson
JA
McCormick
M
, et al.  . 
Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial
Cancer Chemother Pharmacol
 , 
1985
, vol. 
15
 (pg. 
283
-
9
)
3
Grose
WE
Lehane
DE
Dixon
DO
Fletcher
WS
Stuckey
WJ
Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: a Southwest Oncology Group Study
Cancer Treat Rep
 , 
1985
, vol. 
69
 (pg. 
577
-
81
)
4
Forastiere
AA
Metch
B
Schuller
DE
Ensley
JF
Hutchins
LF
Triozzi
P
, et al.  . 
Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study
J Clin Oncol
 , 
1992
, vol. 
10
 (pg. 
1245
-
51
)
5
Jacobs
C
Lyman
G
Velez-Garcia
E
Sridhar
KS
Knight
W
Hochster
H
, et al.  . 
A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck
J Clin Oncol
 , 
1992
, vol. 
10
 (pg. 
257
-
63
)
6
Forastiere
AA
Leong
T
Rowinsky
E
Murphy
BA
Vlock
DR
DeConti
RC
, et al.  . 
Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393
J Clin Oncol
 , 
2001
, vol. 
19
 (pg. 
1088
-
95
)
7
Gibson
MK
Li
Y
Murphy
B
Hussain
MH
DeConti
RC
Ensley
J
, et al.  . 
Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
3562
-
7
)
8
Burtness
B
Goldwasser
MA
Flood
W
Mattar
B
Forastiere
AA
Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
8646
-
54
)
9
Clavel
M
Vermorken
JB
Cognetti
F
Cappelaere
P
de Mulder
PH
Schornagel
JH
, et al.  . 
Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group
Ann Oncol
 , 
1994
, vol. 
5
 (pg. 
521
-
6
)
10
Vermorken
JB
Hitt
R
Geoffrois
L
Erfan
J
Kawecki
A
Zabolotnyy
D
, et al.  . 
Cetuximab plus platinum-based therapy first-line in recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): efficacy and safety results of a randomized phase III trial (EXTREME) abstract #5501
Eur J Cancer Suppl
 , 
2007
, vol. 
5
 pg. 
324
 
11
Kish
J
Drelichman
A
Jacobs
J
Hoschner
J
Kinzie
J
Loh
J
, et al.  . 
Clinical trial of cisplatin and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck
Cancer Treat Rep
 , 
1982
, vol. 
66
 (pg. 
471
-
4
)
12
Hayashi
K
Ando
N
Watanabe
H
Ide
H
Nagai
K
Aoyama
N
, et al.  . 
Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407)
Jpn J Clin Oncol
 , 
2001
, vol. 
31
 (pg. 
419
-
23
)
13
Iizuka
T
Kakegawa
T
Ide
H
Ando
N
Watanabe
H
Tanaka
O
, et al.  . 
Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japanese Esophageal Oncology Group Trial
Jpn J Clin Oncol
 , 
1992
, vol. 
22
 (pg. 
172
-
6
)
14
Miller
AB
Hoogstraten
B
Staquet
M
Winkler
A
Reporting results of cancer treatment
Cancer
 , 
1981
, vol. 
47
 (pg. 
207
-
14
)
15
Kaplan
EMP
Nonparametric estimation from incomplete observations
J Am Stat Assoc
 , 
1958
, vol. 
53
 (pg. 
457
-
81
)
16
Psyrri
A
DiMaio
D
Human papillomavirus in cervical and head-and-neck cancer
Nat Clin Pract Oncol
 , 
2008
, vol. 
5
 (pg. 
24
-
31
)
17
D'souza
G
Kreimer
A
Viscidi
R
Pawlita
M
Fakhry
C
Koch
W
, et al.  . 
Case–control study of human papillomavirus and oropharyngeal cancer
N Engl J Med
 , 
2007
, vol. 
356
 (pg. 
1944
-
56
)
18
Fakhry
C
Westra
W
Li
S
Cmelak
A
Ridge
J
Pinto
H
, et al.  . 
Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial
J Natl Canc Inst
 , 
2008
, vol. 
100
 (pg. 
261
-
9
)
19
Argiris
A
Li
Y
Forastiere
A
Prognostic factors and long-time survivorship in patients with recurrent or metastatic carcinoma of the head and neck
Cancer
 , 
2004
, vol. 
101
 (pg. 
2222
-
9
)
20
Recondo
G
Armand
J
Tellez-Bernal
E
Recurrent and/or metastaic head and neck cancer treated with cisplatin-based chemotherapy
Laryngoscope
 , 
1991
, vol. 
101
 (pg. 
494
-
501
)
21
Grandis
J
Melhem
M
Bames
E
Quantitative immunohistochemical analysis of transforming growth factor receptor in patients with squamous cell carcinoma of the head and neck
Cancer
 , 
1996
, vol. 
78
 (pg. 
1284
-
92
)
22
Dassonville
O
Formento
J
Francoul
M
Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer
J Clin Oncol
 , 
1993
, vol. 
11
 (pg. 
1873
-
8
)
23
Fan
Z
Lu
Y
Wu
X
Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells
J Biol Chem
 , 
1994
, vol. 
269
 (pg. 
27595
-
602
)