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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 4  |  Page : 607-612

Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab


1 Radiation, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
2 Systemic Therapy Programs, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

Date of Web Publication11-Feb-2014

Correspondence Address:
Cheryl C Ho
600 W. 10th Avenue, Vancouver, BC, V5Z 4E6
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.126455

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 > Abstract 

Aims: The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is radiation therapy (RT) with concurrent cisplatin (CIS). Patients with renal or cardiac dysfunction, hearing loss or poor performance status (PS) may receive RT and cetuximab (CET) at our institution. This study compares treatment toxicities and outcomes.
Methods and Materials: All patients treated with curative intent RT and concurrent CIS (100 mg/m 2 Day 1, 22, 43) or CET (400 mg/m 2 Day -7, 250 mg/m 2 weekly during RT) between August 2007 and July 2010 were reviewed and toxicity and outcomes analyzed.
Results: Among 349 subjects (262 RT-CIS, 87 RT-CET) characteristics were similar except in age, head and neck subsite and RT fractionation. RT-CIS required more dose reductions, delays, and unplanned admissions and received less intended systemic therapy (ST). Weight loss and gastrostomy-tube use were similar. RT-CIS caused more nausea/vomiting, while RT-CET was associated with more dermatitis and acneiform rash. With mean follow-up of 20 months and 16 months, RT-CIS subjects experienced improved 1-year locoregional control (LRC) (90% vs. 72%, P < 0.01), disease-free survival (DFS) (83% vs. 67%, P < 0.01) and overall survival (OS) (90% vs. 80%, P = 0.04). On multivariate analysis type of ST was associated with LRC and DFS, but not OS.
Conclusions: In patients with locally advanced HNSCC, CIS and CET were associated with different toxicity profiles. RT-CIS was associated with improved LRC and DFS, but similar OS compared to RT-CET.

Keywords: Cetuximab, cisplatin, locally advanced head and neck cancer, overall survival, toxicity


How to cite this article:
Ye AY, Hay JH, Laskin JJ, Wu JS, Ho CC. Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab. J Can Res Ther 2013;9:607-12

How to cite this URL:
Ye AY, Hay JH, Laskin JJ, Wu JS, Ho CC. Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab. J Can Res Ther [serial online] 2013 [cited 2019 Nov 22];9:607-12. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/607/126455


 > Introduction Top


Cetuximab (CET) is a monoclonal antibody, which binds epidermal growth factor receptor (EGFR) inhibiting cell growth and inducing apoptosis. EGFR over-expression is common in head and neck squamous cell carcinoma (HNSCC). [1] Bonner, et al. reported a Phase III trial demonstrating improved local control (LC) and overall survival (OS) with the addition of CET to radiation therapy (RT). [2],[3] Standard fractionation RT with concurrent cisplatin (CIS) was shown to provide superior LC and OS in HSNCC over RT alone by the American Intergroup trial published by Adelstein, et al. [4]

The use of CET is common on the basis of Bonner's results, but to date there have been no published randomized controlled trials directly comparing RT in combination with CIS to RT with CET. There have been retrospective reviews, and a randomized controlled trial is underway. [5],[6],[7] The Head and Neck 6 (HN6) Phase III study compares standard RT with concurrent CIS versus accelerated RT with panitumumab (another EGFR antibody), but no results are available yet. [8] Despite this, use of CET is widespread. This retrospective study was conducted to assess feasibility, toxicity, and outcomes of RT-CIS compared to RT-CET. It is the largest population-based review to date which assesses both toxicity and outcomes.


 > Materials and Methods Top


A multi-center retrospective review was conducted including all patients with Stage III or IV HNSCC diagnosed and treated with radical RT and concomitant systemic therapy (ST). Ours is a provincial institution responsible for the delivery of RT and management of ST based on the provincial standards and guidelines established by the agency, for all residents in the province. Approval was obtained from the local research ethics board.

Subjects

Pharmacy and chart databases were used to identify patients with Stage III and IV HNSCC treated with concomitant therapy between August 1, 2007 and July 31, 2010. This time period corresponds with the first approval of the use of CET with RT in HNSCC. Exclusion criteria were previous head and neck malignancies, primary treatment with surgery, induction chemotherapy or nasopharyngeal primaries. Electronic charts, including RT treatment plans, were reviewed in 262 RT-CIS and 87 RT-CET cases to collect data on treatment, toxicity, response, and outcomes.

Treatment

All patients were assessed by radiation and medical oncologists and dentists prior to treatment. They were also followed by a registered dietician throughout.

Subjects were treated with standard (70 Gy in 2 Gy daily fractions over 7 weeks), hypofractionated (60 Gy in 2.4 Gy daily fractions over 5 weeks) or concomitant boost (66-70 Gy in 2 Gy fractions with additional second daily fraction once per week separated by greater than 6 h over 5.5-6 weeks) RT. These regimens are commonly used across all our centers. [9] High dose (60-70 Gy) was delivered to the primary and involved nodes, with an intermediate dose (50-56 Gy) to the uninvolved neck. Gross tumor and clinical target volumes were expanded by 3-5 mm to generate planning target volumes. Most treatment was with intensity modulated RT (IMRT) and some with 3-dimensional conformal RT (3D-CRT), reflecting the evolution of practice over the study era. Varian Medical Systems Eclipse treatment planning systems were used.

According to the local policy, RT-CET is used as an alternative to RT-CIS in subjects who are not eligible for CIS because of comorbidities. Receipt of CET depends on approval from the Compassionate Access Program (CAP), which reviews applications on a case-by-case basis. Subjects were candidates for RT-CET if they had Stage III or IV HNSCC, were suitable for radical RT, and not eligible for concurrent RT-CIS. RT-CIS ineligibility criteria included poor performance status (PS) (Eastern Cooperative Oncology Group (ECOG) 3 or 4), inadequate renal function (creatinine clearance less than 45 ml/min), cardiac dysfunction, inadequate marrow function (based on evaluation of blood counts, at the discretion of the treating medical oncologist), neuropathy or hearing impairment. RT-CIS was delivered per protocol as in-patient 100 mg/m 2 on days 1, 22, and 43, out-patient 75 mg/m 2 on days 1-3 and 29-31 or less frequently as out-patient 40 mg/m 2 weekly. RT-CET was delivered as a single loading dose of 400 mg/m 2 on Day- 7 and then 250 mg/m 2 weekly for 5-7 weeks, depending on the RT fractionation. All patients were treated with the standard anti-emetic and supportive regimens.

Toxicity

Toxicities were graded per the Common Terminology Criteria for Adverse Events Version 4. [10] This was carried out retrospectively through RT completion notes, ST and nutrition progress notes, and hospital admission and discharge summaries. The two most severe toxicities, including grade, for each subject were recorded. Unplanned or prolonged hospital admissions beyond the planned admission for administration of CIS, and rates of gastric feeding-tube usage were collected. The use of prophylactic enteral feeding varied between centers. If tubes were placed prophylactically, they were recorded as 'necessary' when they were first used. ST dose reductions, delays and cancellations, RT interruptions, and cancellations were recorded. Cancellations were defined as the cessation of ST prior to the planned number of cycles.

Deaths during or within one month of treatment were reviewed to determine the association with treatment.

Treatment outcomes and follow-up

Response to treatment was first assessed 3-6 months after RT. Persistence was defined as residual disease on clinical, radiological or pathological examination. Examination varied from physical examination including endoscopy, to radiologic investigation via computed tomography, magnetic resonance imaging or positron emission tomography and pathologic examination with biopsy. As surgery for persistent disease represents initial management of disease, these patients were not defined to have a recurrence unless they recurred at a later date. Locoregional control (LRC) was defined from the beginning of RT to primary or neck relapse and included untreated persistent disease. Disease-free survival (DFS) included locoregional relapses and distant metastases but did not include second malignancies. Both DFS and OS were measured from the beginning of RT to the date of documented disease, last follow-up or death.

Statistical analyses

Statistical Package for the Social Sciences version 14.0 was used to examine data within and between the groups using the descriptive statistics, independent sample t-tests, and Pearson Chi-square cross-tabulations. Kaplan-Meier with Log-Rank and Cox-Regression were employed for univariable (UVA), multivariable (MVA) and survival analysis. Factors were included in the MVA if, on UVA, their P values were less than 0.3. MVA was performed with manual step-wise testing, using the enter method, and the least significant factors were removed one at a time based on P values.


 > Results Top


Subjects

Subject characteristics were similar except in age, and HN subsite. RT-CET subjects were significantly older with a median age of 62 years versus 57 years, and a higher percentage older than 70 years (28 vs. 3%), both P < 0.01. Oropharyngeal cancers made up 72% versus 59% of the RT-CIS versus RT-CET groups. There were more laryngeal cancers (8 vs. 16%) in the RT-CET group [Table 1].
Table 1: Baseline subject characteristics

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Treatment

There was a statistically significant difference between RT fractionation (P = 0.006) and intended RT dose (P = 0.022) between the two groups, as hypofractionation was commonly employed with RT-CET subjects. Overall, RT was well-tolerated. Both groups received a mean 99% of prescribed RT. RT-CIS subjects received 11-103% of intended RT, with the majority (96%) receiving all intended RT. Five RT-CIS subjects received 11%, 26%, 54%, 69%, and 97% of intended RT because they died during treatment. RT-CET subjects received 37-103% of intended RT, with 93% receiving the prescribed RT. Three RT-CET subjects received 37%, 51% and 88% of intended RT because of discovery of metastatic disease, disease progression or death during treatment. Two subjects (one RT-CIS, one RT-CET) received 103% of intended RT because an additional fraction was added for gaps in treatment. Overall, a minority (5% CIS vs. 7% CET, P = 0.40) of subjects required treatment interruptions or delays [Table 2].
Table 2: Treatment planned and received

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Subjects had multiple indications for RT-CET. The most common were otopathy (30%), comorbid illness (17%) cardiac disease (15%), advanced age (13%), neuropathy (9%), and nephropathy (9%).

Of the 262 RT-CIS subjects, six had switches to other agents : 0 Four to carboplatin and two to CET. Three of these were due to otopathy, one to severe hyperglycemia related to dexamethasone, one to severe weight loss and one planned switch from CIS to CET after delayed approval from the access program. No CET subjects had switches to other agents. The RT-CIS group received less of their intended ST (83% vs. 90%, P < 0.01). One RT-CET subject received two extra cycles of CET because RT was prolonged due to treatment interruptions secondary to toxicity. There were significantly more ST dose reductions and delays in the RT-CIS group, but similar rates of cancellation [Table 2].

Toxicity

Rates of oral mucositis greater than Grade 3 were high and comparable between groups. There was more nausea and emesis in the RT-CIS group, but radiation dermatitis and acneiform rash were more common among RT-CET subjects. Rates of unplanned or prolonged hospital admissions were higher in RT-CIS subjects. Enteral feeding was similar between RT-CET and RT-CIS subjects. The amount of weight lost during treatment, and the proportion of subjects who lost more than 10% of their initial weight was similar between the two groups [Table 3].
Table 3: Toxicities

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A total of 10 subjects (seven RT-CIS and three RT-CET) died during or less than one month after treatment completion. Three (RT-CIS) were due to disease progression. Two RT-CIS subjects died of treatment-related complications, and two were found dead at home. Of these latter two, one was felt not to be related as it was very early on during treatment; for the other, the cause of death remains unclear and could be treatment related. Two of the RT-CET subjects died of treatment related complications within one month of treatment completion. One of these subjects declined medical support. The final RT-CET subject was found at home towards the end of treatment, presumably due to a cardiac event. As there is a black box warning for sudden cardiac death with CET it is possible this is a treatment related death.

Cancer recurrence and survival outcomes

There were 17 (6.5%) RT-CIS and 6 (6.9%) RT-CET subjects who had persistent disease after treatment (P = 0.625). Of the RT-CIS subjects, one subject underwent pre-planned neck dissection, eight had salvage neck dissections, one had laryngectomy, one was followed closely and the mass eventually resolved, and the remainder received palliative chemotherapy or no treatment. In the RT-CET group, one subject was treated with salvage neck dissection and two with palliative chemotherapy. The remainder received no treatment.

After a median follow-up of 20 (RT-CIS) and 16 (RT-CET) months, the one-year LRC was 90.3% and 71.5% in favor of the RT-CIS subjects [Table 4], [Figure 1]a. Among RT-CIS subjects, approximately half of the recurrences were at the primary site, half in the neck and a few had both primary and neck recurrences. Among RT-CET subjects, approximately 60% were at the primary site, 40% in the neck, and only one had recurrences at both sites. On UVA, younger age, better PS, oropharyngeal subsite and CIS were associated with improved LRC. MVA revealed that better PS, oropharyngeal subsite, Stage III disease and CIS predicted for improved LRC. The hazard ratio for treatment with RT-CIS versus RT-CET was 2.64 (95% confidence interval [CI], 1.56-4.50) [Table 5].
Table 4: Disease control and survival outcomes at 1 year by Cox-regression

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Table 5: Prognostic factors for locoregional control, disease free-survival and overall survival by Cox-regression models on multivariate analysis

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Figure 1: Kaplan-Meier curves for (a) locoregional control (b) disease-free survival and (c) overall survival by systemic therapy regimen

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There were 18 (6.9%) RT-CIS and 5 (5.7%) RT-CET subjects who developed second malignancies, P = 0.714. The most common sites were lung, other HN and esophagus.

A similar proportion of subjects developed metastatic disease (12.2% RT-CIS, 18.4% RT-CET, P = 0.147). The most common sites were lung and bone, with liver and brain metastases also seen.

One-year DFS was 82.9% and 66.5% in favor of RT-CIS subjects (P < 0.01) [Table 4], [Figure 1]b. UVA showed that younger age, better PS, oropharyngeal subsite, Stage III disease and CIS predicted for improved DFS. On MVA age did not predict for improved DFS. RT-CET was associated with reduced DFS compared to RT-CIS, 2.12 (95% CI, 1.38-3.27).

Type of ST did not correlate with OS; CET versus CIS HR 1.2 (95% CI, 0.74-1.95), P = 0.46. The one year OS was 89.5% and 80.1% in favor of RT-CIS (P = 0.04) [Table 4], [Figure 1]c. On UVA younger age, better PS, oropharyngeal subsite, standard/concomitant boost RT and CIS were associated with improved OS. On MVA improved, OS was associated with better PS, oropharyngeal subsite and standard/concomitant boost RT.


 > Discussion Top


Bonner et al., reported improved treatment outcomes and low toxicity rates for RT-CET over RT alone, but no randomized trials have compared RT-CIS to RT-CET. [2],[3] As RT-CIS is the current accepted standard of care, [11] but RT-CET is commonly used as an alternative, the relative efficacy of RT-CET is an area of interest. This series is the largest population-based review to compare both toxicity and disease outcomes between RT-CIS and RT-CET.

Subjects receiving RT-CIS had more chemotherapy dose modifications, Grade 3/4 nausea and/or vomiting and increased rates of unplanned hospital admissions, indicating more severe traditional toxicities, and subsequent treatment modifications. As expected, the RT-CET subjects had higher rates of acneiform rash. However, although oral mucositis rates were similar between the two groups, radiation dermatitis was significantly higher in the RT-CET group. Despite requiring fewer modifications to treatment, RT-CET subjects had similar rates of enteral feeding tube requirements, and weight loss outcomes.

With short follow-up, OS trended towards an improvement with RT-CIS but was not statistically different. There was better LRC and prolonged DFS in the RT-CIS group. These results must be interpreted in the setting of significant differences between subject groups. Selection bias due to the rationale for treatment with RT-CET likely contributes. Based on the selection criteria for CET, there would likely be more patients with significant co-morbid disease. In addition, there was a higher proportion of oropharyngeal cancers in the RT-CIS group. Oropharyngeal subsite was consistently associated with improved outcomes. With the known association between human-papillomavirus (HPV) and oropharyngeal cancers, [12] the rising prevalence of oropharyngeal cancers [13] and the differences in prognosis, [14] the increased prevalence of oropharyngeal cancer in the RT-CIS group limits the confidence with which one can attribute the observation of superior disease endpoints to the ST received. An attempt was made to assess the distribution of HPV status, but low rates of testing during the study era limited this analysis. This imbalance is possibly further exacerbated by the increased prevalence of laryngeal cancers (which are traditionally known to be associated with smoking) in the RT-CET group.

Concordant with the practice of using hypofractionated RT with CET, as it was felt more likely to be well-tolerated, there was more hypofractionated RT used in for RT-CET subjects. A recent analysis of oropharyngeal cancers showed poorer outcomes for hypofractionated RT alone in comparison with accelerated RT alone and RT-CIS. [9] In this analysis, hypofractionated RT was associated with reduced OS, but not significantly associated with LRC or DFS. It is difficult; however, to separate the contribution of the RT schedule from the choice of ST.

Three other institutions have published their experiences with RT-CIS as compared to RT-CET in the management of locally advanced HNSCC. At Memorial Sloan-Kettering Cancer Center (MSKCC), 174 subjects treated with RT-CIS (n = 125) or RT-CET (n = 49) were reported. [5] Radiation was 70 Gy in 2 Gy fractions using IMRT techniques. CIS was given at 100 mg/m 2 every three weeks. CET was given at a loading dose of 400 mg/m 2 the week prior to RT and then 250 mg/m 2 weekly during RT. The 2-year LRC, failure-free survival and OS all favored RT-CIS, and results were upheld on MVA. The MSKCC report did not include acute toxicity rates, but noted that late toxicity and feeding tube dependence did not differ between the two groups. This study differed from the current study in that only oropharynx, hypopharynx and larynx cancers were included, and a uniform RT schema was employed.

Bonner et al., from the University of Alabama-Birmington compared 103 subjects treated with a platinum based ST with 29 case-matched subjects treated with RT-CET. [6] RT (70-82 Gy) via 3D-CRT techniques was delivered concurrently with ST. Subject groups were similar except the T-stage was higher in the platinum arm. With a median follow-up of 83 months and 53 months, no difference in LRC, distant-metastases free survival, or disease-specific survival were observed. Although there was a difference in OS between the two groups, with control of potential confounders on MVA, no difference was seen. Toxicities were not reported. 63 subjects in the chemotherapy group received a two-chemotherapy regimen, which included a platinum agent rather than CIS alone. Only subjects with larynx, oral cavity and oropharynx cancers were included.

St. Luke's Hospital in Dublin described the toxicity experience comparing 33 historical controls, matched for stage and RT parameters, treated with RT-CIS to 34 RT-CET subjects. [7] RT via 2D-CRT and 3D-CRT was used to deliver a median total dose of 66-70 Gy. CIS was given at 40 mg/m 2 weekly, and CET was given at the same dosing as in our study. More Grade 3 or 4 oral mucositis, skin dermatitis, greater than or equal to 10% weight loss, and higher enteral feeding requirements were reported for the RT-CET group. A major difference between the current study and St. Luke's was the RT technique. The majority of our subjects were treated with IMRT as compared to 2D- and 3D-CRT in Dublin. The weekly dosing regimen of CIS also differs from the majority of our subjects. Survival outcomes were not discussed.

The inherent biases associated with retrospective reviews (including selection bias and verification bias) are a limitation in this study and underestimation of toxicity rates is a possibility. With a difference in rates of distant metastases between the two groups, it is possible that OS differences will be seen with more mature follow-up. However, as the largest population based review, which represents a practice spanning a large geographic area with multiple cancer centers, to examine both toxicities and outcomes it plays a role in informing current clinical practice. This is particularly the case as the results of the HN6 trial are awaited. [8] Although panitumumab is not identical to CET, it may play a role in providing a more definitive answer in the choice between traditional cytotoxic chemotherapy and targeted antibody therapy.


 > Conclusions Top


In conclusion, the current study found that RT-CIS was associated with more favorable LRC and DFS, but similar OS, albeit with short follow-up, as compared to RT-CET in subjects with Stage III or IV HNSCC. Although chemotherapy dosing regimens required more modifications in the RT-CIS group due to toxicities, Grade 3 and 4 toxicities were also seen in the RT-CET group, suggesting that treatment may not be as benign as believed. These results suggest RT-CIS may provide superior outcomes to RT-CET. As the Bonner trial showed RT-CET is superior to RT alone, it is reasonable to continue to use CET in the population who are ineligible for CIS. However, within the limitations of a retrospective investigation, we would recommend against RT-CET as a routine alternative to RT-CIS in the fit patient.

 
 > References Top

1.Zimmermann M, Zouhair A, Azria D, Ozsahin M. The epidermal growth factor receptor (EGFR) in head and neck cancer: Its role and treatment implications. Radiat Oncol 2006;1:11.  Back to cited text no. 1
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2.Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.  Back to cited text no. 2
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3.Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.  Back to cited text no. 3
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4.Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.  Back to cited text no. 4
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5.Koutcher L, Sherman E, Fury M, Wolden S, Zhang Z, Mo Q, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81:915-22.  Back to cited text no. 5
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6.Caudell JJ, Sawrie SM, Spencer SA, Desmond RA, Carroll WR, Peters GE, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: A comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008;71:676-81.  Back to cited text no. 6
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7.Walsh L, Gillham C, Dunne M, Fraser I, Hollywood D, Armstrong J, et al. Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC). Radiother Oncol 2011;98:38-41.  Back to cited text no. 7
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8.Radiation Therapy and Cisplatin or Panitumumab in Treating Patients with Locally Advanced Stage III or Stage IV Head and Neck Cancer [Internet]. Bethesda (MD): National Library of Medicine (US); c2000-12. Available from : 0 http://www.clinicaltrials.gov/ct2/show/NCT00820248?term=hn6&rank=2. [updated 2013 July 11; cited October 1, 2012].  Back to cited text no. 8
    
9.Kader HA, Mydin AR, Wilson M, Alexander C, Shahi J, Pathak I, et al. Treatment outcomes of locally advanced oropharyngeal cancer: A comparison between combined modality radio-chemotherapy and two variants of single modality altered fractionation radiotherapy. Int J Radiat Oncol Biol Phys 2011;80:1030-6.  Back to cited text no. 9
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10.National Institute of Health. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Bethesda (MD): US Department of Health and Human Services. 2009.  Back to cited text no. 10
    
11.Pfister DJ, Ang KK, Brizel D, Burtness BA, Busse PM, Cmelak AJ, et al. NCCN clinical practice guidelines in oncology (NCCN Guidelines TM ): Head and neck cancers, version 2. Fort Washington (PA): National Comprehensive Cancer Network. 2011.  Back to cited text no. 11
    
12.Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709-20.  Back to cited text no. 12
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14.Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int J Cancer 2007;121:1813-20.  Back to cited text no. 14
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