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Early Brain Recurrences are Potentially Detectable in Asymptomatic, Early Stage Lung Adenocarcinoma
718
Letters / Clinical Oncology 23 (2011) 716e721
References [1] Maubec E, Duvillard P, Velasco V, Crickx B, Avril MF. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005;25(2B):1205e1210. [2] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354(6):567e578. [3] Kim S, Eleff M, Nicolaou N. Cetuximab as primary treatment for cutaneous squamous cell carcinoma to the neck. Head Neck 2011;33(2):286e288. [4] Arnold AW, Bruckner-Tuderman L, Zuger C, Itin PH. Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa. Dermatology 2009;219(1):80e83.
[5] Suen JK, Bressler L, Shord SS, Warso M, Villano JL. Cutaneous squamous cell carcinoma responding serially to single-agent cetuximab. Anticancer Drugs 2007;18(7):827e829. [6] Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol 2007;143(7):889e892. [7] Jalili A, Pinc A, Pieczkowski F, Karlhofer FM, Stingl G, Wagner SN. Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2008;6(12): 1066e1069. [8] Maubec E, Petrow P, Duvillard P, et al. Cetuximab as first-line monotherapy in patients with skin unresectable squamous cell carcinoma: final results of a phase II multicenter study. Oral Session ASCO, 2010; abstract #8510. http://meeting. ascopubs.org/cgi/content/abstract/28/15_suppl/8510.
doi:10.1016/j.clon.2011.07.007
Reply to: Clinically Significant Human Papilloma Virus in Squamous Cell Carcinoma of the Head and Neck in UK Practice Sir d We would like to commend Heath et al. [1] for their timely publication detailing the clinically significant role of human papillomavirus-16 (HPV16) in squamous cell carcinoma of the head and neck within the UK. We recently highlighted comparable findings from an analysis of 108 oropharyngeal squamous cell carcinomas in Merseyside and Cheshire [2]. Using quantitative HPV16 viral gene expression (RNA qPCR), our analysis showed that the proportion of oropharyngeal squamous cell carcinomas that were HPV16 positive had increased from 14% (1988e1997 cohort) to 57% (2008e2009 cohort) in two decades. Using a methodology comparable with that applied by Heath et al. (combined p16 immunohistochemistry [IHC]/HPV DNA qPCR), we found a slightly lower HPV-positive rate of 41% (cf. 65%) in a corresponding era (2004e2007). Overall, we note that the rates are broadly similar in differing regions of the UK despite quite distinct demographics. In contrast to oropharyngeal tumours, a series of 110 oral cavity squamous cell carcinomas (2003e2010) from our region were tested by combined p16 IHC and in situ hybridisation for high-risk HPV. This revealed an HPV-positive rate of only 4.5%. We did not find the 44% positive rate for p16 IHC
in the oral tongue site recently seen by Harris et al. [3] and conclude that HPV is an insignificant factor to date in strictly classified oral cavity squamous cell carcinoma. These data highlight the importance of accurate discrimination of site when discussing the role of HPV16 in the aetiology of squamous cell carcinoma of the head and neck. A.G. Schache, R.J. Shaw University of Liverpool, Liverpool, UK
References [1] Heath S, Willis V, Allan K, et al. Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice. Clin Oncol 2011 [Epub ahead of print]. [2] Schache AG, Liloglou T, Risk JM, et al. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity and prognostic discrimination. Clin Cancer Res in press. [3] Harris SL, Thorne LB, Seaman WT, et al. Association of p16 overexpression with improved outcomes in young patient with SCC of the oral tongue. Head Neck 2010 [Epub ahead of print].
Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.09.003
Early Brain Recurrences are Potentially Detectable in Asymptomatic, Early Stage Lung Adenocarcinoma Sir d Preoperative staging for early stage non-small cell lung cancer is inconsistent. According to the National Comprehensive Cancer Network non-small cell lung cancer
guidelines, preoperative brain imaging is not recommended for asymptomatic patients with stage IA disease [1]. For the first time in the 3.2011 version, brain magnetic resonance
Letters / Clinical Oncology 23 (2011) 716e721
719
Table 1 Patient characteristics Variable
n
Brain metastasis 16 (9%) n (%)
No brain metastasis 158 (91%) n (%)
P value
Age (years) median Female Non-smoker Pack years, median Race White Black Asian Other Stage I II III
174 174 170 151 174 143 29 1 1 173y 123 25 25
59 8/16 (50) 0/14 (0) 38
66 86/158 (54) 14/156 (9) 40
0.298 0.798 0.609 0.874 0.301*
11/143 (8) 5/29 (17) 0/1 (0) 0/1 (0)
132/143 (92) 24/29 (83) 1/1 (100) 1/1 (100)
5/123 (4) 6/25 (24) 5/25 (20)
118/123 (96) 19/25 (76) 20/25 (80)
* ** y
0.0013**
Fisher’s exact P value testing independence in the following four groups with respect to brain metastasis. Fisher’s exact P value testing independence in stages IeIII with respect to brain metastasis. Numbers do not sum to total due to missing data.
imaging (MRI) for stage IB tumours is included as a National Comprehensive Cancer Network work-up recommendation with a category 2B designation. A more thorough search for distant metastasis may benefit patients, especially those with adenocarcinoma [2e5]. We report on 174 neurologically asymptomatic patients with clinically staged T1-T2N0 lung adenocarcinoma who underwent pulmonary resection (wedge, lobectomy, pneumonectomy) from 1 January 1990 to 31 December 2005 without preoperative brain imaging. Patient characteristics are shown in Table 1. There were 94 women and 80 men. The median age was 65 years (range: 34e90 years). Sixteen of 174 patients (9.2%) developed brain metastasis within 18 months of surgery; 14/174 (8%) developed brain metastasis within 13 months and 12/174 (6.9%) within 12 months. Patients most frequently presented with extremity weakness (five patients), ataxia and falls (three patients), dizziness (three patients) and visual changes (three patients). The mean time to recurrence was 236 days (median: 217.5 days; range: 22e507 days) and the mean lesion size was 1.9 cm in the greatest diameter (mean tumour volume about 3.6 cm3) at the time of detection. Based on a conservative volumetric tumour doubling time of 58.5 days [6], the mean lesion size at the time of operation would have been about 7.5 mm (tumour volume 224 mm3) and 13/14 patients would have had tumours measuring >2 mm in diameter (tumour volume 4.2 mm3) (Figure 1). It is expected that on a modern contrasted MRI with careful review of axial, sagital and coronal images, lesions 2 mm can be seen. A significantly higher percentage of pathological stage II and III patients developed brain metastases compared with stage I patients (stage I, 4%; II, 24%; III, 20%; P ¼ 0.0013). Patients with early brain recurrence tended to be younger (median age 59 years versus 66 years; P ¼ 0.298) and black (17% Black versus 8% White; P ¼ 0.301), and all were
smokers. Patients with brain metastasis had significantly worse survival among stage III patients (P ¼ 0.024). This work highlights that clinical stage I patients often have a higher pathological stage. Final pathological staging offers a guide towards patients at highest risk of early brain recurrence. Survival analysis of our study population showed that about 60% of stage I patients with early brain recurrence were still alive at 5 years, implying that some patients with brain metastases can have long-term, positive outcomes. Thus, even though stage I patients are at lower risk of developing brain recurrence, there is a significant incentive to diagnose them as early as possible. In conclusion, we observed a 9.2% (14/174) rate of early postoperative brain recurrence among patients with cT1 or
Fig 1. Estimated tumour growth of metastatic brain tumours found in study population.
720
Letters / Clinical Oncology 23 (2011) 716e721
cT2 adenocarcinoma of the lung, and it is reasonable that 13/14 would have had visible lesions at operation. Consequently, we recommend consideration of routine preoperative staging brain MRI in patients with adenocarcinoma of the lung, including stage IA, and postoperative scans if the pathological stage is high. Early detection of brain metastases will facilitate the timely initiation of appropriate treatment. J.S. Nelson*, L.D. Alleny, L.A. Parkerz, M.C. Haywardx, N. Zhaojj, D.N. Hayesx *Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7050, USA yUniversity of North Carolina School of Medicine, Chapel Hill, NC 27599, USA zDepartment of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA xDepartment of Internal Medicine, Division of Medical Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7295, USA jjDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7050, USA
References [1] NCCN Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer, Version 3.2011. [2] Park HY, Kim YH, Kim H, et al. Routine screening by brain magnetic resonance imaging decreased the brain metastasis rate following surgery for lung adenocarcinoma. Lung Cancer 2007;58:68e72. [3] Metintas M, Ak G, Akcayir IA, et al. Detecting extrathoracic metastases in patients with non-small cell lung cancer: is routine scanning necessary? Lung Cancer 2007;58:59e67. [4] Canadian Lung Oncology Group. Investigating extrathoracic metastatic disease in patients with apparently operable lung cancer. Ann Thorac Surg 2001;71:425e434. [5] Sorensen JB, Hansen HH, Hansen M, et al. Brain metastasis in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474e1480. [6] Yoo H, Nam BH, Yang HS, et al. Growth rates of metastatic brain tumors in nonsmall cell lung cancer. Cancer 2008; 113(5):1043e1047.
Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.09.002
Letters / Clinical Oncology 23 (2011) 716e721
References [1] Maubec E, Duvillard P, Velasco V, Crickx B, Avril MF. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005;25(2B):1205e1210. [2] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354(6):567e578. [3] Kim S, Eleff M, Nicolaou N. Cetuximab as primary treatment for cutaneous squamous cell carcinoma to the neck. Head Neck 2011;33(2):286e288. [4] Arnold AW, Bruckner-Tuderman L, Zuger C, Itin PH. Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa. Dermatology 2009;219(1):80e83.
[5] Suen JK, Bressler L, Shord SS, Warso M, Villano JL. Cutaneous squamous cell carcinoma responding serially to single-agent cetuximab. Anticancer Drugs 2007;18(7):827e829. [6] Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol 2007;143(7):889e892. [7] Jalili A, Pinc A, Pieczkowski F, Karlhofer FM, Stingl G, Wagner SN. Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2008;6(12): 1066e1069. [8] Maubec E, Petrow P, Duvillard P, et al. Cetuximab as first-line monotherapy in patients with skin unresectable squamous cell carcinoma: final results of a phase II multicenter study. Oral Session ASCO, 2010; abstract #8510. http://meeting. ascopubs.org/cgi/content/abstract/28/15_suppl/8510.
doi:10.1016/j.clon.2011.07.007
Reply to: Clinically Significant Human Papilloma Virus in Squamous Cell Carcinoma of the Head and Neck in UK Practice Sir d We would like to commend Heath et al. [1] for their timely publication detailing the clinically significant role of human papillomavirus-16 (HPV16) in squamous cell carcinoma of the head and neck within the UK. We recently highlighted comparable findings from an analysis of 108 oropharyngeal squamous cell carcinomas in Merseyside and Cheshire [2]. Using quantitative HPV16 viral gene expression (RNA qPCR), our analysis showed that the proportion of oropharyngeal squamous cell carcinomas that were HPV16 positive had increased from 14% (1988e1997 cohort) to 57% (2008e2009 cohort) in two decades. Using a methodology comparable with that applied by Heath et al. (combined p16 immunohistochemistry [IHC]/HPV DNA qPCR), we found a slightly lower HPV-positive rate of 41% (cf. 65%) in a corresponding era (2004e2007). Overall, we note that the rates are broadly similar in differing regions of the UK despite quite distinct demographics. In contrast to oropharyngeal tumours, a series of 110 oral cavity squamous cell carcinomas (2003e2010) from our region were tested by combined p16 IHC and in situ hybridisation for high-risk HPV. This revealed an HPV-positive rate of only 4.5%. We did not find the 44% positive rate for p16 IHC
in the oral tongue site recently seen by Harris et al. [3] and conclude that HPV is an insignificant factor to date in strictly classified oral cavity squamous cell carcinoma. These data highlight the importance of accurate discrimination of site when discussing the role of HPV16 in the aetiology of squamous cell carcinoma of the head and neck. A.G. Schache, R.J. Shaw University of Liverpool, Liverpool, UK
References [1] Heath S, Willis V, Allan K, et al. Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice. Clin Oncol 2011 [Epub ahead of print]. [2] Schache AG, Liloglou T, Risk JM, et al. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity and prognostic discrimination. Clin Cancer Res in press. [3] Harris SL, Thorne LB, Seaman WT, et al. Association of p16 overexpression with improved outcomes in young patient with SCC of the oral tongue. Head Neck 2010 [Epub ahead of print].
Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.09.003
Early Brain Recurrences are Potentially Detectable in Asymptomatic, Early Stage Lung Adenocarcinoma Sir d Preoperative staging for early stage non-small cell lung cancer is inconsistent. According to the National Comprehensive Cancer Network non-small cell lung cancer
guidelines, preoperative brain imaging is not recommended for asymptomatic patients with stage IA disease [1]. For the first time in the 3.2011 version, brain magnetic resonance
Letters / Clinical Oncology 23 (2011) 716e721
719
Table 1 Patient characteristics Variable
n
Brain metastasis 16 (9%) n (%)
No brain metastasis 158 (91%) n (%)
P value
Age (years) median Female Non-smoker Pack years, median Race White Black Asian Other Stage I II III
174 174 170 151 174 143 29 1 1 173y 123 25 25
59 8/16 (50) 0/14 (0) 38
66 86/158 (54) 14/156 (9) 40
0.298 0.798 0.609 0.874 0.301*
11/143 (8) 5/29 (17) 0/1 (0) 0/1 (0)
132/143 (92) 24/29 (83) 1/1 (100) 1/1 (100)
5/123 (4) 6/25 (24) 5/25 (20)
118/123 (96) 19/25 (76) 20/25 (80)
* ** y
0.0013**
Fisher’s exact P value testing independence in the following four groups with respect to brain metastasis. Fisher’s exact P value testing independence in stages IeIII with respect to brain metastasis. Numbers do not sum to total due to missing data.
imaging (MRI) for stage IB tumours is included as a National Comprehensive Cancer Network work-up recommendation with a category 2B designation. A more thorough search for distant metastasis may benefit patients, especially those with adenocarcinoma [2e5]. We report on 174 neurologically asymptomatic patients with clinically staged T1-T2N0 lung adenocarcinoma who underwent pulmonary resection (wedge, lobectomy, pneumonectomy) from 1 January 1990 to 31 December 2005 without preoperative brain imaging. Patient characteristics are shown in Table 1. There were 94 women and 80 men. The median age was 65 years (range: 34e90 years). Sixteen of 174 patients (9.2%) developed brain metastasis within 18 months of surgery; 14/174 (8%) developed brain metastasis within 13 months and 12/174 (6.9%) within 12 months. Patients most frequently presented with extremity weakness (five patients), ataxia and falls (three patients), dizziness (three patients) and visual changes (three patients). The mean time to recurrence was 236 days (median: 217.5 days; range: 22e507 days) and the mean lesion size was 1.9 cm in the greatest diameter (mean tumour volume about 3.6 cm3) at the time of detection. Based on a conservative volumetric tumour doubling time of 58.5 days [6], the mean lesion size at the time of operation would have been about 7.5 mm (tumour volume 224 mm3) and 13/14 patients would have had tumours measuring >2 mm in diameter (tumour volume 4.2 mm3) (Figure 1). It is expected that on a modern contrasted MRI with careful review of axial, sagital and coronal images, lesions 2 mm can be seen. A significantly higher percentage of pathological stage II and III patients developed brain metastases compared with stage I patients (stage I, 4%; II, 24%; III, 20%; P ¼ 0.0013). Patients with early brain recurrence tended to be younger (median age 59 years versus 66 years; P ¼ 0.298) and black (17% Black versus 8% White; P ¼ 0.301), and all were
smokers. Patients with brain metastasis had significantly worse survival among stage III patients (P ¼ 0.024). This work highlights that clinical stage I patients often have a higher pathological stage. Final pathological staging offers a guide towards patients at highest risk of early brain recurrence. Survival analysis of our study population showed that about 60% of stage I patients with early brain recurrence were still alive at 5 years, implying that some patients with brain metastases can have long-term, positive outcomes. Thus, even though stage I patients are at lower risk of developing brain recurrence, there is a significant incentive to diagnose them as early as possible. In conclusion, we observed a 9.2% (14/174) rate of early postoperative brain recurrence among patients with cT1 or
Fig 1. Estimated tumour growth of metastatic brain tumours found in study population.
720
Letters / Clinical Oncology 23 (2011) 716e721
cT2 adenocarcinoma of the lung, and it is reasonable that 13/14 would have had visible lesions at operation. Consequently, we recommend consideration of routine preoperative staging brain MRI in patients with adenocarcinoma of the lung, including stage IA, and postoperative scans if the pathological stage is high. Early detection of brain metastases will facilitate the timely initiation of appropriate treatment. J.S. Nelson*, L.D. Alleny, L.A. Parkerz, M.C. Haywardx, N. Zhaojj, D.N. Hayesx *Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7050, USA yUniversity of North Carolina School of Medicine, Chapel Hill, NC 27599, USA zDepartment of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA xDepartment of Internal Medicine, Division of Medical Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7295, USA jjDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7050, USA
References [1] NCCN Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer, Version 3.2011. [2] Park HY, Kim YH, Kim H, et al. Routine screening by brain magnetic resonance imaging decreased the brain metastasis rate following surgery for lung adenocarcinoma. Lung Cancer 2007;58:68e72. [3] Metintas M, Ak G, Akcayir IA, et al. Detecting extrathoracic metastases in patients with non-small cell lung cancer: is routine scanning necessary? Lung Cancer 2007;58:59e67. [4] Canadian Lung Oncology Group. Investigating extrathoracic metastatic disease in patients with apparently operable lung cancer. Ann Thorac Surg 2001;71:425e434. [5] Sorensen JB, Hansen HH, Hansen M, et al. Brain metastasis in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474e1480. [6] Yoo H, Nam BH, Yang HS, et al. Growth rates of metastatic brain tumors in nonsmall cell lung cancer. Cancer 2008; 113(5):1043e1047.
Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.09.002