- Email: [email protected]
Lymphangitis Carcinomatosis as a Potential Predictor for a Response to Gefitinib
LETTERS Table 1 e Summary of responses Response: Yes
Question Preference for a male doctor Would you like a nurse to be present during the consultation? Would you prefer a family member to be present? Would you feel comfortable discussing with a female doctor? Would you feel comfortable discussing with a nurse alone? Would you feel comfortable discussing with a male doctor in the presence of a female nurse?
All patients 10 (11.2%)
All patients by Prostate age distribution patients (%) [18e30 vs (% of yes 30e50 vs 51e70 responses) vs O70 years] 6 (60%)
28.6 14.3 39 (43.8%) 32 (82.1%) 14.3 54.3 50 (56.2%) 36 (72%)
vs vs vs vs
3.7 vs 10 25.9 vs 60
57.1 vs 40.7 vs 68.6 vs 55
80 (89.9%) 47 (58.8%) 100 vs 92.6 vs 82.9 vs 95 75 (84.3%) 45 (60%)
71.4 vs 92.6 vs 80 vs 85
78 (87.6%) 44 (56.4%) 100 vs 96.3 vs 74.3 vs 95
a female doctor. Upon subgroup analysis there was no significant effect of age group on physician gender preference. There was, however, an effect of both age group and cancer type on whether the men preferred a nurse in the
doi:10.1016/j.clon.2006.05.004
Lymphangitis Carcinomatosis as a Potential Predictor for a Response to Gefitinib Sir d Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has a therapeutic effect on previously treated patients with non-small cell lung cancer, especially women, Japanese patients, or patients with adenocarcinoma or a good performance status (PS) [1]. In a placebo-controlled phase III trial, a subgroup analysis showed a significant survival benefit in patients with Asian origin and in never-smokers, although gefitinib did not provide a survival benefit in the overall population [2]. When focusing on adenocarcinoma histology, the presence of multiple pulmonary metastases was reported to be associated with a good response [3]. Lymphangitis carcinomatosis (LC) is also the characteristic feature of adenocarcinoma and we have experienced some cases of LC that responded dramatically. The aim of our study was to determine whether a new predictive factor, LC, is associated with a response to gefitinib. We retrospectively reviewed 97 consecutive Japanese patients
573
consultation. Sixty per cent of men over 70 years of age preferred a nurse to be present, whereas only 14.3% of men aged 18e30 years preferred a nurse to be present (P ¼ 0.022). Men with prostate cancer were significantly more likely to prefer the presence of a nurse (60.4%) than men with testicular cancer (19.4%) (P ! 0.0001). None of the men expressed a preference for the gender of the nurse in the consultation. Our survey shows that most men with urological malignancies do not have a preference for the gender of the doctor they consult in the clinic, although in line with other studies, the 11.2% who did express a preference requested a samegender physician. A significant proportion of our patients (56.2% overall) preferred not to have a nurse present in the clinic. We feel that the views of these patients should be considered when providing outpatient services. M. GRIFFIN A. DHADDA A. WADE M. SOKAL S. SUNDAR
Department of Oncology, Nottingham City Hospital, Nottingham, UK
References 1 Kerssens JJ, Bensing JM, Andela MG. Patient preference for genders of health professionals. Soc Sci Med 1997;44:1531e1540. 2 Graffy J. Patient choice in a practice with men and women general practitioners. Br J Gen Pract 1990;40(330):13e15. 3 Fisher WA, Bryan A, Dervaitis KL, et al. It ain’t necessarily so: most women do not strongly prefer female obstetricianegynaecologists. J Obstet Gynaecol Can 2002;24:885e888. 4 Johnson AM, Schnatz PF, Kelsey AM, et al. Do women prefer care from female or male obstetricianegynecologists? A study of patient gender preference. J Am Osteopath Assoc 2005;105:369e379.
who had received gefitinib (250 mg/day) for advanced adenocarcinoma of the lung from July 2002 to September 2003 in our institutions. Sixty-six patients (68.0%) were pretreated with chemotherapy and 31 patients (32.0%) were chemotherapy naive. Thirteen patients (13.5%) had PS R 3. The criteria for LC were as follows: (1) presenting with dyspnoea or breathlessness; (2) having hypoxia on blood gas analysis; and (3) having characteristic high-resolution computed tomography findings (thickening of peribronchovascular interstitium, interlobular septa and fissures with preservation of normal parenchymal architecture). Twelve patients were diagnosed as having LC, whereas the remaining 85 patients were entered into the non-LC group. There was no significant difference between both groups in terms of gender, PS, smoking history and disease stage. In the LC group, two patients had a complete response and four patients had a partial response; the response rate was 50.0% (95% confidence interval [CI] ¼ 25.4e74.6). Most of the responded cases showed rapid improvement, occurring within 1 week and continuing for more than 10 months. In addition, their response rate was significantly higher than the non-LC group (21.2% [95% CI ¼ 13.8e31.0], Fisher’s
574
CLINICAL ONCOLOGY
Table 1 e Predictors for objective tumour response Predictor
Crude odds ratio (95% CI)
Lymphangitis carcinomatosis Performance status (grade 0) Female gender Never-smoker
3.72 3.24 2.86 2.68
Adjusted odds ratio (95% CI)
(1.05e13.30) (1.23e8.64) (1.12e7.55) (1.10e7.17)
7.74 5.58 5.28 0.74
(1.74e38.88) (1.83e18.80) (1.06e30.00) (0.14e3.50)
P value 0.009 0.003 0.048 0.706
CI, confidence interval.
exact test, P ¼ 0.018) and the crude odds ratio was 3.72 (95% CI 1.05e13.30, Wald test, P ¼ 0.039). In the logistic regression analysis including proven predictors such as gender, smoking history and PS (Table 1), LC was an independent predictor for response and its adjusted odds ratio was the highest (7.74 [95% CI 1.74e38.88], Wald test, P ¼ 0.009) among the included predictors. In the present study, we showed that LC was a potential predictor for response in the Japanese adenocarcinoma population. Although the pathogenesis of LC is not fully understood, we thought it noteworthy that many of our patients with LC had shown a dramatic response. Recently, several studies have shown that specific mutations of the EGFR gene or the increased copy number of the EGFR gene were correlated with a response to gefitinib [4,5]. Larger prospective studies will be needed to confirm our finding and to clarify the associations between those gene alterations and LC. T. NAITO H. HASEGAWA K. ASADA T. SUDA K. CHIDA
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
doi:10.1016/j.clon.2006.05.006
Hepatocellular Carcinoma Presenting as Multifocal Haemorrhagic Encephalitis Sir d Paraneoplastic neurological disorders are autoimmune inflammatory disorders affecting the nervous system [1]. Neurological manifestations precede the detection of underlying malignancy in most patients. The immunological response initiated against tumour antigens causes damage to neural tissues that co-express onconeural proteins. We report a patient who presented with acute multifocal haemorrhagic encephalitis leading to early detection of hepatocellular carcinoma (HCC). A 69-year-old man with good past health presented with acute confusion and disorientation followed by memory loss. He had no fever or influenza-like illness in the preceding weeks. An examination revealed no meningism or focal neurological signs and other systems were normal. He developed generalised tonic clonic convulsions after admission.
References 1 Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237e2246. 2 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527e1537. 3 Goto K, Kim E, Kubota S, et al. Association of multiple pulmonary metastases with response to gefitinib in patients with non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 2004;22:679. 4 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350: 2129e2139. 5 Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829e6837.
His complete blood picture and renal function test were normal. The liver function test showed mildly raised bilirubin to 23 mmol/l only. The thyroid function test, syphilis serology, vitamin B12 and folate levels, and vasculitis markers were normal or negative. Magnetic resonance imaging (MRI) showed multifocal T2-weighted hyperintense signals in white matter, and small areas of cortical grey matter. There were small T1-weighted hyperintense signals compatible with haematomas (Fig. 1). MRI of cervical and thoracic spine were normal. A magnetic resonance (MR) angiogram revealed normal major arteries. MR spectroscopy showed a normal N-acetylaspartate peak, suggesting that neoplasm was unlikely. Cerebrospinal fluid was unremarkable, except for raised cerebrospinal fluid IgG to 6.3 mg/dl without oligoclonal bands; microbiological studies for bacterial, mycobacterial, fungal and viral infection were negative. Tumour markers including a-fetoprotein were normal. Computed tomography of the thorax was normal but computed tomography of the abdomen revealed a liver mass over the right lobe. He was seropositive for hepatitis B
Question Preference for a male doctor Would you like a nurse to be present during the consultation? Would you prefer a family member to be present? Would you feel comfortable discussing with a female doctor? Would you feel comfortable discussing with a nurse alone? Would you feel comfortable discussing with a male doctor in the presence of a female nurse?
All patients 10 (11.2%)
All patients by Prostate age distribution patients (%) [18e30 vs (% of yes 30e50 vs 51e70 responses) vs O70 years] 6 (60%)
28.6 14.3 39 (43.8%) 32 (82.1%) 14.3 54.3 50 (56.2%) 36 (72%)
vs vs vs vs
3.7 vs 10 25.9 vs 60
57.1 vs 40.7 vs 68.6 vs 55
80 (89.9%) 47 (58.8%) 100 vs 92.6 vs 82.9 vs 95 75 (84.3%) 45 (60%)
71.4 vs 92.6 vs 80 vs 85
78 (87.6%) 44 (56.4%) 100 vs 96.3 vs 74.3 vs 95
a female doctor. Upon subgroup analysis there was no significant effect of age group on physician gender preference. There was, however, an effect of both age group and cancer type on whether the men preferred a nurse in the
doi:10.1016/j.clon.2006.05.004
Lymphangitis Carcinomatosis as a Potential Predictor for a Response to Gefitinib Sir d Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has a therapeutic effect on previously treated patients with non-small cell lung cancer, especially women, Japanese patients, or patients with adenocarcinoma or a good performance status (PS) [1]. In a placebo-controlled phase III trial, a subgroup analysis showed a significant survival benefit in patients with Asian origin and in never-smokers, although gefitinib did not provide a survival benefit in the overall population [2]. When focusing on adenocarcinoma histology, the presence of multiple pulmonary metastases was reported to be associated with a good response [3]. Lymphangitis carcinomatosis (LC) is also the characteristic feature of adenocarcinoma and we have experienced some cases of LC that responded dramatically. The aim of our study was to determine whether a new predictive factor, LC, is associated with a response to gefitinib. We retrospectively reviewed 97 consecutive Japanese patients
573
consultation. Sixty per cent of men over 70 years of age preferred a nurse to be present, whereas only 14.3% of men aged 18e30 years preferred a nurse to be present (P ¼ 0.022). Men with prostate cancer were significantly more likely to prefer the presence of a nurse (60.4%) than men with testicular cancer (19.4%) (P ! 0.0001). None of the men expressed a preference for the gender of the nurse in the consultation. Our survey shows that most men with urological malignancies do not have a preference for the gender of the doctor they consult in the clinic, although in line with other studies, the 11.2% who did express a preference requested a samegender physician. A significant proportion of our patients (56.2% overall) preferred not to have a nurse present in the clinic. We feel that the views of these patients should be considered when providing outpatient services. M. GRIFFIN A. DHADDA A. WADE M. SOKAL S. SUNDAR
Department of Oncology, Nottingham City Hospital, Nottingham, UK
References 1 Kerssens JJ, Bensing JM, Andela MG. Patient preference for genders of health professionals. Soc Sci Med 1997;44:1531e1540. 2 Graffy J. Patient choice in a practice with men and women general practitioners. Br J Gen Pract 1990;40(330):13e15. 3 Fisher WA, Bryan A, Dervaitis KL, et al. It ain’t necessarily so: most women do not strongly prefer female obstetricianegynaecologists. J Obstet Gynaecol Can 2002;24:885e888. 4 Johnson AM, Schnatz PF, Kelsey AM, et al. Do women prefer care from female or male obstetricianegynecologists? A study of patient gender preference. J Am Osteopath Assoc 2005;105:369e379.
who had received gefitinib (250 mg/day) for advanced adenocarcinoma of the lung from July 2002 to September 2003 in our institutions. Sixty-six patients (68.0%) were pretreated with chemotherapy and 31 patients (32.0%) were chemotherapy naive. Thirteen patients (13.5%) had PS R 3. The criteria for LC were as follows: (1) presenting with dyspnoea or breathlessness; (2) having hypoxia on blood gas analysis; and (3) having characteristic high-resolution computed tomography findings (thickening of peribronchovascular interstitium, interlobular septa and fissures with preservation of normal parenchymal architecture). Twelve patients were diagnosed as having LC, whereas the remaining 85 patients were entered into the non-LC group. There was no significant difference between both groups in terms of gender, PS, smoking history and disease stage. In the LC group, two patients had a complete response and four patients had a partial response; the response rate was 50.0% (95% confidence interval [CI] ¼ 25.4e74.6). Most of the responded cases showed rapid improvement, occurring within 1 week and continuing for more than 10 months. In addition, their response rate was significantly higher than the non-LC group (21.2% [95% CI ¼ 13.8e31.0], Fisher’s
574
CLINICAL ONCOLOGY
Table 1 e Predictors for objective tumour response Predictor
Crude odds ratio (95% CI)
Lymphangitis carcinomatosis Performance status (grade 0) Female gender Never-smoker
3.72 3.24 2.86 2.68
Adjusted odds ratio (95% CI)
(1.05e13.30) (1.23e8.64) (1.12e7.55) (1.10e7.17)
7.74 5.58 5.28 0.74
(1.74e38.88) (1.83e18.80) (1.06e30.00) (0.14e3.50)
P value 0.009 0.003 0.048 0.706
CI, confidence interval.
exact test, P ¼ 0.018) and the crude odds ratio was 3.72 (95% CI 1.05e13.30, Wald test, P ¼ 0.039). In the logistic regression analysis including proven predictors such as gender, smoking history and PS (Table 1), LC was an independent predictor for response and its adjusted odds ratio was the highest (7.74 [95% CI 1.74e38.88], Wald test, P ¼ 0.009) among the included predictors. In the present study, we showed that LC was a potential predictor for response in the Japanese adenocarcinoma population. Although the pathogenesis of LC is not fully understood, we thought it noteworthy that many of our patients with LC had shown a dramatic response. Recently, several studies have shown that specific mutations of the EGFR gene or the increased copy number of the EGFR gene were correlated with a response to gefitinib [4,5]. Larger prospective studies will be needed to confirm our finding and to clarify the associations between those gene alterations and LC. T. NAITO H. HASEGAWA K. ASADA T. SUDA K. CHIDA
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
doi:10.1016/j.clon.2006.05.006
Hepatocellular Carcinoma Presenting as Multifocal Haemorrhagic Encephalitis Sir d Paraneoplastic neurological disorders are autoimmune inflammatory disorders affecting the nervous system [1]. Neurological manifestations precede the detection of underlying malignancy in most patients. The immunological response initiated against tumour antigens causes damage to neural tissues that co-express onconeural proteins. We report a patient who presented with acute multifocal haemorrhagic encephalitis leading to early detection of hepatocellular carcinoma (HCC). A 69-year-old man with good past health presented with acute confusion and disorientation followed by memory loss. He had no fever or influenza-like illness in the preceding weeks. An examination revealed no meningism or focal neurological signs and other systems were normal. He developed generalised tonic clonic convulsions after admission.
References 1 Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237e2246. 2 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527e1537. 3 Goto K, Kim E, Kubota S, et al. Association of multiple pulmonary metastases with response to gefitinib in patients with non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 2004;22:679. 4 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350: 2129e2139. 5 Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829e6837.
His complete blood picture and renal function test were normal. The liver function test showed mildly raised bilirubin to 23 mmol/l only. The thyroid function test, syphilis serology, vitamin B12 and folate levels, and vasculitis markers were normal or negative. Magnetic resonance imaging (MRI) showed multifocal T2-weighted hyperintense signals in white matter, and small areas of cortical grey matter. There were small T1-weighted hyperintense signals compatible with haematomas (Fig. 1). MRI of cervical and thoracic spine were normal. A magnetic resonance (MR) angiogram revealed normal major arteries. MR spectroscopy showed a normal N-acetylaspartate peak, suggesting that neoplasm was unlikely. Cerebrospinal fluid was unremarkable, except for raised cerebrospinal fluid IgG to 6.3 mg/dl without oligoclonal bands; microbiological studies for bacterial, mycobacterial, fungal and viral infection were negative. Tumour markers including a-fetoprotein were normal. Computed tomography of the thorax was normal but computed tomography of the abdomen revealed a liver mass over the right lobe. He was seropositive for hepatitis B