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Symptoms of Colorectal Liver Metastases: Correlation with CT Findings
Clinical Oncology (2003) 15: 78–82 doi:10.1053/clon.2002.0139
Original Article Symptoms of Colorectal Liver Metastases: Correlation with CT Findings J. N. Harris*, P. Robinson*, J. Lawrance*, B. M. Carrington*, P. Hopwood†, M. Dougal‡, W. Makin§ *Departments of Radiology, †Psychiatry, ‡Medical Statistics and §Oncology, Christie Hospital, Manchester, U.K. ABSTRACT: Aim: To correlate CT appearances of colorectal liver metastases (LM) with pattern and severity of symptoms. Materials and methods: One hundred and twenty patients with treated primary colorectal carcinoma were prospectively assessed by questionnaire for recent symptoms when attending for CT examination. Thorax, abdomen and pelvic CT scans were prospectively assessed for LM and extrahepatic disease (EHD). The number of LM, percentage liver replaced by LM and distribution of LM were recorded. Results: Patients’ ages ranged from 35 to 89 years (median 60) and 74/120 (62%) were male. Four subgroups were compared: group 1 – LM only (n=30); 2 – EHD only (n=22); 3 – both LM and EHD (n=28); 4 – neither LM/EHD (n=40). Anorexia was significantly worse in gp2 vs gp4 (P=0.016) and lower abdominal pain (LAP) was significantly worse in gp2 vs gp1 (P=0.019). General pain was the worse symptom in all groups but notstatistically greater in any group. Patients with more than 10 LM had significantly worse anorexia (P=0.002), general pain (P<0.001) and LAP (P=0.001). There was a trend (P>0.05) towards worse symptoms with either volume of diseased liver or subcapsular LM. Conclusion: With increasing liver tumour burden there was an increase in symptomatology but extrahepatic abdominal metastatic tumour produced more symptoms than LM alone. Symptoms, particularly pain, therefore are not good predictors of hepatic metastatic disease. Lawrence, J. et al. (2003). Clinical Oncology 15, 78–82 2003 Published by Elsevier Science Ltd on behalf of The Royal College of Radiologists Key words: Colorectal carcinoma, liver metastases, computed tomography, symptoms, pain Received: 29 May 2002
Final revised form: 8th July 2002
Introduction
Colorectal carcinoma is the second most prevalent malignancy in the United Kingdom accounting for an annual mortality of 20,000 in the U.K. and 95,000 in Europe [1]. However approximately one fifth of cases will present initially with metastatic or locally advanced disease and recurrence usually occurs within 24 months of diagnosis [2]. This is most frequently due to liver metastases [3] and the median survival with secondary liver deposits is less than 12 months without chemotherapy [4]. Treatment options for liver metastases include potentially curative surgical resection [5], palliative chemotherapy [6], intrahepatic chemotherapy, radiofrequency thermal ablation [7] and cryotherapy [8]. Earlam et al. [9] have examined the relationship between intrahepatic tumour load, quality of life and life expectancy and shown that the volume of diseased liver was a Author for correspondence: Dr Jeremy A. L. Lawrance, Department of Radiology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, M20 4BX, U.K.Tel: 0161 446 3324; E-mail: [email protected] 0936–6555/03/020078+05 $30.00/0
Accepted: 15 July 2002
less accurate predictor of survival than a quality of life score. However the relationship between specific symptoms, especially pain, and the nature of colorectal liver metastases has not, to the best of our knowledge, been addressed. The aim of this study was to test the hypothesis that the nature and intensity of abdominal symptoms correlates with the extent and distribution of metastatic liver disease in patients with primary colorectal carcinoma.
Materials and Methods Patients
Following institutional ethics committee approval 120 consecutive patients with histologically confirmed colorectal carcinoma were recruited over 26 months. There were 74 (62%) men and 46 (38%) women. Ages ranged from 35 to 89 years with a median of 60 years. All patients had undergone complete primary tumour resection and, although Dukes’ classification varied, no patient had evidence of metastatic disease at the time of surgery. Following treatment all subjects attended
2003 Published by Elsevier Science Ltd on behalf of The Royal College of Radiologists
for routine computed tomography (CT) of the thorax, abdomen and pelvis at 6 monthly intervals. Some patients were scanned at 12 or 18 months and others were referred a month or so early because of symptoms.
Symptom Assessment
Patients were issued with a questionnaire at the time of their CT. They were asked to complete a 15 item self report scale which was a protocol specific measure based on the format of other standardized quality of life questionnaires [10]. Areas assessed included abdominal swelling, lower limb oedema, anorexia, heartburn, hiccups, nausea, vomiting, itch, breathlessness and pain. The specific sites of pain were also documented: shoulder, lower chest, upper/lower abdomen, back or other site. A body marker was also printed for patients to annotate the site of any pain. A response on a scale of 1 to 4 depending on severity was required. (1=‘not at all’, 2=‘a little’, 3=‘quite a bit’ and 4=‘very much’.) A numerical value was applied to each response (‘not at all’=score 0, ‘a little’=score 1, ‘quite a bit’=score 2 and ‘very much’=score 3) to enable analysis in the form of a ‘symptom score’.
CT and Imaging Analysis
CT sections on all patients were acquired on a GE Pace or CTi scanner (General Electric, Wisconsin, U.S.A.) employing non-ionic, intra-venous, contrast-enhanced contiguous 10 mm slices from the lung apices to the symphysis pubis. (Sections through the liver were acquired after a 70 s delay.) Two experienced oncological radiologists, blinded to the patient’s history and symptoms, assessed hard copy images of the CT examinations. Liver metastases were characterized as either cystic or solid. The number of deposits and the location of metastases were documented. The percentage of liver involved was assessed by visual assessment of the scan, a method considered to correlate closely with surgical findings [11]. Presence of disease in a subcapsular or subdiaphragmatic location was recorded and deposits adjacent to the porta hepatis, bare area or falciform ligament were also noted. Extrahepatic metastatic disease (ascites, subcapsular fluid, extrahepatic or coeliac axis lymph nodes and lung or bone metastases), gall stones and other lung disease were also documented.
Statistical Analysis
Statistical analysis was performed using SPSS statistics software package (SPSS Inc., Chicago, Illinois, U.S.A.) Mean symptom scores and frequencies of all radiological findings were calculated. Ordinal data was
79
Table 1 – Nature and frequency of extrahepatic disease Pathology Ascites Subcapsular fluid Gall stones Extrahepatic lymph nodes Coeliac axis nodes Lung metastases Other lung disease Bone metastases
Number of patients 8 9 11 10 17 31 9 5
analysed using the Kruskal–Wallis test. Where contingency tables were generated a variant of the chi-square test (likelihood ratio test) was employed to test for independence between variables. Differences were considered significant if the calculated probability was less than 5% (P<0.05).
Results
Fifty-eight (48%) patients had liver metastases and 62 (52%) had no hepatic deposits. Of those patients with liver disease there were 55 cases with solid metastases and three with cystic lesions. Fifty (60%) patients had extrahepatic disease with or without liver metastases. The nature of extrahepatic disease encountered and documented at the time of the CT examination is described in Table 1. Several patients had multiple sites of extrahepatic disease. Subjects were divided into four subgroups based on imaging findings. Those with only liver metastases and no extrahepatic disease formed group 1 (n=30), those with extrahepatic disease only and no liver metastases, group 2 (n=22), those with both liver metastases and extrahepatic disease, group 3 (n=28), and those with neither liver metastases nor extrahepatic disease, group 4 n=40). The symptom profiles for each group were compared using the mean symptom score for every symptom questioned. Pain was clearly the most important symptom for all groups, especially those with neither liver metastases nor extrahepatic disease (group 4; Fig. 1). However pain was not statistically worse in any one group. Anorexia was a statistically more important symptom in those with only extrahepatic disease (group 2) when compared to those with neither liver metastases nor extrahepatic disease (group 4) (P=0.016). Lower abdominal pain was also statistically worse in those with only extrahepatic disease (group 2) when compared to those with liver deposits only (group 1) (P=0.019). No other significance was revealed between the groups. When comparing all patients with 10 or more metastases to those with fewer deposits, anorexia,
80
Fig. 1 – Symptom scores for all four groups. Scores are corrected for the number in each group, allowing direct comparison of the intensity of each symptom between groups. ‘a’=Abdominal swelling; ‘b’=lower limb swelling; ‘c’=anorexia; ‘d’=heartburn; ‘e’=hiccoughs; ‘f’=nausea; ‘g’=vomiting; ‘h’=itching; ‘i’=short of breath; ‘j’=general pain; ‘k’=shoulder pain; ‘l’=lower chest pain; ‘m’= upper abdominal pain; ‘n’=lower abdominal pain; ‘o’=back pain. ( ) Gp 1 (LM only); ( ) Gp 2 (EHD only); ( ) Gp 3 (LM+EHD); ( ) Gp 4 (neither LM/EHD).
Fig. 2 – Comparison of symptom scores according to number of LM. Each bar represents the percentage of cases with a symptom score of 0 or 3 (i.e. ‘no’ or ‘a lot’ of a symptom) for one to nine liver metastases ( ) and more than 10 metastases ( ).
general pain and lower abdominal pain were all statistically worse in those with more disease (P=0.002, P<0.001 and P=0.001 respectively; Fig. 2). However shoulder and upper abdominal pain, symptoms which may be expected to be related to the presence of liver metastases, were not significantly different (P>0.05). To establish if the volume of liver involved with metastases correlated with symptoms, cases were divided according to the percentage hepatic replacement (Table 2). As the numbers in each decile were small it was inappropriate to analyse across the percentage groups. Instead, for each symptom, the percentage liver involved was assessed. A greater percentage liver involved was
seen in patients with more severe (symptom score of 3) lower limb swelling, anorexia, itching, general pain, shoulder pain and back pain. However no statistical significance could be deduced, even by excluding those with extrahepatic disease (P>0.05), as the standard deviations were close to or greater than the means in all cases. A final analysis examined the intensity of symptoms according to the location of liver deposits. Patients were divided into those with lesions placed either deep within the liver or peripherally located. Forty-five of the 58 subjects with liver disease (78%) had at least some peripheral involvement. Only general pain appeared to
Table 2 – Number (%) cases according to the percentage hepatic replacement Percentage liver involved 0 1 to 9 10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 >60 No Data TOTAL
Number of cases 62 (52) 28 (23) 5 (4) 4 (3) 4 (3) 7 (6) 3 (3) 3 (3) 4 (3) 120 (100)
be more important in those with peripheral disease but this was not statistically significant (P=0.17). Excluding the presence of extrahepatic disease did not reveal any significance either (P>0.05). Discussion
Colorectal carcinoma may cause many symptoms of varied intensity. Pain is usually the symptom of greatest concern and its mechanism depends on the extent of disease. It is recognized that hepatic metastases may stretch the liver capsule and induce discomfort, the so-called hepatic distension syndrome [12]. As pain sensitive nociceptors innervate Glisson’s capsule that encloses the liver, stretching by metastases may cause right subcostal, right mid-back and flank discomfort. Pain may even be referred to the right neck and shoulder [12]. In this study pain was the most frequent and intense symptom reported irrespective of disease spread. In fact, although not statistically significant, pain appeared to be worse in subjects with neither liver metastases nor extrahepatic disease. In patients with liver deposits there was a trend, although not statistically significant, towards greater discomfort with a large volume of liver disease and also with metastases close to the liver surface. Statistical insignificance may be partially due to the subjective nature of pain, which is therefore difficult to quantify and may vary according to an individual’s experiences. Also some lack of statistical significance may be attributed to the inherent heterogeneity within the study population in terms of initial local staging of disease and the exact treatment received following diagnosis. Other important symptoms revealed include loss of appetite. This symptom was statistically worse in those with widespread extrahepatic disease compared to those with no evidence of dissemination (P=0.016). Lower abdominal pain was also significantly more severe in patients with extrahepatic disease compared to individuals with liver infiltration only (P=0.019). Larger numbers of liver metastases were seen to correlate
81
significantly with more general pain, lower abdominal pain and anorexia. Earlam et al. [9] have previously examined the impact of colorectal liver metastases on quality of life and survival. They prospectively assessed psychological and physical symptoms from the time of CT confirmed liver infiltration by the use of monthly questionnaires. Initial Dukes’ classification of the primary tumour was not associated with a worse survival although the percentage liver replaced by metastases was. Life expectancy however was more accurately predicted by a quality of life score than the degree of liver disease. The volume of liver affected by metastases appeared to be statistically associated with a worse physical symptom score but the number and distribution of deposits was not addressed as in our study. We have demonstrated a trend towards more severe symptoms and extent of liver disease. However, of all the symptoms addressed, only pain and anorexia were statistically worse with greater numbers of metastases. No significant differences were revealed with volume or distribution of liver disease. Also we did not demonstrate a statistically significant difference in both the nature and intensity of pain between patients with no CT evidence of disease spread and those with established liver or other secondary disease. There is still no consensus therefore to support the commonly accepted notion that more severe symptoms are intrinsically related to the degree of secondary hepatic malignant disease. Symptoms may have more than one origin and therefore we conclude that symptoms, especially pain, are difficult to use as predictors for possible metastatic spread. References 1 Schofield JH. ABC colorectal cancer. Screening. BMJ 2000; 321:1004–1006. 2 McArdle C. ABC of colorectal cancer. Effectiveness of follow up. BMJ 2000;321:1332–1335. 3 Thoeni RF, Moss AA. The gastrointestinal tract. In: Moss AA, Gamsu G, Genant HK, eds. Computed tomography of the body. Philadelphia, PA,U.S.A.: Saunders, 1992;643–735. 4 Alexander HR, Allegra CJ, Lawrence TS. Metastatic cancer to the liver. In: DeVita T, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology, Philadelphia, U.S.A.: Lippincott Williams and Williams, 6th edn. 2001;2690–2713. 5 Scheele J, Altendorf-Hofman A. Resection of colorectal liver metastases. Langenbecks Arch Surg 1999;384:313–327. 6 Michael, Zalcberg. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531–535. 7 Soliati L, Ierace T, Tonolini M, Osti V, Cova L. Radiofrequency thermal ablation of hepatic metastases. Eur J Ultrasound 2001;13:149–158. 8 Adam R, Akpinar E, Johann M et al. Place of cryosurgery in the treatment of malignant liver tumours. Ann Surg 1997;225:39–50. 9 Earlam S, Glover C, Fordy C, Burke D, Allen-Mersh TG. Relation between tumour size, quality of life, and survival in patients with colorectal liver metastases. J Clin Oncol 1996;14:171–175. 10 Aaronson N, Ahmedzai S, Bergman B, Bullinger M et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Nat Cancer Institute 1993;85: 365–376.
82
11 Hunt TM, Flowerdew AD, Taylor I et al. A comparison of methods to measure the hepatic replacement with colorectal metastases. Ann R Coll Surg Engl 1989;71:11–13.
12 Cherney NI, Portenoy RK. Cancer pain: principles of assessment and syndromes. In: Wall PD, Melzack R, eds. Textbook of Pain. Hong Kong: Churchill Livingstone, 1999;1017–1064.
Original Article Symptoms of Colorectal Liver Metastases: Correlation with CT Findings J. N. Harris*, P. Robinson*, J. Lawrance*, B. M. Carrington*, P. Hopwood†, M. Dougal‡, W. Makin§ *Departments of Radiology, †Psychiatry, ‡Medical Statistics and §Oncology, Christie Hospital, Manchester, U.K. ABSTRACT: Aim: To correlate CT appearances of colorectal liver metastases (LM) with pattern and severity of symptoms. Materials and methods: One hundred and twenty patients with treated primary colorectal carcinoma were prospectively assessed by questionnaire for recent symptoms when attending for CT examination. Thorax, abdomen and pelvic CT scans were prospectively assessed for LM and extrahepatic disease (EHD). The number of LM, percentage liver replaced by LM and distribution of LM were recorded. Results: Patients’ ages ranged from 35 to 89 years (median 60) and 74/120 (62%) were male. Four subgroups were compared: group 1 – LM only (n=30); 2 – EHD only (n=22); 3 – both LM and EHD (n=28); 4 – neither LM/EHD (n=40). Anorexia was significantly worse in gp2 vs gp4 (P=0.016) and lower abdominal pain (LAP) was significantly worse in gp2 vs gp1 (P=0.019). General pain was the worse symptom in all groups but notstatistically greater in any group. Patients with more than 10 LM had significantly worse anorexia (P=0.002), general pain (P<0.001) and LAP (P=0.001). There was a trend (P>0.05) towards worse symptoms with either volume of diseased liver or subcapsular LM. Conclusion: With increasing liver tumour burden there was an increase in symptomatology but extrahepatic abdominal metastatic tumour produced more symptoms than LM alone. Symptoms, particularly pain, therefore are not good predictors of hepatic metastatic disease. Lawrence, J. et al. (2003). Clinical Oncology 15, 78–82 2003 Published by Elsevier Science Ltd on behalf of The Royal College of Radiologists Key words: Colorectal carcinoma, liver metastases, computed tomography, symptoms, pain Received: 29 May 2002
Final revised form: 8th July 2002
Introduction
Colorectal carcinoma is the second most prevalent malignancy in the United Kingdom accounting for an annual mortality of 20,000 in the U.K. and 95,000 in Europe [1]. However approximately one fifth of cases will present initially with metastatic or locally advanced disease and recurrence usually occurs within 24 months of diagnosis [2]. This is most frequently due to liver metastases [3] and the median survival with secondary liver deposits is less than 12 months without chemotherapy [4]. Treatment options for liver metastases include potentially curative surgical resection [5], palliative chemotherapy [6], intrahepatic chemotherapy, radiofrequency thermal ablation [7] and cryotherapy [8]. Earlam et al. [9] have examined the relationship between intrahepatic tumour load, quality of life and life expectancy and shown that the volume of diseased liver was a Author for correspondence: Dr Jeremy A. L. Lawrance, Department of Radiology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, M20 4BX, U.K.Tel: 0161 446 3324; E-mail: [email protected] 0936–6555/03/020078+05 $30.00/0
Accepted: 15 July 2002
less accurate predictor of survival than a quality of life score. However the relationship between specific symptoms, especially pain, and the nature of colorectal liver metastases has not, to the best of our knowledge, been addressed. The aim of this study was to test the hypothesis that the nature and intensity of abdominal symptoms correlates with the extent and distribution of metastatic liver disease in patients with primary colorectal carcinoma.
Materials and Methods Patients
Following institutional ethics committee approval 120 consecutive patients with histologically confirmed colorectal carcinoma were recruited over 26 months. There were 74 (62%) men and 46 (38%) women. Ages ranged from 35 to 89 years with a median of 60 years. All patients had undergone complete primary tumour resection and, although Dukes’ classification varied, no patient had evidence of metastatic disease at the time of surgery. Following treatment all subjects attended
2003 Published by Elsevier Science Ltd on behalf of The Royal College of Radiologists
for routine computed tomography (CT) of the thorax, abdomen and pelvis at 6 monthly intervals. Some patients were scanned at 12 or 18 months and others were referred a month or so early because of symptoms.
Symptom Assessment
Patients were issued with a questionnaire at the time of their CT. They were asked to complete a 15 item self report scale which was a protocol specific measure based on the format of other standardized quality of life questionnaires [10]. Areas assessed included abdominal swelling, lower limb oedema, anorexia, heartburn, hiccups, nausea, vomiting, itch, breathlessness and pain. The specific sites of pain were also documented: shoulder, lower chest, upper/lower abdomen, back or other site. A body marker was also printed for patients to annotate the site of any pain. A response on a scale of 1 to 4 depending on severity was required. (1=‘not at all’, 2=‘a little’, 3=‘quite a bit’ and 4=‘very much’.) A numerical value was applied to each response (‘not at all’=score 0, ‘a little’=score 1, ‘quite a bit’=score 2 and ‘very much’=score 3) to enable analysis in the form of a ‘symptom score’.
CT and Imaging Analysis
CT sections on all patients were acquired on a GE Pace or CTi scanner (General Electric, Wisconsin, U.S.A.) employing non-ionic, intra-venous, contrast-enhanced contiguous 10 mm slices from the lung apices to the symphysis pubis. (Sections through the liver were acquired after a 70 s delay.) Two experienced oncological radiologists, blinded to the patient’s history and symptoms, assessed hard copy images of the CT examinations. Liver metastases were characterized as either cystic or solid. The number of deposits and the location of metastases were documented. The percentage of liver involved was assessed by visual assessment of the scan, a method considered to correlate closely with surgical findings [11]. Presence of disease in a subcapsular or subdiaphragmatic location was recorded and deposits adjacent to the porta hepatis, bare area or falciform ligament were also noted. Extrahepatic metastatic disease (ascites, subcapsular fluid, extrahepatic or coeliac axis lymph nodes and lung or bone metastases), gall stones and other lung disease were also documented.
Statistical Analysis
Statistical analysis was performed using SPSS statistics software package (SPSS Inc., Chicago, Illinois, U.S.A.) Mean symptom scores and frequencies of all radiological findings were calculated. Ordinal data was
79
Table 1 – Nature and frequency of extrahepatic disease Pathology Ascites Subcapsular fluid Gall stones Extrahepatic lymph nodes Coeliac axis nodes Lung metastases Other lung disease Bone metastases
Number of patients 8 9 11 10 17 31 9 5
analysed using the Kruskal–Wallis test. Where contingency tables were generated a variant of the chi-square test (likelihood ratio test) was employed to test for independence between variables. Differences were considered significant if the calculated probability was less than 5% (P<0.05).
Results
Fifty-eight (48%) patients had liver metastases and 62 (52%) had no hepatic deposits. Of those patients with liver disease there were 55 cases with solid metastases and three with cystic lesions. Fifty (60%) patients had extrahepatic disease with or without liver metastases. The nature of extrahepatic disease encountered and documented at the time of the CT examination is described in Table 1. Several patients had multiple sites of extrahepatic disease. Subjects were divided into four subgroups based on imaging findings. Those with only liver metastases and no extrahepatic disease formed group 1 (n=30), those with extrahepatic disease only and no liver metastases, group 2 (n=22), those with both liver metastases and extrahepatic disease, group 3 (n=28), and those with neither liver metastases nor extrahepatic disease, group 4 n=40). The symptom profiles for each group were compared using the mean symptom score for every symptom questioned. Pain was clearly the most important symptom for all groups, especially those with neither liver metastases nor extrahepatic disease (group 4; Fig. 1). However pain was not statistically worse in any one group. Anorexia was a statistically more important symptom in those with only extrahepatic disease (group 2) when compared to those with neither liver metastases nor extrahepatic disease (group 4) (P=0.016). Lower abdominal pain was also statistically worse in those with only extrahepatic disease (group 2) when compared to those with liver deposits only (group 1) (P=0.019). No other significance was revealed between the groups. When comparing all patients with 10 or more metastases to those with fewer deposits, anorexia,
80
Fig. 1 – Symptom scores for all four groups. Scores are corrected for the number in each group, allowing direct comparison of the intensity of each symptom between groups. ‘a’=Abdominal swelling; ‘b’=lower limb swelling; ‘c’=anorexia; ‘d’=heartburn; ‘e’=hiccoughs; ‘f’=nausea; ‘g’=vomiting; ‘h’=itching; ‘i’=short of breath; ‘j’=general pain; ‘k’=shoulder pain; ‘l’=lower chest pain; ‘m’= upper abdominal pain; ‘n’=lower abdominal pain; ‘o’=back pain. ( ) Gp 1 (LM only); ( ) Gp 2 (EHD only); ( ) Gp 3 (LM+EHD); ( ) Gp 4 (neither LM/EHD).
Fig. 2 – Comparison of symptom scores according to number of LM. Each bar represents the percentage of cases with a symptom score of 0 or 3 (i.e. ‘no’ or ‘a lot’ of a symptom) for one to nine liver metastases ( ) and more than 10 metastases ( ).
general pain and lower abdominal pain were all statistically worse in those with more disease (P=0.002, P<0.001 and P=0.001 respectively; Fig. 2). However shoulder and upper abdominal pain, symptoms which may be expected to be related to the presence of liver metastases, were not significantly different (P>0.05). To establish if the volume of liver involved with metastases correlated with symptoms, cases were divided according to the percentage hepatic replacement (Table 2). As the numbers in each decile were small it was inappropriate to analyse across the percentage groups. Instead, for each symptom, the percentage liver involved was assessed. A greater percentage liver involved was
seen in patients with more severe (symptom score of 3) lower limb swelling, anorexia, itching, general pain, shoulder pain and back pain. However no statistical significance could be deduced, even by excluding those with extrahepatic disease (P>0.05), as the standard deviations were close to or greater than the means in all cases. A final analysis examined the intensity of symptoms according to the location of liver deposits. Patients were divided into those with lesions placed either deep within the liver or peripherally located. Forty-five of the 58 subjects with liver disease (78%) had at least some peripheral involvement. Only general pain appeared to
Table 2 – Number (%) cases according to the percentage hepatic replacement Percentage liver involved 0 1 to 9 10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 >60 No Data TOTAL
Number of cases 62 (52) 28 (23) 5 (4) 4 (3) 4 (3) 7 (6) 3 (3) 3 (3) 4 (3) 120 (100)
be more important in those with peripheral disease but this was not statistically significant (P=0.17). Excluding the presence of extrahepatic disease did not reveal any significance either (P>0.05). Discussion
Colorectal carcinoma may cause many symptoms of varied intensity. Pain is usually the symptom of greatest concern and its mechanism depends on the extent of disease. It is recognized that hepatic metastases may stretch the liver capsule and induce discomfort, the so-called hepatic distension syndrome [12]. As pain sensitive nociceptors innervate Glisson’s capsule that encloses the liver, stretching by metastases may cause right subcostal, right mid-back and flank discomfort. Pain may even be referred to the right neck and shoulder [12]. In this study pain was the most frequent and intense symptom reported irrespective of disease spread. In fact, although not statistically significant, pain appeared to be worse in subjects with neither liver metastases nor extrahepatic disease. In patients with liver deposits there was a trend, although not statistically significant, towards greater discomfort with a large volume of liver disease and also with metastases close to the liver surface. Statistical insignificance may be partially due to the subjective nature of pain, which is therefore difficult to quantify and may vary according to an individual’s experiences. Also some lack of statistical significance may be attributed to the inherent heterogeneity within the study population in terms of initial local staging of disease and the exact treatment received following diagnosis. Other important symptoms revealed include loss of appetite. This symptom was statistically worse in those with widespread extrahepatic disease compared to those with no evidence of dissemination (P=0.016). Lower abdominal pain was also significantly more severe in patients with extrahepatic disease compared to individuals with liver infiltration only (P=0.019). Larger numbers of liver metastases were seen to correlate
81
significantly with more general pain, lower abdominal pain and anorexia. Earlam et al. [9] have previously examined the impact of colorectal liver metastases on quality of life and survival. They prospectively assessed psychological and physical symptoms from the time of CT confirmed liver infiltration by the use of monthly questionnaires. Initial Dukes’ classification of the primary tumour was not associated with a worse survival although the percentage liver replaced by metastases was. Life expectancy however was more accurately predicted by a quality of life score than the degree of liver disease. The volume of liver affected by metastases appeared to be statistically associated with a worse physical symptom score but the number and distribution of deposits was not addressed as in our study. We have demonstrated a trend towards more severe symptoms and extent of liver disease. However, of all the symptoms addressed, only pain and anorexia were statistically worse with greater numbers of metastases. No significant differences were revealed with volume or distribution of liver disease. Also we did not demonstrate a statistically significant difference in both the nature and intensity of pain between patients with no CT evidence of disease spread and those with established liver or other secondary disease. There is still no consensus therefore to support the commonly accepted notion that more severe symptoms are intrinsically related to the degree of secondary hepatic malignant disease. Symptoms may have more than one origin and therefore we conclude that symptoms, especially pain, are difficult to use as predictors for possible metastatic spread. References 1 Schofield JH. ABC colorectal cancer. Screening. BMJ 2000; 321:1004–1006. 2 McArdle C. ABC of colorectal cancer. Effectiveness of follow up. BMJ 2000;321:1332–1335. 3 Thoeni RF, Moss AA. The gastrointestinal tract. In: Moss AA, Gamsu G, Genant HK, eds. Computed tomography of the body. Philadelphia, PA,U.S.A.: Saunders, 1992;643–735. 4 Alexander HR, Allegra CJ, Lawrence TS. Metastatic cancer to the liver. In: DeVita T, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology, Philadelphia, U.S.A.: Lippincott Williams and Williams, 6th edn. 2001;2690–2713. 5 Scheele J, Altendorf-Hofman A. Resection of colorectal liver metastases. Langenbecks Arch Surg 1999;384:313–327. 6 Michael, Zalcberg. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531–535. 7 Soliati L, Ierace T, Tonolini M, Osti V, Cova L. Radiofrequency thermal ablation of hepatic metastases. Eur J Ultrasound 2001;13:149–158. 8 Adam R, Akpinar E, Johann M et al. Place of cryosurgery in the treatment of malignant liver tumours. Ann Surg 1997;225:39–50. 9 Earlam S, Glover C, Fordy C, Burke D, Allen-Mersh TG. Relation between tumour size, quality of life, and survival in patients with colorectal liver metastases. J Clin Oncol 1996;14:171–175. 10 Aaronson N, Ahmedzai S, Bergman B, Bullinger M et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Nat Cancer Institute 1993;85: 365–376.
82
11 Hunt TM, Flowerdew AD, Taylor I et al. A comparison of methods to measure the hepatic replacement with colorectal metastases. Ann R Coll Surg Engl 1989;71:11–13.
12 Cherney NI, Portenoy RK. Cancer pain: principles of assessment and syndromes. In: Wall PD, Melzack R, eds. Textbook of Pain. Hong Kong: Churchill Livingstone, 1999;1017–1064.