Estimation of the Time of Pulmonary Metastasis in Colorectal Cancer Patients with Isolated Synchronous Liver Metastasis

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1 Jpn J Clin Oncol 2005;35(1)18 22 doi: /jjco/hyi010 Estimation of the Time of Pulmonary Metastasis in Colorectal Cancer Patients with Isolated Synchronous Liver Metastasis Sotaro Sadahiro 1, Toshiyuki Suzuki 1, Kenji Ishikawa 1, Tomoki Nakamura 1, Yoichi Tanaka 1, Kazuhiro Ishizu 1, Seiei Yasuda 1, Hiroyasu Makuuchi 1 and Chieko Murayama 2 1 Department of Surgery and 2 Radiology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan Received September 5, 2004; accepted November 20, 2004 Objective: The aim of this study was to estimate the time when pulmonary metastases began to grow in colorectal cancer (CRC) patients with isolated synchronous liver metastasis based on the tumor doubling time (DT). Methods: We examined 23 pulmonary metastases in 14 patients detected after resection of liver metastases from CRC (group 1) and 19 pulmonary metastases in eight patients detected after initiation of hepatic arterial infusion chemotherapy for synchronous unresectable liver metastases (group 2). The regression line was determined from the chest X-ray films, and the DT was calculated. Results: We estimated the DTs of pulmonary metastases as and days in groups 1 and 2, respectively, and the time when pulmonary metastases began to grow as and days before the resection of liver metastases for 19 lesions in 12 out of 14 patients of group 1 and before resection of primary CRC in group 2, respectively. Conclusion: It appears that in some CRC patients in whom the metastatic site is considered to be limited to the liver at diagnosis, occult pulmonary metastasis has already taken place. Key words: colorectal cancer liver metastasis pulmonary metastasis tumor doubling time INTRODUCTION In patients with colorectal cancer (CRC), the most frequent metastatic site is the liver (1,2). When the liver is the only metastatic site, liver resection is performed in resectable cases, and hepatic arterial infusion (HAI) chemotherapy or systemic chemotherapy is performed in unresectable cases. Among them, liver resection and HAI chemotherapy are both local therapies. In patients with resectable hepatic metastases from CRC, recurrences are found in two-thirds of those who undergo liver resection, with the 5-year disease-free survival variously reported to be 15% (3), 28% (4) or 34% (5) after curative resection of liver metastases, which is not satisfactory at all. The percentage of patients whose recurrence site after liver resection is limited to the liver is variously reported as 41% (6), 47% (7) or 48% (8), with a high frequency of metastasis to other organs (9), the lung being the highest (10,11). In patients with unresectable hepatic metastases, development of extrahepatic metastases during the HAI chemotherapy period is often experienced (12 14). For reprints and all correspondence: Sotaro Sadahiro, Department of Surgery, Tokai University, Bohseidai Isehara, Kanagawa , Japan. sadahiro@is.icc.u-tokai.ac.jp Recently, significantly favorable disease-free survival was reported in patients who received combined HAI chemotherapy and systemic chemotherapy after liver resection for resectable hepatic metastases (15). On the other hand, in patients with unresectable hepatic metastases, favorable outcomes have been reported in those who underwent liver resection after the hepatic metastases became resectable because of systemic chemotherapy or HAI chemotherapy (16 18). A meta-analysis comparing HAI chemotherapy and systemic chemotherapy for unresectable hepatic metastases showed that the former yielded a significantly favorable response rate as compared with the latter, but no survival benefit (19). These findings strongly suggest that sufficient survival benefit cannot be obtained by liver resection or HAI chemotherapy alone, because both are local therapies and cannot prevent new development of extrahepatic metastases. Accordingly, we should consider suppressing possible extrahepatic metastases as well in order to improve the therapeutic outcome of hepatic metastases from CRC. To investigate the treatment strategy for synchronous liver metastasis from colorectal cancer, we need to estimate the time when extrahepatic metastases took place in patients whose extrahepatic metastases were discovered after hepatic metastases had been treated. Therefore, we examined in this study the patients with CRC having isolated synchronous liver metastases whose pulmonary metastases were detected after # 2005 Foundation for Promotion of Cancer Research

2 Jpn J Clin Oncol 2005;35(1) 19 liver resection and also whose pulmonary metastases were detected while undergoing HAI chemotherapy for unresectable liver metastases. PATIENTS AND METHODS Between 1981 and 1999, there were 117 CRC patients with isolated synchronous liver metastasis in our hospital. In 49 patients, liver resection was performed in addition to colorectal resection at the initial surgery. In 68 patients whose liver metastases were diagnosed as unresectable, resection of the primary CRC alone was performed. Fifty-one out of 68 patients received HAI chemotherapy with 5-fluorouracil (5-FU) post-operatively. 5-FU was infused continuously for 7 days biweekly and repeated in most cases (20,21). We investigated 23 pulmonary metastatic lesions in 14 patients who had undergone liver resection (group 1) and 19 pulmonary metastatic lesions in eight patients who had received HAI chemotherapy (group 2), the patients in both groups having assessable pulmonary metastases, followed by three or more chest X-ray examinations. In eight out of 14 patients who had undergone liver resection (group 1), HAI chemotherapy with 5-FU was performed postoperatively as adjuvant chemotherapy. Oral fluoropyrimidine alone was administered to the other two patients for >3 months. The other two patients received both HAI and oral fluoropyrimidines. The remaining two patients received no adjuvant chemotherapy. Eight patients who were diagnosed as having unresectable metastasis (group 2) received 5-FU HAI chemotherapy without systemic chemotherapy. We retrospectively measured the size of pulmonary metastases in two directions on the chest X-ray films. Tumor doubling time (DT) was calculated from the following equations (22). Using the equation DT = 0.1(t t 0 )/log dt log d 0, the regression line log d = at + b was obtained, and DT = log 2/3 a was calculated. At the time of resection of the primary colorectal cancer, t equals 0 (t = 0), and thus the size of the pulmonary metastatic lesion at the time of resection of primary colorectal cancer was calculated from log d = b. RESULTS Table 1 shows the DT of 23 pulmonary metastases in 14 patients who underwent liver resection (group 1), the estimated time when pulmonary metastasis began to grow, and the estimated size of pulmonary metastases at the time of resection of the primary CRC and liver metastasis. The DT of pulmonary metastases was days. The time when pulmonary metastases began to grow for 19 lesions in 12 out of 14 patients was estimated to be days (median, 373 days) before the resection of primary CRC and liver metastases. The size of these pulmonary metastases at the time of resection of the primary CRC and liver metastases was estimated to be mm (median, 3.1 mm). The time when pulmonary metastases began to grow for four lesions in three out of 14 patients was estimated to be days after the resection of the primary CRC and liver metastases. In all of these three cases where the pulmonary metastases were considered to have occurred after the resection of primary CRC and liver metastases, other metastases had already been detected in the remnant liver or at local sites before the detection of pulmonary metastasis. Table 2 shows the DT of 19 pulmonary metastases in eight patients who received HAI chemotherapy after resection of the primary CRC alone because the liver metastasis was diagnosed as unresectable (group 2), the estimated time when pulmonary metastases began to grow, and the estimated size of pulmonary metastases at the time of resection of the primary CRC. The DT of pulmonary metastases was days, with no significant difference from that of group 1. In one out of eight patients, peritoneal metastasis was detected synchronously with pulmonary metastases. The time when pulmonary metastases began to grow in 19 lesions was estimated to be before the resection of primary CRC, being days (median, 502 days) before the resection. The size of pulmonary metastases at the time of resection of the primary CRC was estimated to be mm (median, 4.2 mm). No difference was observed in the DT between the seven lesions in four patients who received systemic chemotherapy with oral fluoropyrimidine after liver resection, and the 16 lesions in 10 patients without (Table 3). There was also no difference in the DT between the 37 lesions in 18 patients who received 5-FU HAI chemotherapy after liver resection or for unresectable liver metastases and the five lesions in four patients without. DISCUSSION HAI chemotherapy for liver metastasis from CRC has yielded a significantly favorable response rate compared with systemic chemotherapy, but no survival benefit (19). It may be mainly because both liver resection and HAI chemotherapy are local therapies and thus cannot prevent new development of extrahepatic metastases. Safi et al. reported that the combined use of HAI chemotherapy and systemic chemotherapy for liver metastasis from CRC reduced the frequency of extrahepatic spread of cancer as compared with HAI chemotherapy alone (23). Significantly favorable disease-free survival was also reported recently with the combined use of HAI chemotherapy and systemic chemotherapy after liver resection (15). These results indicate that we need to suppress extrahepatic metastases along with treating liver metastases to improve further the therapeutic outcome in patients with isolated liver metastasis from CRC. In order to do so, it is crucial that we know the time when extrahepatic metastasis begins to grow. Based on the chest X-ray films, Collins (24) reported the mean DT of pulmonary metastases in CRC to be 116 days (range, days) in 25 lesions, whereas Spratt and Spratt (25) reported it to be 109 days in 10 lesions. The overall DT of 42 lesions that we examined in this study was days, being shorter compared with those previously reported. Basing our calculations on this DT, we estimated the time

3 20 Time of development of CRC metastasis Table 1. Lung metastasis (MET) from colorectal cancer in patients who underwent liver resection (group 1) Case MET site following liver resection prior to lung MET Lesion Interval between initial surgery and clinical lung MET (days) Tumor doubling time (days) Development of lung MET prior to initial surgery (days) 1 Liver, local Local Liver None Local None Local None Liver None Lymph node Local Liver Liver Size of lung MET at initial surgery (mm) when pulmonary metastases began to grow in 14 patients in whom pulmonary metastases were newly detected during the follow-up period after resection of primary site and liver metastasis (group 1) to be days (median, 373 days) before the resection in 19 lesions in 12 patients, with the size of pulmonary metastases estimated as having already reached mm (median, 3.1 mm) at the time of resection of the primary CRC and liver metastases. In four lesions in three patients, the development time of pulmonary metastases was estimated to be days after the resection. In all these three cases, new metastases had been detected in the remnant liver or at local sites before pulmonary metastasis was diagnosed, indicating that the pulmonary metastasis may be a secondary metastasis from the remnant liver or local sites. In addition, in patients in whom pulmonary metastases were detected during or after receiving HAI chemotherapy for liver metastases (group 2), the time when pulmonary metastases began to grow was estimated to be days (median, 502 days) before the resection of the primary site of the CRC and initiation of HAI chemotherapy. The size of pulmonary metastases was estimated to have already reached mm (median, 4.2 mm) by the time of surgery for the primary lesion, thus indicating that the pulmonary metastases did not develop during HAI chemotherapy. Adjuvant chemotherapy has been reported to prolong disease-free survival (26 28). We have reported that, in cases where recurrence occurred after curative resection, the intervals between surgery and recurrence with or without adjuvant chemotherapy were and months, respectively, in colon cancer, and and months, respectively, in rectal cancer, indicating that adjuvant chemotherapy significantly prolonged the interval until recurrence (29). In this study, however, although the DT of pulmonary metastases with systemic chemotherapy or HAI chemotherapy after liver resection tended to be longer compared with that of patients without chemotherapies, the difference was not significant and the effect of chemotherapy on the tumor DT was not clear. Using the reverse transcription polymerase chain reaction (RT PCR) technique, detection of a minute amount of cancer cells in the blood has become possible. Hayashi et al. (30) and Miyazono et al. (31) reported that an increase in detection rate of cancer cells in the blood due to intraoperative manipulation could accelerate metastasis. However, we have reported that using semi-nested RT PCR with CEA mrna as a target, we

4 Jpn J Clin Oncol 2005;35(1) 21 Table 2. Lung metastasis (MET) from colorectal cancer in patients who underwent hepatic arterial infusion chemotherapy (group 2) Case MET site following liver resection prior to lung MET Lesion Interval between initial surgery and clinical lung MET (days) Tumor doubling time (days) Development of lung MET prior to initial surgery (days) 15 None None None Peritoneum None None None None Size of lung MET at initial surgery (mm) Table 3. Relationship between the tumor doubling time and chemotherapy No. of lesions Doubling time (days) P-value Hepaticarterial infusion chemotherapy Yes No Systemic chemotherapy Yes No detected cancer cells in the portal vein and peripheral blood immediately after celiotomy and before examining the tumorbearing bowel, and that there was no significant difference in the expression level of CEA mrna between the blood from the portal vein and from peripheral blood, with a detection rate reaching as high as 38% even in early cancer of stage I (32). From these results, it was assumed that in many patients with CRC, cancer cells are shed into the bloodstream before a clinical diagnosis of cancer is made. Our results show that most of the pulmonary metastases which developed during the follow-up period in patients with synchronous liver metastases were already present at the time when CRC was diagnosed, at a size of 34 mm. In conclusion, it appears that some CRC patients already have pulmonary metastases even when the metastatic sites are considered to be limited to the liver. Therefore, we should consider suppressing possible extrahepatic metastases as well to improve the therapeutic outcome of synchronous hepatic metastases from CRC. However, we cannot at present differentiate these patients with occult metastasis from others. References 1. Galandiuk S, Wieand HS, Moertel CG, Cha SS, Fitzgibbons RJ Jr, Pemberton JH et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet 1992;174: Tominaga T, Sakabe T, Koyama Y, Hamano K, Yasutomi M, Takahashi T et al. Prognostic factors for patients with colon or rectal carcinoma treated with resection only. Five-year follow-up report. Cancer 1996;78: Nordlinger B, Guiguet M, Vaillant J, Balladur P, Boudjema K, Bachellier P et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer 1996;77: Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235: Scheele J, Stangl R, Altendorf-Hofmann A, Gall FP. Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 1991;110: Gennari L, Doci R, Bignami P, Bozzetti F. Surgical treatment of hepatic metastases from colorectal cancer. Ann Surg 1986;2003: Hohenberger P, Schlag P, Schwarz V, Herfarth C. Tumor recurrence and options for further treatment after resection of liver metastases in patients with colorectal cancer. J Surg Oncol 1990;44: Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15: Cady B, Jenkins RL, Steele GD Jr, Lewis WD, Stone MD, McDermott WV et al. Surgical margin in hepatic resection for colorectal metastasis: a

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