Treatment and outcome of intrahepatic cholangiocellular carcinoma

The American Journal of Surgery 189 (2005) 173–177

Rapid communication

Treatment and outcome of intrahepatic cholangiocellular carcinoma Harald Puhalla, M.D.a, Birgit Schuell, M.D.b, Herwig Pokorny, M.D.a, Gabriela Verena Kornek, Prof.b, Werner Scheithauer, Prof.b, Thomas Gruenberger, Prof.a,* a

Department of General Surgery, General Hospital, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria b Department of Internal Medicine I–Division of Clinical Oncology, General Hospital, University of Vienna, Vienna, Austria Manuscript received July 16, 2004; accepted manuscript July 20, 2004

Abstract Background: Treating intrahepatic cholangiocarcinoma (ihCCC) tumor resection leads to the best patient survival. The aim of this study was to investigate prognostic factors in resected patients. Methods: This was a clinical observational series of 31 resected patients with ihCCC. Univariate analysis of clinical and pathologic factors in relation to patient survival and tumor recurrence were performed. Possible benefit of chemotherapy, although not given randomly, was investigated separately. Results: The median follow-up time was 37.3 months. Of 31 resected patients a tumor-free resection (R0) was achieved in 26; 2 patients died postoperatively. Chemotherapy was administered to 19 patients. Overall survival was significantly better in patients with R0 resection, negative lymph nodes, a solitary tumor, and a width of resection margin greater than 3 mm. Recurrence-free survival was prolonged in patients with negative lymph nodes, early International Union Against Cancer (UICC) stages and solitary tumors. In UICC stages III and IV, patients receiving chemotherapy experienced a better overall survival. Conclusions: Impact of various parameters on recurrence-free and overall survival was identified; a possible beneficial effect of adjuvant chemotherapy in advanced tumor stages was observed. A prospective, randomized trial is necessary to fully evaluate the role of adjuvant therapy. © 2005 Excerpta Medica Inc. All rights reserved. Keywords: Cholangiocarcinoma; Resection; Chemotherapy; Survival; Tumor-free survival

Worldwide, an increasing incidence and mortality from intrahepatic cholangiocarcinoma (ihCCC) has been recognized [1– 4]. Radical resection offers the best survival [5–22] but is amenable to less than two thirds of patients admitted to surgical departments [8,9,11,13,15–17,19,23]. Orthotopic liver transplantation has been offered to unresectable patients in some units, but high rates of early recurrence led to the abandonment of ihCCC as an indication for transplantation [5,8,9,24]. Most published series reported a small number of patients over a long time period in which surgical techniques and oncological treatment options have changed considerably [9]. Reports of a greater number of patients treated in a single center over an acceptable time period are rare [7]. Therefore, the parameters influencing patients outcome af-

* Corresponding author. Tel.: ⫹0043-1-404005621; fax: ⫹0043-1404005641. E-mail address: [email protected]

ter curative resection under current treatment protocols are not well defined. The aim of this observational study was to investigate prognostic factors associated with overall and recurrencefree survival in patients treated with curative intent by resection and chemotherapy or resection alone, based on a review of our experience with resected ihCCC.

Material and Methods Between 1994 and 2002 the primary attempt of curative resection was performed in 31 of 48 patients diagnosed with ihCCC at our institution and they form the basis of this analysis; in the remaining 17 patients, exploration revealed contraindications for curative resection. Typical features of ihCCC were diagnosed radiologically (multislice computed tomography/magnetic resonance imaging) and/or by fineneedle aspiration histology. Patients suffering from hilar cholangiocarcinoma or gallbladder cancer were excluded.

0002-9610/05/$ – see front matter © 2005 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.11.009

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The mean age of the study group was 62.3 years (SD 10.1) and 15 patients were male. Operative procedures included 12 left hepatectomies, 1 left trisectionectomy, 14 right hepatectomies, 1 bisegmentectomy, and 3 segmentectomies. Modern dissection devices were used in the vast majority, including cavitron ultrasonic surgical aspirator, water jet, and bipolar forceps. All patients underwent a lymph node dissection of the hepatoduodenal ligament. The Internation Union Against Cancer (UICC) tumornode-metastasis (TNM) classification was used for tumor staging [25]. Tumor-free resection margin was defined as R0, microscopic positive resection margin as R1, and macroscopic positive resection margin as R2. All liver specimens were serially sectioned. Chemotherapy was administered according to interdisciplinary clinical oncologists’ and surgeons’ decision. In patients in whom chemotherapy was given, it consisted of 5-fluorouracil (5-FU)– based regimens in the early study period and changed to gemcitabine combined with the oral 5-FU prodrug capecitabine in 1998. Nineteen of 31 patients received chemotherapy, whether neoadjuvant (n ⫽ 3) or adjuvant (n ⫽ 16); of the latter 16 patients, 5 received palliative chemotherapy after R1 resection. Patients in the combination group (n ⫽ 14) received gemcitabine (2000 mg/m2, days 1 and 14 every 4 weeks) and capecitabine (2500 mg/m2, days 1–7 and 14 –21 every 4 weeks). Patients in the 5-FU/leucovorin group (n ⫽ 5) received 5-FU 425 mg/m2 days 1 to 5 and leucovorin 20 mg/m2 day 1 to 5 every 4 weeks. Treatment was given for 6 months or until relapse or disease progression. The influence of adjuvant therapy was evaluated in regards to disease recurrence and overall survival (Table 1). The clinical data of all patients were recorded prospectively. After hepatic resection, follow-up included physical examination, routine blood tests, and computed tomography or magnetic resonance imaging of the upper abdomen every 3 months postoperatively for the first 2 years and twice a year thereafter. Disease-free survival time was calculated in R0-resected patients from the date of operation to the date when tumor recurrence was diagnosed. Survival was calculated in terms of resection margin, pT, pN, UICC stage, tumor nodules, vascular infiltration, tumor size, and tumor differentiation. The width of resection margin was calculated for R0-resected patients. In some variables the median survival was not yet reached. Comparison between groups was performed using ␹2 or Student t test as appropriate. Overall and recurrence-free survival curves were calculated from the date of operation using the Kaplan-Meier method. The log-rank test was used to assess survival differences. Patient survival and diseasefree survival were summarized using medians. Statistical significance was defined as P ⬍.05 [26]. The analyses were performed using SPSS 10.0 for Windows (Statistical Package for Social Science, Chicago, IL).

Table 1 Characteristics of all patients with ihCCC (n ⫽ 31) receiving chemotherapy or no chemotherapy Variable Resection margin R0 R1 pT T1 T2 T3 T4 pN N0 N1 UICC stage I or II III or IV Tumor no. Solitary Multiple Vascular infiltration No Yes Tumor size ⱕ5 cm ⬎5 cm Width of resection margin* ⱕ 3 mm ⬎ 3 mm Grade Well or moderate Poor Age, y (mean) Karnofsky index (%) Postoperative morbidity

Chemotherapy (n ⫽ 19)

No chemotherapy (n ⫽ 12)

14 5

12 0

0 4 8 7

1 3 5 3

13 6

10 2

2 17

4 8

10 9

6 6

12 7

10 2

4 15

6 6

3 7

3 7

15 4 62.8 84.3 5

9 3 61.7 84.1 3

* Six of 26 R0-resected patients were missing this measurement.

Results Tumor-free resection margins were found in 26 patients. Microscopic infiltration of the surgical margin was observed in 5 cases (UICC III and IV), no R2 resection was performed. Twenty-four R0-resected patients survived the early postoperative period (30 days). The width of resection margin was documented in 19 patients. Median follow-up time was 37.3 months. No patient was lost to follow-up and 14 patients are still alive at the time of analysis. Overall survival Two patients died postoperatively after potentially curative resection, leading to a perioperative mortality rate of 6%. The overall median survival (n ⫽ 31) was 23.2 months and the overall 5-year survival was 31%. Twenty-nine patients survived the early postoperative period (30 days), of which 14 died due to recurrence during follow-up, and 1 patient died due to heart failure without evidence of tumor recurrence (Fig. 1).

H. Puhalla et al. / The American Journal of Surgery 189 (2005) 173–177

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Significant prolonged survival was achieved in patients with UICC stages III and IV disregarding R0 or R1 resection when chemotherapy was given. Patients (n ⫽ 6) without chemotherapy survived a median 7.2 months compared to 23.2 months in the chemotherapy group (n ⫽ 17, P ⫽ .044). If only R0-resected patients were considered, an overall median survival of 27.4 months in the chemotherapy group was achieved (P ⫽ .048). In curative resected UICC stages III and IV, tumor recurrence occurred a median of 4.3 months postoperatively without additive therapy and after a median of 8.9 months following chemotherapy (P ⫽ .860).

Discussion

Fig. 1. Overall survival of all resected patients (n ⫽ 31) with ihCCC. ⫹ ⫽ censored patient.

Univariate analysis demonstrated that a curative resection (R0), negative lymph nodes (pN ⫽ N0), a solitary tumor, and a width of resection margin greater than 3 mm were associated with a significantly better survival (Table 2). Recurrence-free survival In 18 of 24 curatively resected patients (perioperative death excluded) tumor recurrence occurred after a median of 8.9 months. Recurrence of disease was found in the remnant liver in 12 patients; in 3 other patients, tumor recurred both intra- and extrahepatically. Bone metastases were detected in 2 patients and 1 patient had tumor recurrence at the stomach wall. In the 5 R1-resected patients, progression of disease was confined to the liver (n ⫽ 3), liver and other organs (n ⫽ 1), and lymph nodes (n ⫽ 1) after a median of 5.3 months. In early tumor stages (UICC I or II) 3 of 6 and in advantaged stages (UICC III or IV) 15 of 18 patients experienced recurrent disease (P ⫽ .139). Recurrence-free survival was significantly prolonged in patients without lymph node involvement, in those with early UICC stages, and in those with a solitary tumor; in tumors below 5 cm in diameter, delayed recurrence was borderline significant (Table 3). Neoadjuvant/adjuvant chemotherapy In early tumor stages (UICC I and II) patients receiving chemotherapy (n ⫽ 2) survived 10.9 and 34.1 months and tumor recurrence was observed 7.3 and 9.9 months postoperatively. Patients (n ⫽ 4) without chemotherapy had a median survival of 37 months and a tumor recurrence after a median of 23.7 months.

In patients diagnosed with ihCCC it is well documented that curative resection leads to a superior outcome compared to all other treatment modalities [7,11,15,17,19]. The main problem of treating ihCCC curatively is the time of diagnosis, where a high percentage of tumors are already at an unresectable stage. Even in patients explored with curative intent, advanced tumor stage will be detected intraoperatively in 46.8% and 100% [6,12,23]. Curative resection (R0) offers the best overall survival, but positive resection margins can be detected in up to 40% of patients [2]. However, prolongation of survival in patients after R1 resection has been noted in several reports [6,7,9 –11,14,16,18,27,28]. Patients with histologically determined positive resection margins had a significantly worse overall survival compared to the curative group in our analyses but still did notably better than results reported from palliative treatment attempts [29,30]. Patients after R1 resection had a shorter median time to disease progression of 5.3 months compared to 9 months recurrence-free survival in the R0 group. We achieved a median overall survival rate of 18 months in this R1-resected group and all of these patients received adjuvant/palliative chemotherapy. Similar results were published in noncurative resected patients without additive therapy [18], but most authors reported a median survival between 9 and 11 months without palliative treatment in these patients [6,7,10,11,14]. Roayaie et al [16] offered a 5-FU– based multimodal therapy including adjuvant irradiation to these patients and reported no difference in the overall survival rate between tumor-free and tumor-positive resection margins. The benefit of an additional therapy in palliatively resected patients is therefore still under discussion. Patients in whom the width of the resection margin was ⱕ3 mm survived a significantly shorter duration (20.7 months) than patients in whom a wider resection margin was achieved (median survival in this group was not yet reached; median follow-up time was 33.8 months; and 3-year survival was 41%). As 50% of patients in whom the resection margin was ⱕ3 mm had multiple tumors and 33% had lymphatic nodes metastases, compared to only 30% with multiple tumors and 15% with positive nodes in the group with a wider margin, this

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Table 2 Univariate survival analysis of 29 patients with ihCCC (postoperative death excluded) Variable Resection margin R0 R1 pT T1 T2 T3 T4 pN N0 N1 UICC stage I or II III or IV Tumor no. Solitary Multiple Vascular infiltration No Yes Tumor size ⱕ5 cm ⬎5 cm Width of resection margin* ⱕ 3 mm ⬎ 3 mm Grade Well or moderate Poor Chemotherapy No Yes

resectional approach have varied in the literature [11,16,18,27]. The present data substantiate the reported influence of positive lymphatic nodes on patient survival [7,9 –11,13,14,17– 21,23,27,28,32,33] and disease-free survival [10,20]. Longterm survival following resection of ihCCC with positive hilar nodes has been described, but it is rare [11,34]. Hilar lymph node dissection should be part of the surgical procedure because nodal status not only has important prognostic relevance but we can thereby remove a frequent recurrence site as well. Of interest in our analysis is the results achieved in the higher staged curatively resected group, where we added adjuvant chemotherapy. These patients reached a quadrupled overall survival time compared with the untreated group, which was significantly different. Although these are nonrandomized data in a small group of patients, we are highly motivated to initiate a prospective randomized trial on a multi-institutional level. There are reports supporting our findings, eg, Serafini et al [35] and De Vreede et al [36], who observed a better outcome following curative resection and transplantation adding a 5-FU– based chemotherapy including radiation. Most reports about the efficacy of gemcitabine in ihCCC deal with the palliative setting and have reported promising response rates [29]. In contrast some authors reported unchanged patient survival following re-

No. of patients

Median Survival (mo)

P

24 5

33.6 18.1

.017

1 7 11 10

33.6 34.1 20.8 8.3

.328

21 8

34.1 11.9

.001

6 23

34.1 20.8

.183

15 14

37.1 (61%)† 15.2

.005

21 8

27.4 37.1 (71%)†

.448

10 19

37.1 (52%)† 20.8

.085

6 13

20.7 33.8 (41%)†

.005

23 6

31.0 20.8

.454

Table 3 Univariate analysis of tumor-free survival in 24 R0 ⫽ resected patients with ihCCC

10 19

33.6 27.4

.924

Variable

* Five of 24 R0 ⫽ resected patients (n ⫽ 29) were missing this measurement. † The median survival in this group was not yet reached; therefore, median follow-up time is reported. Percentage of patients, who are alive at 3 years postoperatively in parenthesis

survival benefit could be due to inadequate distribution of other risk factors. Reviewing the current literature, we recognize that modern dissection devices lead to an anticipated smaller resection margin without increasing the risk of local recurrence [31]. We were able to confirm the negative prognostic influence of multiple intrahepatic lesions [6,9 –11,13,15,16,23,27,28,32], which proves the hypothesis that the existence of intrahepatic satellites may be a strong indication of dispersed disease [15]. An association was noted between the appearance of multiple lesions and tumor size [23], which is consistent with tumor diameter as a strong prognostic indicator. Our results demonstrate a significant earlier tumor recurrence in patients with a tumor diameter greater than 5 cm, but size was not significantly associated with overall survival. The size of ihCCC does certainly influence prognosis, but due to small reported series sensible size limits for

pT T1 T2 T3 T4 pN N0 N1 UICC stage I or II III or IV Tumor no. Solitary Multiple Vascular infiltration No Yes Tumor size ⱕ5 cm ⬎5 cm Width of resection margin* ⱕ 3 mm ⬎ 3 mm Grade Well or moderate Poor

No. of patients

Median tumor-free survival (mo)

P

1 7 10 6

23.7 9.9 8.2 4.3

.196

18 6

9.9 5.3

.007

6 18

23.7 7.9

.017

13 11

13.0 7.9

.023

18 6

9.9 7.2

.385

9 15

8.9 7.3

.051

6 13

7.3 13.0

.750

20 4

8.9 6.4

.582

* Five patients were missing this measurement.

H. Puhalla et al. / The American Journal of Surgery 189 (2005) 173–177

section or liver transplantation, when adjuvant chemotherapy and irradiation was applied [10,19,21,23]. Both oncologists and surgeons should perceive that ihCCC has a potentially improved treatment option that should initiate prospective data evaluation on a multi-institutional level to provide further insight into the best treatment plans for this disease.

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