Adjuvant photodynamic therapy for bile duct carcinoma ... - Springer Link

J Gastroenterol 2004; 39:1095–1101 DOI 10.1007/s00535-004-1449-z

Adjuvant photodynamic therapy for bile duct carcinoma after surgery: a preliminary study Atsushi Nanashima1, Hiroyuki Yamaguchi1, Shinichi Shibasaki1, Noboru Ide1, Terumitsu Sawai1, Takashi Tsuji1, Shigekazu Hidaka1, Yorihisa Sumida1, Tohru Nakagoe1, and Takeshi Nagayasu1 1

Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan

Background. Photodynamic therapy (PDT) is a new palliative option in patients with non-resectable bile duct carcinoma (BDC). Here, we assessed the efficacy of adjuvant photodynamic therapy in eight patients with BDC who underwent surgical resection. Methods. Five patients had extrahepatic BDC, two had intrahepatic cholangiocarcinoma, and one had ampullary carcinoma. Cancer cells were microscopically detected in the stump of the hepatic duct in six patients, and biliary stenosis caused by remnant tumor was observed in one patient. One patient had tumor recurrence with occlusion of the bile duct. At 48 h prior to PDT, porfimer sodium was injected intravenously. A pulse laser by an eximer dye laser (50–100 J/cm2) with a wavelength of 630 µm was applied through an endoscope to the hepatic stump or tumor lesion. Results. Marked destruction of the tumor and ductal epithelium was observed on day 1 after PDT. After PDT, four patients developed mild dermatitis, but no severe morbidity or mortality was noted. In patients who underwent PDT for the stump, one patient showed distant metastasis at 31 months, and four patients did not show tumor recurrence at 17, 12, 12, and 6 months, respectively. However, one of the eight patients died at 2 months, of an unrelated cause. In two patients with occlusion caused by tumor growth, resolution of bile duct stenosis was noted on day 7. These patients showed re-occlusion by tumor at 20 and 8 months. Conclusions. Adjuvant PDT is a safe and useful option for a better survival benefit in patients with BDC undergoing surgical resection. Key words photodynamic therapy, porfimer sodium, eximer dye laser, bile duct carcinoma, adjuvant treatment

Received: February 2, 2004 / Accepted: April 21, 2004 Reprint requests to: A. Nanashima

Introduction Advances in imaging diagnostic technology in the past two decades have allowed early detection of bile duct carcinoma (BDC).1–3 Accordingly, the number of patients with resectable BDC has increased, and patient survival has improved in recent years.3,4 However, curative resection is often difficult, because BDC spreads extensively along the bile duct beyond the lesion noted at the preoperative diagnosis.4 Positive surgical margins in the stump of the hepatic duct are a significantly poor prognostic feature compared to positive duodenal margin or exposed margin of the bile duct, as reported previously.5 To date, there are no data supporting the survival advantage of adjuvant radiotherapy and/or chemotherapy after surgery for BDC.6,7 On the other hand, for recurrence in the bile duct after surgery, placement of a metallic stent for stenosis has improved quality of life. However, stent occlusion by tumor ingrowth or other causes is frequent, and local ablation therapies have been used for recanalization.2,8 To resolve these problems in BDC treatment, effective local treatment is necessary. Photodynamic therapy (PDT), which is a form of laser treatment, has led to remarkable regression of malignant tumors, including BDC, since the 1980s.9 In this treatment, a photosensitizing drug known to accumulate in the mitochondria or lysosomes of tumor cells is intravenously administered, and the photosensitizer, activated by laser light of the appropriate wavelength, forms a cytotoxic reaction in cancer cells or neovascular cells surrounding tumors.9 At present, PDT is used for superficial cancers or premalignant lesions in the upper digestive tract, lung, cervix, or skin, and the cost for these purposes is covered by national health insurance in Japan.10 In the latter half of the past decade, several investigators have reported the clinical usefulness and survival benefits of PDT for non-resectable BDC in a randomized multicenter trial.11–14 Subsequently, Berr et

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A. Nanashima et al.: Photodynamic therapy for cholangioma

al.15 and Wiedmann et al.16 recently reported the usefulness of PDT as a neoadjuvant therapy for resectable BDC. Thus, PDT is also apparently a useful modality for local treatment in BDC. In the present study, we describe our experience using PDT as an adjuvant local treatment to control remnant tumor in the hepatic duct stump after surgical resection, and to place metallic stents in severely obstructed bile ducts after surgery. We report here the short- and long-term clinical effectiveness and outcome after PDT.

each patient before the procedure. As PDT for bile duct carcinoma is not covered by the national health insurance scheme in Japan, the National Expense for Special Research Programs at NUGSBS was used for medical expenses associated with PDT in all patients.

Patients and methods Patients The subjects were eight patients with extrahepatic or intrahepatic BDC who were admitted to the Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences (NUGSBS), Japan, between May 2001 and January 2004. The mean age of the patients at the time of surgery was 64. 0 years (range, 55–69 years), and there were five men and three women. Prior to surgery for cholangiocarcinoma, the patients had been treated with percutaneous transhepatic biliary drainage (PTBD) to alleviate obstructive jaundice, but none had received chemo- or radiotherapy. None had any other major disease and all had good performance status before surgery and PDT. Tumors were assessed by computed tomography (CT) scan, magnetic resonance imaging cholangiography (MRC), cholangiography or cholangioscopy (via drainage tubes), or intraductal ultrasonography (IDUS; 20 MHz). The surgical procedures comprised extended left or right hemihepatectomy, with total resection of the caudate lobe and resection of the extrahepatic bile duct, or pancreaticoduodenectomy. Resections were performed en bloc, based on the preoperative imaging diagnosis; lymph node dissection was performed on the hepatosduodenal ligament, surrounding pancreas head, and paraaortic lesions. All hepatic tumors were resected without macroscopic exposure of the amputated section; however, microscopic infiltration of cancer cells was diagnosed by pathological examination during and after surgery. Complete resection failed, requiring additional resection of the hepatic duct in five patients, or failed because of poor hepatic function in two. We used the Classification of biliary tract carcinoma17 and the General rules for the clinical and pathological study of primary liver cancer.18 We referred to the BismuthCorlette classification for hilar bile duct carcinoma.19 The study design was approved by the Ethics Committee of NUGSBS, and signed consent was obtained from

Photodynamic therapy All patients who received PDT were in a stable condition, based on physical examination and laboratory tests after operation or biliary drainage (mean ⫾ SD; 29 ⫾ 13 days, ranging 21 to 41 days). Porfimer sodium (Photofrin; Wyeth Pharmaceuticals, Collegeville, PA, USA, and Wyeth, Tokyo, Japan), a hematoporphyrin derivative,20 was intravenously injected, at a dose of 2 mg/kg body weight, 48 h before PDT. After the injection of Photofrin, the patient stayed in a dark room (100–300 luces of light, shielded by a curtain) for 4 weeks to prevent skin phototoxicity.21 Protoporphyrin, uroporphyrin, and conventional blood parameters were monitored before the administration of Photofrin and every week after PDT. Prior to PDT, a 16- to 18-Fr plastic tube was placed via the trans-hepatic or trans-intestinal route to facilitate endoscopy. The apparatus used was PDT EDL-1 (Hamamatsu Photonics, Hamamatsu, Japan).10 A pulse laser by the eximer dye laser with a wavelength of 630 µm (4 millijoules/pulse, 40 Hz) was applied to two or three target lesions through an endoscope to the anastomotic site of the hepaticojejunostomy or occluded tumor lesion, for 10 min. The mean amount of work was 50–100 joules per cm2 of surface.21 Endoscopic observation and evacuation of debris were performed on days 1, 7, and 28 following PDT. Antibiotic prophylaxis was administered after cholangioscopy. Statistical analysis Values for continuous variables were expressed as means ⫾ SD. For the univariate analysis, categorical data were analyzed by the χ2 test. Differences between variables were analyzed by Student’s t-test. A two-tailed P value of less than 0.05 was considered significant. Statistical analyses were performed with the computer software Statistica (StatSoft, Tulsa, OK, USA).

Results Of the eight patients, five had extrahepatic bile duct carcinoma, two had intrahepatic cholangiocarcinoma, and one had ampullary carcinoma (Table 1). In six patients, cancer cells were detected in the stump of the bile duct (Table 2). PDT was administered at the anastomotic site of the hepaticojejunostomy in five patients,


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Table 1. Patient demographics before PDT Patient no.

Age (years)

Sex

Disease

Preoperative biliary drainage

1 2 3

63 57 69

M F F

Yes Yes No

Rt. HH (Sg 5–8, Sg 4a, Sg 1) Rt. HH (Sg 5–8, Sg 4a, Sg 1) Lt. HH (Sg 2–4)

4 5 6 7

63 77 69 55

M M M F

HBDC, Bismuth type IV HBDC, Bismuth type IV BD cystadenocarcinoma with hilar infiltration AC with skip infiltration to hilar BD CCC with hilar infiltration Lower BDC with hilar infiltration Recurrent CCC in remnant BD

Yes No No Yes

8

69

M

HBDC, Bismuth type IV

Yes

PpPD Lt. HH (Sg 2–4) PD Rt. HH (Sg 5–8, Sg 1) plus PpPD; disease-free for 2 years Lt. HH (Sg 1–4)

Prior procedures

PDT, photodynamic therapy; BD, bile duct; HBDC, hilar bile duct carcinoma; CCC, cholangiocarcinoma; AC, ampullary carcinoma; HH, hemihepatectomy; PD, pancreaticoduodenectomy; PpPD, pylorus-preserving pancreaticoduodenectomy; Sg, Couinaud’s segment of the liver

a Fig. 1. Cholangioscopic findings of bile duct at hepaticojejunostomy by photodynamic therapy (PDT). There was marked mucosal degeneration on day 1

and at the stump of the right hepatic duct in one patient, in whom tumor was not macroscopically observed during surgery (Table 2). Mucosal degeneration in the bile duct on day 1 after PDT was marked (Fig. 1) and had changed to fibrotic scars on day 7. IDUS revealed thickening of the entire bile duct wall (Fig. 2). In patient 3, PDT was administered to a remnant tumor in the common hepatic duct, which had not been detected during operation and was observed by cholangioscopy via Ttube after hepatectomy. In patient 7, a recurrent tumor occluded the intrahepatic bile duct after curative resection. The tumor, which penetrated into the lumen, was markedly degenerated on day 1 after PDT, and the occlusion was resolved on day 7 after PDT (Fig. 3). Mild transient cholangitis occurred after PDT in two patients, but they had recovered by day 7

b Fig. 2a,b. Findings of bile duct wall (arrows) after PDT, by intraductal ultrasonography (IDUS). a Before PDT. b Thickening of the entire wall after PDT

100 J/cm2, 4 lesionsd 100 J/cm2, 4 lesionsd 100 J/cm2, 8 lesions of B2 and B3c,e 50 J/cm2, 3 lesionsd

Anastomotic site of HJ Tumor occlusion of duct Anastomotic site of HJ

pt4n0, c-stage IVaa /positive stump of HD

Recurrent CCC (2 cm) invading proximal B2 and B3c

pt1n0, c-stage Ia /positive stump of HD

6

7

8

b

a

HD, hepatic duct; CHD, common hepatic duct; p, pathological findings; HJ, hepaticojejunostomy Tumor stage by according to the Classification of biliary tract carcinoma;17 s, surgical stage; c, comprehensive stage Tumor stage according to the classification system of the General rules for the clinical and pathological study of primary liver cancer18 c Intrahepatic bile duct in segments 2 and 3 d For 1 day e For 2 days

lesionsd lesionsd lesionsd lesionsd

Rt. HD

5

3 3 4 3

100 J/cm2, 100 J/cm2, 100 J/cm2, 100 J/cm2,

Anastomotic site of HJ Anastomotic site of HJ CHD Anastomotic site of HJ

pt2n1, c-stage IIa /positive stump of HD pt4n2, c-stage IVaa /positive stump of HD pT4N0M0, s-stage IV Ab /remnant tumor in CHD pt3n0, c-stage IIIa /skip infiltration, positive stump of HD pt3n1, s-stage IV Ab /positive stump of HD

1 2 3 4

Light dose

Target area for PDT

TNM stage and reason for PDT

Patient no.

Table 2. Demographics of patients with PDT

Mucosal degeneration. No malignant cells (by biopsy) Mucosal degeneration. No malignant cells (by biopsy) Relief of tumor stenosis and resolution of mass lesion but remnant tumor cells detected by biopsy Mucosal degeneration

Mucosal degeneration Mucosal degeneration Incomplete necrosis of tumor Mucosal congestion

Evaluation

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a

b

Fig. 3a,b. Cholangioscopic findings of tumor occlusion in the bile duct. a Severe occlusion was seen in the bile duct (arrow). b Tumor occlusion had dramatically resolved on day 7 after PDT, and drainage of the bile duct was improved

(Table 3). Table 4 shows that the inflammatory parameters and hepatobiliary enzymes increased transiently on day 1, but had recovered by day 7. Although the protoporphyrin level was not significantly changed, the uroporphyrin level increased steadily from day 1 to day 28. Four patients developed mild photodermatitis, resembling sunburn or tanning, on exposed skin in the early and late periods after PDT, and were treated only with sunscreen cream. No patient developed serious complications or died of photodermatitis. Patients 1 received adjuvant oral chemotherapy with a 5-fluorouracil analog. Patient 3 underwent additional biliary stenting because of incomplete tumor necrosis. Patient 7 underwent additional irradiation (30 Gy by an extracorporeal route and 30 Gy by an intraluminal route)

Alive with recurrence (33 months); Tumor-free for 30 months Dead, caused by portal thrombosis (2 months) Alive with local recurrence (21 months); re-stenosis at 20 months Alive without recurrence (17 months) Alive without recurrence (12 months) Alive without recurrence (12 months) Alive with intrahepatic tumor (9 months); re-stenosis at 8 months Alive without recurrence (6 months) None — Liver abscess Tanning Tanning Tanning Tanning None Chemotherapy None Metallic stent None None None Irradiation None Mild cholangitis and diarrhea None None Mild photodermatitis None None Mild cholangitis None 1 2 3 4 5 6 7 8

Short-term complications Patient no.

Table 3. Patient outcome after PDT

Adjuvant treatment

Long-term complications (⬎1 month)

Status


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following the detection of remnant tumor cells in the lumen of the bile duct at biopsy. This patient did not require a biliary stent for 8 months. Patient 2 died of a cause unrelated to PDT. Patient 1 was tumor-free for 30 months after PDT. However, pleural and bone metastases were observed at 31 months. Four patients had no tumor recurrence, and patient 3 had a local remnant tumor on CT scan, but no re-occlusion of the biliary tract for 20 months. In patient 7, biliary re-occlusion was not observed until 8 months after PDT (Table 3).

Discussion The effect of PDT is specific to cancer tissues compared to normal surrounding tissue, because of the trapping and accumulation of the photosensitizer in cancer cells.22 Pahernik et al.22 reported that accumulation of the photosensitizer in cancer cells at 48 h was two to three times that in normal tissue. In the present study, normal epithelium also showed mild degeneration, which may reflect a lower level of accumulation of the photosensitizer. However, this change was not critical, and improved within 7 days. We examined changes in the bile duct wall by IDUS. The entire wall was affected by PDT, although the total light dose in our protocol was lower than that in other reports.12,13,15,16 Mimura et al. 23 reported that the eximer-dye laser penetrated tissues deeper than did other laser beams. Therefore, we anticipate the effects of PDT to include tumor cells located in deeper lesions. Compared to ablation therapies,2 PDT creates milder damage but provides similar effectiveness.2,11–13 To our knowledge, there is no report in the Englishlanguage literature of PDT as an adjuvant therapy after resection, although our group24 and Suzuki and Nakamura25 have reported this therapy in Japaneselanguage journals. In our series,24 non-curative operation due to a positive bile duct stump was observed in five patients with biliary tract cancer before 2000. Three of the five died of tumor recurrence. The mean tumorfree and overall survival times in these three patients were 8 and 22 months, respectively. Compared to these results, PDT could be effective in preventing tumor recurrence and tumor ingrowth after a biliary stent has been controlled for a long time. As the effect of adjuvant chemotherapy or irradiation remains controversial,6 the addition of PDT to surgical resection may increase the curability of BDC resection, which must lead to prolonged patient survival. In the present study, we also attempted to treat intrahepatic recurrence of cholangiocarcinoma after curative resection. The recurrence rate of BDC after curative resection remains high. In one of our patients, recurrent tumor rapidly occluded the hepatic duct, but there were

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Table 4. Changes in laboratory data after photodynamic therapy Pre-PDT White blood cells (/mm3) CRP (mg/dl) Hemoglobin (g/dl) International normalized ratio Total bilirubin (mg/dl) Alanine aminotransferase (IU/l) Alkaline phosphatase (IU/l) Amylase (IU/l) Creatinine (mg/dl) Protoporphyrin (µg/dl) Uroporphyrin (µg/gC)

4 838 ⫾ 1.46 ⫾ 10.2 ⫾ 1.28 ⫾ 0.99 ⫾ 56 ⫾ 678 ⫾ 61 ⫾ 0.74 ⫾ 46 ⫾ 18 ⫾

1 849 0.93 0.92 0.05 0.59 38 472 24 0.21 22 9

Day 1 6 850 ⫾ 2.89 ⫾ 10.4 ⫾ 1.06 ⫾ 1.31 ⫾ 84 ⫾ 841 ⫾ 57 ⫾ 0.71 ⫾ 51 ⫾ 28 ⫾

3 353* 2.28* 0.90 0.02 0.50* 77* 529 22 0.22 20 10*

Day 7 4 987 ⫾ 2.23 ⫾ 10.3 ⫾ 1.05 ⫾ 0.86 ⫾ 43 ⫾ 1 007 ⫾ 55 ⫾ 0.66 ⫾ 52 ⫾ 27 ⫾

1 140 1.21 0.84 0.01 0.55 24 746 21 0.19 20 9*

Day 14 4 788 ⫾ 1.68 ⫾ 10.3 ⫾ 1.06 ⫾ 0.79 ⫾ 39 ⫾ 962 ⫾ 55 ⫾ 0.68 ⫾ 47 ⫾ 33 ⫾

1 251 1.13 0.78 0.03 0.51 15 645 22 0.12 19 14*

Day 28 4 892 ⫾ 1.28 ⫾ 10.4 ⫾ 1.07 ⫾ 0.71 ⫾ 48 ⫾ 1 083 ⫾ 55 ⫾ 0.70 ⫾ 46 ⫾ 32 ⫾

1 423 1.53 1.03 0.03 0.35 40 1 057 19 0.13 21 12*

* P ⬍ 0.05 vs pre-PDT Data valves are means ⫾ SD

no other metastases. Therefore, we considered the possibility of tumor control by local treatment, including PDT, and local control was achieved. The higher accumulation of a photosensitizer in the bile duct wall may be an advantage for the treatment of biliary carcinomas.26 On the other hand, PDT damage to surrounding organs is of concern.21 In the present study, such complications were not observed, and the mild increase in hepatic enzymes may have been caused by endoscopic procedures. Van Hillegersberg and colleagues 27 also reported mild hepatic damage by PDT. In our present study, although one patient died of portal thrombosis, which may not have been related to PDT, there were no severe complications. We experienced skin phototoxicity from the photosensitizer in this study, as has been reported by Rumalla et al.28 Theoretically, the level of Photofrin in normal tissues decreases at 35 days.22 However, in the present study, four patients had significant photodermatitis more than 1 month after the PDT. Although no patients in our series developed serious phototoxicity, such side effects must be anticipated, and patients must be instructed on skin care and should have detailed examinations and follow-up with dermatologists. At present, the need to remain confined in a dark room is one of the problems with PDT treatment. According to our present results, the level of uroporphyrin, a metabolite of porphyrin, remained high on day 28; therefore, porphyrin derivatives may remain in the skin for more than 1 month after PDT. It may be necessary to cover the exposed body parts for a longer period of time. New photosensitizers with less skin phototoxicity than Photofrin may improve this treatment in the future.29–31 In conclusion, PDT was performed in eight patients with BDCs, who had remnant tumor cells in the hepatic duct after surgical resection, or tumor recurrence after curative surgical resection. PDT was effective for the local control of tumor growth for a prolonged period,

and led to no serious adverse effects. Adjuvant PDT therapy is therefore apparently a safe and useful option for improved survival in patients with resectable and non-resectable bile duct carcinomas. Acknowledgments. We gratefully appreciate the cooperation of Dr. H. Isomoto, Dr. K. Nagaoki, Mr. K. Kawazoe, and all the nurses in the surgical ward for the present PDT program. We also thank Dr. K. Shimizu for the seminar on skin phototoxicity. The present study is dedicated to the late Professor Hiroyoshi Ayabe, who introduced the PDT system at Nagasaki University Hospital in 1997 and who died midway through this work, on August 17, 2002.

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