Adjuvant chemoradiation for resected gallbladder cancer: Treatment ...

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Adjuvant chemoradiation for resected gallbladder cancer: Treatment strategies for one of the leading causes of cancer death in Chilean women

Original Article

Bettina Müller, José A. Sola, Marcela Carcamo1, Ana M. Ciudad2, Cristián Trujillo3, Berta Cerda Department of Medical Oncology, 1Department of Clinical Research, 2Department of Radiotherapy, 3 Oncological Surgeon, Department of Surgery. Instituto Nacional del Cáncer, Santiago, Chile Correspondence to: Dr. Bettina Müller, E-mail: [email protected]

Abstract BACKGROUND: Gallbladder cancer (GBC) is the second leading cause of cancer death in women in Chile. Even after curative surgery, prognosis is grim. To evaluate acute and late toxicity and efficacy of adjuvant chemoradiation (CRT) after curatively resected GBC. MATERIALS AND METHODS: We retrospectively analyzed the cohort of patients diagnosed between January 1999 and December 2009, treated with adjuvant CRT at our institution. Treatment protocol considered external beam radiation (RT) (45–54 Gy) to tumor bed and regional lymph nodes with or without concurrent 5-fluorouracil (5-FU) (500 mg/m2/day by 120-hours continuous infusion on days 1–5 and 29–33). Data was obtained from medical records, mortality from death certificates. Survival was estimated by Kaplan– Meier curves. RESULTS: 46 patients with curatively resected GBC received adjuvant CRT. Median age was 57 years (range 33–76); 39 patients were female. After diagnosis, a second surgery was performed in 42 patients. Cholecystectomy with hepatic segmentectomy and lymphadenectomy was the curative surgery in 41 patients. All patients received RT with a planned dose of 45 Gy in 25 fractions, 11 patients received a boost to the tumor bed up to 54 Gy and 34 patients had concurrent 5-FU. Therapy was well tolerated. Five patients experienced grade 3 toxicities. No grade 4 or 5 toxicity was observed. No grade >2 late toxicity was observed. Three- and 5-year overall survival (OS) were 57% and 51%, respectively. CONCLUSIONS: Adjuvant chemoradiation is well tolerated and might impact favorably on survival in patients with curatively resected GBC. Key words: Adjuvant, chemotherapy, gallbladder cancer, radiotherapy

tract cancer. Currently, this disease is classified as a separate entity.

Introduction On a worldwide basis, cancers of the biliary tract are uncommon tumors. They are subdivided into neoplasms of the gallbladder (ICD9 156.0), extrahepatic bile ducts (or hilar, i.e. Klatskin tumor) (ICD9 156.1), and ampulla of Vater (or distal bile duct) (ICD9 156.2).[1] Gallbladder cancer (GBC) is the most frequent biliary Access this article online Quick Response Code:

Website: www.indianjcancer.com DOI: 10.4103/0019-509X.118723 PMID: *******

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The incidence of GBC varies significantly by geographic area, ranging from areas of low incidence like the USA with an age standardized incidence rate of 1.7 to rates as high as 10.4 in Chile, where GBC constitutes the leading cause of cancer death in the female population, with a mortality rate of 11.5 per 100.000.[2] Other areas of high incidence of this neoplasm include northern India, Pakistan, Korea, Slovakia, the Czech Republic, and Ecuador. The pathogenia of this disease remains unknown although chronic inflammation has been identified as Indian Journal of Cancer | July–September 2013 | Volume 50 | Issue 3

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a risk factor. Cholelithiasis is often present in GBC, but the rates of incidental GBC in cholecystectomy specimens resected for cholelithiasis vary from as low as 0.35% reported from Israel[3] to up to 3% reported from a high incidence area in Chile. Obesity, female gender, Aymara or Mapuche ethnicity, high rates of typhoid fever, and low socioeconomic status are associated with an increased GBC risk.[4,5] Prognosis is disappointing, as the majority of patients are diagnosed at advanced stage, and overall survival (OS) is only 8.5% at 5 years for all stages.[6] Even after aggressive surgery, cure is achieved in only 35%.[7] In Chile, surgical series have reported 5 year survival rates between 30% and 49%.[8,9] Given this dismal prognosis, adjuvant therapies have been investigated although no standard treatment has been identified yet. The U.S. National Cancer Data Base Report on GBC, 1989–1995, notes a survival benefit for patients receiving surgery, radiotherapy, and chemotherapy. At our institution, a treatment protocol of adjuvant chemoradiation (CRT) for curatively resected GBC was implemented in 1998. Before this, adjuvant radiation (RT) without chemotherapy had been offered to patients. The aim of this study is to evaluate efficacy and toxicity of CRT or RT after curatively resected GBC. Materials and Methods After approval by the Institutional Review Board, we retrospectively reviewed all patients with curatively resected GBC diagnosed between January 1999 and December 2009 who received adjuvant RT or CRT. To identify the eligible patients, we reviewed the data bases available at our institution for the diagnosis: biliary tract cancer. The inclusion criteria were patients with histologically proven carcinoma of the gallbladder treated with curative surgery who received at least one dose or fraction of postoperative chemotherapy or RT. Patients with metastatic, residual or unresectable tumors, histology other than carcinoma, or treatment received in another institution were excluded. Data was obtained from medical records and the following characteristics were recorded: age, sex, performance status (PS), body mass index (BMI), date of histologically proven GBC, date and type of first surgery, date and type of second surgery, histological features including resection margins, TNM classification and stage, starting date of adjuvant treatment, planned and received RT dose and fields, planned and received number of cycles and schema of Indian Journal of Cancer | July–September 2013 | Volume 50 | Issue 3

chemotherapy, acute and late adverse events, date of first recurrence, localization of first recurrence, treatment received post-recurrence, date of last visit or death. For patients lost for follow-up, the date of death was obtained by death certificate. Primary endpoint was OS. Survival was calculated from the day of histologically proven cancer until death from any cause or from the last date known to be alive. Secondary endpoints were acute and late toxicity and progression-free survival (PFS). For estimation of PFS and OS, the method of Kaplan and Meier was used. A comparison of survival curves was done using the log-rank test. NCI CTCAE v 3.0 was used for toxicity grading, and the worst grade of each adverse event was recorded for each patient. AJCC 6th Edition was used for staging classification. For potential prognostic factors a Cox univariate and multivariate analyses was done, evaluating resection margin status, T1/2 vs T3/4, N0 vs N1, and RT vs CRT. A P value of 0.05 was considered statistically significant. Data analysis was calculated with STATA 10.0. Results We identified 259 patients with biliary tract cancer (BTC): 19 (7.3%) had extrahepatic cholangiocarcinoma, 16 (6.2%) cancer of the ampulla of Vater, and 224 (86.5%) GBC. Of them, 112 (50%) presented advanced disease at diagnosis and 112 (50%) were classified as localized disease. Data of treatment details for potentially curable patients were available for 104 patients: 12 received no further treatment after cholecystectomy, 29 had re-resection for oncological surgery without further adjuvant treatment, 17 proved to have irresectable disease at laparotomy, and 46 received adjuvant CRT after curative resection: the population which we studied was based on this series. Patient characteristics are presented in Table 1. The median age was 57 years (range 33 – 76), with 39 female patients (85%). The histological types were adenocarcinoma NOS (12 patients, 20%); intestinal type adenocarcinoma (33 patients, 72%); and papillary carcinoma (1 patient, 2%). The tumor grade was available for 41 patients and the distribution was as follows: well-differentiated (9 patients, 22%); moderately differentiated (26 patients, 63%); poorly differentiated (5 patients, 12%); and undifferentiated (1 patient, 2%). Baseline PS had been recorded in 32 patients; all of them had ECOG 0 or 1. BMI was obtained in 35 185

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patients prior to CRT: 9 (26%) had normal BMI and 26 (74%) were overweight or obese (mean BMI: 28). In 42 patients, a second surgery was performed for curative resection, with a median delay between the two procedures of 90 days (range 4-230 days). Only 3 patients had R1 resection after definitive surgery. Delay between definitive surgery and adjuvant treatment was 88 days (range: 31–190). The treatment protocol consisted in locoregional external beam radiation (EBRT) (45 Gy in 25 fractions in 5 weeks with or without boost up to 54 Gy to the tumor bed and regional lymph nodes) with or without concurrent 5-Fluorouracil (5FU). All 46 patients received RT. Seven received a boost up to 50.4 Gy and 4 patients up to 54 Gy. Compliance to treatment was good. Only three patients stopped treatment early, one due to progressive disease, one for toxicity (grade 3 thrombocytopenia), and one for non-specified reasons having completed 43.2 of 45 Gy. The median duration of RT was 37 days (range 20–50 days). Twelve patients received RT alone. Chemotherapy (CT) consisted in concurrent continuous IV infusion of 5-FU 500 mg/m 2/day by 120-hours continuous infusion on days 1–5 and 29–33 of EBRT and was administered in 34 patients. Compliance to CT was good: all but three completed the planned cycles. Reasons for discontinuation of the CT were: grade 3 fatigue (1 case), administrative reasons (1 case), and Table 1: Patient, tumor and treatment characteristics Total n (%)

All: 46 (100) RT: 12 (100)

Age years (range) Female n (%) ECOG 0 ECOG 1 ECOG unknown Stage IA (T1N0) IB (T2N0) IIA (T3N0) IIB (T1-3N1) III (T4N0-1) Definitive surgery CC + LA CC + LA + HS

57 (33-76)

R1 resection

The selection of treatment modality (RT vs CRT) varied through time: all patients who received RT alone had been treated between 1999 and 2004, whereas CRT had been planned for patients treated between 1999 and 2009. Toxicity data are presented in Table 2. Therapy was well tolerated. None of the patients receiving RT alone presented grade ³ 3 adverse events. Only five patients receiving CRT experienced grade 3 acute toxicities, including one grade 3 thrombocytopenia; one grade 3 neutropenia; two grade 3 elevation of liver enzymes; one grade 3 emesis; one grade 3 fatigue; and one grade 3 abdominal pain. No grade 4 acute adverse events were observed. Three of 9 evaluable patients (33%) in the RT alone group presented late toxicity: one hepatic failure with portal hypertension and ascites, one grade 1 diarrhea and 1 gastritis. Seven of 33 evaluable patients in the CRT group (21%) presented late toxicity: three duodenal ulcers, three gastritis, and one second malignancy. No grade > 2 late toxicity was reported. As of February 2011, 25 patients died; 22 presented recurrent or metastatic GBC, and 3 died of other causes more than 5 years after the diagnosis of GBC, 1 of them presented a second malignancy (gastric cancer). One patient was lost for follow up. The survival curve is shown in Figure 1. Three and five year OS rates for the whole series were 57.0% and 50.8%, respectively.

Table 2: Toxicity CRT: 34 (100)

55 (33-70)

57 (38-76)

39 16 16 14

(85) (35) (35) (30)

10 (83) 2 (17) 0 10 (83)

29 (85) 14 (41) 16 (47) 4 (12)

3 14 10 18 1

(7) (30) (22) (39) (2)

1 (8) 3 (25) 3 (25) 5 (42) 0

2 (6) 11 (32) 7 (21) 13 (38) 1 (3)

3 (7) 43 (93)

0 12 (100)

3 (9) 31 (91)

3 (7)

1 (8)

2 (6)

CC = cholecystectomy, LA = lymphadenectomy, HS = hepatic segmentectomy

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grade 3 thrombocytopenia (1 case, RT in this patient was also stopped).

Acute toxicity Evaluable patients All: 44 (100) RT: 10 (100) n (%) Grade 3-4 5 (11) 0 Neutropenia 1 Thrombocytopenia 1 Elevation of ALT/AST 2 Fatigue 1 Abdominal pain 1 Emesis 1 Late toxicity Evaluable patients All: 42 (100) RT: 9 (100) n (%) Any 10 (24) 3 (33) Gastritis or duodenitis 5 1 Gastric or duodenal 2 0 ulcer Diarrhea 1 1 Hepatic failure 1 1 Second malignancy

1

0

CRT: 34 (100) 5 (15) 1 1 2 1 1 1 CRT: 33 (100) 7 (21) 4 2 0 0 1

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up for the patients alive, defined as the time between histological diagnosis and last visit to the hospital was 4,6 years, which allowed us to report consistent data for late toxicity. The vast majority of our patients had been diagnosed by cholecystectomy performed for cholelythiasis. This explains the high rate of second surgeries for oncological management in our experience.

Figure 1: Overall survival (OS)

Analyzed by the treatment group, a trend toward longer survival in the group which received CRT compared with only RT was observed, with a 3 and 5 year OS of 61.6 versus 46.2 and 56.0% versus 38.5%, respectively, but this difference was not statistically significant (P = 0.397). Twenty-three patients have progressed; 12 had locoregional recurrence only (52%); 3 presented local and distant recurrence; and 8 recurred at distant sites exclusively (35%). Recurrence occurred early after diagnosis. The median time to progression was 18 months: 15 patients (65%) recurred during the first two years, and 22 patients (95%) recurred during the first 3 years of follow-up. Survival after diagnosis of recurrence was low, with a median survival of 3 months after diagnosis of recurrence. Only five patients received palliative chemotherapy. On univariate analysis using log-rank analysis, T-stage, type of adjuvant treatment, and histological grade did not show statistically significant impact on survival, whereas N1 and R1 resection were associated with poor prognosis. Only N1 remained significant on multivariate analysis using Cox regression model (HR 2.759 (IC 95% 1.14 – 6.66). Discussion We did a retrospective analysis of patients treated under a predefined treatment protocol at a public hospital in Chile to assess the outcome in terms of survival and acute and late toxicity in a daily practice setting. Acute and late toxicity could be assessed for 96% and 91% of the patients, respectively. As reporting of mild adverse events was considered not to be consistent outside a prospective trial, we only reported Grades 3–5 acute toxicity. The median follow Indian Journal of Cancer | July–September 2013 | Volume 50 | Issue 3

The role of adjuvant CRT in the treatment of GBC has not been clearly established. There are suggestions that adjuvant CRT has a favorable impact on OS, as reported based on the data of the SEER data base, where the use of RT was associated with a benefit in OS (14 vs 8 months, P < 0.0001),[10] however, no chemotherapy details were available for the analyzed patient population. Based on this data, a prediction model for estimating the survival benefit of adjuvant radiotherapy has been proposed.[11] The potential benefit of adjuvant CT following CRT was explored by Lim et al. for patients with radically resected biliary tract carcinoma, and a favorable impact for adjuvant 5FU-based CT could be demonstrated in this non-randomized study (HR 0.429, P = 0.01).[12] No randomized controlled trials have been published on this issue. Most institutions use RT with 5FUbased chemosensitization.[13,14] One trial suggests a role for adjuvant chemotherapy in the subgroup of GBC patients.[15] Given that nearly half of the patients who recur present distant spread, a more active chemotherapy regimen is clearly needed to improve the results of adjuvant treatments in GBC. In the metastatic setting, palliative chemotherapy with Gemcitabine (Gem) + Oxaliplatin increased survival compared to best supportive care (HR 0.44), whereas 5FU + Folinic Acid did not. [16] Another recent phase III trial showed that Gem + Cisplatin improve survival compared to Gem (HR 0.61).[17] Local recurrence has an important impact despite adjuvant CRT, and R0 resection is one of the most important pronostic factor, as shown by the series of the University of Michigan, [14] the Mayo Clinic, [15] and the University College Hospital and Royal Free Hospital, London, UK. [18] In our series, very few patients with positive surgical margins received adjuvant CRT; despite this, nearly two-thirds presented local recurrence. More active CRT regimens, incorporating newer agents like oxaliplatin, capecitabine, [19] or gemcitabine,[20] should be tested to reduce local failure. 187


In our experience, only 20% of all GBC patients seen at the tumor board received adjuvant CRT, mostly because of advanced stage at presentation or after re-operation.

5. 6.

A recent report from three cancer centers (Fundación Arturo López Perez, Chile; Memorial Sloan Kettering Cancer Center, USA; Yokohama City University, Japan) shows that even for potentially resectable GBC submitted to operation, curative surgery was achieved in only 61.3% of the cases.

7. 8. 9.

[21]

10.

Neoadjuvant strategies could offer the opportunity to benefit more patients by downstaging the tumors and increasing R0 resection, which could translate into survival benefits and should, therefore, be explored. In the era of genomics and proteomics, great progress has been made in understanding some cancer types. Some of these findings even have opened the field for individualized prognostic and therapeutic assessments. In contrast, very little is known about carcinogenesis and molecular subtypes in GBC.[22] Since GBC mainly affects middle income countries, which dedicate less than 1% of their GDP to research and development, international collaboration is needed in order to improve prevention, early diagnosis, and treatment of this challenging and deadly disease. Adjuvant treatment with radiotherapy or CRT might improve outcome in terms of OS, as our results compare favorably to series reporting outcome with surgery only. The treatment used was well tolerated and CRT with 5FU administered over 120 h in two cycles could be given safely. Although adjuvant CRT showed better OS compared to RT, this difference was not statistically significant and should be confirmed by a randomized trial. Given the poor prognosis of GBC even at a localized stage, after curative surgical treatment, adjuvant or neoadjuvant strategies with improved systemic treatments should be explored.

11.

12.

13.

14. 15.

16.

17. 18.

19.

20.

21.

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How to site this article: Müller B, Sola JA, Carcamo M, Ciudad AM, Trujillo C, Cerda B. Adjuvant chemoradiation for resected gallbladder cancer: Treatment strategies for one of the leading causes of cancer death in Chilean women. Indian J Cancer 2013;50:184-8. Source of Support: Nil. Conflict of Interest: Non-declare.

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