Adjuvant Chemoradiotherapy for Squamous Cell Carcinoma of Gallbladder
Supriya Mallick, Rony Benson, P. K. Julka & Goura Kishor Rath
Journal of Gastrointestinal Cancer ISSN 1941-6628 J Gastrointest Canc DOI 10.1007/s12029-014-9641-8
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Author's personal copy J Gastrointest Canc DOI 10.1007/s12029-014-9641-8
CASE REPORT
Adjuvant Chemoradiotherapy for Squamous Cell Carcinoma of Gallbladder Supriya Mallick & Rony Benson & P. K. Julka & Goura Kishor Rath
# Springer Science+Business Media New York 2014
Background Gallbladder carcinoma (GBC) is a relatively rare gastrointestinal tract malignancy in developed countries [1]. Epidemiology of this disease varies widely in different parts of the world and is one of the common malignancies of female population in northern part of India [2]. Adenocarcinoma is the commonest histological subtype of GBC, and squamous cell carcinoma accounts for only 2–10 % of all GBC [3]. Surgery with R0 resection is considered the cornerstone of therapy. Even after radical surgical resection, the 3-year survival is dismal, attributed to both locoregional and systemic failure. However, there is paucity of data about the optimum treatment of GBSCC. Hence, efforts have been made to optimize adjuvant therapy and improve survival. Recent reports have shown a benefit of adjuvant chemoradiation for gallbladder carcinoma [4–7]. This report is aimed to present the demography, treatment, and outcome of three GBSCC treated with a uniform approach of post-operative radio-chemotherapy.
The demography, treatment details, and outcome data were retrieved in predesigned pro-forma.
Results Patients Three patients were identified to have squamous histology. Median age was 45 years (range, 41–50 years). The patient characteristics and treatment details have been tabulated in Table 1. All the three patients were female. Surgery Two patients presented with features of gallstone disease and underwent simple cholecystectomy. Subsequently, one underwent re-exploration and completion radical cholecystectomy. The third patient was evaluated for malignancy and underwent radical cholecystectomy. The post-operative histopathology of all three patients revealed squamous cell carcinoma. All three patients had pathological T3N0 disease. However, less than 10 lymph nodes were dissected in these cases.
Methods Adjuvant Chemoradiotherapy Protocol Patient We retrieved treatment charts of patients of GBC treated with curative intent in multidisciplinary gastrointestinal malignancy clinic. Data was retrieved for 104 GBC patients. The histology was found to be squamous cell in three patients. S. Mallick (*) : R. Benson : P. K. Julka : G. K. Rath AIIMS, New Delhi, India e-mail:
[email protected]
Adjuvant therapy was started within 4–6 weeks of surgery. Adjuvant external beam radiotherapy of 45 Gy in 25 fractions over 5 weeks was prescribed. Adjuvant chemotherapy was planned with 5-fluorouracil and leucovorin. 5-fluorouracil was prescribed 425 mg/m2 with leucovorin 20 mg/m2 D1– D5 every 4 weeks for the 1st, 4th, and 5th cycles. The 2nd and 3rd cycles were delivered concurrent with radiation for the first 4 days and the last 3 days of radiation with 5-flurouracil 370 mg/m2 and leucovorin 20 mg/m2.
Author's personal copy J Gastrointest Canc Table 1 Patient characteristic and treatment details Patient Characteristics Age Sex Mode of diagnosis Stage Surgery Adjuvant RT dose Adjuvant Chemotherapy Status at last follow
Site of recurrence
Number Median 45 (Range 41–50 years) Female-3 Planned-2 Incidental-1 IIIA-3 Simple Cholecystectomy-1 Radical Cholecystectomy-2 45 Gray/25 fractions/5 weeks FUFA NED-1 PD-1 Defaulted-1 Lung, Spleen
Target Volume Delineation for Radiotherapy Radiotherapy was planned by 2-dimensional (2D) or 3dimensional conformal radiation therapy (3D) planning. The planning CT scan was done with a thermoplastic immobilization cast covering the abdomen with 3-mm slice thickness. Oral and intravenous contrast was used for the CT scan. The
target volume constituted of gallbladder fossa and regional lymph node stations. The CTV primary included the GB fossa as evident in the preoperative CECT image and the surgical clips with 1-cm isotropic expansion (after radical cholecystectomy). The CTV nodal included the portal, celiac axis, superior mesenteric, and aorto-caval group of lymph nodes. The portal vein was delineated from the confluence of superior mesenteric vein and the splenic vein to the bifurcation into right and left portal vein. The celiac axis was delineated for proximal 1.5–2 cm and the superior mesenteric artery for proximal 2.5–3 cm. An isotropic 1 cm expansion was added to generate the lymph node station. The aorta was delineated from at least 1 cm cranial to the CTV primary or portal lymph node station and caudally extending up to the L2 level. An asymmetric expansion, 3–3.5 cm to the right, 2–2.5 cm anteriorly, 1–1.5 cm to the left, and 0.2 cm posteriorly was added to generate the aorto-caval lymph node. The CTV nodal and CTV primary was added to form the composite CTV. An isotropic 1-cm expansion was added for PTV. The spinal cord, bilateral kidney, liver, and bowel were delineated as organ at risk (OAR). Radiation planning was done in Eclipse treatment planning system version 6.5 (Varian Medical Systems, Palo Alto, CA). A total dose of 45 Gy in 25 fractions over a period of 5 weeks was prescribed to the PTV (Fig. 1).
Fig. 1 Contouring, 3DCRT planning and dose volume histogram in a case of GBSCC
Author's personal copy J Gastrointest Canc
Survival and Pattern of Failure At a median follow up of 11.4 months, one patient developed metastasis in lung and spleen and one patient lost to follow up after adjuvant radiotherapy.
Discussion Gallbladder carcinoma (GBC) is the fifth most common GI malignancy and the commonest malignancy of the biliary tract. GBC is a relatively uncommon malignancy, with an ASR (age standardized rate) of 1.5. GBC shows wide geographic and ethnic variation across the globe [7–9]. A recent review of the epidemiology of GBC reported highest incidence in Delhi (21.5/100,000), followed by Karachi (12.9/100,000) [10]. Adenocarcinoma has been reported to be the most common histological subtype of GBC followed by SCC and ASC (adenosquamous carcinoma). SCC of GB comprises only 2– 10 % of all GBC [3]. GBSCC has been reported to have high proliferative rate and local invasiveness [11, 12]. The tumor doubling time of GBAC has been reported to be double that of GBSCC [13]. Therefore, GBSCC presents in advanced stage with extensive local infiltration. However, the literature seems discordant about the lymphatic metastasis and distant metastasis from GBSCC. Chan et al. and Kim et al. reported high rate of lymph node metastasis in GBSCC [11, 14]. Though discordant, authors have reported as high as 43.8 % systemic metastasis [11, 12]. Over the years, surgery has remained the cornerstone of therapy. In a recent review, Matsumoto et al. compared 3-year survival of stage II GBC treated with simple vs. radical cholecystectomy [15]. The authors reported 29– 57 % vs. 100 % 3-year survival favoring radical cholecystectomy, making radical cholecystectomy the standard in stage II GBC. However, in stage III and stage IV, the 3-year survival ranged from 7–80 % even after extended surgical resection. In the absence of level I evidence and randomized trial data, the adjuvant therapy varies widely across the globe. The relative rarity of the disease has left the treatment of GBC based upon small case series and retrospective analysis. The SEER database has been analyzed several times to find the optimum therapy. Recently, Hyder et al. analyzed the SEER database to redefine the role of adjuvant radiotherapy for GBC [16]. The authors identified 5,011 patients with GBC who underwent surgical resection from 1998 to 2009. Seventyfive percent had a localized disease, and only 17.9 % patients received adjuvant radiation. Adjuvant radiation was used mostly for younger age, tumor extension beyond the serosa, intermediate to poorly differentiated tumors, and lymph node metastasis. In a propensity-matched multivariate analysis, the authors reported significantly improved 1-year survival with
the use of adjuvant radiotherapy, and the survival benefit was more pronounced for N1 disease and poorly differentiated tumors. However, the benefit was not significant at 5 years. Czito et al. reported 23 year experience with the use of 5flurouracil based chemoradiotherapy for GBC [6]. Local failure was reported in seven patients (35 %). The authors concluded that extended resection was associated with improved survival, although not statistically significant. A median survival of 27.5 months was reached with the aggressive approach in the study with a 5-year DFS of 47 %. Horgan et al. conducted a systematic review and metaanalysis of published institutional and registry data to evaluate the benefit of adjuvant therapy for GBC [17]. The authors reported a nonsignificant benefit of adjuvant therapy. When analyzed separately, outcome was found better in patients treated with chemoradiotherapy when compared with radiotherapy alone. The benefit was significantly higher for node positive and R1 resection. However, there is paucity of data regarding the treatment of GBSCC. Oohashi et al. in a review of 28 patients reported residual disease as the most important prognostic factor [18]. On the contrary, Kim et al., when reviewed the data of 25 patients of GBSCC and GBAC, found worse survival in the former group; however, the difference was not appreciable when adjusted for extent of resection. The authors concluded that a R0 resection improves survival for GBSCC [14]. Roa et al. identified 41 cases of GBSCC in a cohort of 606 patients of GBC and reported worse outcome for GBSCC (median survival 4 months vs. 12 months; p = 0.003) [19]. Locoregional and distant recurrence precludes long-term disease control and hence merits incorporation of adjuvant chemoradiotherapy in the treatment schedule of GBSCC. Isolated case reports have reported long-term disease control with adjuvant chemotherapy and radiotherapy [20]. The biological aggressive nature and higher propensity of systemic metastasis merits aggressive treatment of this subtype of GBC. Therefore, it looks reasonable to deliver adjuvant treatment in the form of radiotherapy and chemotherapy to optimize local disease control and survival. Over the last decade, the radiotherapy technique has witnessed a paradigm shift from 2D planning to conformal radiation with an aim to optimize tumor control and minimize both acute and chronic radiation morbidity. The improvement in radiation treatment delivery including intensity-modulated radiotherapy, image-guided radiotherapy has further paved for exploration of adjuvant radiation for GBC. Fuller et al. in a series of 24 patients highlighted the feasibility of IGIMRT (image-guided intensity-modulated radiotherapy) for GBC with minimal radiation morbidity [21]. The IGIMRT arm experienced a better survival compared to the 3D CRT arm though not statistically significant. However, it’s worth exploring in the adjuvant setting for GBC to optimize local disease control and better sparing of OAR [21].
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Conclusion SCC of GB is an uncommon and an extremely aggressive hepatobiliary carcinoma with dismal prognosis. The diagnosis often is late and limits curative treatment for large majority of patients. A radical surgical resection is the cornerstone of therapy for GBSCC. Adjuvant chemoradiation appears to improve DFS and minimize locoregional failure.
Conflict of Interest The authors declare that they have no conflict of interest
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