A Pathologic Complete Response in the Surgical Specimen After Systemic Chemotherapy for a Gallbladder Carcinoma

CASE REPORT

A 58-year-old woman was admitted to our hospital in November 2004 because of abdominal pain associated with a weight loss of 4 kilograms during the past 2 months. She had scleroderma with lung fibrosis, but was asymptomatic at the time of admission. Computed tomography (CT) revealed a gallbladder carcinoma with celiac and hilar nodes in contact with the pancreatic head (Figure 1). Biliary magnetic resonance imaging also showed lymph node involvement. Serum tumor markers (CEA and CA19.9) were not elevated. A cystadenocarcinoma of the gallbladder was diagnosed by fine-needle aspiration of the lesion.

Figure 1.

In November 2004, the CT scan showed a gallbladder carcinoma with celiac and hilar nodes in contact with the pancreatic head.

The patient underwent intravenous (IV) chemotherapy 1 day every 2 weeks with gemcitabine 1000 mg/m² combined with oxaliplatin 100 mg/m². After 4 chemotherapy sessions, repeat CT showed disappearance of the celiac lymph nodes and a decrease in the size of the hilar lymph nodes, along with a decrease in the gallbladder tumor from 80 to 45 mm (Figure 2).

Figure 2.

In January 2005, the CT scan showed a decrease in tumor size and hilar nodes compared with the first CT Scan (Figure 1) after 4 cycles of chemotherapy.

Because of grade III neurologic toxicity, the oxaliplatin dose was decreased by 25% for the next cycle of chemotherapy.

In February 2005, after the fifth cycle, the patient presented with acute respiratory distress syndrome and was successfully treated with corticosteroids. CT and lung function studies showed an infiltrate and a restrictive syndrome (a decreased total pulmonary capacity of 41% [normal, >70%], a normal Tiffeneau coefficient of 92%, and a decreased alveolocapillary diffusion of 48%). The acute respiratory distress syndrome was related to gemcitabine, which was withdrawn.

Because of the good response and the contraindication of further gemcitabine, surgery was performed in April 2005. During the surgery, no carcinoma or ascites was seen. The surgeon found a gallbladder lesion extended to the liver in the fifth segment. There were also nodes in the liver hilum, behind and along the liver artery. Perioperative liver ultrasonography confirmed that the gallbladder lesion extended to the liver, but without liver metastasis elsewhere. The gallbladder and the fourth and fifth liver segments were removed. A 2 × 2.5-cm lesion of the gallbladder wall was observed, and gallstones were found within the gallbladder. The specimens were sectioned every 3 millimeters, and histologic analysis was performed on 5-μm segments of each. Necrotic tissue was found, surrounded by inflammatory cells, but no tumor cells were detected in the surgical specimens. The lymph nodes were negative for disease. Because of previous toxicity, a decision was made not to administer adjuvant chemotherapy.

One year after the surgery, the patient presented with an adenocarcinoma lymph node recurrence in the liver hilum confirmed by cytologic examination. She was treated with FOLFOX (5-fluorouracil [5-FU]/leucovorin/oxaliplatin). Unfortunately, she died of a liver abscess associated with bone marrow aplasia in June 2006, after her third treatment cycle.

DISCUSSION

To our knowledge, this case is only the second reported one of gallbladder carcinoma showing a pathologic complete response after systemic chemotherapy without radiotherapy. Recently, Sharma et al¹ reported another case of gallbladder cancer with a complete pathologic response after the same protocol of chemotherapy. Another excellent response described in the literature concerns a negative autopsy after chemotherapy (5-FU 500 mg/m² for 5 days every 3 weeks, for a total of six cycles) combined with radiotherapy (51 Gy over 5 weeks). After a recurrence 4 years later, the patient was treated with endobiliary radiotherapy using iridium 192 combined with 5-FU (500 mg/m²) and then with paclitaxel chemotherapy. The patient died 18 months later of a liver abscess and hepatorenal impairment. Postmortem examination of the hepatobiliary system revealed no microscopic evidence of cholangiocarcinoma.² Three other cases of pathologic complete response were described by McMasters et al.³ Those patients were also treated with 5-FU (300 mg/m² per day) combined with external beam radiotherapy (at a dose of 1.8 Gy per day to a total dose of 50.4 Gy).

Many drugs, including 5-FU/leucovorin, cisplatin, oxaliplatin, mitomycin C, doxorubicin, gemcitabine, epirubicin, capecitabine, irinotecan, and docetaxel continue to be used alone and in combination for the treatment of advanced biliary cancer.^4,5 Gemcitabine/oxaliplatin (GEMOX) efficacy has been established in pancreatic cancer, in terms of response rate, progression-free survival, and safety, but with no statistically significant advantage in terms of overall survival compared with gemcitabine alone.⁶ GEMOX activity and tolerability in advanced biliary tract adenocarcinoma was studied in patients who presented with a variety of tumor sites (gallbladder, extrahepatic bile ducts, ampulla of Vater, and intrahepatic bile ducts). The response rates seem better for patients with gallbladder tumors than for those with carcinomas of the intrahepatic bile ducts (54% vs. 21%).⁷

Two recent phase III trials showed that gemcitabine plus oxaliplatin or cisplatin is superior to gemcitabine alone in terms of overall survival.^1,8 In another study, 30 patients with unresectable biliary cancer were treated with cetuximab and GEMOX.⁹ Objective response on CT occurred in 19 patients, of whom 3 achieved complete response and 16 achieved partial response. Nine patients underwent potentially curative secondary resection after major response to therapy but no histologic complete response was observed.⁹

CONCLUSION

A pathologic complete response after 5 cycles of GEMOX is rare in gallbladder carcinoma. Unfortunately, our patient developed severe treatment-related pulmonary toxicity that precluded further exposure to gemcitabine.