Increases in the duration of the second stage of labor past the first half-hour resulting in spontaneous vaginal birth were associated with increased morbidity, according to researchers.

The researchers performed a retrospective analysis of more than 103,000 pregnancies from the Consortium on Safe Labor, a study of electronic medical records from 12 U.S. sites from 2002 to 2008, according to a study published in Obstetrics & Gynecology.

[email protected]

SOURCE: Grantz KL et al. Obstet Gynecol. 2018 Feb;131(2):345-53.

Increases in the duration of the second stage of labor past the first half-hour resulting in spontaneous vaginal birth were associated with increased morbidity, according to researchers.

The researchers performed a retrospective analysis of more than 103,000 pregnancies from the Consortium on Safe Labor, a study of electronic medical records from 12 U.S. sites from 2002 to 2008, according to a study published in Obstetrics & Gynecology.

[email protected]

SOURCE: Grantz KL et al. Obstet Gynecol. 2018 Feb;131(2):345-53.

Increases in the duration of the second stage of labor past the first half-hour resulting in spontaneous vaginal birth were associated with increased morbidity, according to researchers.

The researchers performed a retrospective analysis of more than 103,000 pregnancies from the Consortium on Safe Labor, a study of electronic medical records from 12 U.S. sites from 2002 to 2008, according to a study published in Obstetrics & Gynecology.

[email protected]

SOURCE: Grantz KL et al. Obstet Gynecol. 2018 Feb;131(2):345-53.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).