The evidence of 2nd line chemotherapy has not been validated. We investigated the treatment outcomes of 2nd line palliative chemotherapy in patients with biliary tract cancer (BTC) and analyzed the factors affecting response or survival.
We retrospectively reviewed and analyzed the outcomes in advanced BTC patients who underwent 2nd line chemotherapy in Soonchunhyang Universitiy Hospitals (Bucheon, Seoul, and Cheonan).
From December 2004 to May 2014, 65 patients were enrolled. The median age was 56 years (range, 40 to 76 years) and the ratio of cholangiocarcinoma (intrahepatic or extrahepatic), gall bladder cancer, and ampulla of Vater cancer was 41 (63.1%):18 (27.7%):6 (9.25%). Half of the patients (33 patients, 50.8%) were treated with gemcitabine-based and 28 patients (43.1%) with 5-fluorouracil-based therapy. The response rate was 3.0% and disease control rate was 21.5% in intention-to-treat analysis. Median overall survival (OS) was 7.2 months (95% confidence interval [CI], 3.9 to 10.5 months) and median progression free survival (PFS) was 3.7 months (95% CI, 2.5 to 4.9 months). In multivariate analysis, patients with good performance status (PS) (P=0.001) and chemo-sensitive tumor to 2nd line chemotherapy (P=0.000) had longer PFS as compared to the others. In addition, patients with good PS (P=0.003), chemo-sensitive tumor to 1st line (P=0.046), and 2nd line chemotherapy (P=0.004) were good prognostic factors for OS.
The effect of 2nd line chemotherapy in advanced BTC was modest and maybe beneficial in select patients.
Biliary tract cancer (BTC) is generally rare in Western countries but common in Korea where approximately 5,130 new patients were diagnosed in 2012 [
From December 2004 to May 2014, the patients with histologic confirmed adenocarcinoma locally advanced or metastatic BTC patients (including extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma [IHCC], gallbladder cancer [GB ca], and ampulla of Vater cancer), who underwent 2nd line chemotherapy in Soonchunhyang University Hospitals (Bucheon, Seoul, and Cheonan), were retrospective reviewed through medical records. Patients who were previously treated with radiotherapy or concurrent chemoradiotherapy were eligible if treated with other systemic 1st line palliative chemotherapy. This study was approved by the institutional review board of Soonchunhyang University Hospitals (2014-11-007-002).
Tumor response measured by the RECIST ver. 1.0 (Response Evaluation Criteria in Solid Tumors) was evaluated with the same imaging modality used at baseline, including contrast enhanced computed tomography or magnetic resonance imaging. Hematologic and non-hematologic toxicities were evaluated using the NCI-CTCAE ver. 3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events; National Cancer Center, Goyang, Korea). All patients were included in the intention-to-treat (ITT) analysis of efficacy. The response rate was calculated as the ratio of the number of patients who achieved complete or partial responses to the number of patients enrolled in the study. The disease control rate (DCR) was calculated as the ratio of the number of patients who achieved complete or partial responses or stable disease (SD) to the number of patients enrolled in the study.
Factors that influence treatment response were analyzed through chi-square or Fisher’s exact test. PFS was calculated from the first day of 2nd line treatment to the date on which progression of the disease was first observed or the date of last follow-up. OS was defined from the first date of 2nd line treatment to the date of death or last follow-up. OS and PFS were assessed using the Kaplan-Meier method, and the 95% confidence intervals (95% CIs) for the median time to an event were calculated. Significant variables in the univariate analysis were considered as variables for the multivariate analysis performed using Cox’s proportional hazard regression model. The SPSS ver. 14.0 statistical software program (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
From December 2004 to May 2014, 65 patients were enrolled in the retrospective study. The baseline characteristics of patients were summarized in
Among 65 patients, most had undertaken gemcitabine-based (gemcitabine alone, gemcitabine/cisplatin, gemcitabine/oxaliplatin; n=33; 50.8%) and 5FU-based chemotherapy (5FU/cisplatin, 5FU/leucovorin, 5FU/leucovorin/oxaliplatin, oral 5FU alone; n=29; 44.6%). Few others (n=3, 4.6%) were treated with anthracyline or bevacizumab combination. Response evaluation was done in 54 patients. Two of 65 patients had a PR to 2nd line chemotherapy and 12 patients (18.5%) had SD. In ITT analysis, overall response rate (ORR) and DCR were calculated as 3.0% and 21.5%, respectively (
Treatment related toxicities were assessable in all patients (
Among the types of 2nd line therapy, sex, age, primary tumor site, disease pattern, carbohydrate antigen 19-9 value, efficacy to the 1st line therapy, ECOG PS, albumin level, and eGFR, none was a significant factor on the effect of the 2nd line therapy (
In multivariate analysis, patients with good PS (P=0.001) and chemo-sensitive tumor to 2nd line chemotherapy (P=0.000) had longer PFS as compared to the others (
BTC is a highly lethal tumor and the prognosis of patients with advanced BTC is poor. The survival benefit of chemotherapy over best supportive care for advanced BTC was initially suggested in a phase III trial on advanced pancreatic and biliary tract cancers [
In case of advanced BTC, patients progressing after 1st line chemotherapy show rapidly worsening PS, and only a small number of patients sustain a general condition conducive to the administration of salvage treatment. Therefore, only a few clinical trials on salvage treatment of BTC have been conducted. Generally, experience of salvage therapy in advanced BTC has been sparse with disappointing results. There are very few active chemotherapy drugs besides gemcitaibine plus cisplatin combination therapy. Other cytotoxic drugs such as 5FU, adriamycin, oxalipatin, and mitomycin were used in phase II study in the salvage setting and other biologic agent included erlotinib, bevacizumab, cetuximab, or mTOR inhibitor.
In case of 5FU-based therapy in 1st line therapy, phase II study of salvage therapy with gemcitabine was reported by Oh et al. [
The ABC-06 trial is a phase III randomized trial to determine whether patients with advanced BTC benefit from the addition of mFOLFOX chemotherapy over active symptom control in the 2nd line setting, after progression of 1st line treatment with gemcitabine and cisplatin. It will be the first randomized phase III in the 2nd line setting. We expect that the benefit of 2nd line therapy in advanced biliary tract cancer could be demonstrated in this study.
In a recent review on 2nd line chemotherapy by Lamarca et al. [
We analyzed several factors by univariate and multivariate analysis to determine affecting and prognostic factors to chemo-response and survival. We identified no significant factors affecting the chemo-response in 2nd line chemotherapy.
In multivariate analysis, the patients with good PS status (P= 0.001) and chemo-sensitive tumor to 2nd line chemotherapy (P= 0.000) had longer PFS as compared to others. In addition, patients with good PS status (P=0.003), chemo-sensitive tumor to 1st line (P=0.046), and chemo-sensitive tumor to 2nd line chemotherapy (P=0.004) were good prognostic factors for OS. Other prognostic factors such as albumin level reported by Oh et al. [
Based on these results, we suggest that patients with poor PS should not be offered 2nd line chemotherapy. Patients with good PS and chemo-sensitive in 1st line may be considered as candidates for 2nd line chemotherapy.
Novel agents that target anti-angiogenic or eGFR/Her2/RAS/RAF pathway inhibitors have been tested mainly in 1st line, alone, or in combination with cytotoxic chemotherapy, however, the outcomes have been disappointing so far. Cetuximab was tested as combination regimen with gemcitabine and oxaliplatin in the 1st line setting, however the randomized phase II trial did not demonstrate the additional effect of cetuximab [
Our study was a retrospective study with a small number of patients. Therefore, there is limitation to the interpretation of the results. However, we found that outcomes of the 2nd line chemotherapy in patients with advanced BTC and prognostic factors. Our results indicated that prospective study on advanced biliary tract cancer with good PS and chemo-sensitive tumor for 2nd line chemotherapy is warranted.
Kaplan-Meier curves for (A) the overall survival and (B) progression free survival in patients with advanced biliary tract cancer who underwent 2nd line chemotherapy. OS, overall survival; PFS, progression free survival; CI, confidence interval.
Kaplan-Meier survival curves of the overall survival according to (A) ECOG PS, (B) efficacy to 1st line chemotherapy and (C) efficacy to 2nd line chemotherapy, and (D) Kaplan-Meier survival curves of the progression free survival according to ECOG PS. ECOG PS, European Cooperative Oncology Group performance status; PR, partial responses; SD, stable disease; PD, progressive disease.
Baseline characteristics of patients with advanced BTC (N=65)
Characteristic | Value |
---|---|
Men | 34 (52.3) |
| |
Median age (range) (yr) | 56 (40–76) |
| |
Primary tumor site | |
Extrahepatic BTC | 7 (10.8) |
Intrahepatic BTC | 34 (52.3) |
Gallbladder cancer | 18 (27.7) |
Ampulla of Vater cancer | 6 (9.2) |
| |
ECOG PS | |
0–1 | 42 (64.6) |
2–3 | 23 (35.4) |
| |
Disease pattern | |
Locally advanced | 12 (18.5) |
Recurrent or metastatic | 53 (81.5) |
| |
Previous chemotherapy | |
5-Fluorouracil-based | 38 (58.5) |
Gemcitabine-based | 24 (36.9) |
Others | 3 (4.6) |
| |
Best response to previous chemotherapy | |
Partial response | 15 (23.1) |
Stable disease | 13 (20.0) |
Progressive disease | 37 (56.9) |
| |
Median albumin (range) (g/dL) | 3.8 (2.5–4.8) |
| |
Median estimated glomerular filtration rate (range) | 89 (32.2–149.5) |
Values are presented as number (%), unless otherwise stated.
BTC, biliary tract cancer.
European Cooperative Oncology Group performance status.
The kinds of 2nd line therapy and response to 2nd line therapy (N=65)
Variable | Value |
---|---|
The kinds of 2nd line chemotherapy | |
5-Fluorouracil-based | 28 (43.1) |
Gemcitabine-based | 33 (50.8) |
Others | 4 (6.2) |
| |
Response to 2nd line therapy | |
Complete response | 0 |
Partial response | 2 (3.1) |
Stable disease | 12 (18.5) |
Progressive disease | 40 (61.5) |
Not assessed | 11 (16.9) |
| |
Response rate by ITT analysis (%) | 3.0 |
Disease control rate by ITT analysis (%) | 21.5 |
Values are presented as number (%), unless otherwise stated.
ITT, intention to treat.
Treatment–related toxicities
Toxicities | Grade 1–2 | Grade 3–4 |
---|---|---|
Hematologic toxicities | ||
Neutropenia | 18 (27.7) | 24 (36.9) |
Neutropenia fever | - | 3 (4.6) |
Anemia | 35 (53.9) | 9 (13.8) |
Thrombocytopenia | 30 (46.2) | 13 (20.0) |
| ||
Non-hematologic toxicites | ||
Anorexia | 40 (63.0) | 5 (7.7) |
Fatigue | 22 (33.8) | 4 (6.2) |
Emesis | 37 (56.9) | 2 (3.1) |
Stomatitis | 22 (33.9) | 2 (3.1) |
Diarrhea | 2 (3.0) | 1 (1.5) |
Peripheral neuropathy | 13 (20.0) | 0 |
Values are presented as number (%).
Factors that influence treatment response to 2nd line therapy
Factors | P-value |
---|---|
Kinds of 2nd line therapy | 0.562 |
Sex (male vs. female) | 0.546 |
Age (≥56 yr vs. <56 yr) | 0.371 |
Primary tumor site | 0.763 |
Disease pattern | 0.164 |
Carbohydrate antigen 19-9 value (≥800 vs. <800) | 0.721 |
Efficacy to 1st line therapy | 0.129 |
European Cooperative Oncology Group performance status (0 or 1 vs. 2 or 3) | 0.464 |
Albumin level (≥3.8 vs. <3.8) | 0.06 |
Estimated glomerular filtration rate (>89 vs. ≤89) | 1.0 |
This value was analyzed by cross-table analysis through SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA).
Prognosis factors for survival by univariate analysis
Factors | P-value | |
---|---|---|
| ||
Overall survival | Progression free survival | |
Kinds of 1st line therapy | 0.232 | 0.268 |
| ||
Kinds of 2nd line therapy | 0.856 | 0.144 |
| ||
Sex (male vs. female) | 0.557 | 0.872 |
| ||
Age (≥56 yr vs. <56 yr) | 0.942 | 0.376 |
| ||
Primary tumor site | 0.111 | 0.719 |
| ||
Disease pattern | 0.837 | 0.762 |
| ||
Carbohydrate antigen value (≥800 vs. <800) | 0.370 | 0.434 |
| ||
European Cooperative Oncology Group performance status (0 or 1 vs. 2 or 3) | 0.000 | 0.001 |
Efficacy to 1st line therapy | 0.012 | 0.115 |
| ||
Efficacy to 2nd line therapy | 0.003 | 0.000 |
| ||
Albumin (≥3.8 vs. <3.8) | 0.085 | 0.070 |
| ||
Estimated glomerular filtration rate (>89 vs. ≤89) | 0.582 | 0.895 |
This value was analyzed by Kaplan-Meier method through SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA).
Prognosis factors for survival by multivariate analysis
Factors | P-value | |
---|---|---|
Overall survival | Progression free survival | |
European Cooperative Oncology Group performance status | 0.003 | 0.001 |
Efficacy to 1st line therapy | 0.046 | - |
Efficacy to 2nd line therapy | 0.004 | 0.000 |
This value was analyzed by Cox’s proportional hazard regression model through SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA).