A Systematic Review The primary evidence informing the new ASCO guidelines for BTC was the results of the phase III study, “Capecitabine or Observation after Surgery in Treating Patients with Biliary Tract Cancer (BILCAP),” a randomized clinical trial conducted in the U.K. (Lancet Oncol ;20 (5)). The primary objective of this systematic review is to present collated evidence from randomized and nonrandomized prospective studies for the efficacy of gemcitabine-cisplatin in . Biliary tract carcinoma (BTC), also termed cholangiocarcinoma (CCA), is a rare malignant disease comprising less than 1% of all cancers (1), but up to 30% of all primary liver tumors (2). Incidence is highest in South-East Asia (/,) (2). Rates are low in Cited by: 1.
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Surgery is the only potential cure for TNM R0 resected patients without lymph node metastases 11 ; however, even with surgery, life expectancy remains limited. While an extensive liver resection is almost always required to achieve R0 28 , liver transplantation is only performed in 2.
Therefore, this review focuses only on outcomes following standard resection surgery. Key literature points for surgical treatment are:. Therefore, unsurprisingly, resected patients survive significantly longer than unresected patients. Other studies also support these findings, with surgery improving outcomes in both early and advanced stages of disease Thus, as could be anticipated, resected patients have longer survival than unresected patients when treated with the same therapy.
In order to allow a full and fair assessment of different treatment regimens, studies should ideally not enroll a mixed population of resected and unresected patients.
In a retrospective study, iCCA patients were divided into two groups: Period 1 [—] prior to new therapies adjuvant chemotherapy, multimodal therapy after recurrence , and Period 2 [—] after the arrival of new therapies Survival improvements were evident from Period 1 to 2 with mOS increasing from The advent of structured GBC staging was also associated with improved survival There is a confusingly wide range of post-surgical survival estimates in the literature.
Improved survival over time and differences in prognostic factor distribution of study populations may explain this variability. However, contemporary mOS may range from While surgery strongly influences the outcome of subsequent treatment, variations in survival post-surgery have been observed. In these patients, variation in baseline prognostic factors altered median OS In another meta-analysis 23 studies, 2, dCCA patients prognostic factor-dependent 5-year survival ranged from Negative resection margin, absence of lymph node metastases and absence of perineural invasion were associated with longer survival Table 4 Survival after surgery therefore varies widely between prognostic factor subgroups and patients benefit differently from surgery depending on their individual prognostic factor profile.
The rationale for adjuvant therapy is high recurrence and poor survival after surgery 46 , despite safety concerns after hepatectomy, as standard doses of chemotherapy are not well tolerated; conversely dose reduction limits efficacy Key literature findings for adjuvant therapy are:.
Adjuvant therapy is controversial Thus adjuvant therapy is often recommended in patients with a less favorable prognostic factor profile 48 , Other retrospective studies also present conflicting viewpoints, with some demonstrating 14 , 47 , 50 and others not showing a benefit with the use of adjuvant therapy compared with BSC 40 , Nevertheless, capecitabine was not associated with a statistically significant increase in mRFS Median RFS after resection is 12—30 months Table 5.
Rates for 5-year RFS worsened with an increasing number of risk factors Several models to estimate patient prognosis exist In a study of iCCA patients with post-surgical recurrence, A study of iCCA patients with post-surgical relapse demonstrated that the mOS from time of recurrence was Furthermore, in patients undergoing surgery for recurrent BTC systematic review, 10 studies , median mOS was Therefore, repeat therapy including surgery may offer a better choice for recurrent BTC than chemotherapy alone.
In the absence of an established first-line standard of care treatment, due to a lack of evidence from RCTs, Eckel et al. These findings were further supported by RCTs, retrospective studies and prospective observational studies 61 , 62 ; importantly, however, none of these studies included BSC as a reference point.
Eckel et al. A review of BTC treatment suggested that no survival benefit for chemotherapy compared with BSC alone had been shown The latest published findings from the second-line ABC study 23 further support this, with mOS in those from the control arm who received active symptom control ASC noted as 5. Given the potential impact of chemotherapy on patient quality of life, the question of clinical relevance of such a blanket treatment approach seems warranted in this era of personalized medicine.
Therefore, chemotherapy-containing regimens are not the only option for consideration. Overall, this leads to a complex evidence-based therapeutic decision model for CCA, where static average survival figures for different therapy options are no longer the only consideration, but the influence of prognostic factors on outcome should also be considered in order to arrive at truly evidence-based therapeutic decisions for individual patients.
The ABC trials excluded such patients; however, a benefit of chemotherapy has been shown in this patient group No standard second-line therapy for BTC currently exists, and no clear advantage of one regimen over another has yet been established 72 - Furthermore, a systematic review of 20 studies produced a weighted mOS of 7. Overall, however, patients demonstrate poor outcomes with no clear advantage shown for one therapeutic regimen over another.
Another consideration for improving patient outcomes is first-line chemotherapy duration. These observations suggest the potential for continuation of first-line chemotherapy to improve survival.
However, given the similarity of these results to other second-line regimens, it could be argued that the most appropriate second-line regimen still remains to be defined. Although not commonly used, etoposide-based regimens were initially amongst the most promising options for the treatment of patients with BTC.
ECF: mOS 9. Furthermore, these results were achieved despite a known high prevalence of multi-drug resistance for etoposide in CCA 82 - 84 leading to further potential survival benefits if multi-drug resistance can be overcome. In a Phase I trial conducted in 19 patients with advanced refractory solid tumors, median OS was 6.
A review by Sahu et al. These figures compare to mPFS of 8. Recently, potential new drug targets were discovered through identification of genetic aberrations in anatomical subtypes Table 7 90 - In addition, the journal had over 1. The journal would like to thank all of our authors, reviewers, editors and readers for their continued support. As a result of the significant disruption that is being caused by the COVID pandemic we are very aware that many researchers will have difficulty in meeting the timelines associated with our peer review process during normal times.
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