HIGHLIGHT ARTICLE
JOP. J Pancreas (Online) 2014 July 28; 15(4):348-350.
Adjuvant Treatment for Pancreatic Cancer
Highlights from the “50th ASCO Annual Meeting”. Chicago, IL, USA. May 30-June 3, 2014
Vladimir Daoud1, Muhammad Wasif Saif2, Martin Goodman1
1Departments of Surgery, and 2Division of Hematology and Oncology, Tufts Medical Center and Tufts University School of Medicine. Boston, MA, USA
ABSTRACT
Pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. Surgical resection has been shown to be the only curable treatment available. Unfortunately only 20% of all patients diagnosed with pancreatic cancer are surgical candidates due to the aggressive biology of this disease. There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. The survival of these patients, even status post resection and adjuvant therapy, remains poor and therefore the need for alternative adjuvant therapies is needed. We will therefore discuss Abstracts #4124, #TPS4162, #4120 and #E15191 in this paper which are relevant to the issues described above.
What We Knew Before the 2014 ASCO Annual Meeting?
Pancreatic cancer continues to be an elusive disease with a 5 year overall survival of 4% accounting for approximately 7% of all cancer-related deaths in the United States [1]. Estimates call for a total of 46,420 newly-diagnosed cases of pancreatic cancer in 2014, resulting in 39,590 deaths from the disease [2]. The only chance for a prolonged survival and cure is with surgery. Even after R0 resection, the optimal adjuvant treatment approach remains unclear with a 5-year survival rate for early stage patients less than 25%. This is despite improvements in radiation, systemic therapies, and targeted agents.
There have been multiple studies looking to improve survival in the adjuvant setting however there remains considerable controversy regarding the optimal adjuvant treatment. The current accepted standard of care is adjuvant gemcitabine following curative resection. This is based on the CONKO-001 Trial, comparing adjuvant chemotherapy with gemcitabine to observation alone. It showed an increase in both overall survival and disease-free survival in patients receiving gemcitabine for 6 months [3].
The randomized trials evaluating adjuvant therapy in pancreatic cancer are summarized in Table 1.
|
Table 1. Randomized trials evaluating adjuvant therapy in pancreatic cancer. |
||
|
Study |
Treatment |
Impact of Adjuvant Therapy |
|
GITSG [4] |
Observation vs. 5-FU plus radiation therapy |
Median survival improvement from 11 months to 20 months |
|
EORTC [5] |
Observation vs. 5-FU plus radiation therapy |
A trend toward median survival
improvement |
|
ESPAC-1[6] |
5-FU/L vs. chemoradiation vs. chemoradiation + 5-FU/L vs. observation |
Chemotherapy vs. observation (20.1
months vs. 15.5 months; P=0.009) |
|
RTOG 9704 [7] |
5-FU with radiation vs. Gemcitabine plus 5-FU with radiation |
Median survival (16.7 months vs. 18.8 months; P=0.047) (pancreatic head tumors only) |
|
CONKO-001 [3] |
Gemcitabine vs. observation |
Disease-free survival doubled (13.4
months vs. 6.9 months) |
|
ESPAC-3 [8] |
Gemcitabine vs. 5-FU vs. observation |
No difference in survival advantage between Gemcitabine and 5-FU however, safety and dose intensity favored gemcitabine |
|
JASPAC-01 [9] |
Gemcitabine vs. S-1 |
The two-year survival rates were 70% and 53% for S-1 and gemcitabine, The two-year relapse free survival rates were 49% and 29% for S-1 and gemcitabine |
What We Learned at the 2014 ASCO Annual Meeting?
This review summarizes the abstract presentations of pancreatic cancer at recent ASCO Annual Meeting (Table 2).
|
Table 2. 2014 American Society of Clinical Oncology (ASCO) Annual Meeting: Adjuvant treatment for pancreatic cancer. |
|
|
Abstract |
Title |
|
#4124 [10] |
hENT1 expression in patients with pancreatic cancer treated with gemcitabine after curative intended resection: Results from the CONKO-001 trial |
|
#TPS4162 [11] |
APACT: A phase 3 randomized, open-label, multicenter trial evaluating the use of adjuvant nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with surgically resected ductal pancreatic adenocarcinoma |
|
#4120 [12] |
A phase II study of perioperative therapy for patients with resectable and borderline-resectable pancreatic adenocarcinoma |
|
#E15191 [13] |
Prognostic factors of response to adjuvant chemotherapy after curative resection for pancreatic ductal adenocarcinoma: Prognostic impact of CDA, predictive value of DPD for 5-FU efficiency and hENT1 for gemcitabine |
hENT1 Expression in Patients with Pancreatic Cancer Treated with Gemcitabine after Curative Intended Resection: Results from the CONKO-001 Trial
Sinn et al. (Abstract #4124), utilizing data from the CONKO-001 trial, attempted to define the role of hENT1 expression levels with respect to response rates of various treatments for pancreatic cancer [10]. Tumor samples were taken from 156 patients (88 of which were in the gemcitabine group; 68 were in the observation group) and hENT1 expression was analyzed via immunohistochemistry; the results were divided into hENT1 high expression (membranous staining in more than 50% of tumor cells).
High hENT1 expression was not associated with either increased median disease-free survival or increased median overall survival; none of the differences were found to be statistically significant (Table 3). The authors could therefore not confirm a predictive role for hENT1 expression in this study population.
|
Table 3. hENT1 expression and survival in patients receiving either gemcitabine or observation alone. No differences were statistically significant. |
||
|
|
Median Disease-Free Survival |
Median Overall Survival |
|
Gemcitabine group: |
|
|
|
Observation group: |
|
|
APACT: A Phase 3 Randomized, Open-Label, Multicenter Trial Evaluating the Use of Adjuvant Nab-Paclitaxel (Nab-P) plus Gemcitabine (G) Versus G Alone in Patients with Surgically Resected Ductal Pancreatic Adenocarcinoma
Temporo et al. (Abstract #TPS4162) are evaluating the efficacy and safety of nab-paclitaxel (nab-P) and gemcitabine versus gemcitabine alone as adjuvant chemotherapy in patients following resection of pancreatic ductal adenocarcinoma. The study will include 800 patients in a 1:1 randomization scheme to receive either nab-P plus G or G alone in patients with R0 or R1 resection having not received any prior neoadjuvant therapy or radiation therapy. Patients will be serially assessed by CT scan until disease recurrence for up to 5 years, with a primary endpoint of disease-free survival and secondary endpoints of overall survival and safety [11].
A Phase II Study of Perioperative Therapy for Patients with Resectable and Borderline-Resectable Pancreatic Adenocarcinoma
It is well known that adjuvant chemotherapy improves survival in patients undergoing pancreatic resection; however, the numbers are still relatively grim in terms of duration of both disease-free and overall survival. Therefore, Coveler et al. (Abstract #4120) examined the use of multi-agent adjuvant chemotherapy in patients deemed to have resectable and borderline-resectable pancreatic adenocarcinoma. In a prospective, single arm and single institution study with overall survival as the primary endpoint, they enrolled 35 patients, who received neoadjuvant therapy with gemcitabine, docetaxel and capecitabine followed by radiotherapy and oxaliplatin and adjuvant gemcitabine, oxaliplatin and radiotherapy. Median overall survival of all 35 patients in the study was 31.1 months and median disease-free survival was 27.6 months, both of which are significantly longer than those shown in other studies comparing adjuvant chemotherapy to observation [12].
Prognostic Factors of Response to Adjuvant Chemotherapy after Curative Resection for Pancreatic Ductal Adenocarcinoma: Prognostic Impact of CDA, Predictive Value of DPD for 5-FU Efficiency and Hent1 for Gemcitabine
In an attempt to offer patients a more tailored approach to adjuvant chemotherapy after pancreatic cancer resection using certain histologic markers (including DPD, TS, CDA, hENT1, hCNT3, S100A2 and SMAD4), Truchet et al. (Abstract #E15191) retrospectively studied tissue samples from 123 patients having undergone pancreatic resection for cancer using tissue micro arrays. Importantly, the authors showed that high hENT1 expression is indeed predictive of improved relapse-free survival in patients treated with gemcitabine, increasing the interval from 11.5 months to 14.9 months (p = 0.045). Furthermore, loss of expression of CDA within the tumor is indicative of better survival in patients undergoing curative pancreatic resection and low expression of DPD is predictive of improved overall survival and relapse-free survival in patients having received 5-FU [13].
Discussion
The optimal adjuvant therapy for resected pancreatic cancer continues to be elusive. Approximately 20% of patients with newly diagnosed pancreatic cancer have resectable disease which gives the only chance for a cure or prolonged survival. Despite the use of adjuvant therapy, the 5-year overall survival is 25-30% for node-negative disease and 10% for node-positive disease. The high risk of local and systemic disease recurrence laid down the rationale for adjuvant therapy after resection of pancreatic adenocarcinoma.
Rigorous research is currently being conducted including chemotherapeutic, immunotherapeutic, radiation and other agents to be used in the adjuvant setting for pancreatic cancer. Currently, the adjuvant treatment options are fluorouracil, gemcitabine, chemoradiation, and chemoradiation plus fluorouracil or gemcitabine. The CONKO-001 and ESPAC-03 have shown that chemotherapy can almost double the disease free survival with an improved overall survival compared to observation. GITSG, ESPAC-1 EORTC, and RTOG 9407, have shown that the addition of chemoradiation compared to observation alone can also improve survival.
However what is the best adjuvant treatment? To try and answer this question Liao et al. did a meta-analysis of all controlled randomized trials for adjuvant therapy for resected pancreatic cancer [14]. They concluded that fluorouracil or gemcitabine was the most favorable adjuvant treatment which reduces mortality from cancer after surgery by 30%. Chemoradiation plus chemotherapy, either fluorouracil or gemcitabine, is more toxic and less effective in prolonging survival compared to chemotherapy alone.
Sinn et al. (Abstract #4124) evaluated hENT1 as a marker for the use of gemcitabine. Human equilibrative nucleoside transporter 1 (hENT1) has been shown to predict clinical outcomes after gemcitabine chemotherapy for several types of cancer. Santini et al. evaluated the levels of hENT1 in patients with biliary cancers [15]. They found that hENT1 expression correlated with time to progression (TTP) with a median of 6.33 versus 2.83 months, respectively in patients with positive versus negative hENT1 staining. Patients with a positive hENT1 expression showed a longer median overall survival when compared with patients with low hENT1 expression (14 versus 7 months, respectively). They conclude that hENT1 may be a pertinent predictive marker of benefit of gemcitabine in patients with advanced biliary tract cancers.
Greenhalf et al. evaluated tumor cell expression of hENT1 of patients in the ESPAC-3 trial [16]. They found that the median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs. 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression. They concluded that gemcitabine should not be used for patients with low tumor hENT1 expression as long as their findings are validated by prospective data.
Truchet et al. (Abstract #E15191) showed that a patient with a high hENT1 did had a better overall and relapse free survival compared to a low hENT1. These findings are very similar to the fore mentioned studies. They also concluded that a low expression of DPD is predictive of improved overall survival and relapse-free survival in patients having received 5-FU [13].
However, Sinn et al. did not have the same conclusions as the 2 prior studies or the abstract presented by Truchet et al. In fact, they found that a low hENT1 had a better median overall survival of 24.4 months vs. 19.7 months in the high hENT1 group. This finding in their study was very similar to the observation group of 20.4 months in the high hENT1 group.
The APACT trial (Abstract #TPS4162) is evaluating the use of adjuvant nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with surgically resected ductal pancreatic adenocarcinoma. Von Hoff DD, et al. had previously shown that nab-P and gemcitabine was superior to gemcitabine alone for overall survival in patients with metastatic pancreatic adenocarcinoma [17]. They found that the median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (P<0.001). Also the survival rate at 1 year was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group.
Coveler et al. (Abstract #4120) has shown that we still have a lot of options to evaluate to find the best treatment options available for patients with pancreatic cancer. Their multi-combinational approach with different chemotherapies and radiation did show an improved median overall and disease free survival of 31.1 months and 27.6 months. Albeit small phases II study, this is significantly longer than those shown in other studies comparing adjuvant chemotherapy to observation [12].
ASCO 2014 irradiates the fact that there is still a lot of work that needs to be done in evaluating adjuvant therapy for pancreatic cancer. Whether it is using different markers such as hENT1, multi-combinational therapies, or the APACT trial (Abstract #TPS4162) evaluating the use of adjuvant nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone, will hopefully get us closer to finding better adjuvant therapies for this disease.
Key words 130-nm albumin-bound paclitaxel; Chemotherapy, Adjuvant; gemcitabine; Pancreatic Neoplasms; SLC29A1 protein, human
Abbreviations CONKO: Charité Onkologie; EGFR: epidermal growth factor receptor; EORTC: European Organization of Research and Treatment of Cancer; ESPAC: European Study Group for Pancreatic Cancer; JASPAC: Japanese Adjuvant Study Group of Pancreatic Cancer; RTOG: Radiation Therapy Oncology Group
Conflict of Interests Authors report no conflict of interest.
Correspondence
Martin
Goodman
Tufts Medical Center
800 Washington St.
#9248
Boston, MA 02067
USA
Phone: +1-617.636.9248
E-mail: mgoodman@tuftsmedicalcenter.org
References
1. Jemal A, Siegel R, Xu J. Cancer statistics, 2010. CA Cancer J Clin. 2010; 60: 277-300. [PMID:20610543]
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA Cancer J Clin. 2014; 64(1): 9-29. [PMID:24399786]
3. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297: 267-77. [PMID:17227978]
4. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985; 120: 899-903. [PMID:4015380]
5. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999; 230: 776-82. [PMID:10615932]
6. Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, et al. Fluorouracil vs. gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008; 299(9): 1019-26. [PMID:18319412]
7. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004; 350(12): 1200-10. [PMID:15028824]
8. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010; 304(10): 1073-81. [PMID:20823433]
9. Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, Uesaka K. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer (JASPAC-01 study). J Clin Oncol. 30: 2012 (suppl 34; abstr 145). [PMID:18272475]
10. Sinn M, Sinn BV, Stieler J, et al. HENT1 expression in patients with pancreatic cancer treated with gemcitabine after curative intended resection: Results from the CONKO-001 trial. J Clin Oncol. 32: 5s, 2014 (suppl: abstr 4124).
11. Tempero MA, Cardin DB, Biankin A, et al. APACT: A phase 3 randomized, open-label, multicenter trial evaluating the use of adjuvant nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with surgically resected ductal pancreatic adenocarcinoma. J Clin Oncol. 32: 5s, 2014 (suppl; abstr TPS4162).
12. Coveler AL, Pillarisetty VG, Gyurkey G, et al. A phase II study of perioperative therapy for patients with resectable and borderline-resectable pancreatic adenocarcinoma. J Clin Oncol. 32; 5s, 2014 (suppl: abstr 4120).
13. Truchet XE, Mallaret C, Secq V, et al. Prognostic factors of response to adjuvant chemotherapy after curative resection for pancreatic ductal adenocarcinoma: Prognostic impact of CDA, predictive value of DPD for 5-FU efficiency and hENT1 for gemcitabine. J Clin Oncol. 32; 2014 (suppl: abstr E15191).
14. Liao WC, Chien KL, Lin YL, Wu MS, Lin JT, Wang HP, Tu YK. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013; 14(11): 1095-103. [PMID:24035532]
15. Santini D, Schiavon G, Vincenzi B, Cass CE, Vasile E, Manazza AD, Catalano V, et al. Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC). Curr Cancer Drug Targets. 2011 Jan; 11(1): 123-9. [PMID:20578980]
16. Greenhalf W, Ghaneh P, Neoptolemos JP, Palmer DH, Cox TF, Lamb RF, Garner E, et al. Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial. J Natl Cancer Inst. 2014; 106(1). [PMID:24301456]
17. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013; 369(18): 1691-703).