Treatment for Pancreatic Cancer: Current Therapy and Continued Progress

doi:10.1053/j.gastro.2005.03.039

Gastroenterology

Volume 128, Issue 6, May 2005, Pages 1642-1654

https://doi.org/10.1053/j.gastro.2005.03.039 Get rights and content

In the last decade, continued efforts in pancreas cancer research have led to the development of new, more effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for the development of more effective treatment strategies. Recent clinical trials have provided reason for hope that novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for patients with this disease. This article will summarize the data that has led to the current standards of therapy for patients with resectable and advanced pancreatic cancer and review new treatment strategies for this disease.

Section snippets

Adjuvant therapy of pancreas cancer

Patients with resectable disease comprise the smallest subgroup of pancreas cancer patients (∼10%). Although all visible disease may be removed by surgery, the cure rate for patients managed with surgery alone is low.⁵ Therefore, researchers have focused on adjuvant therapy in an effort to increase the rate of long-term survival. Adjuvant therapy is postoperative treatment administered to patients with no detectable evidence of residual disease but who are likely to harbor microscopic tumor

Locally advanced disease

Locally advanced disease refers to extension of the tumor to adjacent organs such that complete surgical excision with negative pathologic margins is impossible. Local extension includes nearby organs, such as the liver or duodenum, regional lymph nodes, or, most commonly, vascular structures such as the superior mesenteric artery or celiac trunk that cannot be resected.

Treatment of locally advanced disease in the United States has been defined by 2 early GITSG trials and an Eastern Cooperative

Chemotherapy for advanced disease

Metastatic pancreatic cancer tends to be a rapidly progressing disease, often accompanied by a constellation of debilitating symptoms. More than half of all patients with advanced pancreatic cancer suffer from weight loss, visceral abdominal pain, anorexia, nausea, and/or depression. Although no curative treatment exists for this group of patients, newer systemic therapies have emerged over the past decade that provide meaningful alleviation of tumor-related symptoms and prolong survival.

Recent phase II and III clinical trials in metastatic pancreatic cancer

The FDA approval of gemcitabine for the treatment of patients with advanced pancreatic cancer in 1996 was a major step forward in the treatment of this disease. However, the 1-year survival rate was only 18%, indicating that metastatic pancreatic cancer remains a devastating illness. Several recent clinical trials in patients with metastatic pancreatic cancer have tried to improve on the clinical outcomes of these patients (Table 2). The design of these trials falls into 2 broad categories:

Conclusion

Although significant advances have occurred in our knowledge of the factors that lead to the development and progression of pancreatic cancer, this knowledge has not yet translated into clinical breakthroughs in this disease. However, the emergence of molecularly targeted agents has led to a dramatic increase in research activity and the number of new clinical trials in patients with all stages of pancreatic cancer. In addition to trying to improve survival, in patients with advanced stage

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Prediction of survival after left-sided pancreatic resection for adenocarcinoma: Introduction of a new prognostic score
2019, Hepatobiliary and Pancreatic Diseases International
Due to the clinically unapparent course the entity of left-sided pancreatic adenocarcinoma is often diagnosed at advanced stages, resulting in small numbers of patients qualifying for pancreatectomy. This study strives to develop a prognostic model for survival after left-sided pancreatic resection.
A total of 54 patients were analyzed. Pre- and intra-operative predictive factors for 18-month mortality were identified with multivariable binary logistic regression analysis and compiled into a prognostic model. The applicability was evaluated by assessment of the area under the receiver operating characteristic curve (AUROC). The model was internally validated applying a randomized backwards bootstrapping analysis.
The 18-month mortality rate was 74.1% (n = 40). Mean survival was 19.1 months. A prognostic model for 18-month mortality after left sided-pancreatectomy showed an AUROC >0.800:
18-month mortality risk in% = Exp(Y) / (1 + Exp(Y)) with
y= -0.927 + (1.724, if CA 19-9 elevated, otherwise 0) + (1.212 × number of intra-operative transfused packed red blood cells) + (2.771, if prior abdominal surgery, otherwise 0) − (3.612, if gastric resection, otherwise 0)
This model was internally validated in 40 randomized backwards bootstrapping steps with AUROCs ranging from 0.757 to 0.971.
The 18-month mortality risk for patients after left-sided pancreatectomy for adenocarcinoma of the pancreatic body can be assessed with the number of intra-operatively transfused packed red blood cells, elevated CA 19-9 levels, additional gastric resection and prior abdominal surgeries in the patient's history.
EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer
2017, Gastrointestinal Endoscopy
Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy.
In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death.
Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection.
Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.
Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma
2016, HPB
Citation Excerpt :
This poor survival results from not only its aggressive biology but also presentation at an advanced stage. There are no definitive signs or symptoms associated with the early stage and no effective screening tests.2 Currently, complete surgical resection is the only chance of cure.3
Palliative resection of stage IV pancreatic ductal adenocarcinoma (PDAC) has not shown its benefit until now. In our retrospective review, we compared the results of palliative resection to non-resection.
Between 2000 and 2009, metastasis of PDAC was confirmed in the operating room in 150 patients. 35 underwent palliative resection (resection group; R) and 115 did bypass or biopsy. 35 patients (biopsy or bypass group: NR) in the 115 patients were matched with the patients undergoing resection for tumor size and the metastasis of peritoneal seeding. Demographic, clinical, operative data and survival were analyzed.
There was no significant difference of major complication (Clavien–Dindo classification 3–5) between two groups. There was no 30-day mortality in either group. More patients in R received postoperative chemotherapy (82.9% vs. 57.1%; P = 0.019). Multivariate analysis showed resection and postoperative chemotherapy as independent factor related to survival (hazard ratio, 0.44; 95% CI, 0.25–0.76; P = 0.003). Patients in R showed better survival rates compared to those in NR (P < 0.001).
Our study suggests resection for stage IV PDAC can be associated with increased survival. In patients of stage IV PDAC, palliative resection with chemotherapy could have some benefit in selected patients.
Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma
2015, Seminars in Cancer Biology
Autophagy is a highly dynamic, evolutionary conserved cellular homeostatic process that occurs at baseline levels in most cells. It exerts predominantly cytoprotective effects by removing damaged organelles and protein aggregates. In cancer, however, autophagy acts as both a tumor suppressor by preventing ROS-induced tumorigenesis and as a tumor inducer by providing nutrients to tumor cells under hypoxic, low-energy conditions and protecting them against therapeutically induced stress. Pancreatic Ductal Adenocarcinoma is an extremely lethal and aggressive neoplasm with a 5 year-survival rate between 1% and 5%. One of the most important factors affecting its poor prognosis is its high resistance to most of the existing chemotherapeutic regimens. The role of autophagy in PDAC has been investigated by different research groups and the results are quite divergent; some research lines point at autophagy as a tumor promoting mechanism, whereas other studies assign oncosuppressive functions to it. Nevertheless, several distinct preclinical studies and clinical trials have evaluated the efficacy of both autophagy inducers and autophagy inhibitors as therapeutic compounds against PDAC, many of them providing promising results. Although a better understanding of the complexity of autophagy is needed, the modulation of this process opens new opportunities for prognostic and therapeutic purposes.
DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells
2014, Biochemical and Biophysical Research Communications
Citation Excerpt :
Thus, early diagnosis and curative treatments are almost impossible, and the prognosis of pancreatic cancer is very low [1,2]. The fast majority of pancreatic cancer patients present in advanced stages, with only a minority (10–20%) being amenable to surgical intervention [3–5]. Chemotherapy has become an essential adjunct for pancreatic cancer treatment [6].
Pancreatic cancer is one of the most aggressive human malignancies with extremely poor prognosis. The moderate activity of the current standard gemcitabine and gemcitabine-based regimens was due to pre-existing or acquired chemo-resistance of pancreatic cancer cells. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in gemcitabine resistance, and studied the underlying mechanisms. We found that NU-7026 and NU-7441, two DNA-PKcs inhibitors, enhanced gemcitabine-induced cytotoxicity and apoptosis in PANC-1 pancreatic cancer cells. Meanwhile, PANC-1 cells with siRNA-knockdown of DNA-PKcs were more sensitive to gemcitabine than control PANC-1 cells. Through the co-immunoprecipitation (Co-IP) assay, we found that DNA-PKcs formed a complex with SIN1, the latter is an indispensable component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). DNA-PKcs–SIN1 complexation was required for Akt activation in PANC-1 cells, while inhibition of this complex by siRNA knockdown of DNA-PKcs/SIN1, or by DNA-PKcs inhibitors, prevented Akt phosphorylation in PANC-1 cells. Further, SIN1 siRNA-knockdown also facilitated gemcitabine-induced apoptosis in PANC-1 cells. Finally, DNA-PKcs and p-Akt expression was significantly higher in human pancreatic cancer tissues than surrounding normal tissues. Together, these results show that DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.
Prognostic value of alkaline phosphatase and gamma-glutamyl transferase in patients with metastatic pancreatic cancer
2023, Future Oncology

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Treatment for Pancreatic Cancer: Current Therapy and Continued Progress

Section snippets

Adjuvant therapy of pancreas cancer

Locally advanced disease

Chemotherapy for advanced disease

Recent phase II and III clinical trials in metastatic pancreatic cancer

Conclusion

Eur J Cancer

Lancet

Lancet

Am J Surg

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Oncol

Ann Oncol

Ann Oncol

Am J Med Sci

Semin Oncol

Ann Oncol

Ann Oncol

Eur J Cancer

Eur J Cancer

Eur J Cancer

Semin Oncol

Semin Oncol

A prospective study of cigarette smoking and the risk of pancreatic cancer

Arch Intern Med

Familial pancreatic cancera review

Semin Oncol

Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer

Br J Cancer

Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience

Ann Surg

Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection

Arch Surg

Improving adjuvant therapy for rectal cancer by combining infusion fluorouracil with radiation therapy after curative surgery

N Engl J Med

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary regionphase III trial of the EORTC gastrointestinal tract cancer cooperative group

Ann Surg

A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer

N Engl J Med

Adjuvant therapy for pancreatic cancer—the debate continues

N Engl J Med

Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction

N Engl J Med

Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction

Semin Radiat Oncol

Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancera phase I study

J Clin Oncol

Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study

Cancer

Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group

Cancer

Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group

J Natl Cancer Inst

Treatment of locally unresectable cancer of the stomach and pancreasa randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil—an Eastern Cooperative Oncology Group study

J Clin Oncol

Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinomaa phase I Eastern Cooperative Oncology Group Trial

J Clin Oncol

Gemcitabine: in vitro and in vivo evidence of its radiation sensitizing activity and studies using fluorine-19 magnetic resonance spectroscopy to determine the optimal dosing schedule—preclinical observations relevant to gemcitabine clinical trials

Proc Am Soc Ther Radiol Oncol

Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer

J Clin Oncol

Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer

J Clin Oncol

A phase II trial of full-dose gemcitabine with concurrent radiation therapy in patients with resectable or unresectable non-metastatic pancreatic cancer

Proc Am Soc Clin Oncol Gastrointest Cancers Symp

Combined radiation and 9-nitrocamptothecin (rubitecan) in the treatment of locally advanced pancreatic cancer

Ann N Y Acad Sci

Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin

Br J Cancer

Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine)

Cancer Res