Stages of Pancreatic Cancer
Stage I-II Pancreatic Cancer
Stage I-II pancreatic cancer, refers to cancer that is confined to the pancreas, does not involve any adjacent organs, has not spread to any of the local lymph nodes and cannot be detected in other locations in the body.
Currently treatment for stage I-II adenocarcinoma of the pancreas is surgical removal of the cancer. The most common surgical procedure is a pancreaticoduodenectomy, or Whipple procedure, which involves removal of a portion of the pancreas, small intestine (duodenum), and stomach, as well as the entire gallbladder. The exact surgical procedure may differ based on the location and extent of the cancer within the pancreas.
Despite undergoing surgical removal of all visible cancer, a majority of patients will experience a recurrence of their cancer because prior to surgery a small amount of cancer spread outside the pancreas and therefore, was not removed by surgery. It is necessary to develop effective systemic treatments that can find and destroy cancer cells anywhere in the body in order to reduce the risk of cancer recurrence.1
Systemic therapy: precision cancer medicines, chemotherapy, and immunotherapy
Systemic therapy is treatment directed at destroying cancer cells throughout the body. Because patients with pancreatic cancer have small amounts of cancer that have spread away from the pancreas, an effective systemic treatment is needed to cleanse the body of these cells in order to prolong survival and improve the chance of cure.
Systemic treatment can be administered after surgery (adjuvant therapy) or before surgery (neoadjuvant therapy). Systemic therapy may include chemotherapy, precision cancer medicines, immunotherapy or a combination of these therapies.2,3
A combination of chemotherapy drugs consisting of Gemzar (gemcitabine) plus Xeloda (capecitabine) is the most widely recommended standard therapy because the combination has an improved response rate and 5 year survival without a concomitant increase in side effects.3
Radiation therapy
Radiation therapy, or radiotherapy, uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment used to eliminate or eradicate visible cancers. Radiation therapy is not useful in eradicating cancer cells that have already spread to other parts of the body. It is particularly effective as an adjuvant therapy (therapy given in addition to the primary treatment) to surgery by helping to eliminate any microscopic cancer cells leftover after surgery. Clinical studies that have evaluated adjuvant radiation therapy have yielded conflicting results and there currently remains no consensus whether radiation should be used as adjuvant therapy or combined with chemotherapy for the treatment of pancreatic cancer although it is offered to many patients.4 Patients should clearly understand the risks and benefits of being treated with radiation and discuss them with their physician.
Strategies to improve treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. In addition to continued development of chemotherapy treatment regimens active investigation aimed at improving the treatment of early stage pancreatic cancer includes the following:
Development of Precision Cancer Medicine: Research is ongoing to develop new medications that specifically target cancer cells in clinical trials. These trials typically require a sample of the cancer or liquid biopsy to be available in order to evaluate for biomarkers. Patients should learn about options to participate in these trials prior to surgery in order to ensure that cancer tissue is obtained correctly.
Germline BRCA – mutated pancreatic cancer: can be treated with a precision cancer medicine known as a PARP inhibitor. BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA. When either of these genes is mutated, or altered DNA damage may not be repaired properly, and the cells are more likely to develop additional genetic alterations that can lead to cancer.5,6
Neoadjuvant Therapy: In an effort to increase the chance that a cancer may be surgically removed, some cancer centers use radiation therapy and chemotherapy before surgery to shrink the cancer. The use of treatment before surgery is referred to as “neoadjuvant therapy.” In addition to potentially shrinking the cancer so that it can be removed, neoadjuvant therapy allows patients to avoid the difficulty of undergoing treatments after surgery, which is a time when they may be experiencing side effects. Approximately 25% to 33% of patients are unable to receive chemotherapy or radiation treatment following surgery.
A treatment plan that includes neoadjuvant therapy guarantees that systemic therapy is delivered immediately, which may increase the chance of eradicating small amounts of cancer that may have already spread to distant locations in the body and cannot be removed by surgery. Clinical trials are ongoing to evaluate neoadjuvant chemotherapy administered alone or in combination with adjuvant therapy, and the results of some small studies suggest that neoadjuvant therapy may improve survival.7
References
1 National failure to operate on early stage pancreatic cancer. Annals of Surgery. 2007;246:173-180.
2 Oettle H, Neuhaus P. Adjuvant therapy in pancreatic cancer: a critical appraisal.Drugs. 2007;67:2293-310.
3 Neoptolemos J, Palmer D, Ghaneh P, et al. ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol 34, 2016 (suppl; abstr LBA4006)
4 Hazard L, Tward JD, Szabo A, Shrieve DC. Radiation therapy is associated with improved survival in patients with pancreatic adenocarcinoma: results of a study from the Surveillance, Epidemiology, and End Results (SEER) registry data. Cancer. 2007;110:2191-201.
5 Pancreatic Cancer Action. Facts and statistics. Accessed February 2019 from https://pancreaticcanceraction.org/about-pancreatic-cancer/medical-professionals/stats-facts/facts-and-statistics/
7 Takai S, Satoi S, Yanagimoto H et al. Neoadjuvant chemoradiation in patients with potentially resectable pancreatic cancer. Pancreas. 2008 Jan;36(1):e26-32.
Stage III Pancreatic Cancer
Pancreatic cancer is referred to as stage III cancer if the final pathology report shows that the cancer has only spread to local lymph nodes and major blood vessels. A patient may be diagnosed with stage III cancer following surgical removal of the pancreas and surrounding lymph nodes or after surgical sampling of the lymph nodes. Pancreatic cancer diagnosed at this stage is difficult to cure. When the cancer cannot be removed by surgery, a combination of anticancer drugs and/or radiation therapy may be given instead. A clinical trial is often recommended following surgery because these standard treatment options are not very effective.
When complete surgical removal of the cancer is possible, stage III pancreatic cancer is best managed by surgery. The most common surgical procedure is a pancreaticoduodenectomy, or Whipple procedure, which involves removal of a portion of the pancreas, small intestine (duodenum), stomach and the entire gallbladder. The exact surgical procedure may differ based on the location and extent of the cancer within the pancreas.
Despite undergoing surgical removal of all visible cancer, a majority of patients will still experience a recurrence of their cancer because prior to surgery a small amount of cancer spread outside the pancreas and therefore, was not removed by surgery. It is necessary to develop effective systemic treatments that can find and destroy cancer cells anywhere in the body in order to reduce the risk of cancer recurrence.1,2,3,4
Radiation therapy
Radiation therapy, or radiotherapy, uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment used to eliminate or eradicate visible cancers. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. It is particularly effective as an adjuvant therapy (therapy given in addition to the primary treatment) to surgery by helping to eliminate any microscopic cancer cells leftover after surgery. Clinical studies that have evaluated adjuvant radiation therapy have yielded conflicting results and there currently remains no consensus whether radiation should be used as adjuvant therapy or combined with chemotherapy for the treatment of pancreatic cancer although it is offered to many patients.4 Patients should clearly understand the risks and benefits of being treated with radiation and discuss them with their physician.
Strategies to improve treatment
Most new treatments are developed in clinical trials, which are studies that evaluate the effectiveness of new treatment strategies in cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of pancreatic cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits with their physician.
Development of Precision Cancer Medicines: Research is ongoing to develop new medications that specifically target cancer cells in clinical trials. These trials typically require a sample of the cancer or liquid biopsy to be available in order to evaluate for biomarkers. Patients should learn about options to participate in these trials prior to surgery in order to ensure that cancer tissue is obtained correctly.
Germline BRCA – mutated pancreatic cancer: can be treated with a precision cancer medicine known as a PARP inhibitor. BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA. When either of these genes is mutated, or altered DNA damage may not be repaired properly, and the cells are more likely to develop additional genetic alterations that can lead to cancer.5,6
Neoadjuvant Therapy: In an effort to increase the chance that a cancer may be surgically removed, some cancer centers use radiation therapy and chemotherapy before surgery to shrink the cancer. The use of treatment before surgery is referred to as “neoadjuvant therapy.” In addition to potentially shrinking the cancer so that it can be removed, neoadjuvant therapy allows patients to avoid the difficulty of undergoing treatments after surgery, which is a time when they may be experiencing side effects. Approximately 25% to 33% of patients are unable to receive chemotherapy or radiation treatment following surgery.
A treatment plan that includes neoadjuvant therapy guarantees that systemic therapy is delivered immediately, which may increase the chance of eradicating small amounts of cancer that may have already spread to distant locations in the body and cannot be removed by surgery. Clinical trials are ongoing to evaluate neoadjuvant chemotherapy administered alone or in combination with adjuvant therapy, and the results of some small studies suggest that neoadjuvant therapy may improve survival.7
References
1 National failure to operate on early stage pancreatic cancer. Annals of Surgery. 2007; 246:173-180.
2 Oettle H, Neuhaus P. Adjuvant therapy in pancreatic cancer: a critical appraisal. Drugs. 2007; 67:2293-310.
3 Neoptolemos J, Palmer D, Ghaneh P, et al. ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol 34, 2016 (suppl; abstr LBA4006)
4 Hazard L, Tward JD, Szabo A, Shrieve DC. Radiation therapy is associated with improved survival in patients with pancreatic adenocarcinoma: results of a study from the Surveillance, Epidemiology, and End Results (SEER) registry data. Cancer. 2007; 110:2191-201.
5 Pancreatic Cancer Action. Facts and statistics. Accessed February 2019 from https://pancreaticcanceraction.org/about-pancreatic-cancer/medical-professionals/stats-facts/facts-and-statistics/
6 https://news.cancerconnect.com/pancreatic-cancer/lynparza-first-promising-new-drug-to-treat-pancreatic-cancer-in-years-H6BzHID6FUiWnbz7R-Oe8A/
7 Takai S, Satoi S, Yanagimoto H et al. Neoadjuvant chemoradiation in patients with potentially resectable pancreatic cancer. Pancreas. 2008 Jan;36(1):26-32.
Stage IV Pancreatic Cancer
Pancreatic cancer is considered stage IV if it has spread to distant locations in the body, such as the liver, lungs, or adjacent organs including the stomach, spleen, and/or the bowel. Sometimes it can only be determined that a pancreatic cancer is in stage IV once surgery is completed.1
Stage IV Pancreatic Cancer is Broadly Divided into Two Groups:
- Stage IVA pancreatic cancer is locally confined, but involves adjacent organs or blood vessels, thereby hindering surgical removal. Stage IVA pancreatic cancer is also referred to as localized or locally advanced.
- Stage IVB pancreatic cancer has spread to distant organs, most commonly the liver. Stage IVB pancreatic cancer is also called metastatic. The goal of treatment for patients with localized IVA disease is to induce a remission, or a disease-free period that may last months or years. Management of patients with Stage IVB disease is often aimed at controlling symptoms and pain from the cancer.
Treatment of localized stage IVA pancreatic cancer
Pancreatic cancer is often not diagnosed until it is in Stage IVA, meaning the cancer has invaded adjacent organs or major blood vessels. When this occurs surgical removal of the cancer (which provides a chance at long-term cure) is seldom an option. Therefore, the goal of treatment of patients with Stage IVA pancreatic cancer is to induce a remission, which is a cancer-free period that may last months or years, and to prevent and control symptoms.
Treatment for Stage IVA pancreatic cancer may include palliative surgery, and systemic chemotherapy, or chemoradiation, which is chemotherapy and radiation delivered together. Occasionally, a surgical bypass procedure may be performed to alleviate complications of the cancer, such as jaundice, intestinal obstruction, or pain, thereby improving quality of life.1,2
Treatment of non-localized stage IVB (metastatic) pancreatic cancer
The majority of patients with Stage IV cancer have metastatic disease (Stage IVB), which means that cancer has spread to distant locations in the body that often include the liver and other areas of the abdominal cavity. To kill cancer cells that have spread throughout the body, a systemic treatment is necessary, and this is typically chemotherapy.
Systemic therapy: precision cancer medicines, chemotherapy, and immunotherapy
Systemic therapy is treatment directed at destroying cancer cells throughout the body. Because patients with pancreatic cancer have small amounts of cancer that have spread away from the pancreas, an effective systemic treatment is needed to cleanse the body of these cells in order to prolong survival and improve the chance of cure. Systemic therapy may include chemotherapy, precision cancer medicines, immunotherapy or a combination of these therapies.3,4,5,6,7,8
The results of a phase III trial presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) show that the Lynparza PARP inhibitor delays cancer progression and improves survival when used to treat BRCA-mutated pancreatic cancer and is the first precision cancer medicine to become available for the treatment of pancreatic cancer.
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA. When either of these genes is mutated, or altered DNA damage may not be repaired properly, and the cells are more likely to develop additional genetic alterations that can lead to cancer. All patients should undergo genomic biomarker testing for these and other markers.8
Chemotherapy
Chemotherapy is any treatment involving the use of drugs to kill cancer cells and may consist of single drugs or combinations of drugs and can be administered through a vein or delivered orally in the form of a pill. Chemotherapy is commonly used to treat both locally advanced (Stage IVA) and metastatic (Stage IVB) pancreatic cancer.
Gemzar® (gemcitabine): The standard treatment of stage IV pancreatic cancer is systemic therapy with Gemzar® based chemotherapy or participation in a clinical trial evaluating new chemotherapy or precision cancer medicines.5
Chemoradiation therapy
Combining chemotherapy with radiation therapy, a technique called chemoradiation, may provide more benefit than chemotherapy alone for some patients with Stage IVA pancreatic cancer but is not typically a treatment for patients with Stage IVB disease.2,3
Strategies to improve treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of pancreatic cancer include the following:
Precision cancer medicines
Research is ongoing to develop new medications that specifically target cancer cells in clinical trials. These trials require a sample of the cancer or liquid biopsy to be available in order to evaluate for biomarkers. Patients should learn about options to participate in these trials prior to surgery in order to ensure that cancer tissue is obtained correctly.3,4,5,6,7,8`
Phase I clinical trials
New chemotherapy drugs continue to be developed and evaluated in patients with advanced cancers in Phase I clinical trials. The purpose of Phase I trials is to evaluate new drugs in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients.
References
1 Pancreatic Cancer Action. Facts and statistics. Accessed February 2019 from https://pancreaticcanceraction.org/about-pancreatic-cancer/medical-professionals/stats-facts/facts-and-statistics/
2 Hazard L, Tward JD, Szabo A, Shrieve DC. Radiation therapy is associated with improved survival in patients with pancreatic adenocarcinoma: results of a study from the Surveillance, Epidemiology, and End Results (SEER) registry data. Cancer. 2007; 110:2191-201.
3 http://news.cancerconnect.com/preliminary-results-suggest-that-pamrevlumab-is-promising-in-pancreatic-cancer/
5 Safran H, Ramanathan R, Schwartz J, King T, et al. Herceptin and Gemcitabine for Metastatic Pancreatic Cancers That Overexpress her-2/neu. Proceedings from the 37th Annual Meeting of the American Society of Clinical Oncology 2001, San Francisco CA, Abstract #517.
6 Cascinu S, Berardi R, Labianca R, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, Phase II trial. Lancet Oncology. 2008;9:39-44.
7 Toubaji A, Achtar M, Provenzano M et al. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers.Cancer Immunol Immunother. 2008 Feb 23.
8 https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2019/lynparza-significantly-delayed-disease-progression-as-1st-line-maintenance-treatment-in-germline-brca-mutated-metastatic-pancreatic-cancer-26022019.html
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