The pancreatic cancer treatment depends on the overall stage, a location of the tumor, the performance status of the patient, along with other factors.
Following are the preferred pancreatic cancer treatment approach for different stages of cancer but the final decision is taken by oncologist after detailed clinical assessment of the patient.
T1-2 N0 M0 (Stage I) – Tumors are considered resectable
Radical pancreatic resection such as Whipple procedure (resection of pancreas and duodenum), or partial pancreatic resection (depending on location, extent of tumor, etc) is considered the preferred treatment approach in case of resectable tumors
T1-3 N0-1 M0 (Stage II) – Tumors are considered borderline resectable
Chemotherapy with or without radiation therapy is generally employed followed by surgery (if disease become resectable)
T4 N0-1 M0 (Stage III) – Chemotherapy and/or radiation therapy is generally warranted along with palliative therapy such as surgery (biliary/gastric bypass) or endoscopic biliary stent placement
Any T Any N M1 (Stage IV) – Chemotherapy is the mainstay of treatment in case the disease has spread to distant body parts
Along with the chemotherapy, palliative therapy to relieve pain or stent placement may be employed as and when required
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Now we will discuss the resectability of the pancreatic tumor, depending upon the extent of tumor.
Tumor located within the pancreas, without extension to adjacent structutes, is considered to be resectable.
This figure shows a resectable tumor located in the head of pancreas.
Similarly, this is a resectable tumor located in the tail of pancreas.
A tumor located in the head of the pancreas, that extends to involve the duodenum, is also considered to be resectable.
Similarly, tumors arising from the tail of pancreas, that involve the spleen, left kidney, or left suprarenal gland, may also be resected.
Superior mesenteric vein involvement maybe considered resectable, boderline resectable or unresectable, depending upon the extent of arterial involvement.
Similarly, involvement of portal vein maybe considered resectable, borderline resectable or unresectable, depending upon the extent of arterial involvement.
Infiltration of tumor into common hepatic artery only, is borderline resectable in most of the cases.
Infiltration of tumor into the superior mesentric artery maybe considered borderline resectable or unresectable, depending upon the extent of arterial involvement.
Celiac artery involvement may also be borderline resectable or unresectable, depending upon the extent of arterial involvement.
Now we will discuss the treatment for all the three, that is resectable, borderline resectable, and unresectable disease.
Surgery is the treatment of choice of resectable disease, but chemotherapy may be added rarely for some high risk patients.
For borderline resectable patients, chemotherapy with or without radiotherapy is used, and then the decision for surgery is taken, depending upon the response to treatment.
And for unresectable patients, chemotherapy is the treatment of choice, and radiotherapy maybe used very rarely.
The final decision is taken by the oncologist, on an individual patient basis, depending upon the performance status of the patient and exact stage of the disease.
And in the following video, CancerBro explains the TREATMENT OF METASTATIC PANCREATIC CANCER.
It may present as metastasis to peritoneum, in form of multiple peritoneal deposits.
Or metastatis to liver,Lungs.
Very rarely, it may also spread to brain or bones.
Chemotherapy is the treatment for choice for metastatic disease.
Also, radiotherapy, surgery, or bone directed therapy may be used for palliation.
Treatment for metastatic disease is not generally curative.
Main intent of the treatment is prolongation of life, reduction of symptoms, and improvement in quality life.
With this, we come to the end of the treatment for pancreatic cancer.
Following is the brief description of various treatment types employed for pancreatic cancer:
Surgery: Surgery provides significantly longer survival and is considered as the treatment of choice for resectable pancreatic cancers. Radical pancreatic resection such as Whipple procedure (resection of pancreas and duodenum), partial, or complete pancreatic resection are some common surgical procedures employed with a curative intent for resectable and borderline resectable pancreatic cancers. For unresectable pancreatic cancers, surgery is employed for palliation of symptoms, which may include biliary/gastric bypass surgery and biliary stent placement to relieve bile duct blockage. Surgery is associated with the risk of serious complications, such as infection, bleeding, blood clots, leakage from the incisional areas, and various post-surgery complications like improper stomach emptying or digestion, weight loss, diabetes, abdominal pain, and change in bowel habit.
Chemotherapy: Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly growing cancer cells. Chemotherapy is considered the mainstay of treatment for advanced stage disease that has spread to distant body organs. Depending on the physician’s preference and patient’s condition, it may also be combined with other treatment options to accelerate the benefit achievement.
Targeted Therapy: Targeted drugs work differently than chemotherapy drugs that they target a specific gene or protein characteristic of the pancreatic cancer cells, for example, erlotinib targets epidermal growth factor receptor (EGFR). They are generally used alone or in combination with chemotherapy for the treatment of higher stage disease.
Radiation Therapy: Radiation therapy uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancerous cells. It can be employed either by using an external radiation source or by directly placing the source of radiation near the cancer tissue. Radiotherapy is commonly combined with other treatment options such as surgery and chemotherapy. It can be given prior to surgery to shrink the tumor or after surgery to reduce the chance of recurrence. It is sometimes used for palliation of symptoms of the disease such as pain.
Palliative Treatment: It helps in improving the overall quality of life by providing relief from the symptoms and by reducing the suffering caused by pancreatic cancer. Palliation may include but is not limited to: bypass surgery and placing stent to remove the blockage in the bile duct, using drugs to reduce pain and other symptoms, and external-beam radiation therapy for pain.
It is very important to assess the benefits of each treatment option against the possible risks and side effects before making a treatment decision. Sometimes patient’s choice and health condition are also important to make a treatment choice.
Following are goals of treating pancreatic cancer:
- Prolongation of life
- Reduction of symptoms
- Improvement in quality of life
Pancreatic cancer is assessed to be the fourth leading causes of cancer-related deaths in the United States (US). The overall incidence and mortality rate of pancreatic cancer has increased during the last few decades despite the declining trend in mortality rate associated with other cancer types. Pancreatic cancer is considered as a deadly disease with an overall 5-year survival rate of 5% to 7%.
Pancreatic Cancer Treatment
The treatment of pancreatic cancer depends on many factors including the overall stage assigned to the disease, age, and performance status of the patient. Based on the results obtained from various clinical research studies carried out so far, the following are the preferred treatment approach for different stages of pancreatic cancer:
Type of Disease
Non-metastatic /Limited disease
For resectable tumors, radical pancreatic resection such as pancreatoduodenectomy (Whipple procedure) or distal pancreatectomy with en-bloc splenectomy and obtaining negative resection margin with preserving most organ functions is considered the preferred treatment approach.
However, surgical resections with negative margins are not possible in more than 80% of patients due to advanced disease at presentation. Moreover, due to a high recurrence rate of the disease, even with negative margin resection, additional treatment is generally required for all patients. Post-operative (adjuvant) chemotherapy with gemcitabine alone, 5-fluorouracil (5-FU)/leucovorin, gemcitabine/capecitabine, or continuous infusion 5-FU may be employed within 12 weeks of adequate recovery from surgery as per the patient’s requirement and physician discretion.
Preoperative (neoadjuvant) chemotherapy with or without prior chemoradiation therapy may be employed for patients with resectable disease and high-risk features (elevated CA 19-9; extreme pain; large primary tumors; large regional lymph nodes; and excessive weight loss). Acceptable neoadjuvant regimens for such patients include 5-FU/leucovorin + oxaliplatin + irinotecan (FOLFIRINOX) +/- radiotherapy, gemcitabine/nanoparticle albumin-bound paclitaxel +/- radiotherapy, and gemcitabine/cisplatin (for patients with known BRCA1/2 mutations).
For borderline resectable tumors, neoadjuvant chemotherapy with or without radiotherapy (regimen listed above) is generally employed before surgery despite the fact that is debatable and not supported by concrete evidence. Proposed advantages include to downstage the disease to resectable, more likelihood of negative margin resectable, improve response to therapy.
Adjuvant chemotherapy with above-listed regimen (based on response to neoadjuvant therapy) within 12 weeks of adequate recovery from surgery should be employed as per the patient’s requirement and physician discretion.
For patients with recurrent disease after adjuvant chemotherapy and when recurrence occurs >/=6 months after previous treatment, same treatment may be repeated or treatment may be switched (to a gemcitabine-based regimen from previous ﬂuoropyrimidine-based regimen or vice-versa), especially in the case of recurrence within 6 months of initial therapy.
Locally Advanced or Metastatic Disease
For locally advanced or metastatic disease, systemic therapy with or without radiation therapy is generally warranted along with palliative treatments such as surgery (biliary/gastric bypass) or endoscopic stent placement.
Chemotherapy is the mainstay of treatment and may be administered via any of the following regimens: gemcitabine monotherapy, gemcitabine + nanoparticle albumin-bound paclitaxel, gemcitabine + erlotinib, gemcitabine + cisplatin (only for patients with BRCA1/2 mutations), gemcitabine + docetaxel + capecitabine, FOLFIRINOX, capecitabine monotherapy and continuous infusion 5-FU, 5-FU/leucovorin or capecitabine with oxaliplatin.
Patients who progressed on initial chemotherapy and have good performance status should be administered second-line therapy with a different regimen than the initial one. For example, gemcitabine-based therapy should be given to patients who previously received fluoropyrimidine-based therapy and vice-versa.
For patients with poor performance status, monotherapy with gemcitabine, capecitabine, or continuous infusion 5-FU is generally recommended as both first-line or second-line treatment.
Patients who are not candidates for chemotherapy treatment may receive chemoradiation therapy or stereotactic body radiation therapy (SBRT) (only for patients with the locally advanced disease without systemic metastases). Radiation therapy is indicated as a palliative treatment in the case of the metastatic disease.
Recent Findings and Potential new Treatment for Pancreatic Cancer Treatment:
- A retrospective review carried out at a single center in Brazil reported that a modified FOLFIRINOX regimen (flexible dosing according to patient’s characteristics) has similar efficacy and better tolerability compared to that of the standard FOLFIRINOX regimen for the treatment of metastatic pancreatic cancer.
- A Bayesian meta-analysis of 46 research studies on patients with metastatic pancreatic cancer concluded that FP regimen (leucovorin + 5-FU + nanoparticle albumin-bound paclitaxel) produced the best overall survival response; gemcitabine + erlotinib + bevacizumab regimen produced the best progression-free survival response; gemcitabine + capecitabine + erlotinib regimen was graded as the most hematologically toxic regimen.
- A retrospective study carried out at 2 centers in France has reported the benefit of induction chemotherapy intensification in patients with locally advanced pancreatic cancer, both in terms of PFS and time without treatment.
- Another meta-analysis of 17 studies involving 36791 patients reported the beneficial effect of metformin in conjunction with chemotherapy and radiotherapy on the pancreatic cancer cells via circulating insulin down-regulation, cell division arrest, apoptosis and autophagy promotion, the immune system activation, and irradiation-resistance reversal.
The results showed a statistically significant survival benefit in favor of metformin. Thus, it was proposed that this finding should be confirmed in prospective randomized clinical trials.
- A preclinical study demonstrated that cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to radiotherapy via thioredoxin 1 (TRX1) oxidation and c-Jun terminal kinase (JNK) activation.
Thus, it was proposed that more research should be carried out to explore the potential of CONPs in conjunction with radiotherapy or other potential radical inducing agents for the treatment of pancreatic cancer.
- An in-vitro study demonstrated the beneficial effect of silver nanoparticles (AgNPs) via oxidative and nitro-oxidative stress and mitochondrial disruption in pancreatic cancer cells. Thus, it was proposed that AgNPs can be utilized to develop a novel anti-cancer treatment for pancreatic cancer.
- Considering the role of the extracellular matrix (or the stroma) in the survival, proliferation, and metastasis of pancreatic cancer cells, various agents targeting the stroma are being tested in different pre-clinical studies.
Different agents such as Vitamin D analog paricalcitol, all-trans retinoic acid (ATRA), enalapril, losartan (renin-angiotensin system inhibitors), hydroxychloroquine (inhibitor of lysosomal degradation), PEGPH20 (hyaluronic acid degrader), and Defactinib (focal adhesion kinase inhibitor) are being tested in various clinical studies for their potential role in the treatment of pancreatic cancer.
- Pancreatic cancer does not respond well to immune checkpoint inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) alone or in combination with chemotherapy. Thus, a combination of ICI or other immunotherapeutic agents with a variety of therapeutic agents is being tested in different clinical studies.
Some potential futuristic treatment includes ICI + chemotherapy + radiotherapy, ICI + vaccine, chemotherapy + vaccine, radiotherapy + vaccine, and adoptive cell therapy among others.
- Endoplasmic reticulum stress response has recently been utilized for different treatment approaches targeting both proliferating and dormant tumor cells. Many different pathways have been explored and targeted to trigger apoptosis, cell cycle arrest, and chemosensitivity.
Examples of such approaches include induction of endoplasmic reticulum stress by the inhibition of GRP78/BiP (glucose-regulated protein) unbinding from transmembrane sensors PERK (protein kinase RNA-like endoplasmic reticulum kinase), ATF6α (activating transcription factor 6 isoform α), and IRE1α (inositol-requiring enzyme 1 isoform α). More studies are warranted for a better understanding of the pathways and targeting them with specific agents.
- Epigenetic dysregulation of oncogenes and tumor suppressor genes is recognized as a novel therapeutic target for pancreatic cancer treatment. Drugs targeting epigenetic changes, such as DNA methyltransferases or histone deacetylase inhibitors, have shown promising results in preclinical studies and are currently being evaluated in different clinical trials.
Combinations of drugs targeting epigenetic changes with the established chemotherapeutic regimen or targeted agents can be very effective for the treatment of pancreatic cancer.