Pancreatic cancer medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Sudarshana Datta, MD [2]

Overview

The therapy for pancreatic cancer depends largely on the disease progression and the stage of cancer. There are five different types of treatment for patients with pancreatic cancer: surgery, radiation therapy, chemotherapy, chemoradiation therapy and targeted therapy. In patients with pancreatic cancer, surgery is the primary modality of treatment. Extrapancreatic disease, in contrast, requires palliative therapy and curative resection is not performed in such patients. Patients with unresectable disease may be treated with chemotherapy and/or radiation therapy as a part of adjuvant or neoadjuvant therapy. Chemotherapy may be administered when surgical intervention is not deemed appropriate. The National Comprehensive Cancer Network (NCCN) has recommended guidelines for treatment in patients based on their performance status, which is a major prognostic factor. Performance status assesses extent of metastatic disease, size of the tumor and degree of weight loss. In patients with locally advanced unresectable or metastatic disease with good performance status, a combination of Leucovorin,5-fuorouracil, Oxaliplatin and Irinotecan (FOLFIRINOX) is preferred. Radiotherapy may form part of neoadjuvant therapy to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial. Neoadjuvant therapy may be used as the toxic effects of chemotherapy can be tolerated more easily before surgery as compared to after resection. Moreover, shrinkage of the tumor with neoadjuvant therapy makes resection easier and improves patient prognosis.


Medical Therapy

  • There are five different types of treatment for patients with pancreatic cancer.
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Chemoradiation therapy
    • Targeted therapy
  • New types of treatment are being tested in clinical trials.
    • Biologic therapy
  • In patients with pancreatic cancer, surgery is the primary modality of treatment.
  • Extrapancreatic disease requires palliative therapy and curative resection is not performed in such patients.
  • Patients with unresectable disease are treated with chemotherapy and/or radiation therapy as a part of adjuvant or neoadjuvant therapy.
  • Curative resection is not contraindicated in all patients with vascular invasion.[1][2][3][4][5]
    • Involvement of the portal or superior mesenteric vein can be resected and reconstructed with the help of splenic, saphenous or internal jugular veins.[6][7][8][9]
    • The involvement of arteries such as the hepatic, celiac or superior mesenteric are contraindications to resection.[10]
  • Various methods of surgical resection may be employed and each of these has its own sets of risks and perioperative complications. The facts are discussed by the patient and surgical team before arriving at a well-informed decision. The method of surgical resection depends on the following features:[11][12][13]
    • Locally invasive characteristics of the neoplasm
    • Size
  • Surgical methods of curative resection include:
    • Distal Pancreatectomy
    • Total pancreatectomy
    • Pancreaticoduodenectomy, where pylorus may or may not be spared on an individual basis.
  • The National Comprehensive Cancer Network (NCCN) has recommended certain guidelines on resectability of pancreatic neoplasms based on a statement passed by the American pancreatic association:[14][15][16][17][18]
  • Patient selection is based on:
    • Resection margins
    • High probability of cure
    • Patient's age
    • Comorbidities
  • The European Society for Medical Oncology (ESMO) has certain guidelines on the treatment of metastatic pancreatic cancer:[19][20][21]
    • Chemotherapy not preferred.
    • Gemcitabine is preferred over 5 FU.
    • Treatment is symptomatic with bypass surgery or stent placement for gastric outlet obstruction or obstructive jaundice.
  • In case of locally advanced disease which is unresectable, the following methods of treatment are preferred:[22][22]
    • Microwave ablation
    • Photodynamic therapy
    • Irreversible electroporation
    • Photodynamic therapy
    • High-intensity focused ultrasound (HIFU)
    • Iodine-125–cryosurgery
    • Iodine-125
    • Stereotactic body radiation therapy (SBRT)
    • Radiofrequency ablation (RFA)

Chemotherapy

  • The National Comprehensive Cancer Network (NCCN) has recommended guidelines for treatment in patients based on their performance status.
  • In order to predict survival of patients in various stages of pancreatic cancer, the performance status of a patient is a major prognostic factor.
  • Patients with poor prognostic factors have poor performance status. This includes:[23]
    • Metastatic disease
    • Large tumor
    • Severe weight loss
  • Therapy proposed for patients based on the resectability of disease and performance status is as follows:[24][25][26][27][28][29][30][31][32][33][34][35][36]
    • In patients with locally advanced unresectable or metastatic disease with good performance status:
    • In patients with locally advanced unresectable or metastatic disease with good performance status with intolerance to FOLFIRINOX:
      • Preferred treatment: Paclitaxel protein bound+ Gemcitabine
    • In patients with locally advanced unresectable or metastatic disease with poor performance status:
    • In patients with locally advanced unresectable or metastatic disease with poor performance status refractory to Gemcitabine:
      • Preferred treatment: Capecitabine or capecitabine+erlotinib[50]
  • One year survival of FOLFIRINOX (leucovorin+5-lfuorouracil [LV5-FU]+oxaliplatin+irinotecan)>Gemcitabine[51][52][53][38][54][55][56]
  • One year survival of Gemcitabine+ Erlotinib> Gemcitabine[57][58][35][35]
  • One year survival of Gemcitabine+ Capecitabine ≥ Gemcitabine [59][60][61][25][62]
  • One year survival of Gemcitabine+ nanoparticle albumin-bound (nab)-paclitaxel > Gemcitabine[63][64]

List of Drugs Approved for Pancreatic Cancer

  • Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation)
  • Adrucil (Fluorouracil)
  • Afinitor (Everolimus)
  • Efudex (Fluorouracil)
  • Erlotinib Hydrochloride
  • Everolimus
  • Fluoroplex (Fluorouracil)
  • Fluorouracil
  • Gemcitabine Hydrochloride
  • Gemzar (Gemcitabine Hydrochloride)
  • Mitomycin C
  • Mitozytrex (Mitomycin C)
  • Mutamycin (Mitomycin C)
  • Paclitaxel Albumin-stabilized Nanoparticle Formulation
  • Sunitinib Malate
  • Sutent (Sunitinib Malate)
  • Tarceva (Erlotinib Hydrochloride)

List of Drug Combinations Used in Pancreatic Cancer

  • FOLFIRINOX
  • GEMCITABINE-CISPLATIN
  • GEMCITABINE-OXALIPLATIN
  • OFF(Oxaliplatin,Fluorouracil and Folinic Acid)

Radiation Therapy

  • The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery is controversial. [65][66]
  • Radiotherapy may form part of neoadjuvant therapy to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial.[41][67]

Palliative Therapy

  • Pain:
    • There are various techniques for pain management as palliative therapy in patients with advanced stage of pancreatic cancer:
      • Narcotic analgesics
      • Narcotic analgesics+ tricyclic antidepressants/ antiemetics
      • Radiation therapy

Adjuvant and Neoadjuvant therapy

  • Neoadjuvant therapy may be used as a form of therapy due to the following reasons:[76][77][78][27][79][80][81][82][83][41]
    • Toxic effects of chemotherapy can be tolerated more easily before surgery as compared to after resection.
    • Shrinkage of tumor with neoadjuvant therapy makes resection easier and improves patient prognosis.
    • Systemic treatment for cancer involving various systems improves prognosis.
  • No therapy is considered as first line therapy under this category.
  • Decisions for treatment are made on an individual basis.

New Treatments

  • Irinotecan in an encapsulated form inside a nanoliposome is being used in advanced pancreatic cancer patients who have been earlier been treated using gemcitabine-based chemotherapy. [84]
  • Liposomal Irinotecan is used along with leucovorin and fluorouracil.[85]

References

  1. ↑ Al-Haddad M, Martin JK, Nguyen J, Pungpapong S, Raimondo M, Woodward T, Kim G, Noh K, Wallace MB (2007). "Vascular resection and reconstruction for pancreatic malignancy: a single center survival study". J. Gastrointest. Surg. 11 (9): 1168–74. doi:10.1007/s11605-007-0216-x. PMID 17632763.
  2. ↑ Donahue TR, Isacoff WH, Hines OJ, Tomlinson JS, Farrell JJ, Bhat YM, Garon E, Clerkin B, Reber HA (2011). "Downstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery". Arch Surg. 146 (7): 836–43. doi:10.1001/archsurg.2011.152. PMID 21768431.
  3. ↑ Tseng JF, Raut CP, Lee JE, Pisters PW, Vauthey JN, Abdalla EK, Gomez HF, Sun CC, Crane CH, Wolff RA, Evans DB (2004). "Pancreaticoduodenectomy with vascular resection: margin status and survival duration". J. Gastrointest. Surg. 8 (8): 935–49, discussion 949–50. doi:10.1016/j.gassur.2004.09.046. PMID 15585381.
  4. ↑ Martin RC, Scoggins CR, Egnatashvili V, Staley CA, McMasters KM, Kooby DA (2009). "Arterial and venous resection for pancreatic adenocarcinoma: operative and long-term outcomes". Arch Surg. 144 (2): 154–9. doi:10.1001/archsurg.2008.547. PMID 19221327.
  5. ↑ Castleberry AW, White RR, De La Fuente SG, Clary BM, Blazer DG, McCann RL, Pappas TN, Tyler DS, Scarborough JE (2012). "The impact of vascular resection on early postoperative outcomes after pancreaticoduodenectomy: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database". Ann. Surg. Oncol. 19 (13): 4068–77. doi:10.1245/s10434-012-2585-y. PMID 22932857.
  6. ↑ Leach SD, Lee JE, Charnsangavej C, Cleary KR, Lowy AM, Fenoglio CJ, Pisters PW, Evans DB (1998). "Survival following pancreaticoduodenectomy with resection of the superior mesenteric-portal vein confluence for adenocarcinoma of the pancreatic head". Br J Surg. 85 (5): 611–7. doi:10.1046/j.1365-2168.1998.00641.x. PMID 9635805.
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  41. ↑ 41.0 41.1 41.2 41.3 Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, Sabbatino F, Santos DD, Allen JN, Blaszkowsky LS, Clark JW, Faris JE, Goyal L, Kwak EL, Murphy JE, Ting DT, Wo JY, Zhu AX, Warshaw AL, Lillemoe KD, Fernández-del Castillo C (2015). "Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer". Ann. Surg. 261 (1): 12–7. doi:10.1097/SLA.0000000000000867. PMC 4349683. PMID 25599322.
  42. ↑ Mellon EA, Hoffe SE, Springett GM, Frakes JM, Strom TJ, Hodul PJ, Malafa MP, Chuong MD, Shridhar R (2015). "Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma". Acta Oncol. 54 (7): 979–85. doi:10.3109/0284186X.2015.1004367. PMID 25734581.
  43. ↑ Sadot E, Doussot A, O'Reilly EM, Lowery MA, Goodman KA, Do RK, Tang LH, Gönen M, D'Angelica MI, DeMatteo RP, Kingham TP, Jarnagin WR, Allen PJ (2015). "FOLFIRINOX Induction Therapy for Stage 3 Pancreatic Adenocarcinoma". Ann. Surg. Oncol. 22 (11): 3512–21. doi:10.1245/s10434-015-4647-4. PMC 4849545. PMID 26065868.
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