Healthcare Professionals

Targeted therapy

• Recent advances in understanding the molecular biology of tumors have led to development of targeted therapy. The agents selectively act on the signaling pathways that induce growth of the tumor.
• Various classes of targeted agents like human epidermal growth factor receptor-1/EGFR family inhibitors, angiogenesis inhibitors, signal transduction inhibitors, modulators of apoptotic activity, and eicosinoid pathway inhibitors have evolved.
• Targeted therapy inhibits the growth and spread of the tumors by influencing the signaling pathways of the tumor cells.
• Molecularly targeted agents are distinguished from traditional chemotherapy by the fact that they have 'cytostatic' effects on tumor cells only. By comparison, the actions of cytotoxic agents are rather less selective. Targeted agents therefore hold the promise both of improved clinical benefits and a reduced side effect profile compared with standard chemotherapy.
• The performance status of a patient is an important factor to be considered in cytotoxic chemotherapy. The patient should have the ability to undertake chemotherapy and recover from the adverse effects. Most of the patients diagnosed with pancreatic cancer are above the age of 60 and may not be able to tolerate cytotoxic chemotherapy. Targeted therapy does not produce the typical chemotherapy like adverse effects and so can be an effective treatment option for the old and weak patients who may not be able to withstand regular chemotherapy.
• Resistance to chemotherapy is a major problem encountered in pancreatic cancer. Reduced response of tumor to chemotherapy leads to treatment failure and poor prognosis. Targeted therapy is a valuable option in treating resistant cases.
• The Initial studies conducted to assess the benefits of systemic monoclonal antibodies in pancreatic cancer have reported insignificant benefits but more trials are in process to study benefits of locoregional chemotherapy with immunotherapy.²²
• The PA.3 trial was a prospective, multicentre, randomised, double-blind, placebo-controlled phase III study. The trial was led by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG), and was co-sponsored by OSI Pharmaceuticals.
• The PA.3 study was the first to show a survival benefit with an EGFR inhibitor in advanced pancreatic cancer, and the first to show that an EGFR TKI can be successfully combined with concomitant chemotherapy.
• The PA.3 study demonstrated that Erlotinib in combination with gemcitabine produced a significant and clinically meaningful benefit in OS (the primary endpoint) and PFS compared with placebo+ gemcitabine; there was a 22% improvement in OS and a 30% improvement in PFS.

Effect of Erlotinib on OS in patients with advanced pancreatic cancer (100mg/day dose cohorts)

• While in patients with metastatic disease there was a 25% improvement in OS and a 22% improvement in PFS. The PA.3 study was the first study to show a survival benefit from the addition of any drug to gemcitabine in advanced pancreatic cancer. The addition of erlotinib to gemcitabine was generally well tolerated and was not detrimental to patient QoL.

Effect of Erlotinib (100mg/day) on OS in patients with distant metastases



• Most of the patients treated with erlotinib or any other EGFR inhibitor reported a rash and studies have now related development of the rash as an indicator of effective therapy and increased overall survival.

Combined chemotherapy and targeted therapy

Targeted therapy is cytostatic and not cytocidal. The therapy targets molecules and pathways involved in growth and development of tumors. The signaling pathways and molecular targets are vulnerable to mutations, molecular abnormalities and complementary pathways. Changes due to mutations and molecular abnormalities make the tumor cells resistant to therapy. Combining targeted therapy and cytotoxic chemotherapy is an advanced option of treating cancer. Erlotinib-gemcitabine combination has shown a survival advantage over gemcitabine alone and has been recently approved by US FDA for treating locally advanced, unresectable and metastatised pancreatic carcinoma.

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