A Phase I/II Trial Of Gefitinib Given Concurrently With Radiotherapy In Patients With Nonmetastatic Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology;  Radiology / Nuclear Medicine
Article Date: 21 Jun 2010 - 5:00 PDT

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UroToday.com - Combining radical radiotherapy with targeted drugs: a new primary treatment for aggressive prostate cancer? Current treatment results for prostate cancer are at an excellent level. According to the Finnish Cancer Registry, relative five-year survival rates for patients with prostate cancer followed between 2003-2005 are at 89% (Dec 12th 2009). However, prostate cancer is still the second leading cause of male cancer death, after lung cancer.

Aggressive prostate cancer and / or cancer that has spread beyond the prostate capsule tends to recur regardless of the choice of primary treatment (radiation therapy or surgery). Combining radical radiotherapy with targeted drugs has been one of the least investigated treatment strategies for prostate cancer. Using targeted drugs to increase the radiosensitivity of cancer cells has been proven to improve treatment results in many cancers, without a need to increase radiation doses.

The purpose of this study was to estimate the safety and tolerability of the daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy to patients with nonmetastatic prostate cancer.

A total of 42 men were treated. The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer. Well-known adverse effects, typical with both radiation therapy and the drug in question, were predictable and resolved during a short break in the treatment. EGFR (epidermal growth factor receptor) is a cell-surface receptor that exists in mucosa for example and especially in the prostate. Growth factors binding to EGFR of malignant cells increase cell division, angiogenesis and the spread of cancer.

Mutations that lead to EGFR over expression or overactivity have been associated with many cancers. In prostate cancer EGFR is overexpressed in 40 % of the cases. The activation of EGFR and downstream signaling pathways are implicated in cell survival and proliferation following radiation therapy. Gefitinib is an orally administered EGFR inhibitor that selectively targets proteins in malignant cells and inhibits their activity. It is already indicated for the treatment of lung cancer for example.

After five years follow-up the treatment results were compared to those of matched patients treated with higher doses of radiation only. The study was then in phase II, thus all patients were treated with a similar strategy. In order to compare the treatment results with the results of a matched patient group, the research group contacted Patrick Kupelian, as he had investigated in Cleveland the most common strategy for prostate cancer: increasing the radiation dose.

The research group had a survival rate of 100 % and PSA-relapse free cumulative survival rate of 97%. Only 9% had hormone treatment during the five-year period. As a whole, the results are slightly better than among the group treated with radiation only at higher doses. However, due to the lack of randomization any conclusions about the favorable treatment method cannot be made. In order to recommend the combination treatment, the results would need to be proved with a randomized study among a considerably wider group of patients.

Asymptomatic liver enzyme elevations were frequently observed, but they were easily managed by temporarily interrupting gefitinib therapy. Referring to literature (and our own observations) we believe that the modification of radiation delivery might reduce gefitinib's effect on the liver. For example the utilization of modern imaging, the RapidArc technique and HDR brachytherapy would improve the precision of treatment and reduce the total duration of therapy.

New radiotherapy technologies enable increased doses and better treatment results

The results of prostate radiation therapy (RT) can be improved by increasing the dose delivered to the prostate. However, by increasing the dose, the detriments of the treatment become more common. The detriments can be avoided using state-of-the-art planning software and therapy techniques. Combined computed tomography (CT) imaging, magnetic resonance (MR) imaging and cancer cell metabolism based positron emission tomography (PET), create an excellent basis for the RT treatment planning. Also the long experience of the specialist doctors and medical physicists improve the accurate targeting of the treatment. In addition, with the chosen radiation therapy techniques and RT-software, the dose distribution can be substantially optimized in order to deliver a high dose to the target without exceeding the dose constraints of the organs at risk nearby. Modern radiation therapy devices are linear accelerators, which produce roughly similar radiation output independent of the device type.

However, the radiation beam shaping possibilities vary. The most advanced technology enables the beam to be shaped with very narrow computer guided lead leaves while the gantry is rotating 360 degrees around the patient. With this RapidArc technique, minimal radiation doses are delivered all around the body, and the normal tissue is protected better than before. In practice, the RapidArc combines the best features of the stereotactic radiation therapy and intensity modulated radiation therapy, which have been earlier stated as being the best RT techniques.

For the medium risk and high-risk prostate cancers, the high dose rate (HDR) brachytherapy enables the highest possible dose to be delivered internally to the prostate. The HDR technique has the best radiobiological efficiency and the expectation of better treatment results has been increased even more. The results of the HDR booster treated patients have been better when compared to the patients treated only with external radiation. The promising future of the HDR- treatments is especially supported by the fact, that regardless of the highest target doses, the detriments have been milder when compared to the traditional techniques.

Docrates Clinic - the background The researchers represented eight different research institutions from Finland and the USA. This study was supported by Finnish Cancer Society, Sigrid Juselius Foundation, HUCH Research Funds (EVO), Academy of Finland, University of Helsinki, Biomedicum Helsinki and AstraZeneca. Patients in this clinical investigation were treated in Helsinki University Hospital. The analysis and article writing were mainly carried out at Docrates Clinic, a cancer clinic Timo Joensuu founded with physicists Pekka Aalto and Harri Puurunen in 2006.

Principal investigator of the study, Timo Joensuu, specialized in oncology at Helsinki University Hospital and worked there for approximately 15 years. The priority among his interests has always been prostate cancer. In 1995 he began to use CadPlan, the first in Finland, a dose planning software in radiotherapy for prostate cancer. In the year 2000 he made his first IMRT plan.

Research and radiotherapy for prostate cancer is one of the specialist fields of Docrates. For diagnostics the clinic uses transrectal magnetic imaging, HistoScanning, ultrasound, computerized tomography, PET-CT and SPECT-CT. For dose planning options Docrates has Varian Eclipse and Variseed, Brainlab's IPlan and Nucletron's Oncentra and treatment modalities include LDR-brachy, HDR-Brachy, 3DCRT, IMRT, IGRT, RapidArc, Stereotactic RT and stereotactic radiosurgery. Docrates Clinic started gene therapy for cancer with oncolytical adenoviruses in November 2007. Since then about 200 patients have been treated.

Written by Timo Joensuu, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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