Key Words: radiation sensitizers; 5-fluorouracil; platinum; gemcitabine; topoisomerase; epidermal growth factor inhibitors; vascular endothelial growth factor inhibitors

J Nucl Med 2005; 46:187S–190S

Surgery, radiation, and chemotherapy have been the mainstays of treatment for human malignancies for more than 40 y. The use of a combination of radiation and chemotherapy is often called chemoradiation in the medical literature. For most of the last 4 decades, this has involved the use of cytotoxic agents with external beam radiation. Recently, however, with newer molecules that target very specific pathophysiology or molecular pathways and the use of radiation delivered systemically by antibodies or hormones labeled with radionuclides, the concept of radiation sensitizers has been expanded.

Heidlberger’s preclinical studies in 1958 were the first to establish the concept of giving drugs concomitantly with radiation to enhance the effect of radiation (1). In the 1960s, Moertel et al. from the Mayo Clinic reported improved survival of patients with stomach and pancreatic cancer  

Received Nov. 2, 2004; revision accepted Nov. 9, 2004.  

For correspondence or reprints contact: Larry K. Kvols, MD, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Dr., Tampa, FL 33615.  

when the 2 modalities were combined (2). Initial reports showed only modest improvement; however, with a disease that had such a dismal prognosis, any improvement was welcome. In 1974, Nigro’s trial of 5-fluorouracil (FU) in combination with mitomycin C as concurrent therapy with radiation for cancer of the anal canal demanded the attention of both the radiation and medical oncology communities (3). Combined modality therapy is now well established in the following cancers: head and neck, esophagus, lung, stomach, pancreas, anal canal, and cervix (4–14).  

External beam radiation therapy and the combination of drugs and systemically administered radiation show interesting pharmacokinetic differences. Unlike drugs and systemically administered radiation, external beam radiation will penetrate tissue and cellular boundaries without any of the usual pharmacokinetic barriers. The dose delivered can be preplanned with external beam radiation and brachytherapy. Chemotherapy and radionuclides attached to carrier molecules, such as monoclonal antibodies or peptides, require distribution from the site of administration to the blood, tissue, interstitial space, cell, and subcellular target.  

An ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today.  

This review will discuss the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies. These drugs may be traditional chemotherapeutic agents or some of the newer molecular targeting agents. Much of the published clinical research has reported on the traditional cytotoxic agents, nucleoside analogs and platinum compounds. Substantially more information is currently available from basic and clinical research with these agents in combination with standard external beam radiation therapy than with systemically administered therapy, such as radiolabeled peptides or radiolabeled monoclonal antibodies. The concepts, however, should be applicable in both arenas.  

REVIEW OF RADIATION SENSITIZERS • Kvols 187S  

Some of the newer agents, such as growth factor inhibitors, cyclooxygenase enzyme 2 (COX-2) inhibitors, farnesyltransferase inhibitors, and inhibitors of new vessel formation, will also be reviewed in this paper.  

HOW DO CONVENTIONAL CHEMOTHERAPY DRUGS BRING ABOUT RADIOSENSITIZATION?

5-Fluorouracil

One of the first agents to be exploited as a radiation sensitizer was 5FU, and the basis for its action is currently thought to be primarily from thymidilate synthase inhibition (15). Interestingly, noncytotoxic concentrations of 5FU can also increase radiation sensitivity in vitro, but only when cells are incubated with drug before radiation. Because of the short half-life of 5FU in plasma, these laboratory studies have suggested that the drug should be given by continuous intravenous infusion (CIVI) during a course of fractionated radiation if radiosensitization of most fractions is to be achieved. In fact, the use of CIVI of 5FU with radiation has become the preferred therapy for both pancreatic and rectal cancer (16,17).  

Of course, this approach requires long-term venous access and specialized pumps over 5–6 wk, which can predispose the patient to thrombosis or infection. An oral form of 5FU, the prodrug capecitabine, may prove to make the protracted combined modality therapy easier and safer in the clinic, but additional studies are necessary.  

Analogs of Platinum

The platinum analogs include cisplatin, carboplatin, and oxaliplatin. These are used clinically in combination with radiation in a variety of solid tumors. When given before or after radiation, these analogs are believed to enhance cell killing by one of several mechanisms. These mechanisms include enhanced formation of toxic platinum intermediates in the presence of radiation-induced free radicals, inhibition of DNA repair, radiation-induced increase in cellular platinum uptake, and cell cycle arrest (18–22).  

The concomitant use of cisplatin or carboplatin has been shown to improve clinical outcome for non–small lung cancer, cervical cancer, and cancers of the head and neck (23–25).  

Oxaliplatin is a third-generation cisplatin analog that has recently been approved for use in colorectal cancer. Freyer et al. (26) have reported using oxaliplatin along with 5FU and folinic acid and concomitant radiation for rectal cancer. The Eastern Cooperative Oncology Group and Cancer and Leukemia Group B also have studies underway looking these same combinations in rectal cancer.  

Gemcitabine

Gemcitabine is an analog of cytarabine (cytosine arabinoside) with a broad spectrum of clinical activity against human cancers, particularly pancreatic and non–small cell lung cancer (27–30). Gemcitabine is a potent radiosensitizer in both laboratory studies and clinical trials. In the laboratory, there was no evidence of radiosensitization when cells were radiated before gemcitabine exposure, and the greatest enhancement ratio was seen when cells were incubated for 24 h before irradiation (31). Maximum sensitization appears to require simultaneous redistribution into S phase along with deoxyadenosine triphosphate (dATP) pool depletion (32). The dATP pool depletion is a result of ribonucleotide reductase inhibition.  

Minimally cytotoxic concentrations of gemcitabine can radiosensitize, and unlike 5FU, do not have to be given continuously. Clinical trials evaluating once-or twice-weekly gemcitabine along with radiation in head and neck cancer and pancreatic cancer are in process (33).