Radiotherapy is the most important nonsurgical treatment for cancer. Still, significant numbers of radiotherapy patients treated with curative intent fail not only because of metastatic spread of the disease but also at the local treatment site. Consequently, the combination of radiotherapy with other treatment modalities continues to hold high interest. The fundamental premise of combining radiation with other agents is that, when viewed in light of critical normal tissue toxicities, the combination affords a greater tumor response than can be achieved by treatment with radiation alone. Such an improved therapeutic result may be achieved in a combination treatment in a number of different ways including spatial cooperation, independent toxicities, and potentiation of therapeutic action.
Historically combined modality investigations have focused predominantly on conventional chemotherapeutic agents used in combination with radiation. Preclinical studies often provided biological rationale for drug-radiation combinations tested clinically. Today, the combined use of chemotherapy with radiotherapy has become a common practice in cancer management. Indeed, the treatment of many advanced cancer patients integrates the combination of chemotherapy and radiotherapy into the definitive treatment strategy.
Solid evidence supporting the notion that chemotherapy administered during the course of radiotherapy increases both local tumor control and patient survival exists. However, the gains may be small and attained only at the expense of an increase in normal tissue toxicity. These concepts are explored in the article by Harari et al who trace the development of chemotherapy-radiation strategies in the evolution of current therapy approaches in 2 common human solid tumors, namely cancer of the head and neck and non–small-cell lung cancer. In an accompanying article Lawrence et al note that despite the clinical successes in the combined modality arena, the mechanisms by which conventional chemotherapeutic agents produce radiosensitization remain largely unknown. In their review of fluoropyrimidines, gemcitabine, and the platinums, the authors speculate that the results of clinical trials will be improved by a better understanding of the underlying mechanisms by which chemotherapy enhances the effectiveness of radiation. And that this to a large part will require better laboratory-clinic interactions.
To improve the therapeutic outcomes of radiotherapy a number of approaches, in addition to the combination with conventional anticancer drugs, are under active investigation. Particularly noteworthy are developing molecular strategies to tumor targeting. A growing body of evidence now suggests that the modulation of signaling pathways in cancer cells may lead to radiation resistance in tumors. In her article, Sartor explores the possibility of using specific inhibitors to interfere with the molecular processes involved to achieve tumor sensitization to radiation.
The reasons for radiotherapy failures are varied and multiple. In addition to intrinsic genetically determined resistance, physiologic properties arising primarily from inadequate vascular networks can play a major role in the lack of responsiveness of neoplasms. For example, the radioprotective effect of hypoxia is well documented. However, it is becoming increasingly clear that tumors with low oxygenation have a poor prognosis not only because of their therapeutic resistance but also because tumor microenvironments can influence both the malignant progression and dissemination of cancer cells. Wouters and colleagues suggest that such microenvironments may lead to a condition of hypoxia tolerance, which could play a positive role in tumor growth by providing angiogenic and metastatic signals. Their article develops the concept of hypoxia tolerance and reviews mechanisms used by cancer cells to acquire this phenotype as well as potential therapeutic implications of such a state.
Although generally considered a therapeutic detriment, the presence of hypoxic cells in tumors also offers a unique and exploitable difference between normal and neoplastic tissues. One method of exploiting hypoxia for therapeutic benefit has been the development of agents designed to be metabolized to toxic species preferentially in the absence of oxygen. These bioreductive drugs have the potential to greatly improve the outcome of radiotherapy by increasing cytotoxicity in the radiation-refractory hypoxic cell fraction. The article by Stratford et al provides not only a historic perspective on these agents but also insights into future approaches that may lead to their most efficient use in a radiotherapy setting. Another key difference between tumors and normal tissues is the process of angiogenesis, which is highly active in tumors but in healthy adults is limited to specific reproductive organs. Because neovascularization is intimately involved in tumor survival, progression, and spread, factors known to contribute significantly to treatment failures in radiotherapy, strategies targeting the tumor blood vessel support network may offer another approach to enhance the antitumor effects of radiation therapy. Siemann and Shi review the basis of combining angiosuppressive or vascular damaging treatments with radiotherapy and assess the principles by which their application in conjunction with radiation may lead to enhanced tumor control.
Although combined modality therapy strategies in radiation oncology traditionally have focused predominantly on increasing the antitumor efficacy radiotherapy, the tactic of avoiding or selectively preventing normal tissue injury by radiation may provide an alternative to improve therapeutic results. Andreassen et al evaluate the utility of such an approach and summarize the criteria necessary for chemical radiation protectors intended to be used clinically with conventional dose radiotherapy to ameliorate normal tissue side effects. The potential of prophylactic prevention and treatment of chronic radiation injuries is the subject of the article by Moulder. Such pharmacologic modulation requires a fundamental change in thinking about late radiation-induced normal tissue injury but offers the possibility of both substantial reductions in the incidence of late radiation effects and dose escalation at other sites.
FULL TEXT