Theoretical Framework for Therapy−The 'Steel Paradigm'
In 1979, Steel and Peckham introduced a theoretical framework to describe the interaction of cytotoxic chemotherapy and radiotherapy.[1] The term spatial cooperation is used to describe the scenario whereby radiotherapy acts locoregionally, and chemotherapy acts against distant micrometastases, without interaction between the agents (Figure 1). This cooperative effect requires the agents to have non-overlapping toxicity profiles in order that both modalities can be used at effective doses without increasing normal tissue effects. When combined concurrently with radiotherapy, however, few chemotherapeutic agents meet this criterion, because limited single-agent activity or toxicity-driven dose reductions preclude the delivery of systemic dosing schedules. Many trials of concomitant chemoradiotherapy, however, have demonstrated decreased incidence of distant metastases compared with radiation alone. This evidence could indicate that chemotherapy delivered at radiosensitizing doses has some systemic spatial cooperative effect, or that the improved local control of chemoradiotherapy decreases subsequent metastases.
Figure 1.
Rationale for adding chemotherapy to radiation. Spatial and in-field cooperation are the two idealized types of cooperation between radiation and chemotherapy. Both mechanisms can contribute synergistically to clinical benefit. aUsually not desirable as this could protect the tumor.
The second interaction between radiation and chemotherapy is radiation 'sensitization', which is either additive or supra-additive: the interaction within the radiation field leads to increased killing of cells (cytotoxic activity) either to the same degree as (additive) or more than (supra-additive) using both modalities sequentially (Figures 1 and 2). Strictly speaking, radiosensitizers shouldn't have inherent cytotoxic activity. The hypoxic cell sensitizers (e.g. misonidazole), and thymidine analogs (e.g. bromodeoxyuridine) are examples of 'true' radiosensitizers; however, the radiosensitizers most commonly used today (cisplatin, 5-fluorouracil [5-FU], and taxanes) do have inherent cytotoxic activity and can increase damage to normal tissues, with a 'true' benefit achieved only if the increase in antitumor effect is larger than the normal tissue damage (Figure 3).
Figure 2.
Schematic example of an isobologram depicting the combination of radiation and a systemic agent. The x and y axes show the isoeffective levels for radiation and drug. The thick line is the line of additivity, and the additivity envelope is based on the combined standard errors. Curves above the envelope represent antagonistic effects and curves below the envelope represent 'synergistic' effects.[1,41] Abbreviation: RT, radiotherapy.
Figure 3.
Schematic dose–response curves for tumor and normal tissue damage with radiation. The offset between the two curves indicates the therapeutic range. Chemoradiotherapy leads to a shift of both curves to the left, ideally with a stronger shift of the tumor curve (as indicated by the longer arrow), increasing overall efficacy of treatment (radiation enhancement).[120]
Infra-additive drugs possess radioprotective properties that lessen the cytoxic effect of radiation on the tumor and/or normal tissue. Ideally, such agents should be selective for normal tissue to allow administration of higher radiation doses. Several agents are being investigated and have shown promising early results with radiation alone, but for concurrent chemoradiotherapy definitive phase III evidence does not currently support their routine use. One such agent, amifostine—an organic thiophosphate—might decrease cisplatin-induced or radiation-induced toxicity by acting as a scavenger of free radicals, as well as by binding to and neutralizing organoplatinums and alkylating agents, thereby preventing DNA adduct formation. Although decreased incidence of xerostomia in patients with head and neck cancer treated with radiotherapy alone was convincingly demonstrated in a large trial,[2] the benefit with concurrent chemoradiotherapy remains unclear, as demonstrated by a phase III study showing no significant difference in xerostomia or mucositis rates.[3] Although a single-institution trial of patients with advanced lung cancer randomized to receive concurrent cisplatin, etoposide, and twice-daily radiation demonstrated a decrease in grade 1–2 esophagitis, grade 3 pneumonitis, and neutropenic fever, an increase in sneezing, dysgeusia (loss of taste), and more importantly hypotension, was observed.[4] In a larger phase III trial conducted by the Radiation Therapy Oncology Group, addition of amifostine to radiotherapy did not demonstrate any difference in grade 3 or greater esophagitis, although patients had a statistically significant, although small (1.3%) decrease in weight loss.[3] Concerns that radiation protectors might have a tumor protective effect has limited their use; however, two large meta-analyses did not confirm this concern.[5,6] At doses lower than those used for normal tissue protection, amifostine has been shown to have antimutagenic properties.[7]
The agent palifermin, a recombinant human keratinocyte growth factor, reduces oral mucositis in patients undergoing radiation and chemotherapy for autologous stem-cell transplant and in metastatic colorectal cancer treated with 5-FU.[8,9] This drug is currently undergoing phase III testing with concurrent chemoradiotherapy in patients with advanced head and neck cancer.
Determination of Additive Effects Between Chemotherapy and Radiation
The type of interaction between chemotherapy and radiotherapy within the radiation field (supra-additivity, additivity, or infra-additivity) can be determined. For this purpose, Steel and Peckham described the isobologram analysis, which is based on an isoeffect concept for chemoradiotherapy interaction (Figure 2).[1] Independent dose−response curves for chemotherapy and radiotherapy are necessary to create a plot, called an isobologram. The isobologram is generated by plotting the dose of each agent (i.e. chemotherapy and radiotherapy) against each other, which produces a cytotoxic effect (isoeffect) on the axes of increasing dose of each agent. Two curves, named 'mode 1' and 'mode 2', can then be generated (Figure 2). The mode 1 curve results from the assumption that radiation and chemotherapy act independently, and is created by plotting a given dose of radiation against the dose of chemotherapy needed to produce an effect equal to the difference between the chosen cytotoxic effect and the effect of the current dose of radiation. The mode 2 curve assumes that radiation and chemotherapy have identical mechanisms of action. Points on this curve are generated by plotting doses of radiation against the doses of chemotherapy needed to increase the effect of the dose of radiation to the chosen cytotoxic effect. Multiple points on both of these lines are obtained by varying the radiation dose and calculating the appropriate doses of chemotherapy. Finally, the true (empiric) survival curve is generated for radiation and chemotherapy given in combination. The doses of each agent needed to produce the chosen cytotoxic effect are plotted. Points that fall below the envelope between mode 1 and 2 curves indicate supra-additivity, data points occurring within the envelope (between the two curves) indicate additivity, and data points above the envelope indicate infra-additivity. Further details and sample calculations are provided elsewhere.[10,11]
Other methods exist to determine types of additivity, including the median effect principle and the response surface approach, both of which are described in detail elsewhere.[12,13,14,15] Unfortunately, the concept of additivity is of limited use in clinical practice, as preclinical prediction of additivity does not translate well into clinical outcomes. The use of this method is, therefore, limited to forming hypotheses, which need to be confirmed empirically.
Quantification of the Chemotherapy and Radiation Interaction
The radiosensitizing ability of a drug can be expressed by the therapeutic ratio. This ratio is derived from sigmoid-shaped dose−response curves, calculated by plotting the response of tissues (both normal and tumor) on the ordinate axis versus the chemotherapy or radiation therapy dose on the abscissa (Figure 3). The therapeutic ratio is defined as the quotient of the dose that produces a 50% tumor control rate and the dose that produces a 50% normal tissue toxicity rate. When chemotherapy is combined with radiation, both normal tissue and tumor control curves produced by radiation alone shift to the left because of the chemotherapy-induced sensitization of cells. Ideally, radiation sensitizers should influence the tumor response curve more than the normal tissue curve, thus resulting in a greater than one therapeutic ratio. Similar to the concept of additivity, therapeutic ratios are mainly hypothesis-forming and need to be tested empirically in phase I and II studies. Such preclinical data may help in the initial dose schedule selection for phase I trials.
Mechanisms of Radiation Resistance or Failure
Tumors have developed multiple strategies to resist radiation damage. Table 2 gives an overview of the most widely accepted mechanisms. Simplistically, larger tumors have a stochastic chance that some cells will survive radiotherapy. Moreover, hypoxic tumor cells have increased resistance to radiation; multiple studies have demonstrated that hypoxic cells exhibit 2.5−3.0 times the resistance to radiotherapy damage compared with normoxic cells.[16,17,18,19,20] As shown in Figure 4, the phases of the cell cycle significantly influence the radiosensitivity of cells.[21]
Figure 4.
Cell-cycle schematic and respective sensitivity to chemotherapeutic agents.
One of the most commonly invoked underlying mechanisms in treatment failure[22,23] is tumor cell repopulation, which results in a rapid growth between radiation fractions. Although incompletely understood, the stimulation of growth factors and the selection of resistant clones lead to rapid emergence of treatment resistance.[22,24,25] In addition, rapidly proliferating tumors contain a high proportion of radioresistant cells in the S phase of the cell cycle. For further information on repopulation, readers should refer to the excellent review by Schmidt-Ullrich et al.[26]
Certain tumors are intrinsically radioresistant, while others acquire mechanisms of radioresistance during treatment. Intrinsic radioresistance is seen when there is an increased surviving fraction of tumor cells after 2 Gy radiotherapy; this result is often depicted in a clonogenic radiation cell survival curve assay. Small increases in radioresistance lead to large, logarithmic decreases in final cell kill after radiotherapy. In some tumors, such evaluation in radioresistance in pretreatment biopsies predicts for radiosensitivity and clinical outcome, although these findings have so far not been widely reproducible.[27,28] Activation of certain prosurvival pathways that prevent apoptosis can induce treatment resistance. Among the many pathways implicated are mutated p53,[29] amplification of DNA repair genes, increased levels of reactive oxygen species scavengers, and activation of prosurvival/poor-prognosis oncogenes such as EGFR,[30,31] or c-MET (also known as MST1R).[32,33] Recently, gene-expression profiling has identified that radiation-resistant tumors overexpress many genes related to interferon pathways or induced by interferon itself, especially STAT1. Radiosensitive cells transfected with STAT1 demonstrated radioprotection after exposure to 3.0 Gy radiation.[34]
General Mechanisms of Chemotherapy and Radiotherapy Interaction
Seven major interactions between chemotherapy and radiation will be explained here and are listed in Table 3 . For most chemotherapeutic agents several interactions apply at the same time. First, DNA damage can be induced by both chemotherapy and radiotherapy and synergy is possible. Ionizing radiation induces DNA base damage, alkali-labile sites, single-strand breaks, and double-strand breaks (DSBs). All of these errors can be rapidly repaired except for DSBs, which if not repaired are considered lethal.[35,36] The integration of cisplatin into DNA or RNA in close proximity to a radiation-induced single-strand break can act synergistically to make the defect significantly more difficult to repair (Figure 5).[37,38] Second, chemotherapy can inhibit post-radiation damage repair. DNA synthesis and repair share common pathways, which provide the rationale for using DNA synthesis inhibitors with radiation as a means of inducing cytotoxic damage to tumor cells. Agents affecting nucleoside and nucleotide metabolism can inhibit the repair of radiation-induced DNA damage in patients, and are among the most potent radiation sensitizers. Examples of such agents include the fluoropyrimidines, thymidine analogs, gemcitabine, and hydroxyurea. Third, administered concurrently, radiotherapy and chemotherapy often target different phases of the cell cycle and may cooperate to produce an additive effect (i.e. cytokinetic cooperation/synchronization). The radiosensitivity of a cell is dependent on the phase of the cell cycle; cells in the S phase are the most radioresistant, and cells in the G2–M phase of the cell cycle are the most radiosensitive (Figure 4).[39,40] In addition, cytokinetic cooperation of S-phase-specific agents (e.g. camptothecins, 5-FU, hydroxyurea) is seen if cells are exposed in close temporal proximity to radiation.[41] Some drugs (e.g. taxanes) are able to synchronize with the cell cycle of tumor cells to allow increased efficacy of subsequent radiotherapy (called synchronization or cell-cycle pooling). This process was successfully shown in vitro, although the concept—especially its applicability in vivo—remains controversional.[11,42,43] Fourth, the increased resistance of hypoxic cells to radiation ( Table 2 ) means that hypoxic cell sensitizers may be beneficial.[18,44]
Figure 5.
Increased DNA damage by addition of cisplatin to radiation. aRadiation can also induce other DNA damage, of which double-strand breaks are considered lethal.
Hypoxia is common in many cancers and was shown to be a marker of aggressive clinical behavior and poor prognosis.[45] Chemotherapy can help eliminate these resistant cells and increase the efficacy of radiotherapy via multiple mechanisms ( Table 3 ). Tirapazamine, and potentially mitomycin C, preferentially kill hypoxic cells. Additionally, paclitaxel,[46] and EGFR inhibitors,[24] were shown to shrink tumors, thereby increasing perfusion and oxygenation and reducing radioresistant hypoxic areas. This hypoxic effect might be applicable for many other agents. Fifth, repopulation of rapidly proliferating tumors is usually mediated by overexpression of growth factors and growth factor receptors, as well as increased activity of downstream signaling pathways, and the presence of activating mutations in genes involved at all levels of the signaling pathways. Agents that target the S phase of the cell cycle, such as 5-FU, irinotecan, and hydroxyurea, as well as those that inhibit proliferation and/or growth factor pathways, such as EGFR inhibitors, may be effective in preventing tumor cell repopulation, thereby radiosensitizing tumor cells.[24,47]
In addition to their antiproliferative effects that prevent tumor cell repopulation, EGFR inhibitors and antiangiogenic agents can block signaling pathways that are responsible for aggressive tumor biology, poor prognosis, and radioresistance. Although the exact mechanisms of various targeted therapies vary and are generally poorly understood, preclinical[48] and clinical[49] data support the rationale for radiosensitizing properties as a consequence of inhibiting the detrimental effects of the agents' targets. Finally, some tumors resistant to 'standard' chemoradiotherapy respond to alterations in radiation fractionation. This phenomenon, termed hyperradiation sensitivity, is observed at radiation doses greater than 1 Gy. Preclinically, for both paclitaxel and docetaxel, low-dose fractionated radiation can overcome radioresistance.[50] Clinical trials evaluating this technique are currently underway.
Specific Mechanisms of Chemotherapy and Radiotherapy Interaction
Platinum Analogs. Cisplatin is one of the most commonly used drugs for concurrent chemoradiotherapy. Through interactions with nucleophilic sites on DNA and RNA, cisplatin introduces intrastrand and interstrand cross-links, thereby distorting the DNA structure, and blocking nucleotide replication and transcription. Active in both hypoxic and well-oxygenated cells,[51] several potential mechanisms for cisplatin-mediated radiation sensitization were reported and summarized by Wilson and co-workers.[41] It has been proposed that radiation induces free radicals and subsequently the formation of toxic platinum intermediates, which increase cell killing.[52] Moreover, ionizing radiation can increase cellular uptake of platinum.[53] Damage to DNA by ionizing radiation that typically would be repairable can become fixed and lethal through cisplatin's free-electron-scavenging capacity. This inhibition of DNA repair (Figure 5)[54] leads to an increased incidence of cell-cycle arrest and apoptotic cell death after radiation.4[1, 55]
In vitro studies have shown that the most synergistic combination of cisplatin and radiation involves low doses of each, either of which would be insufficient to cause cell death if administered alone. Cisplatin would seem to inhibit the sublethal damage repair process implicated in the recovery of insufficiently radiated cells.[41] Radiosensitization by cisplatin and carboplatin may be limited to cells with an intact homologous recombination repair system,[41,56] but radiosensitization is not impacted by hypoxia. Oxaliplatin, a cisplatin-related compound, has been shown to have activity in cisplatin-resistant systems and unaltered sensitivity in mutated mismatch-repair systems.[49] Although less well studied, oxaliplatin is postulated to have similar radiosensitization mechanisms to those of cisplatin.[41]
Antimetabolite-based Chemoradiotherapy
5-fluorouracil. The halogenated pyrimidine nucleoside analog 5-FU is used extensively with radiation.[57,58] This analog impedes nucleic acid synthesis through thymidylate synthase inhibition, depleting the pool of nucleotide triphosphates, leading to cell-cycle changes, DNA fragmentation, and ultimately cell death.[59] When 5-FU is incorporated into RNA and DNA it inhibits not only DNA synthesis, but also transcription and protein synthesis. Optimal 5-FU radiosensitization requires continuous administration of the agent during radiation because of the need for continuous thymidylate synthase inhibition, the short half-life of plasma 5-FU and intracellular phosphorylated 5-FU metabolites.
5-FU radiosensitization is postulated to occur by the agent's effect on the proportion of cells in the radioresistant S phase of the cell cycle. When given in standard doses, 5-FU is able to kill cells in the S phase. Additionally, at sublethal concentrations, 5-FU pre-incubation is hypothesized to radiosensitize tumor cells through changes in the S-phase cell-cycle checkpoint, which allow inappropriate progression out of the S phase into the G2 phase. This conjecture is supported by the fact that blocking the entry of cells into S phase prevents radiosensitization for a similar pyrimidine analog, fluorodeoxyuridine.[57,58] Impaired repair of radiation-induced DSBs might also contribute to 5-FU cytotoxicity and radiosensitization.[57,58]
Capecitabine. Capecitabine is an oral prodrug that is converted to 5-FU via thymidine phosphorylase. Radiation has been shown to preferentially increase tumor thymidine phosphorylase levels via induction of tumor necrosis factor. In a colon cancer fluoropyrimidine-resistant xenograft model, exposure to capecitabine before irradiation demonstrated a supra-additive effect compared with radiation alone.[60] Clinical trials are actively exploring the role of the combination of capecitabine and radiation therapy.
Gemcitabine. Gemcitabine is a widely used S-phase cell-cycle-specific pyrimidine analog that hinders DNA synthesis and repair through depletion of deoxynucleoside triphosphates that are required by two enzymes: DNA polymerase and ribonucleotide reductase. Gemcitabine has shown activity in many solid tumors, either alone or in combination with other agents (e.g. cisplatin or carboplatin).[61] Initial clinical studies of pancreatic and lung cancer demonstrated marked toxicity of gemcitabine-based chemoradiotherapy and dampened enthusiasm for the efficacy of this drug, since only doses much lower than those used without radiation could be administered safely. Recent data from multi-institutional studies have shown that full doses of gemcitabine can be delivered with aggressive conformal radiation techniques.[62,64]
In preclinical models, the potent radiosensitizing properties of gemcitabine were most pronounced with exposure to low doses of the agent at least 24 h before irradiation. Interestingly, sensitization persisted for up to 48 h, and radiation exposure before exposure to gemcitabine did not lead to sensitization. These observations are consistent with the time needed to deplete deoxynucleoside triphosphates (dATP) and transition through the S phase of the cell cycle.[65,66,67] It seems that incorporation of incorrect bases secondary to deoxynucleoside triphosphate depletion and S-phase accumulation are the basis of the radiosensitizing properties of gemcitabine.[65]
Pemetrexed. This compound is a novel multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl-transferase, all of which are key enzymes involved in nucleotide synthesis. Preclinical data suggest synergistic antitumor activity of pemetrexed and concurrent radiotherapy, and interference with DNA synthesis is thought to be the primary cytotoxic mechanism.[68] Pemetrexed is not cell-cycle-specific as it shows equal efficacy in the G1 and S phases of the cell cycle.[69] Although the exact interaction of pemetrexed with radiation is not fully understood, it has been postulated that prolongation of the S phase by radiation increases the intracellular drug exposure time and toxicity. Pemetrexed-based chemoradiotherapy is in phase I clinical testing in several tumor types.[70]
Hydroxyurea. Hydroxyurea acts as a radiation enhancer in vitro and in vivo[51] and is useful for the treatment of head and neck cancer.[71] This drug was previously used for squamous-cell carcinoma of the cervix (replaced by cisplatin)[72] and gliomas (replaced by temozolomide),[73] and was proposed for the treatment of pancreatic cancer (replaced by 5-FU and potentially gemcitabine).[74] Ribonucleotide-reductase inhibition prevents radiation-induced DNA damage repair during nucleotide excision. Furthermore, hydroxyurea might also synchronize cancer cells at the G1–S checkpoint.[74] The double action of hydroxyurea of cell-cycle synchronizing and DNA damage repair inhibition has been suggested as a mechanism for its more efficacious action as a radiation sensitizer at doses lower than for the ribonucleotide-reductase inhibitors gemcitabine and trimidox.[74] Antimetabolites such as hydroxyurea are selectively cytotoxic to cells that are in the relatively radioresistant S phase of the cell cycle, which might contribute to overcoming radioresistance.
Taxane-based Chemoradiotherapy
Paclitaxel and docetaxel form high-affinity bonds with microtubules, promoting tubulin polymerization and stabilization. At high doses, these drugs block prophase to metaphase progression, disrupting the centrosome network and thereby causing cell death.[75] Despite the structural similarities of these two agents, differences in excretion and cell-cycle tropism instigate differing temporal interactions of paclitaxel and docetaxel with radiation.[76]
Two mechanisms for paclitaxel and docetaxel radiosensitization have been proposed. The standard explanation is that cells remain in the G2–M phase of the cell cycle, leading to synchronization (cell-cycle pooling) of tumor cells at a point of maximum radiosensitivity,[11,42] but it is still unclear whether cell-cycle redistribution occurs, especially in vivo.[43] True synchronization in large tumors seems unlikely, and may not increase the therapeutic index as normal cells are also affected.[77] Alternatively, taxanes can induce tumor shrinkage, improving perfusion and subsequent reoxygenation. As hypoxic areas of the tumor are reoxygenated they become more sensitive to radiation-induced cell kill.[46] Paradoxically, low doses of taxanes may induce protection against radiation via possible alterations in signal transduction pathways. Pretreatment of a human laryngeal squamous cell line with 7.5 nmol/l paclitaxel 6 h before irradiation induced subadditive effects via G2 blockade.[78] Extensive single-agent and chemoradiotherapy taxane mechanisms are reviewed by Hennequin and Favaudon.[11]
Mitomycin-C-based Chemoradiotherapy
Mitomycin C inhibits DNA and RNA synthesis by interfering with DNA cross-linking, primarily at the guanine and cytosine pairs. Although mitomycin C is not cell-cycle-specific, this agent is known to induce marked cell-cycle arrest at the G2–M transition.[79,80] In combination with radiation, mitomycin C acts as a hypoxic cell sensitizer and is thought to prevent repopulation, although the exact mechanism remains elusive.[81]
Tirapazamine-based Chemoradiotherapy
Tirapazamine is the lead compound in a class that has selective cytotoxic activity under hypoxic conditions (hypoxic cell cytotoxic).[82] Hypoxic tumor cells that are relatively resistant to radiotherapy exhibit aggressive growth behavior, and portend a poor prognosis. Although widely recognized in its ability to enhance radiation,[83] debate exists as to whether tirapazamine's effects are additive or supra-additive.[84,85] Regardless, theoretical models show that the killing of hypoxic cells might improve outcomes compared with standard radiosensitizers.[86]
Tirapazamine's approximately 100-fold increased potency under anoxic conditions occurs via electron donation, which causes formation of transient oxidizing radicals. In normoxic tissue these radicals quickly bind available molecular oxygen, re-establishing the nontoxic parent compound. In the absence of oxygen, however, these oxidizing radicals induce the formation of DNA radicals by extracting a proton from the C4 location of the deoxyribose ring on the DNA.[87] This process can lead to cytotoxic DNA-strand breaks. Additionally, unknown mechanisms decrease topoisomerase II activity in tirapazamine-treated cells.[88] Although little or no cell killing is observed in normoxic cells, systemic side effects including fatigue, muscle cramps, and reversible ototoxicity were observed during the clinical administration of tirapazamine, and have been attributed to a loss of mitochondrial membrane potential.[89]
Temozolomide-based Chemoradiotherapy
Temozolomide is an orally administered cytotoxic alkylating agent, which readily crosses the blood–brain barrier; 30% of plasma concentrations are achieved in the cerebrospinal fluid.[90] Commonly used to treat gliomas, temozolomide causes DNA damage by methylation of the O-6 position of guanine and activates the p53-controlled DNA damage response pathway.[91] Tumors with methylation of the O-6-methylguanine DNA-methyltransferase (MGMT), a p53 DNA damage repair enzyme, are preferentially radiosensitized.[92,93] Temozolomide also inhibits signaling of radiation-triggered cell migration and invasiveness[94] and decreases tumor cell repopulation.
The aim of combining temozolomide with radiation is the use of an intrinsically active agent that has a different toxicity profile to radiation.[95] In a study by Wedge et al.,[96] a glioblastoma cell line with no MGMT activity was compared with a colorectal cancer cell line with high repair activity. Temozolomide and radiation were additive in the glioblastoma line, whereas antagonism was observed in the colorectal cancer line. This finding is probably attributable to radiation induction of MGMT. Additionally, temozolomide and radiation showed additive and supra-additive activity.[97]
Advances in Radiotherapy
While most advances in concurrent chemoradiotherapy have focused on the integration of novel systemic agents, recent technological improvements in radiotherapy have impacted directly on concurrent chemoradiotherapy. Intensity-modulated radiation therapy (IMRT) has allowed better delivery of radiation to the target volumes, allowing sharp dose gradients between targets and normal tissues. After clinical implementation of IMRT, decreased acute gastrointestinal, skin, hematologic, and salivary toxicity rates were reported, which improved the therapeutic index of radiation.[98] These decreases in normal tissue toxicity could also improve the therapeutic index of chemoradiation. Additionally, implementation of image-guided radiotherapy via linear accelerator-based kilovoltage techniques, and gating radiation delivery with the respiratory cycle, will improve day-to-day targeting and potentially decrease acute and chronic toxicities of chemoradiotherapy.
Molecular-targeted Therapies in Combination with Chemoradiotherapy
In the past decade, the promises of molecular-targeted agents have increasingly come to fruition, and these agents have been combined with radiotherapy in an effort to optimize the therapeutic index of drug dosing. Molecular-targeted therapies are an attractive option combined with chemoradiotherapy because they are more specific for the target and can inhibit radioresistance pathways. An extensive review of molecular-targeted agents and their interaction with radiotherapy has been published by Ma et al.[99]
EGFR-targeted therapies and chemoradiotherapy. The membrane-bound receptor tyrosine kinase EGFR is activated upon binding of the ligand (transforming growth factor α, epidermal growth factor), which induces dimerization and subsequent phosphorylation of the intracellular EGFR tyrosine residues. Upon activation, intracellular signaling cascades mediate various cellular responses important for tumor survival and growth—namely, increased proliferation, invasion, angiogenesis, and metastasis, and concomitant decreased apoptosis.
EGFR (erbB1) and the EGFR family members erbB2–4 are deregulated in head and neck, lung, breast, and colorectal cancers. Increased EGFR protein expression correlates with increased tumor size, recurrence risk, and radioresistance, and with decreased survival.[100,101] Cell culture experiments of radiation-induced EGFR expression and increased radioresistance, demonstrated by the addition of exogenous EGF, indicated a causal link between EGFR and radioresistance.[102]
Preclinical studies with the EGFR inhibitors cetuximab, gefitinib, and erlotinib show enhanced radiosensitivity leading to supra-additive efficacy both in vitro and in vivo.[49,100,103] Proposed mechanisms for radiosensitization via EGFR inhibitors include inhibition of cell proliferation, impairment of DNA damage repair,[104] attenuation of tumor neo-angiogenesis, inhibition of radiation-induced EGFR nuclear import,[105] and promotion of radiation-induced apoptosis.106, 107] In particular, the antiproliferative effects of EGFR inhibition most likely prevent repopulation,[100] a major mechanism implicated in radioresistance. The other mechanisms may well have a role in the supra-additivity of the anti-EGFR radiation combination.
Antiangiogenic and anti-VEGF therapy in combination with radiation. Angiogenesis is essential for sustained tumor growth, and many new cancer therapies are directed against modification of the tumor vasculature.108, 109] The process of angiogenesis is mediated by multiple proangiogenic and antiangiogenic factors, with VEGF having a central role.108,109] Anti-VEGF agents fall into two broad categories: those that target the VEGR ligand, such as bevacizumab, and those that target the receptor, such as PTK787 (an antibody to VEGFR-2). Other antiangiogenic strategies include antiangiogenic factor administration to counterbalance proangiogenic stimuli, inhibition of extracellular matrix degradation enzymes, integrin antagonists, and therapies with direct endothelial cell toxicity.
Two mechanisms for radiosensitization with antiangiogenic agents have been proposed and could exist in parallel.109, 110] The traditional view is that antiangiogenic destruction of tumor vessels leads to hypoxia and starvation, which paradoxically could also increase tumor resistance.[111] Increasingly, however, findings show that increases in blood flow, oxygen, and drug delivery (i.e. a transient normalization of the abnormal structure and function of tumor vessels) is seen as the underlying mechanism of antiangiogenic therapies.[109]
Radiosensitizing properties were first reported for angiostatin when Weichselbaum and colleagues demonstrated that the combination of angiostatin and radiation was synergistic and decreased radioresistance.[112] These results have also been confirmed for antiangiogenic small-molecule tyrosine kinase inhibitors.[113] Additionally, endostatin showed additivity with radiation regarding tumor regression, growth inhibition, angiogenesis, and enhanced apoptosis.[114] These mechanisms could be caused by enhancement of tumor oxygenation, leading to increased radiosensitivity, as well as direct tumor growth delay.110, 112]
Novel targeted therapies with radiosensitizing properties. Receptor tyrosine kinases other than EGFR are also potential targets for novel radiosensitizers. Overexpression of c-Met has been linked to poor prognosis in many cancers,[115] and synergism with radiation has been described in glioblastoma cell lines.[116] Other receptor tyrosine kinases such as insulin-like growth factor receptor or ephrin receptors are additional candidates. Another innovative strategy that has been tested in phase I clinical trials is radiation-induced activation of gene transcription. For example, TNFerade™ (GenVec, Gaithersburg, MD) is a replication-deficient adenovirus vector with an early growth response protein 1 (EGR1) radiation-inducible promoter leading to intratumoral human tumor necrosis factor production. Initial applications of this agent in esophageal, rectal, and pancreatic cancer, as well as in sarcomas, have shown proof of principal, with extensive tumor necrosis as a sign of activity.[117] Additional studies in head and neck cancer are ongoing.
With the increasing understanding of cancer biology, hundreds of novel targeted agents are scheduled to come into preclinical and clinical development in the next decade. Among these agents proteasome inhibitors, and agents that target mammalian target of rapamycin, have shown promising results when combined with radiotherapy.118, 119] For further information on the interaction of targeted agents with radiation, readers are referred to the excellent review by Ma and coauthors.[99]
Nat Clin Pract Oncol. 2007;4(2):86-100. © 2007
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