Interaction of Chemotherapy and Radiation

Oncology has increasingly become a multidisciplinary field: (1) surgery remains the definitive local treatment modality; (2) chemotherapy remains the definitive systemic treatment modality; and (3) radiation therapy is the definitive locoregional treatment modality. Although, historically, these approaches have predominantly been used exclusively of one another, the past 30 years have seen an explosion of both preclinical and clinical efforts to combine these therapies for improved outcomes, including improved local and regional control, overall survival, cosmesis, and organ preservation. We have learned a great deal about the interactions between chemotherapy and radiation from clinical trials that have combined these treatment modalities in sequential and concomitant regimens. In addition, laboratory investigations have demonstrated key molecular targets and pathways that can potentially be exploited for improved outcome. The combination of chemotherapy and radiation has changed the management approach in several disease sites, which are broadly reviewed here.

Historical Perspective

Radiosensitization and chemosensitization are complex concepts that have many different interpretations and have been used to describe many different interactions. The use of radiation and chemotherapy for mutual or even simultaneous sensitization adds to the intricacies of these interactions. Over 100 years ago, radiation treatment and benzene systemic therapy were combined for leukemia treatment. However, probably the best historical model of chemotherapy and radiation therapy interaction is that of 5-fluorouracil (5-FU).

5-Fluorouracil

In the 1950s, the halogenated pyrimidine, 5-FU, was combined with external beam irradiation (EBRT) after this class of drug was determined to have anticancer properties. In the last fifty years, 5-FU has been successfully combined with radiation to treat a variety of gastrointestinal cancers, as well as cervical cancer and head and neck cancer. The route of administration and scheduling of 5-FU has been manipulated many times in an attempt to reduce toxicity and maximize tumor control. What began as bolus delivery at the beginning and end of a fractionated radiation treatment course (Moertel regimen) has progressed to protracted venous infusion (PVI) and now to twice-daily oral 5-FU analog formulations. These approaches have allowed for an increase in cumulative dose of the drug, decreased chemotherapy toxicity, and improved radiosensitization. 5-FU has proven to be a staple drug in the armamentarium of medical oncologists and a key radiosensitizer for the radiation oncologist.

Rationale

Limitations in Current Therapeutic Approach

Over the past several decades, we have seen great technological advances in surgery and radiation while novel systemic agents are being developed at a pace never seen before. Nevertheless, cancer morbidity and mortality remain major problems. The advent of combined modality therapy has sought to improve on the limitations that surgery, chemotherapy, and radiation carry independently. For several decades, radiation has complemented surgery by improving loco regional control. Tumor-specific and patient-specific factors limit the success of both surgical and radiation treatments, however. In this chapter, we will focus on the multiple ways that systemic therapies are used in an attempt to overcome the shortcomings of radiation treatment. The presence of micrometastatic disease, disease outside of our treatment fields, and the inability to deliver adequate dose to the target region owing to normal tissue toxicity risk are some of the most frequently cited reasons. In addition, tumors may contain regions of relative hypoxia or subpopulations of cells with intrinsic or acquired resistance to radiation damage. We will briefly review the current understanding of these topics.

Tumor Detection

If ionizing radiation (IR) was without normal tissue toxicity, tumor detection would be immaterial and radiotherapy could be delivered to the entire body, much like chemotherapy. Obviously, this is not the case; much like surgeons, we must be able to identify the tumor so that we can precisely and accurately target it with radiation, akin to “carving out” a tumor with a scalpel. Advances in radiology have dramatically improved our ability to detect tumor location and extent. Whereas computed tomography (CT) and magnetic resonance imaging (MRI) provide excellent anatomical information, when combined with biological or functional imaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), the radiation oncologist can more confidently define tumor versus nontumor. Emerging MRI sequences—including dynamic contrast enhanced and fast imaging employing steady-state acquisition (FIESTA) ultrafast pulse sequence approaches, MR spectroscopy, and MR/PET—are providing improved anatomical and biological imaging for surgeons and radiation oncologists. Nevertheless, the resolution of our current techniques (on the order of 5 mm for PET resolution ) and high false-negative rates with small tumors still limit our ability to identify microscopic tumor extent and micrometastatic disease. Novel radiopharmaceuticals may provide additional improvements in the future.

Inherent and Acquired Resistance

We know empirically that certain tumors have inherent radiation resistance pathways that manifest with high rates of local failure following irradiation. In some cases, such as in pancreatic cancer, it is difficult to deliver adequate doses of radiation to the target owing to the limitations in dose tolerance of surrounding bowel, kidney, and liver. However, there are other tumors with extremely high local failure rates despite dose escalation. A prime example is glioblastoma multiforme, which has local recurrence rates approaching 100%. Biological factors within the tumor or tumor microenvironment also generate resistance (discussed in other chapters). Later in this chapter, we will describe how chemotherapeutics can potentially mitigate some of these resistance pathways.

Increased Toxicity

In the original treatise by Steel and Peckham on combining chemotherapy and radiation, it was assumed that each modality functioned independently in both beneficence and toxicity. However, it is abundantly clear that concurrent chemoradiation has increased toxicity, suggesting some level of overlapping toxicity, chemosensitization by radiation, or radiosensitization by the chemotherapy. Since chemoradiation is often used when tumors have wide anatomical extension (thus, precluding surgery), the volume of normal tissue irradiated—and, therefore, at risk of toxicity—is larger. In some cases, a patient has comorbid conditions that prevent aggressive therapy as well.

Therapeutic Index

The features described earlier generate the need for a metric to determine efficacy relative to toxicity so that newer approaches can be compared. This metric, known as the therapeutic index (or therapeutic ratio ) refers to the ratio of the probability of tumor control to the probability of normal tissue toxicity and has been covered in previous chapters. Typically, the ratio is calculated based on the 50% control rate of tumor versus the 50% normal tissue toxicity. These sigmoidal-shaped curves determine the estimated efficacy versus toxicity of treatment. Therapeutic index has been, and will continue to be, the “holy grail” of cancer therapy. For this reason, it is no surprise that it takes careful treatment planning to try to achieve maximal tumor cell kill while also sparing normal tissue in hopes of preserving function. There are a host of technological factors that impact this therapeutic ratio. Certainly, our ability to correctly identify tumor versus normal tissue will affect therapeutic ratio. The expanding use of PET, MRI, and SPECT imaging, as described earlier, are allowing radiation oncologists to better differentiate target from nontarget. Obviously, the ability to precisely deliver radiation through techniques such as intensity-modulated radiation therapy (IMRT), stereotactic procedures, and particle therapy allow us to avoid normal tissue while targeting tumor. Moreover, our ability to accurately deliver radiation via image-guided radiation therapy (IGRT) has grown by leaps and bounds; this enables smaller margin expansions, which will also limit dose to normal tissue. Nevertheless, based on the anatomical location of the tumor, there are technological limits to what can be accomplished with radiation in and of itself. Therefore, additional improvement will likely rely on the interaction of systemic agents with our technologically advanced radiation delivery methods.

Strategies to Improve Therapeutic Index

The fundamental approach to improving outcomes through combined modality therapy has its basis in the theoretical strategies set forth by Steel and Peckham in 1979. Their seminal paper defined four potential means by which combined therapy could improve the therapeutic index: (1) independent toxicity, (2) normal tissue protection, (3) spatial cooperation, and (4) enhanced tumor response. As discussed later, the first theoretical concept may not actually function as in the original intent. However, the latter three concepts are relevant for modern strategies of combining drugs with radiation. Additional mechanistic considerations have been identified in recent years that expand on Steel and Peckham's “exploitable mechanisms in combined radiotherapy-chemotherapy” that was described 4 decades ago. These newer concepts of biological cooperation and temporal modulation are impacting current investigative strategies for improving the therapeutic index.

Independent Toxicity

One of the main concepts suggested by Steel and Peckham as a means to improve the therapeutic index is to select a chemotherapeutic regimen with a distinct toxicity profile from that of radiation. This ideal selection of nonoverlapping toxicities could allow for increased tumor cell kill with minimal impact in terms of tissue toxicity. Although this has been pursued in therapy selection, the actual success in finding independent toxicity has been elusive. However, the inverse relationship has been implemented to a great extent. The avoidance of drugs with overlapping toxicities is standard of care practice—for instance, avoiding methotrexate with cranial irradiation, adriamycin with breast irradiation, or bleomycin with lung irradiation.

Normal Tissue Protection

The identification of clinically relevant agents that promote normal tissue protection without protecting tumors has provided very little in terms of therapeutics. Limited success has been achieved with the free radical scavenging agent, amifostine (WR-2721), which appears to be selectively taken up by normal tissue relative to tumor, where it is converted into the active thiol metabolite, WR-1065. Although amifostine has been shown to protect against xerostomia in head and neck cancer treatment ( Table 4.1 ) and to limit renal toxicity from cisplatin, several clinical trials have failed to show an advantage to amifostine use. Investigations into novel radioprotectors will continue, with the potential to impact the therapeutic ratio.

TABLE 4.1

Possible Drug-Radiation Interactions

Mechanism	Example	Notes
Normal tissue protection	Amifostine in head and neck cancer	Reduces xerostomia rates from RT alone
Spatial cooperation	Early-stage breast cancer with adjuvant chemotherapy PCI in SCLC	RT provides locoregional control for breast cancer but no impact on DM SCLC chemo does not effectively cross BBB → RT can effectively treat the brain
Biological cooperation	Targeted therapies inhibit prosurvival/proliferation pathways within tumors	Kinase-targeted agents, including tyrosine kinase inhibitors such as dasatinib and sunitinib as well as monoclonal antibodies such as cetuximab and bevacizumab; mTOR inhibitors
Temporal modulation	Drugs that impact tumor response in between fractions, namely, targeting repair, repopulation, reoxygenation, and redistribution	This is essentially a composite of several of the other mechanisms but requires concomitant delivery of the drug rather than sequential
Increased DNA damage	Drugs that incorporate into DNA	5-FU and platinum are classic examples
Inhibition of DNA repair	DNA intercalators and nucleoside analogs can disrupt repair and enhance radiation cytotoxicity	Alkylators, antimetabolites, platinum, and topoisomerase inhibitors are a few examples
Cell cycle effects	Most chemotherapeutics are cell cycle specific (except alkylators) Cell cycle arrest in radiosensitive phases (microtubule-targeting agents at M phase) Elimination of radioresistant cells (S phase)	Taxanes, epothilones, 5-FU, gemcitabine, topoisomerase inhibitors are good examples
Targeting repopulation	Conceivably any systemic agent that has at least cytostatic properties can prevent repopulation	Molecularly targeted agents as well as chemotherapeutics (particularly antimetabolites) can function this way
Hypoxia targeting	Mitomycin C and tirapazamine selectively targeting hypoxic cells Tumor shrinkage by chemotherapy decreases interstitial pressure and improves oxygenation	Taxanes and other chemotherapies that can produce tumor shrinkage are indirect means (given as induction therapy) while mitomycin C and tirapazamine are directly affecting hypoxic cells
Tumor microenvironment targeting	Antiangiogenesis promotes vascular renormalization	Bevacizumab in glioma

BBB, Blood brain barrier; DM, distant metastasis; 5-FU, 5-fluorouracil; PCI, prophylactic cranial irradiation; RT, radiation therapy; SCLC, small-cell lung carcinoma.

Spatial Cooperation

The concept of spatial cooperation implies that chemotherapy and radiation therapy are independent players with systemic therapy acting systemically, that is, targeting micrometastatic disease, and radiation therapy acting locoregionally. Because these therapies function independently, it could be assumed that a full dose of each will be required to achieve the desired outcome. If the drug and radiation did function completely independently, then concurrent administration should be possible with nonoverlapping toxicities. It is unclear whether a completely independent action can actually be achieved with the chemotherapies that are currently used with radiation treatment, however, since in-field toxicities do occur, suggesting some level of localized radiation sensitization. Therefore, sequential therapy is probably the best means to exploit spatial cooperation. Many clinical examples exist for this approach, such as breast cancer with adjuvant chemotherapy followed by radiation, consolidative radiation to bulky disease in lymphoma, or prophylactic cranial irradiation in small cell lung cancer (see Table 4.1 ).

Enhanced Tumor Response (Cytotoxic Enhancement)

Currently, a tremendous amount of investigative effort is focused on achieving cytotoxic enhancement with combined modality treatment. In other words, the combination of therapies leads to an interaction on some level that generates improved antitumor effect relative to each treatment alone. Interestingly, we have some clinical examples that subtherapeutic or radiosensitizing doses of chemotherapy can impact distant disease control, suggesting either that increased locoregional control can diminish distant metastatic disease potential or that lower-dose chemotherapy can treat micrometastatic disease (i.e., spatial cooperation).

Biological Cooperation

The term biological cooperation is a newer concept that involves independent targeting of subpopulations of cells within the tumor itself (see Table 4.1 ). Although similar to the spatial cooperation concept, biological cooperation implies that some portion of the actual radiation target (i.e., in-field) is resistant to radiation, which is the target of the drug given concomitantly. The most prominent example for biological cooperation is hypoxic cell cytotoxins such as tirapazamine. Since hypoxia is a known radiation resistance condition, tirapazamine will target these subpopulations of cells since it is most potent in anoxic conditions.

Temporal Modulation

The four Rs of classical radiobiology—reoxygenation, repair, redistribution, and repopulation —refer to factors that are particularly important for fractionated radiation therapy. For example, antiproliferative therapies could prevent accelerated repopulation between fractions, which might not be detectable using single-fraction assays in vitro. Conversely, although DNA damage repair blockade may enhance radiation sensitivity in the tumor, if DNA repair is also inhibited in normal tissue, outcomes may be worse in fractionated therapy. Depending on which factors are most prominent in normal and tumor cells, the therapeutic index can be shifted in either beneficial or detrimental directions. Therefore, temporal modulation implies therapeutics that optimize these four radiobiology factors in between fractionated radiation treatments (see Table 4.1 ).

Potential Biological Mechanisms of Drug Radiation Interaction

There are a host of potential mechanisms by which a drug may impact radiation efficacy, summarized in Table 4.1 . Classical definitions of radiosensitizers indicated an enhancement of DNA damage as the critical factor. However, with increased understanding of cancer cell biology, it is apparent that targets other than DNA damage can enhance radiation efficacy. Therefore, a broader defined “radiation enhancer” can impact several potential mechanisms to increase radiation effect.

Increasing Radiation Damage

The classical radiobiology definition of a radiosensitizer implied that the drug would enhance DNA damage. This is accomplished when the drug incorporates itself into the DNA or causes damage to the DNA itself by forming adducts, thereby increasing susceptibility of the DNA to radiation damage. Examples of this type of interaction include 5-FU and cisplatin.

Inhibition of DNA Repair

Cancer cells that can effectively repair DNA damage will have resistance to radiation effect. Therefore, compounds that can interfere with DNA damage repair can potentially enhance radiation damage. Several chemotherapeutics target this process, particularly those that disrupt nucleotide biosynthesis and utilization. Modified nucleotides such as 5-FU, bromodeoxyuridine, gemcitabine, fludarabine, methotrexate, etoposide, hydroxyurea, and cisplatin fall into this category. Additionally, as described later, compounds that alter the cell cycle may indirectly inhibit DNA repair.

Cell Cycle Effects

A multitude of preclinical studies has identified the G2/M as the most radiation-sensitive and S as the most radiation-resistant phases of the cell cycle. In addition, many cytotoxic chemotherapeutics are cell cycle specific. Therefore, agents that can maintain cells in radiation-sensitive phases or eliminate those cells in radiation-resistant phases will cooperate with radiation for enhanced efficacy. Although this is clearly seen in preclinical settings, there is much less direct evidence for this phenomenon in clinical data. Nevertheless, taxanes and nucleoside analogs and modified pyrimidines appear to work in this manner.

Repopulation

In normal adult tissue, the rate of cell loss is balanced by that of cell proliferation. When increased cell loss occurs from injury, including radiation treatment, signaling for proliferation occurs, resulting in a repopulation. Cancers, however, have an excess of cell proliferation relative to cell loss by their very nature. Therefore, when a subtotal cell loss occurs during fractionated radiation, cancers can also promote increased proliferation. This is known as accelerated repopulation. Chemotherapeutics with cytotoxic or even cytostatic effects, when given concurrently with radiation, can counteract this repopulation and enhance efficacy.

Hypoxia/Tumor Microenvironment

As discussed in other chapters, the tumor microenvironment is thought to modulate treatment response due to harsh conditions such as low oxygen tension, reduced nutrients, and acidic pH to produce a niche for therapy-resistant stem-like cells and even cancer-promoting immune cells. This is particularly true of solid tumors that have grown to any significant size, as they will contain these regions owing to the limitations in vascular flow as well as oxygen diffusion within the tumor. Although many tumors trigger angiogenic factors within the tumor, these stimulants manifest as aberrant vasculature often with disorganized architecture. Moreover, larger tumors may have increased interstitial pressure that leads to further collapse of blood vessels, creating hypoxic regions and overt necrosis at times.

Hypoxia is one of the most potent factors of radiation protection known since radiation relies on the production of oxygen free radicals (hypoxia generates 2- to 3-fold less radiation sensitivity). Therefore, drug therapies that mitigate this hypoxia can enhance radiation efficacy. There are four general chemotherapeutic approaches for accomplishing this. (1) Chemotherapy can shrink the tumor through cytotoxic action, thereby decreasing interstitial pressure. Moreover, since chemotherapy typically targets the fastest proliferating cells, those cells located next to blood vessels are removed, bringing the hypoxic regions into closer proximity with the oxygenated region. A good example of this process is demonstrated by taxanes such as paclitaxel. (2) Antiangiogenic therapies such as bevacizumab, an antibody targeting the vascular endothelial growth factor (VEGF), can potentially normalize vascular flow by eliminating the aberrant neovasculature of the tumor. Work by Batchelor et al., Jain, and others provided early evidence of this phenomenon. (3) Hypoxic cell targeting agents, such as tirapazamine, can provide biological cooperation by eliminating the most radiation-resistant cells. (4) Hypoxic cell radiation sensitizers can reverse the inherent radiation resistance of the hypoxic cells. Drugs such as misonidazole, a nitroimidazole compound, can mimic the effects of oxygen within the hypoxic regions.

Cell Death Pathway Effects

All of the potential mechanisms of drug-radiation interaction discussed earlier display their efficacy through cytotoxicity. However, in recent years, it has become clear that there are several ways in which cytotoxicity is manifest. In 2018, the Nomenclature Committee on Cell Death (NCCD) updated their classification system to define and expand cell death subroutines that are broadly grouped into apoptotic versus necrotic morphologies with regulatory cell death modes. As such, 12 interconnected cell death processes have been defined: intrinsic and extrinsic apoptosis, mitochondrial permeability transition-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, and immunogenic cell death. Although these are distinct forms of cell death, the stimuli and processes involved interrelate. Moreover, there is evidence that IR can manifest its cytotoxicity by several of these types of cell death. Therefore, as our understanding of these cell death pathways improves, novel therapeutics targeting these forms of cell death could enhance radiation efficacy. A few key cell death mechanisms related to radiation are briefly described here.

Apoptosis

Apoptosis is the most clearly defined and studied mechanism of cell death. This “programmed cell death” involves characteristic morphological changes, including chromatin condensation (nuclear pyknosis) and nuclear fragmentation (karyorhexis). Apoptotic bodies ultimately form and the cell is removed through phagocytosis but without generating an inflammatory response. Apoptosis can occur with or without caspase activation and does not require DNA fragmentation, though this is a classic hallmark. Apoptosis is considered the major mechanism for chemotherapy-induced cell death. As a mechanism for radiation-induced cytotoxicity, apoptosis occurs readily in “liquid tumors” as opposed to most solid tumors, in which apoptosis is a minor component of cell death. As such, drugs targeting the apoptotic pathway may enhance radiation cytotoxicity in solid tumors.

Autophagy

Whereas apoptosis is a clear self-destruct mechanism for the cell, the role of autophagy in cell death is more controversial. Autophagy, literally meaning “self-eating,” can provide a protective mechanism for a cell during times of stress (such as nutrient deprivation) because it allows recycling of cellular building blocks through a controlled breakdown of cytoplasmic components. However, autophagic cell death does occur that principally differs from apoptosis due to the lack of chromatin condensation.

Necrosis

Type 3 death, or necrosis, is a cell death mechanism in which the cell swells (oncosis), ruptures the plasma membrane, and releases its contents, resulting in a local inflammatory response. The best example of this type of cell death is ischemic injury. Large single-fraction radiation, or radio-ablative doses, can produce this type of cell death, as seen in stereotactic radiosurgery of brain lesions.

Mitotic Catastrophe

Mitotic catastrophe is a unique form of cell death that involves failed mitotic events. Typically, this is manifest as micronucleation and multinucleation, suggesting that a series of mitotic divisions occurs without cytokinesis, which ultimately leads to cell death.

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