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Radiation Oncology and Biology Elaine M. Zeman, Ph.D. Associate Professor UNC Dept. of Radiation Oncology

Pathology 725 April 24, 2007

The Cancer Problem Today Americans today face about a 40% lifetime risk of getting cancer (not including non-melanoma skin carcinoma). Approximately 20-25% will die of it. About 65% of cancer patients receive radiation therapy, either alone or in combination with other modalities (i.e., surgery and/or chemotherapy). Nearly 1.3 million Americans were treated in 2002. Radiation can be used with curative intent (about 75% of the time), or as a means of palliation of disease-associated symptoms.

What is Radiation Oncology? Radiation oncology is a clinical specialty devoted to the management of patients with cancer (plus a few benign conditions) through the delivery of carefully measured and targeted ionizing radiation of sufficient energy to kill cells. The specialty is more commonly referred to as “radiotherapy” or (erroneously) “therapeutic radiology”. Radiation oncology has been a stand-alone medical specialty distinct from radiology for 30 years. Medical students have very little, if any, exposure to radiation oncology during their training; typically, no more than about 1-2% of them opt to enter the field.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

What is Radiation Oncology?

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In the Beginning: The Electromagnetic Spectrum

1895: Roentgen discovers X-rays

1900: Radiation therapy is already big business!

How Does Radiotherapy Work? The types of radiation used to treat cancer are “ionizing”, that is, sufficiently energetic to disrupt atomic bonds and liberate free radicals that go on to damage cellular macromolecules, most notably, DNA. Cells are quite capable of repairing most radiationinduced DNA damage. However, unrepaired or misrejoined DNA damage can lead to chromosomal aberrations that are usually lethal to cells (but may also be mutagenic or even carcinogenic).

How Does Radiotherapy Work? When the goal is to cure the tumor, it is theoretically necessary to kill* every single tumor cell such that the probability of recurrence is zero. Given that the smallest tumor currently detectable is around 0.5 cm in diameter, estimates are that it already contains a billion cells ( 109 ). If so, then radiation therapy needs to reduce the surviving fraction of such tumor cells by at least 10 logs ( 10-10 ) in order to achieve even a modest probability of cure. Usually, it takes a total radiation dose of at least 40 Gy (4,000 rads) to accomplish this, and often, as much as 80 Gy or more.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

How Does Radiotherapy Work?

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Unfortunately, it is impossible to completely exclude normal tissues surrounding the tumor from the radiation field...although every attempt is made to minimize the dose and/or reduce the volume of normal tissue irradiated. Even so, it is highly unlikely that any normal tissue could tolerate 10 logs of cell killing and still maintain its structure, let alone its function (especially true the larger the volume of tissue irradiated). Estimates are that even 2 logs of cell killing can lead to unacceptable damage to normal tissues.

How Does Radiotherapy Work? All of which begs the question: “How does the radiation oncologist cure anybody when the dose to the tumor is necessarily limited by the tolerance of surrounding normal tissues?” Answer: By manipulating the physics of the radiation delivery, or by manipulating the radiobiology of the tissues being irradiated, or both. Sometimes this works, sometimes it doesn’t.

Manipulating the Physics: Type of radiation Delivered externally or internally (”teletherapy” vs. “brachytherapy”) Total dose and fractionation pattern (i.e., how many doses and to what total dose, time interval between doses, overall duration of treatment, etc.) Computer-aided optimization of radiation fields (dosimetry).

From: Leibel and Phillips, Textbook of Radiation Oncology, 2nd Edition, 2004

How Does Radiotherapy Work?

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

The Radiobiology of Radiotherapy Other cellular targets:

Manipulating the Biology:

The “process” by which ionizing radiation kills cells...

Membranes? Mitochondria? Signaling Pathways?

Irradiate

Free Radicals

DNA Damage

Repaired

aka

The Radiobiology Continuum

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Cell Survival

Unrepaired or Mis-rejoined

Innocuous Permanent Genetic Changes

Cell Death

The Radiobiology of Radiotherapy Permanent Genetic Changes

In theory, intervention at any point along this “continuum” can influence the final outcome... even though this outcome might occur decades after irradiation.

Heritable Mutations (Germ Cells)

Innocuous

Genomic Instability

Genetic Cell Disease Death (Offspring)

Cell Survival

Cytogenetic Changes

Neoplastic Transformation

Cell Death

Carcinogenesis

“Bystander” Effects

The Radiobiology of Radiotherapy Cell Transformation

Cell Death

Normal Tissue

Tumor

Recurrence

Cure

Tolerable

Normal Tissue

Intolerable Therapy Complication

Early Effect

Late Effect

Carcinogenesis

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

The Radiobiology of Radiotherapy The radiobiological principles that guide the practice of radiation oncology are commonly referred to as “The Four (Now Five) R’s of Radiotherapy”.

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Radiosensitivity Repair

The radiation oncologist’s choice of total dose, dose fractionation pattern, overall treatment time, and whether or not to add chemotherapy is an attempt to manipulate the “R’s” to therapeutic advantage.

Repopulation Reoxygenation

Radiosensitivity Radiosensitivity of cells is assessed by determining their reproductive integrity as a function of radiation dose. When plotted as the log of the surviving fraction as a function of radiation dose, most mammalian cells have survival curves characterized by near-exponential cell killing at high doses, and a sub-effective, “shoulder” region at low doses. Different cell types have different cell survival curves.

Radiosensitivity

Differences in radiosensitivity between different types of cells in tissues are associated with differences in radiotherapy tolerance dose.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

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Radiosensitivity

Differences in radiosensitivity between different types of tumor cells correlate (roughly) with the total dose necessary to control their corresponding tumor types.

Radiosensitivity Clinical Implications and Applications: Normal tissues have different tolerance doses (above which the likelihood of a complication becomes unacceptable) depending on the radiosensitivity of the component cells. Likewise, tumor control doses vary depending on the radiosensitivity of the component tumor cells. The addition of chemotherapy agents that modify the shapes of radiation survival curves leads to changes in tumor control and normal tissue tolerance doses. This idea is part of the basis for the clinical use of combination radiation and chemotherapy; the likelihood of success however depends on the extent to which the agent is selective for either tumors or normal tissues.

Repair Chemical “Repair” - very rapid free radical interactions (milliseconds) DNA Repair - biochemical repair of DNA damage (minutes to hours) Cellular “Repair” - increased cell survival with increasing fractionation of a radiation dose, i.e., sublethal damage recovery (hours) Tissue “Repair” - increased or decreased tolerance of tissues with changes in time, dose and fractionation pattern (hours to days)

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

Repair:

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Sublethal Damage Recovery

Sublethal damage recovery is operationally defined as an increase in cell survival noted when a large single dose is divided in half and delivered sequentially with a time interval in between. This increase in cell survival is a manifestation of the biochemical repair of DNA damage.

Repair:

Sublethal Damage Recovery Sublethal damage recovery occurs repeatedly and to the same extent with each dose fraction delivered (provided enough time between fractions is allowed for full recovery to occur). This has the net effect of reducing the toxicity of a given total dose compared to what would be expected if the dose were given all at once. This explains why radiotherapy is typically given as many small doses rather than one or a few large ones.

Repair:

Tissue “Repair” and Isoeffects

Isoeffect curves plot the total dose necessary to achieve a certain endpoint, such as local control of a type of tumor or a radiation-induced normal tissue complication, as a function of the dose per fraction. That different normal tissues (and tumors) have different isoeffect curves is a reflection of both the underlying radiosensitivity and the repair capacity of the critical cells whose deaths contribute to the development of the effect. Using a smaller or larger dose per fraction when certain normal tissues are at risk of injury could be used to therapeutic advantage.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

Repair

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Clinical Implications and Applications: Clinicians discovered over the decades that normal tissue tolerance and tumor control varied with dose fractionation pattern. Sublethal damage recovery was subsequently found to be the cellular phenomenon largely responsible for this. It was subsequently discovered to be a manifestation of the biochemical repair of radiation-induced DNA damage. In most tissues, this recovery is complete within six hours (meaning that in practice, no tradiational radiation therapy is given with less than six hours between subsequent doses).

Repopulation Clinicians have long known that acute reactions in normal tissues – such as breakdown of the skin, gut lining or the oral mucosa – would heal more readily if radiation therapy was interrupted by a “break” during the course of treatment. However, that tumors might likewise have mechanisms for compensatory proliferation or repopulation has only been fully appreciated in the last 25 years.

Repopulation - Normal Tissues

Early responding tissues (Iike skin, gut lining or bone marrow) undergo rapid repopulation and “take advantage” of longer overall treatment times. Late responding tissues (like kidney) cannot do this.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

Repopulation - Tumors

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Higher total doses are required for the same level of control of human head and neck tumors the longer the overall treatment time extends beyond about 4-5 weeks.

Repopulation Clinical Implications and Applications: Extending overall treatment time is beneficial in terms of allowing acutely responding normal tissues to heal, but can be detrimental in terms of tumor control, particularly for tumors capable of rapid repopulation. Head and neck cancers are one group that has been shown to be especially capable of rapid repopulation, as have a few others (gynecological tumors, non-small cell lung cancer). Other tumor types do not seem to have this ability (prostate). One clinical response to rapidly growing tumors is to use accelerated fractionation, in the purest sense, the compression of an otherwise standard course of radiotherapy from 6-7 weeks to 4-5 weeks (or less), by giving multiple fractions per day.

Reoxygenation

Latex “cast” of tumor vasculature

Tumors develop regions of hypoxia because, unlike normal tissues, their vasculature is abnormal. Abnormal Abnormal Abnormal Abnormal

Hypoxia (green)

Perfused Vessels (red w/blue)

structurally functionally physiologically angiogenesis

Since normal tissues generally do not contain regions of hypoxia, therapeutic strategies that combat tumor hypoxia have a “built-in” specificity.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

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Reoxygenation Advanced Head and Neck Carcinoma

Less Hypoxic

More Hypoxic

Many clinical studies establish an association between a pretreatment measurement of a high hypoxic fraction or low oxygen tension and poor prognosis. Hypoxic cells are resistant to radiation therapy, some chemotherapy, and their presence is associated with decreased local control, disease-free survival and a more aggressive phenotype (e.g., metastatic potential).

Reoxygenation One type of hypoxia in tumors is diffusion-limited or chronic hypoxia. It occurs in cells just beyond the diffusion distance of oxygen in tumor tissue. Some of these cells, although nutrientdeprived, are still clonogenic.

Canine Mast Cell Tumor Blood Vessel

Approaches to combat chronic hypoxia include decreasing oxygen consumption by intervening cells (such as by tumor shrinkage), correction of anemia, hyperbaric oxygen breathing, and the use of hypoxic cell radiosensitizers (misonidazole), normal tissue radioprotectors (amifostine), or bioreductive drugs (tirapazamine).

Hypoxia

Reoxygenation Tumor vessel = yellow/orange

Time = 0

Perfusion status = blue

Time = 20 min later

Another type of hypoxia is perfusionlimited or acute hypoxia. It occurs in tumor cells during sudden but transient vascular insufficiencies (vasculospasm, high interstitial fluid pressure, changes in red cell flux or O2 carrying capacity, etc.). Approaches to combat acute hypoxia include the use of blood flow modifiers (nicotinamide) that tend to stabilize intermittently perfused vessels. Other therapies target tumor vasculature directly, so as to completely shut down intermittently perfused vessels (combretastatin) and/or prevent neovascularization (angiostatin endostatin, avastin), and kill tumor cells secondary to ischemia. Some of these anti-angiogenic agents also help “normalize” the tumor’s vasculature.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007

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Reoxygenation Do human tumors reoxygenate? Probably... ...although not without exceptions. However what isn’t known yet is: How fast? By how much? The answers likely depend on both the extent and type(s) of hypoxia present in a particular patient’s tumor, and what the treatment plan is.

Rodent tumors do. (although at different rates and to different extents)

Hypoxia might not end up being a treatment impediment in tumors that reoxygenate rapidly and completely.

Reoxygenation Clinical Implications and Applications: Hypoxia is now known to be present in many types of human tumors and is implicated as a cause for treatment failure in some cases. Reoxygenation rates are still poorly understood for human tumors, but if any clonogenic, hypoxic cells do persist through treatment, the addition of hypoxia-directed drugs would be indicated. Decades of research have gone into the development of agents as diverse as radiosensitizers, radioprotectors, bioreductive drugs, and modifiers of blood flow and angiogenesis, in an attempt to overcome treatment resistance conferred by hypoxia. To date, many of these agents have NOT fared well clinically, in part because patients most likely to benefit were not pre-selected. Now that pre-selection is feasible, renewed interest in some of these therapies, and new drug development, are warranted.

E.M. Zeman, Ph.D. UNC Dept. of Radiation Oncology Path 725 Spring, 2007