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Considerations involving reirradiation
Principles of reirradiation
The guiding principle of “Do No Harm” lies at the heart of reirradiation, as the limits of radiation therapy are bounded by the potential for morbidity. Patients are commonly referred for reirradiation in two distinct clinical settings. The first of these situations is for locoregional progression after definitive intent treatment. Generally, these patients do not have competing risks from other sites of metastatic disease. This may imply that the treatment intent for these patients is to provide durable local control, although this is generally dependent on tumor histology and clinical situation. Regardless of the potential for cure, there may be value in offering local therapy to primary tumors that have life-limiting or distressing morbidity, such as recurrent brain, spine, head and neck, lung, and gastrointestinal (GI) tumors. For these patients, the goals of reirradiation must be clearly defined as potentially curative versus palliative and should be supported by evidence when discussing treatment intent with patients.
The second situation for which patients are referred for reirradiation is for patients who received prior courses of palliative radiation, but the recurrence of symptoms impacts their quality of life. Often, these are situations where the functional and neurological outcomes of tumor progression would be equivalent or worse than the most severe toxicity (i.e., myelopathy from cord compression versus myelopathy from radiation). Indications may also include recurrent pain in nonspine bone metastases, where the normal tissue constraints may be less critical and initial palliative doses are lower, making reirradiation more feasible. This is particularly true for patients who have received palliation in the form of single fraction conventional external beam radiotherapy (cEBRT) with 8 Gy/1 fraction, where the tolerance of critical structures can be easily met. For patients with visceral metastases who present with symptoms of obstruction or hemoptysis, reirradiation may be more challenging since the target volume is often the most radiosensitive structure, but with sufficient interval between radiation, some studies have shown modest palliative benefit. ,
Despite what is feasible, reirradiation is ultimately about what makes sense for the patient’s goals. Thus, it is helpful to think of principles of radiation using the framework presented in Fig. 11.1 . This framework involves incorporating overall prognosis, the reason for locoregional failure after initial course of radiation, maximizing potential alternative therapies such as surgical debulking, separation surgery and medical management, and minimizing harm with advanced radiation therapy treatment techniques. For patients with bone, spine, and brain metastases, surgical consultation is always indicated, and a thorough exploration of nonradiation salvage options must occur. If the prognosis of a patient is reasonable, and all other management, including medical and interventional is not providing adequate palliation, then reirradiation becomes a more favorable option. Understanding why prior treatment courses were insufficient can also help guide retreatment decisions: If insufficient dose was used or the tumor itself was radioresistant, then dose and fractionation can be modified to maximize biologic effective dose; if there was a marginal miss, then advanced radiation modalities can be used to treat the area abutting the prior treatment field.
In all cases, goals of care must be carefully described to patients, and the benefits of local treatment must be measured against the potential and likelihood of harm during the patient’s lifetime. Informed consent must be obtained, and radiation should be planned with caution.
Techniques for reirradiation
Maximizing intervals between radiation courses
Several studies using animal models have demonstrated that increasing the interval between courses of radiation therapy allows for increased normal tissue recovery. This has been similarly observed in retrospective cohort studies of patients, where patients who have longer time intervals between radiation courses, ranging from 6 months to years, have better clinical outcomes. This may be due to favorable biology of the tumor or that normal tissue recovery over time permits higher biologic effective doses to be delivered. Generally, a minimum of 6 months may be a reasonable interval to consider reirradiation. Extrapolating from radiation-associated second malignancy data, almost full curative doses of radiation therapy can be given after many years, suggesting that the longer the interval, the safer it is to deliver high doses of radiation.
Best practices for calculating doses to critical structures involves a thorough review of the prior radiation therapy records and importing DICOM files of the dosimetric data whenever possible. Creating composite dose plans with equivalent dose in 2 Gy fractions (EQD2) can be helpful in estimating cumulative doses to structures. Of course, these are imperfect, given the changes in imaging, positioning, and anatomy, but they can be reasonably used to estimate total lifetime dose to normal tissues. Standardized dose discounts per institutional guidelines can be helpful in estimating potential recovery of organs at risk, taking into account time intervals between courses.
Proton therapy
For patients with recurrences or progression after initial definitive radiation therapy, proton therapy may facilitate reirradiation and reduce the risk of exceeding normal tissue tolerance. , Compared to electrons and photons, protons have significantly higher mass, thereby scattering at a much smaller angle. This leads to a sharper lateral distribution than electron or photon beams. , Furthermore, the rate of energy loss of a proton in matter is inversely proportional to its velocity, which results in a characteristic depth-dose distribution, referred to as the Bragg peak. Thus, the dose-distribution can be both laterally and distally conformal, allowing excellent coverage of the target with sparing of adjacent normal tissues. Improvements in proton beam delivery with pencil beam scanning can achieve an even higher degree of conformality, which is key to delivering radiation therapy in areas that have critical structures abutting the target volume either laterally or distally. However, for target volumes that contact or involve critical structures directly, proton therapy may not offer any distinct advantages, since both the target and critical structures will get full-dose radiation therapy.
While proton therapy offers many potential physical and anatomic advantages, the energy and charge properties of protons have potential radiobiological advantages as well, with an estimated radiobiological effectiveness of 1.1, although this remains an active area of research. , Thus, proton therapy is at least as biologically effective as photon therapy, if not slightly greater, and can provide significant benefits in sparing normal structures, particularly when those structures have already received prior radiation therapy.
However, given the relatively higher cost of proton therapy as compared to photon therapy, proton therapy should be judiciously offered to patients who would benefit from such treatment. Interestingly, of all indications for proton therapy, reirradiation is among the most commonly accepted as an important use of this resource. In most cases, this is largely because treatment would otherwise not be feasible without the ability of protons to spare normal tissue. For example, in locations such as the brain and spine, proton therapy can offer a practical way to spare the frontal lobe and esophagus, respectively ( Figs. 11.2 and 11.3 ).
Brachytherapy
While there are other advanced radiation therapy modalities that offer anatomic advantages to facilitate retreatment, ironically, brachytherapy is one of the oldest and simplest forms of radiation therapy, using radioactive isotopes that act over a short distance to deliver high doses directly to the site of the tumor , without exposing excess radiation to critical organs-at-risk. This has most commonly been employed to treat patients with locally recurrent disease after definitive treatment, particularly among patients with recurrent intracranial, spine, head and neck, and gynecologic or pelvic disease. As shown in Figs. 11.4 and 11.5 , brachytherapy can allow for excellent dose-escalation excess radiation, all while protecting normal issues. Even in widely metastatic patients, progression near the brain and spine can pose a significant threat to patients’ functional status, and thus, brachytherapy can be helpful. For most brachytherapy reirradiation cases, it requires multidisciplinary discussion and coordinated care with surgical colleagues.
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