Overview: Proton Radiotherapy in Pediatric Tumors

Radiation Side Effects in Pediatric Patients

With any cancer treatment, there has to be a balance between treatment efficacy and side effects. Radiotherapy is an important component of the treatment of many pediatric tumors, however, it has side effects that are particularly important in children. Radiation is thought to work by damaging the DNA of cells, preventing their further division and cell death. Tumor cells, which divide frequently, are particularly sensitive to DNA damage, however normal cells can also feel the effects of radiation. In fully developed adults, the tissues that are most obviously affected during treatment are those that are growing and dividing, such as the skin, the lining of the gastrointestinal system, and bone marrow where new blood cells are formed. In contrast, pediatric patients are still growing and developing, which involves cell division. This means that developing organs can be affected by radiation. In addition to short-term side effects, radiation can also cause long-term side effects from death of cells and a scarring reaction (fibrosis). Depending on the area treated, radiation can cause cognitive problems, hearing loss, lung scarring, kidney failure, infertility, hormonal problems, short stature, asymmetric bone growth, scoliosis, and heart failure. Radiation can even increase the risk of heart attacks, probably due to increased atherosclerosis ("hardening of the arteries"). Long-term side effects can happen years after radiation. Therefore, pediatric cancer survivors are more likely to have long-term side effects not only because their tissues may be more sensitive, but because they have the rest of their lives to be affected. Another potential side effect from the DNA damage caused by radiation is the development of a radiation induced second cancer. It has been shown that radiation can cause leukemia in the several years following radiation, but also increases the lifetime risk of other solids cancers in the area treated. Pediatric patients seem to be especially sensitive to second cancers, even when accounting for the fact that they have longer to live and develop second cancers.

Unlike chemotherapy, which goes throughout the whole body, radiation is aimed at particular areas. The goal of radiotherapy treatment planning is to deliver radiation dose to the areas where tumor cells are thought to be, but inevitably, some normal tissues will be affected. There are two reasons for this: 1) in order to treat a tumor with certainty, a "margin" of error is built-in so normal tissues near the tumor end up getting radiated, 2) as the radiation beams enter and exit the body, tissues along the path of the beams get radiated. The "entrance dose" and "exit dose" are necessary evils when x-rays are used since they pass right through the body, delivering dose along the way. It is this limitation of x-ray radiotherapy that prompted physicists and oncologist to explore radiotherapy using protons.

Proton Radiotherapy versus X-ray Radiotherapy

Protons are positively charged particles that also can be used to deliver radiation therapy. Proton radiotherapy has the advantage over conventional x-ray radiotherapy in that it can be more conformal. X-rays, which travel all the way through the body, deposit dose in normal tissues beyond a tumor. In contrast, protons travel into the body and release the majority of their energy at the end of their path (called the Bragg peak). Essentially, protons can stop on a dime, and they do not travel any further so there is no exit dose. The better conformality of protons compared to x-rays should allow for better sparing of normal tissues and consequently less short and long-term toxicity. This is why there is so much interest in developing proton radiotherapy for pediatric cancer patients. Unlike x-ray radiotherapy, which has been used widely for years, protons have only been used in a limited number of centers due to the incredibly high cost. As more proton centers are opened, proton radiotherapy is becoming more widely available.

There have been two major U.S. proton sites open for long enough to publish results from treatment of pediatric patients with protons, namely in those in Boston and Loma Linda. Overall, clinical outcomes data from pediatric patients treated with proton radiotherapy are limited in terms of numbers and length of follow-up. It should also be noted that the children with more complicated and difficult to treat tumors are preferentially referred for protons. Therefore, it is difficult to compare results of protons directly with series using x-rays due to this selection bias. To date, there have been reports of treatment of pediatric tumors mostly involving the central nervous system, the head, the orbit, and eye.

Base of Skull Tumors

Malignant tumors that arise in the base of the skull, typically chordomas, chondrosarcomas, and rhabdomyosarcomas, are uniquely challenging due to their location and proximity to critical structures. Surgical resection is typically incomplete. Despite treatment with post-operative photon radiation, these tumors will come back 60-75% of the time. One possible reason for this poor outcome is that the with standard photon radiotherapy, the total dose is limited by the dose to sensitive normal tissues, such as the optic nerves, the optic chiasm, and the pituitary gland. At the Harvard Cylclotron, 67 adults with chordomas or low-grade chondrosarcomas of the base of skull or cervical spine were treated with proton radiotherapy resulting in very good local control (89% at 3 years) 1. This work has established the role of protons in base of skull tumors in adults, but data in children are more limited.

Between 1981 and 1990, 18 children with base of skull or cervical spine chordomas were treated at the Harvard Cyclotron 2. After surgery, the children were treated with a mix of photons and protons to a median dose of 69 CGE (Cobalt Gray Equivalents, the accepted unit of proton radiation that equates to 1 Gray of photon radiation). After a median follow-up of 72 months, the 5-year actuarial survival was 68% and the disease free survival was 63%. Of the 18 children, four had radiation-related morbidity (growth hormone deficits, temporal lobe necrosis, and temporalis muscle fibrosis). Additional children with chordoma were treated with protons in Boston (73 patients total), and with a mean survival of over 7 years, overall survival was 81% 3. Despite the observation that chordoma in children has a better prognosis than in adults, children with poorly differentiated tumors had very poor outcomes compared to those with well differentiated tumors. The Boston experience was updated in 2006 (PTCOG45, Houston, TX) and showed that children with chordoma treated with protons experienced a local control rate of 80% at both 5 and 10 years without gender differences.

At Loma Linda, 20 children with chordomas, chondrosarcomas, and rhabdomyosarcomas of the base of skull were treated with protons between 1992 and 1999 4. They were treated with doses between 50.4 and 78.6 CGE. The results with protons compared favorably with photon treatment, with 5-year local control of 72% and overall survival of 56%. Longer follow-up will be needed to determine the benefit on bone growth & cosmetic outcome.

Craniopharyngioma

Craniopharyngiomas are benign tumors consisting of calcium deposits mixed with cysts arising from Rathke's pouch, which is near the pituitary gland. Resection is frequently incomplete, and the addition of radiotherapy can decrease the chance of the tumor coming back. Incomplete resection plus radiation together can prevent the tumor from recurring in 70-90% of patients. Photon radiotherapy is effective, but necessarily requires irradiation of critical normal tissues. The most common late complication following treatment for craniopharyngioma is hypopituitarism. Other late complications include vision and neurocognitive problems. It is difficult to tell what late effects are from, the surgery, the radiation, or damage from the tumor itself.

At Loma Linda, 16 patients with craniopharyngioma (age 7-34 yr) were treated with protons after at least one resection 5. They were treated with 50.4-59.4 CGE (1.8/day), and 14/15 patients had not recurred after 25 months of follow-up. There were few acute side effects from treatment, but there were late effects observed in four patients, namely panhypopituitarism, one stroke, and one meningioma that occurred out of the proton-field in the patient that had previous photon radiation.

In Boston, 17 children with craniopharyngioma were treated with protons between January 2001 to March 2006 (PTCOG45, Houston, TX, October 2006). Five had recurrent tumors. The median dose was 52.8 GCE treated with a median of 4 proton fields. Interestingly, when patients were rescanned during treatment, three were found to have cyst growth during radiation that required re-planning. After 45 months of follow-up, there were 5 recurrences and 1 patient had died of their disease.

Medulloblastoma

Medulloblastomas are primitive neuroectodermal tumors that arise in the cerebellum. They are treated with resection, and post-operative radiation is used to decrease the risk of recurrence. Medulloblastomas have a tendency to seed the craniospinal fluid, and therefore, comprehensive craniospinal irradiation is employed. Unfortunately, using photon radiotherapy, a large volume of normal tissue is treated as well, including the heart, lung, bowel, gonads, and vertebral bodies. Proton radiotherapy offers a major potential advantage over photons for the radiation of the spinal canal, as the lack of exit dose can prevent treatment of tissue deep to the spine 6, 7. Proton therapy also can prevent radiation dose to normal tissues for the cranial boost, especially for sensitive structures such as middle ear 8, 9.

At Loma Linda, three children with medulloblastoma were treated with craniospinal proton irradiation to a dose of 36 CGE with a18 CGE posterior fossa boost. No clinically significant blood count depression was seen, and only Grade 2 dermatitis was observed. One child was followed for 3 years and did not show any evidence of scoliosis. More patients and longer follow-up will be needed to fully realize the relative benefit PRT in medulloblastoma.

Brain Tumors: Astrocytomas and Gliomas

Astrocytomas are the most common primary brain tumor in children. They arise from glial cells, which are cells in the brain that support the neurons. Depending on the grade and location of the tumor, children can do very well (over 95% survival at 5 years after complete resection of low-grade tumors) or very poorly (5-year survival of 15-30% for high grade tumors and less than 10% for pontine tumors). Depending on the location, grade, and age of the patient, tumors are treated with a combination of surgery, radiation, and/or chemotherapy. The long-term side effects of radiation are related to the dose and the volume that is treated, which can be extensive in astrocytomas. Therefore, long-term neurocognitive complications, such as deficits in memory, learning, and social/emotional adjustment may by minimized by limiting dose to normal brain tissue. To explore this concept, dosimetry studies comparing photon with proton treatment for astrocytomas have shown less normal brain would be treated with proton therapy, even if the tumor dose were increased 10.

At Loma Linda, 27 children with progressive, recurrent, or residual low-grade astrocytomas were treated with protons to a dose of 50.4-63 CGE 11. With a mean follow-up of 3.3 yrs, the local failure rate was 6/27 (22%). The treatment was well tolerated, and all children with local control maintained their performance status. All of the patients with optic pathway tumors (6) who started with useful vision maintained or improved their visual status.

In Boston, 28 patients with astrocytomas (18 with WHO Grade I and 6 with WHO Grade II) were treated with protons (with or without photon radiotherapy) to a median dose of 52.2 CGE from 1995-2005. The patients were followed for a median of 3 years, and progression in was observed in two patients with no marginal failures. Although five patients had endocrine defects prior to proton therapy, new endocrine deficits occurred in 7 patients (Yock et al. PTCOG45, Houston, TX, October 2006).

Optic pathway gliomas account for 1-5% of all childhood gliomas, and their location presents a particular neurosurgical challenge. Resection of anterior tumors can cause blindness in the affected eye, and resection is not always feasible for tumors extending posteriorly. At Loma Linda, seven children with optic pathway gliomas were treated with protons to a dose of 54 GCE 12. With 3.1 years of follow-up, all the patients were alive and free of recurrence. Visual acuity was preserved in all the patients that presented with useful vision.

Uveal Melanoma

Uveal (ocular) melanoma is rare, but it is the most common primary ocular neoplasm. Uveal melanoma is normally treated with plaque therapy for small lesions, but large lesions often require enucleation (removal of the eye). The role of proton radiotherapy in adult uveal melanoma has been well established, and has the advantage potentially preserving vision in eyes with large tumors. Between 1975-1986, 1006 adult patients were treated with protons at the Harvard Cyclotron, and excellent local control and probability of eye retention were achieved 13, 14. Ten children with ocular melanoma were treated with protons in Boston (70 CGE in 5 fractions). All the children were alive and locally controlled at over 10 years of follow-up. (Marcucci et al, 2004).

Retinoblastoma

Retinoblastoma is the most common malignant eye tumor of childhood, although still very rare. Because it is associated with a mutation in the tumor suppressor gene, Rb, 25% of cases are bilateral. Cure rates are generally high, so minimization of adverse effects, especially vision loss is an important goal. Although enucleation can be an effective treatment, vision-preserving treatments are desired. Chemotherapy with vincristine and carboplatin is often supplemented with radiation therapy.

In Belgium, at the cyclotron of Louvain-la-Neuve, three patients with retinoblastoma were treated with protons 15. The short-term outcomes were comparable to treatment with photons, but long-term follow-up with more patients would be needed to determine if the improved dosimetry decreases late toxicity.

Orbital Rhabdomyosarcoma

Rhabdomyosarcomas are tumors of connective tissue that arise from skeletal tissue, and are the most common pediatric tumor. Rhabdomyosarcomas that occur in the orbit have a very good prognosis, and radiation is an effective treatment that can avoid enucleation and preserve vision. However, the proximity of the orbit to the lacrimal gland and lens can lead to late side effects. Two patients with orbital rhabdomyosarcoma were treated with protons at Loma Linda in 1995 and 1996 to a dose of 50 and 55 CGE 16. At 3.4 and 2.5 years after protons, both children were alive and without recurrence. Both had with excellent visual acuity without cataracts, but one had mild enophthalmos (sunken eyeball).

Parameningeal Rhabdomyosarcoma

"Parameningeal" rhabdomyosarcoma arise in certain sites in the head, including the infratemporal fossa, pterygopalatine fossa, middle ear, mastoid, nasal cavity, nasopharynx, and paranasal sinuses. Unlike rhabdomyosarcomas that originate in the orbit, parameningeal rhabdomyosarcoma has a poor prognosis. The location of these tumors makes surgical resection difficult, and standard treatment includes chemotherapy and radiation.

In Boston, 16 patients with parameningeal rhabdomyosarcoma were treated with chemotherapy and protons between 1996 and 2005 (Krejcarek, S. et al. PTCOG 45, Houston, October, 2006). The median age was 41 months (range, 18-212). There were 11 embryonal, three alveolar, and 2 undifferentiated tumors; two children had metastases at presentation, and eight had intracranial extension. After a median dose of 50.4 CGE and a median follow-up of 2 years, the survival was 69% (11/16). There were two local recurrences (one in a regional lymph node, one with distant metastases as well) and two who developed only distant metastases. Several children developed late side effects, including 2 children who failed to maintain height velocity, 3 children with endocrine problems, 6 children with mild facial undergrowth, and 3 children with failure of tooth eruption. As for other pediatric tumors treated with protons, it is difficult to compare side effects with photon therapy because the numbers are so small and the follow-up is short.

Neuroblastoma

The most common extra-cranial solid tumor in childhood is neuroblastoma. It is a tumor of nerve tissue that most commonly arises in the adrenal glands in the abdomen, but can start in other locations. At Loma Linda, a 4 year-old child with neuroblastoma of the right adrenal gland underwent protons to a dose of 25.2 CGE. A boost region was treated to 34.2 CGE 17. The calculated dose to surrounding normal tissues in the abdomen was very low. The child tolerated treatment without any acute intestinal, hepatic, or renal toxicity, and experienced only mild redness of the posterior para-spinal skin.