Abstract
We present a case of an adolescent male with relapsed Hodgkin lymphoma involving the mediastinum two years following chemotherapy without radiotherapy. The patient was treated with second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant and then presented for evaluation of consolidative involved-field proton therapy (PT). Comparative treatment plans were developed with three-dimensional X-ray radiotherapy (3DXRT) and PT. PT substantially reduced the dose to the lungs, heart, esophagus, and total body compared with 3DXRT, resulting in treatment with PT. PT should reduce the risk of late side effects compared with 3DXRT, including secondary malignancies and cardiovascular disease.
After the patient received two cycles of ABVE-PC (adriamycin, bleomycin, vincristine sulfate, etoposide, prednisone, and cyclophosamide) chemotherapy, restaging demonstrated a complete response (CR) by PET scan and a partial response (PR) by CT. The patient received two more cycles of ABVE-PC and a repeat PET-CT scan that demonstrated a CR by PET and CT, so no further therapy was given.
Twenty-five months later, a routine CT scan revealed an enlarging left cervical node of 2.1 cm as well as increasing bilateral supraclavicular/infraclavicular adenopathy. A PET-CT scan demonstrated hypermetabolic left-lower cervical, bilateral supraclavicular/infraclavicular, and anterior mediastinal adenopathy with disease measuring up to 5.6×2.0 cm in the transverse dimension with an SUV of 5.6. A biopsy confirmed relapsed HL.
The patient underwent four cycles of salvage chemotherapy with ifosamide, vinorelbine, and bortezimab, and had a CR by PET-CT scan at the end of two cycles and at the completion of salvage chemotherapy. The patient then received HDT using BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by an ASCT. The patient was subsequently referred to radiation oncology for evaluation.
Patients undergoing salvage HDT/ASCT for relapsed HL are at the highest risk of death from a subsequent relapse of HL, most notably in sites of prior disease involvement.1,2 Consolidative involved-field radiotherapy with HDT/ASCT has been shown to increase rates of freedom from relapse and survival in radiation naïve patients.3,4 The number of patients eligible to receive radiation as part of second-line therapy is increasing due to the growing number of children and adolescents who do not receive radiation as part of first-line therapy out of concern for late radiation toxicity. However, acute and late toxicity following combination radiotherapy and HDT/ASCT still remains a problem. 1 Our patient and his parents were especially concerned about the risk of cardiopulmonary toxicity due to the high doses of cardiotoxic chemotherapy and mediastinal radiotherapy, and thus requested an evaluation for PT instead of conventional three-dimensional conformal X-ray radiotherapy (3DXRT).
The radiation dose distribution with PT differs from X-ray radiotherapy. X-rays pass through the patient and deposit radiation throughout the beam's entire path, affecting both targeted and non-targeted tissue. Modern treatment planning with X-rays, including 3DXRT and intensity-modulated radiotherapy (IMRT), use beams of different angles and intensities to create a high-dose distribution on the targeted tissue while lowering the levels of radiation deposited in non-targeted tissues; however, in doing so, a greater volume of sensitive critical tissues is exposed to low doses of radiation, and thus are at a greater risk for possible long-term complications.
In contrast, protons have mass and charge and can be deposited within the targeted tissue without a significant exit dose. Unlike X-rays, protons lose little energy along their path and release the majority of their radiation energy at a point known as the Bragg peak. PT's ability to deliver highly conformal radiation to the target while minimizing the dose deposited to adjacent critical structures theoretically reduces the risk of acute and late radiation toxicity. A more detailed explanation of PT and potential controversies have previously been reported. 5
Our patient underwent comparative treatment planning to an involved field based on his first sites of involvement, including the bilateral lower neck, bilateral supraclavicular and infraclavicular regions, left axilla, and anterior mediastinum with both a conventional 3DXRT plan to 21 gray and a PT plan to 21 Cobalt Gray Equivalent (CGE) with an additional boost to the sites of involvement at relapse (the same field, but omitting the left axillary field) to a final dose of 30 gray/CGE. Figure 1 demonstrates the color wash isodose treatment plans for the 3DXRT plan (left) and the PT plan (right). Table 1 demonstrates the different dose-volume points for the organs at risk (OARs) for the two plans.
This figure illustrates color wash isodose treatment plans for the three-dimensional conformal radiotherapy plan (left) and the proton therapy plan (right). The radiation dose levels are indicated by the color wash, with red representing the highest radiation doses and blue indicating the lowest doses. As is apparent, there is a higher dose with three-dimensional X-ray therapy than with proton therapy.
V(X) is the % of the entire organ or the volume in cubic centimeters (cc) receiving ≥(X) gray/CGE (cobalt gray equivalent).
Secondary malignancies are the primary cause of mortality in HL survivors. 6 Since radiotherapy is frequently administered to the mediastinum of patients with HL, the most common secondary malignancy in males is from lung cancer. 6 According to Travis et al., irradiation as low as 5 gray to non-targeted lung tissue leads to an elevated risk of developing secondary lung cancers. 7 In comparing the 3DXRT and PT dose distributions, there was a significant difference in the volumes of lung exposed to various levels of radiation (Table 1). The 3DXRT plan irradiated 48% of the lungs with at least 5 gray, while the PT plan only irradiated 31%. Additionally, the mean lung dose with 3DXRT was 10.6 gray versus a mean dose of 5.9 CGE with PT. This difference is expected to decrease the risks of pneumonitis, pulmonary fibrosis, and secondary lung cancers. PT also reduced the total body volume exposed to at least 5 gray from 4509.8 cc to 2954.6 cc with the mean dose to the body being reduced by 42%. This dose reduction to the entire body should reduce the risk of other rarer secondary malignancies such as sarcomas, breast cancer, and gastrointestinal cancers.
While second malignancies are the primary cause of death in HL survivors, cardiac complications are also a major consequence of long-term toxicity from chemotherapy and radiotherapy. These non-malignant causes of death are increased seven-fold in childhood cancer survivors when compared to age-matched peers. 8 Mulrooney et al. demonstrated in a matched-paired analysis that, when compared to other childhood cancer survivors, HL survivors are at the highest risk for myocardial infarctions (hazard ratio [HR]: 12.2). 9 The study also demonstrated that a dose of 15 gray or higher can increase the risk of congestive heart failure (HR: 2.2, p<0.001), myocardial infarction (HR: 2.4, p=0.011), pericardial disease (HR: 2.2, p=0.005), and valvular abnormalities (HR: 3.3, p<0.001). 9 Furthermore, another recent report demonstrated that a mean cardiac dose as low as 5 gray in combination with anthracycline chemotherapy increased the risk of cardiovascular mortality. 10 In our patient's case, PT substantially reduced the dose of radiation to the heart when compared to 3DXRT (with a mean dose of 11.7 gray with 3DXRT versus 5.1 CGE with PT). Thus, the lower radiation dose to the heart with PT is expected to reduce the risk of cardiac dysfunction and cardiac death in the patient.
In addition to lowering the radiation dose to the lungs, total body, and heart in the patient, PT also reduced the dose delivered to the esophagus and vertebral bodies. Inadvertent radiation to the esophagus commonly causes acute effects, such as esophagitis, and rarely late effects, such as esophageal stenosis. 11 The PT plan lowered the mean dose of radiation to the esophagus from 18.6 gray with 3DXRT to 6.9 CGE, which should correspondingly reduce the risk of esophageal toxicity. Radiation to the vertebral bodies has been shown to cause a significant reduction in the height potential of childhood HL patients. The youngest patients and those receiving higher doses of radiation suffered the greatest loss in final height potential. 12 The PT plan was actually able to eliminate irradiation to five of the mid-thoracic vertebral bodies that were irradiated with 3DXRT, which should translate to greater growth potential in this prepubescent patient. Unfortunately, PT was not able to lower the radiation delivered to the thyroid (30.2 CGE versus 29.3 gray with 3DXRT) due to the thyroid's proximity within the involved radiation field.
Out of concern for the long-term toxic effects of radiotherapy, the patient underwent PT in order to spare better the OARs from inadvertent radiation, which should translate into a lower risk of late complications such as cardiotoxicity and secondary malignancies. The use of protons should be explored in other young cancer patients who require radiation therapy. Our patient is well and disease-free 19 months after therapy and he competes successfully in high school cross-country running. It is our hope that he will still be competing many years from now.
Footnotes
Acknowledgments
The authors would like to acknowledge Jessica Kirwan for her editorial support and assistance writing this manuscript.
Disclosure Statement
No competing financial interests exist.