Effective heart-sparing whole lung irradiation using volumetric modulated arc therapy: a case report

Wilms’ tumor (WT) is the most common renal neoplasm of childhood. Radiotherapy has historically had an important role as one of the main therapeutic tools for WT. The prevalence of adverse events in long-term survivors of WT is high, and an increased prevalence of cardiovascular events after chest irradiation has been reported [1]. Whole lung irradiation (WLI) has been widely used in the management of pulmonary metastasis, a concept that was introduced approximately half a century ago [2]. In the National Wilms Tumor Study Group (NWTS)-3 and NWTS-4, the 4-year event-free survival (EFS) and overall survival (OS) in patients with computed tomography (CT)-only lung metastasis was 89% and 91% after WLI compared with 80% and 85% with chemotherapy alone [3]. A UK Children’s Cancer Study Group report showed that patients with a chest X-ray with positive favorable histology for Wilms tumors had improved EFS and OS (79% and 85%) after WLI compared with chemotherapy alone (53% and 73%) [4]. WLI has traditionally been performed by using the anteroposterior–posteroanterior (AP–PA) field technique; however, one of the biggest drawbacks of this technique is the inability to reduce the high-dose volumes to the heart.

The use of volumetric modulated arc therapy (VMAT) has increased steadily in external beam radiotherapy. VMAT is a radiation technique that delivers highly conformal dose distributions through the complete rotation (360°) and speed variation of the linear accelerator gantry. This technique can be considered an extension to dynamic multi-leaf collimator intensity-modulated radiation therapy (IMRT). Compared with fixed-field IMRT, VMAT is capable of creating analogous or better dose distributions while reducing treatment time and monitor units by half [5]. To the best of our knowledge, the only reported case involving use of VMAT for WLI is a study by Papachristofilou et al. [6]. In their case, the radiation dose was much higher (18 Gy) than the dose generally used (12–15 Gy), which made it difficult to serve as a precise clinical reference. We report a case involving a patient who was administered a standard dose (12 Gy) of WLI using VMAT and present a subsequent dosimetry comparison of VMAT with the standard AP–PA field technique.

A 3-year-old Japanese girl with pulmonary metastases of WT was referred to our department for WLI and adjuvant chemotherapy as per standard of care [7]. She had a past medical history of patent ductus arteriosus (PDA) and underwent ligation of PDA at the age of 9 months. She was receiving orally administered furosemide and spironolactone for 6 months after surgery. After surgery, she had normal growth. Her social and family history was unremarkable. Her environmental history revealed no abnormalities. She was diagnosed as having clinical stage I WT of the right kidney at the age of 2.5 years. She received a complete resection of the primary tumor and adjuvant chemotherapy with actinomycin D and vincristine. Since then, she had been taking sulfamethoxazole trimethoprim 500 mg twice daily. Multiple bilateral lung metastases were detected by CT images 1 month after the adjuvant chemotherapy (Fig. 1). A lung biopsy revealed metastatic disease and the response to chemotherapy was determined to be inadequate. Therefore, this patient was referred to our department for WLI and adjuvant chemotherapy as per standard of care [7]. Her physical examination on admission revealed blood pressure of 110/64 mmHg, pulse rate of 120 beats per minute, and temperature of 37.0 °C. Auscultation revealed normal heart sounds and clear lungs. The result of her cardiovascular examination was normal. The rest of her clinical examination was unremarkable. Her laboratory findings were as follows: hemoglobin 11.0 g/dL (normal range, 11.6–14.8 g/dL); hematocrit 33.1% (normal range, 35.1–44.4%); white blood cell count of 5.4 × 10³/mm³ (normal range, 3.3–8.6 × 103/mm³) with 32.4% neutrophils, 56.1% lymphocytes, 0.37% monocytes, and 4.4% eosinophils; platelet count 293 × 10³/mm³ (normal range, 158–348 × 103/mm³); sodium 139 mmol/L (normal range, 138–145 mmol/L); potassium 3.9 mmol/L (normal range, 3.6–4.8 mmol/L); chloride 108 mmol/L (normal range, 101–108 mmol/L); blood urea nitrogen 8.2 mg/dL (normal range, 8–20 mg/dL); creatinine 0.31 mg/dL (normal range, 0.46–0.79 mg/dL); total bilirubin 0.4 mg/dL (normal range, 0.4–1.5 mg/dL); albumin 4.6 g/dL (normal range, 4.1–5.1 g/dL); total protein 6.6 g/dl (normal range, 6.6–8.1 mg/dL); aspartate transaminase 32 IU/L (normal range, 13–30 IU/L); alanine transaminase 13 IU/L (normal range, 7–23 IU/L); alkaline phosphatase 1086 IU/L (normal range, 106–322 IU/L); lactate dehydrogenase 264 U/L (normal range, 124–222 U/L); and C-reactive protein 0.07 mg/dl (normal range, 0.00–0.14 mg/dl). Test results for antibodies to hepatitis B virus surface antigen, hepatitis C virus antibodies, and Treponema pallidum antibodies were negative. Urine analysis revealed no abnormal findings. The NWTS-5 relapse protocol involved 12 Gy of radiation therapy in 8 daily fractions and NWTS-5 relapse protocol regimen chemotherapy, including dactinomycin, vincristine, and doxorubicin [7].

We presented a 3-year-old girl with lung metastases who received WLI using VMAT. We confirmed the dosimetric advantages of VMAT over the traditional AP–PA field technique, including superior cardiac protection and superior dose uniformity in the lungs. To the best of our knowledge, this is the second case treated with WLI using VMAT.

Dramatic improvements in survival have been achieved for children and adolescents with cancer [9]. Now that long-term survival cases can be expected, late adverse-event alleviation has become more important than it was previously. Late adverse events of cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, have been reported to be the leading cause of premature mortality among long-term survivors of childhood cancer [10‐14]. Various studies have demonstrated a substantially increased risk of heart failure, pericardial disease, and valvular disease with higher radiation doses [15‐20]. Pein et al. reported a 6.48-fold risk for cardiac abnormalities in children receiving mean heart doses in the range of 5–20 Gy [21]. Tukenova et al. assessed a total of 4122 5-year survivors of childhood cancer and found that the risk of dying as a result of cardiac diseases was significantly higher in the individuals who received an average radiation dose that exceeded 5 Gy to the heart [12]. Green et al. estimated that the risk of congestive heart failure would increase by a factor of 1.6 for every 10 Gy increase in lung radiation [22]. In addition, radiation to the chest for lung metastases may also result in thyroid disease and portal hypertension [23]. Therefore, radiation oncologists must make efforts to reduce the irradiated doses to normal organs as much as possible.

Recent progress in radiotherapy has been reported to substantially reduce heart doses by IMRT even in WLI [24]. In a study that performed WLI using IMRT by Kalapurakal et al. [24] with different mean prescribed V, the percentage of prescribed radiation doses were 96%, 85%, 65%, and 39% to the target volumes of the heart of V50, V67, V83, and V95, respectively. Comparing their results with those of our study, we used VMAT with a prescribed dose of 12 Gy to achieve 72%, 58%, 41%, and 22% to the target heart volumes of V50, V67, V83, and V95, respectively. The technique developed by Kalapurakal et al. [24] differs from ours mainly in two ways: (1) only fixed-field IMRT techniques, such as “step and shoot” and “sliding window,” were allowed, whereas we used VMAT; and (2) the whole lung IMRT dose consisted of 15 Gy in 10 fractions (14 patients) and 12 Gy in 8 fractions (6 patients), whereas we delivered 12 Gy in 8 fractions to our patient. These factors most probably resulted in better heart sparing in our patient than that achieved by Kalapurakal et al. [24].

Comparisons of VMAT and fixed-field IMRT have been evaluated for a large number of tumor sites, and these studies have largely demonstrated that VMAT is capable of creating analogous or better dose distributions [25‐29]. In addition, VMAT has the extra benefit of more rapid treatment time [5]. Increased treatment time in the management of childhood cancer has more than a few undesirable implications, including requiring patients to spend long periods on the radiotherapy couch, which can lead to patient distress and increases the risk of movement of the patient. Therefore, VMAT may be a desirable technique for treating childhood cancer. To the best of our knowledge, the only case involving WLI using VMAT was in a study of Papachristofilou et al. [6]. Their case received a non-standard dose of 18 Gy of WLI. Our case report, which involved a prescribed standard dose of 12 Gy, will provide more useful clinical information than provided in the previous report. Our results demonstrated the feasibility of the VMAT technique in the treatment of WLI. The radiation delivered by using the VMAT technique was well tolerated without treatment-related toxicities during and after treatment.

This case report had some limitations that should be considered. First, this is a report of a single patient with a short follow-up after VMAT. A prospective study with a large number of patients and longer follow-up should be conducted to validate our results by using standardized procedures. Second, low-dose leakage in normal tissues, which tends to increase with IMRT and VMAT, may increase the risk of secondary malignancies. Further follow-up of patients treated by this technique is necessary to quantify this risk.

In conclusion, our experience with this patient demonstrated that effective heart dose sparing was possible for WLI using VMAT and should be considered by radiologists for use in their practices.