Palliative Re-Irradiation of Bone Metastases-Case Report

1 „Gr. T. Popa” University of Medicine and Pharmacy, Iasi, Romania 2 Regional Institute of Oncology, Iasi, Romania 3 MedEuropa Radiotherapy Center, Constanta, Romania 4 University of Medicine and Pharmacy of Craiova, Romania 5 „St. Spiridon” Emergency University Hospital, Iasi, Romania Corresponding author: C.C. MIRESTEAN, University of Medicine and Pharmacy of Craiova, Romania. E-mail: mc3313@yahoo.com Abstract

Two months after the diagnosis of bone metastases, the patient experienced pain in the pelvis. Pelvic irradiation was proposed for palliative antalgic purposes. Radiation planning was performed using an Acqsim CT simulation scanner with 1 cm slice thickness.
Clinical target volume (CTV) was delineated by making an isotropic expansion in 1.5 cm bone tissue around the metastatic region to include microscopic disease and a 0.5 cm margin was added to defi ne the planning target volume (PTV). Th e bladder and rectum were delineated as organs at risk (OAR) in order to evaluate the dose they received and to be removed from the irradiation fi eld by the medical physicist. Radiotherapy was delivered using the linear Varian Cliniac 2100Sc accelerator using 6MV photons in a total dose of 21Gy / 3 fractions, one fraction per week. Th e reproducibility of the CT simulation in the treatment sessions was ensured by the use of lasers and ink tattoos on the patient's pelvis. A signifi cant reduction in pain intensity was obtained starting from the second week of treatment. A bone scintigraphy performed 2 years after irradiation revealed the stationary aspect of bone metastases compared to the previous examination.Bone scintigraphy performed in 2018 revealed the progression of the disease (more than 3 new lesions compared to the previous examination) with moderate and intense uptake of the radiopharmaceutical in the vertebral column (T8, L3-L4 vertebrae), right sternoclavicular joint, ribs (posterior arch of the C4-C7 ribs, C11 right posterior arch, C5-C7 lateral arch), pelvis Bone metastases (BM) represent a frequent and severe complication of advanced prostate neoplasms associated with skeletal events, pain and hypercalcemia, causing deterioration of quality of life. Vertebroplasty and kyphoplasty are used to treat painful vertebral compression, fractures in the column, and along with bisphosphonates and radionuclides have improved prognosis and survival in these patients. Radiotherapy remains a cornerstone in the treatment of symptoms, providing not only a long-term reducer of pain but also provides vertebral stability and reduces the risk for pathological bone fracture. Th e use of a second irradiation of a painful bone metastasis can be considered, in generally, providing moderate pain relief, regardless the response of the fi rst radiation therapy course. It is generally preferable to irradiate peripheral metastases if the recommended dose limits for healthy tissue are achieved 1,2 .
Androgen deprivation treatment (ADT) is the gold standard for the treatment of metastatic prostate cancer. Although 85% of the hormone naive patients respond to ADT by reducing pain intensity, metastatic regression, and decrease of prostate specifi c antigen (PSA), median survival for patients with metastatic prostate cancer is 30-49 months. Some authors appreciate a benefi t in survival by adding prostate or pelvic radiotherapy to ADT even at the metastatic stage. Using the single 8Gy fraction scheme seems to have the same eff ect in pain relief as multiple fractionation regimens. Th e most commonly used radiotherapy regimens used for pain relief caused by the bone metastases are 30Gy delivered in 10 fractions, 20Gy in 5 fractions, 24Gy in 6 fractions, or regimens with one fraction per week (21Gy in 3 fractions, 3 weeks). Patients who have long-lasting survival and received a single fraction have a higher rate of retreatment (20%) than those treated initially with multiple fractions (8%).

MATERIALS AND METHODS
We present the case of a patient diagnosed in March 2011 with locally advanced prostate cancer. Th e pathology outcome based on prostatic biopsy, revealed a Gleason 7 (3 + 4) acinar adenocarcinoma. After 18 months, bone scintigraphy with 99mTc identifi ed multiple intense focal increased uptakes of radionuclide, suggestive for metastases in the sternum, lumbar spine, pelvis and in the proximal diaphysis of the left femur. ADT with leuprolein acetate and bisphosphonate therapy were initiated (Figure 1). delivered to the target volume: the pubic symphysis and the ischio-pubian branch. In order to limit the acute and tardive toxicity, the dose was reduced to the organs at risk by adapting the dose using the multi-leaf collimator (MLC) and the quality of treatment delivery was assured by Varian On-Board Imager (OBI) kilovoltage (kV) imaging systems, by overlapping the portal images with the imagines obtained from the CT simulation. Adjustment of the treatment table position reduces the dose received by healthy tissues.

RESULTS AND DISCUSSIONS
In the fi rst week after the end of the treatment a pain fl are occurred, followed by a signifi cant reduction in pain intensity.
For patients presenting oligometastatic disease, standard fractionation regimens (40 Gy in 20 fractions or 50 Gy in 25 fractions) off er a survival advantage over hypofractionated regimens. Th e most common localizations of metastasis in prostate cancer are vertebrae and pelvis 3 . From the pain relief point of view, no diff erence was found between sngle and multiple fractions and the intensity of the eff ective dose response (BED) 4-6 .
Analysis of data from 11 trials in 3435 patients with prostatic breast and prostate cancer metastases revealed an increased rate of pathological fractures after single fraction (3%) versus only 1.6% for patients who initially received multiple fractions, the rate of spinal cord compression being identical, the authors conclude that the rate of retreatment and the risk of fracture is higher for 8Gy single fraction 7 .
Extent of disease (EOD) observed on bone scan scintigraphy is considered a good prognostic marker of survival in mPCa. For patients with EOD I score, defi ned as having less than 6 bone metastases per bone or involving less than 50% of the size of the vertebral body for each metastatic site scan, the survival at 2 years is approximately 94%. For these patients the use of radiotherapy as the fi rst option is recommended only in case of medullary compression, fracture on pathological bone or increased risk of skeletal events. Longterm ADT deprivation is associated with osteopenia / osteoporosis in 80% of the patients, and the incidence of osteoporotic fractures is 5-20%. Zoledronic acid and denosumab are the systemic therapies currently recommended for the prevention of mPCa complications, but considering the increased risk of mandibular and (right sacroiliac joint, left ischium, left ischio-pubian branch) (Figure 2, 3).
Th e patient presented an increase in pain intensity in the left ischio-pubian branch and pubic symphysis.
A reirradiation for painful bone metastases was proposed. Radiotherapy planning was performed using Siemens Somatom AS CT simulator with 5mm thickness slices. A 3D-conformal treatment plan using MLC multilamellar collimator was implemented using treatment planning software (TPS) Varian Eclipse 10.0, after and target volumes and OARs were delineated. Reirradiation was performed using the Varian Clinac IX accelerator. Th e total dose was 20Gy in 5 fractions, delivered in one week. Th e radiation dose was  irradiation, a higher proportion of 2.6 fold of patients who were initially treated with single fraction was observed. After palliative irradiation of bone metastases, the complete response rate is considered to be approximately 20% and 50% of patients have partially responded with pain relief. Th e benefi t of re-irradiation seems to be similar to that of initial irradiation, a longer time from the fi rst treatment and the favorable response regarding the pain relief are arguments that plead for the selection of cases using this criterion. A meta-analysis including 2694 patients proved an median benefi t of 58% regarding the pain control for patients who received re-radiation at doses ≥4Gy. Th e most notable toxicities are gastrointestinal (18%), while bone marrow compressions and pathological bone fractures were found in only 2% of cases. Recently, by prolonging survival with the improvement of systemic oncological therapies, considering the possibilities of reducing adverse eff ects by limiting the doses received by radiosensitive structures, Jeremik and collaborators proposed a second palliative reiradiation of bone metastases with a dose of 4Gy. All patients included in the study received twice a single ≥4Gy. With severe caution regarding maximum tolerance of radio-sensitive organs in the vicinity especially of the spinal cord in case of irradiation of the C5 vertebra, the authors report response rates similar to the fi rst re-irradiation with lower rates of acute high-grade toxicity [15][16][17] .

CONCLUSIONS
Re-irradiation is a viable palliative option for patients with painful bone metastases especially for long -time survivors. Th e use of imaging-guided irradiation techniques can reduce toxicities which may aff ect the quality of life of patients. hypocalcemic radionuclides, the treatment of longterm survivors needs to be individualized 8,9 . For patients who have a long-term pain relief after radiotherapy, the time to progression is considered to be the interval between the fi rst radiotherapy sequence and the time when increasing the analgesic dose or increasing the intensity of the pain 10 .
Although there is no recommended primary treatment for stage IV cancer, there is evidence that for metastatic bone cancer with a long evolution (prostate, breast), the existence of the primary tumor will contribute to the increase in metastasis. Radiotherapy can contribute by the systemic abscopal eff ect, the irradiation-induced infl ammatory response, leading to activation of CD8 and cytotoxic T-cell 11 .
Re-irradiation of painful bony metastases has begun to be used frequently in the context of increasing overall patient survival due to systemic progression and surgical techniques, with 58% of these patients responding favorably.
One of the limitations of re-irradiation is the tolerance of healthy tissues at high doses of radiation. Analyzing the quality of life, the goals of palliative medicine and the economic benefi ts, he concluded that the palliative reassertion of painful metastasis is an option to be taken into account. Th ere are no signifi cant diff erences between the response of patients who received single fraction or multiple fractions, but patients who responded to the fi rst irradiation seem to benefi t more from retreatment 12 .
Th e same opinion is also issued by Wong et al. which complies after a systematic review, that partial and overall response rates calculated are 20%, 50% and 68%13. Transient pain is described by patients in the fi rst days after irradiation, the incidence reported by Hird et al. being between 39% after 8 Gy single fraction and 41% after multiple fractions 14 .
Th e indication to perform re-irradiation of a bone metastasis is a diffi cult decision given the fragile balance between the clinical benefi t and a risk of toxicities exacerbation. Recently, a systematic review conducted by Chow et al. demonstrated similar single fraction irradiation response rates versus multiple fractional treatment. However, in groups of patients who received