Pelvic Radiotherapy after Renal Transplantation

Discussion

Organ transplantation is associated with significant short-term complications, such as rejection and infection. However, the results of kidney transplantation regarding the graft, as well as patient survival, have improved over the past decades, mainly due to the introduction of new immunosuppressive therapies. Nowadays, special focus is on the long-term outcome. Some immunosuppressive drugs are associated with an increased risk of cancer which is of higher incidence in the transplant population than in the general population. Therefore, the development of cancer has been shown not to be such a rare complication in this cohort of patients (12-14). A post-transplant malignancy was shown to be the third most common cause of death in renal transplant patients (15, 16). Particularly in patients after kidney transplantation, there is an increased risk by up to 20-fold of lymphoma and by up to two-fold of solid cancer such as prostate cancer (7, 17, 18). However, due to better long-term outcomes with improved patient survival on the one hand, and due to the possibility of transplantation in older patients on the other, the incidence of post-transplant malignancy may even rise. There is evidence that the risk for developing cancer increases with age and long-lasting immunosuppressive medication due to disturbances of the immune system (5-8). The immunosuppressive treatment may support oncogenesis caused by certain viruses, which alter the surveillance of neoplastic cells leading to impaired DNA repair mechanisms and DNA damage (15, 17, 19). However, a definitive explanation is still unknown. On the other hand, patients with transplants are examined more often and more intensively, meaning that malignant disease will be detected earlier and more often in this cohort of patients (20). There are only few reports in the literature dealing with pelvic radiotherapy for patients with a renal transplant in the pelvis. The oncological treatment should take into account the preservation of graft function on the one hand, and possible chance of cure from cancer on the other. External beam radiotherapy is a frequently used treatment option for patients with pelvic malignancies, as a possibility for a non-invasive therapy that is generally well-tolerated. However, the aim of radiotherapy is to deliver a high volume dose to the target, including the tumour, and to avoid damage to the normal tissue, implementing the concept of tolerance-doses of organs at risk. Emami et al. were one of the first to define limits for various organs (21). In 2010, the tolerance doses of the kidneys were redefined by Marks et al. (22). A clinically-relevant renal dysfunction with a probability of <5 % can be started if the mean dose to both kidneys is <15-18 Gy and of <50% in cases of a mean dose of <28 Gy. In cases of radiation nephropathy, structural features include mesangiolysis, sclerosis, tubular atrophy, and tubulointerstitial scarring, leading to loss of the organ function (23). Kal et al. demonstrated that in patients with total-body irradiation as part of the conditioning regimen for hematopoietic stem cell transplantation, a total dose of >16 Gy can lead to an increase of the frequency of dysfunction (24, 25). Linsenmeier et al. detected slight glomerular nephritis in three out of 32 paediatric patients treated with total-body irradiation with a total dose of 12 Gy (26). However, Bölling et al. found a cumulative incidence of kidney toxicity of 25 % in 270 patients undergoing total-body irradiation with total doses ranging from 4-12 Gy (27). However, the tolerance dose for a transplanted organ in patients exposed to immunosuppression may be much lower. Therefore the renal transplant should be exposed to as low a dose as possible on the one hand, but without compromising that to the target volume on the other, in order to obtain a high cure rate. In the literature, there are only case reports or small series regarding this patient cohort. Konety et al. reported on 18 patients with prostate cancer and a renal transplant graft of whom three were treated with radiotherapy with a mean dose of 65 Gy to the target volume and with shielding of the graft (28). Two patients were alive, while one patient died due to other causes. However, the authors did not give details of the exposure, nor on the functioning of the graft. Therefore they only demonstrated the feasibility of the radiotherapy for this cohort of patients. Mouzin et al. described the outcome of eight patients with renal grafts and prostate cancer treated with radiotherapy (29). After a median follow-up of 28 months, two patients had local relapse, two patients died from causes other than cancer, and four patients were alive and free of local recurrence. In seven patients, the function of the renal allograft was unimpaired, while one patient experienced renal failure three months after the end of the radiotherapy due to terminal chronic rejection. The dose delivered to less than 10 % of the graft was 2 Gy in one patient, <5 Gy in five patients (including the patient with chronic rejection), 11 Gy in one patient and 13 Gy in one patient, and therefore below the tolerance dose that is reported for otherwise healthy patients with functioning kidneys. Detti et al. reported a single case with prostate cancer irradiated with a total dose of 70.2 Gy to the target volume, a maximum dose to the graft of 1.88 Gy and a mean dose to the graft of 0.36 Gy, without any impairment of the graft function during further follow-up (30). However, radiotherapy can also be used in patients with acute renal allograft rejection. In this setting, a total dose of 6 Gy with single doses of 1.5-2.0 Gy were applied to the whole kidney, with up to 100 % renal graft salvage (31). In our cohort of patients, we saw no graft failure with impairment of renal function; no patient had to return to dialysis due to transplant failure. The applied mean doses to the kidney were less than 4 Gy in all but one patient, which is clearly below the tolerance dose given by Marks et al. and lower than the dose range of 4-12 Gy reported by Bölling et al. in patients undergoing total-body irradiation.

To conclude, pelvic radiotherapy is feasible for this special cohort of patients by the use of three-dimensional conformal radiotherapy with adequate covering of the target volume while sparing the organs at risk, including the graft. A mean dose of <4 Gy seems to be well-tolerated by the graft.