Stage IV bladder cancer has been previously noted to have poor survival outcomes. The current standard of care is focused on
systemic therapy with radiation only being utilized for the management of painful osseous metastases and controlling other symptoms. Our report introduces a patient with multiple, large mediastinal metastases who failed multiple rounds of systemic herapy, including immune therapy, who responded to radiation therapy twice, and had a complete response to immune therapy accompanying the second round of partial-volume low-dose radiation therapy. The patient, who was initially considered forhospice, is currently alive one year after the second course of radiation followed by immunotherapy and 2 years after the first course of palliative radiation.
Patients with stage IV bladder cancer are noted to have poorsurvival outcomes, only 16% of patients are alive 5 yearsafter diagnosis . Radiation is traditionally only utilized for pain management of osseous metastases and controlling urinarysymptoms in metastatic bladder cancer , however radiati n has been seen to be effective in treating mediastinalmetastases in esophageal cancer patients . In this case, wewill introduce a patient with massive mediastinal metastases who failed multiple rounds of systemic therapy, including immunotherapy trials. This case is interesting as he experienceda dramatic response to radiation therapy twice, and becausefollowing the second course of radiation, which was low dose, partial volume, the patient experienced a complete response to Nivolumab therapy.
This is a 67 year old male diagnosed with high grade transitional cell carcinoma of the bladder, staged as pT4N0M0 inMay 2010. The patient was first treated with gemcitabine and cisplatin, followed by total cystectomy. Adjuvant therapyinvolved cisplatin and gemcitabine with concurrent radiation. After treatment, there was no evidence of disease. In September 2011, a mediastinal metastasis was confirmed as havingbladder origin. The patient was treated with Pemetrexed, followed by Taxol with Cetuximab, and then gemcitabine in September 2013. In October 2013, the patient presented for a Jak 2 inhibitor clinical trial. In April 2014, the patient wastreated on an IDO inhibitor clinical trial. The tumor continued to progress, and weight loss due to progressive dysphagia wasobserved (Figure 1).
Figures 1 (a,b,c,d). Tumor progression, regression, weight loss, and immune cells.
This figure shows changes of tumor size on computed tomography (CT) images (1a and 1b) and changes of weight (1c) before radiation,after radiation, and stable disease 4 months after the final radiation treatment. The upper image displays the subcarinal node, while thelower image displays the paratracheal node. A dramatic response totreatment is seen in both nodes, as the subcarinal node was reduced from 30 cm2 to 4.6 cm2. The paratracheal node shrank from 14.1 cm2 to 2.9 cm2 after the 1st course of radiation. The tumors are seen to increasein size under Jak 2 and IDO inhibitor therapies, and experiencea dramatic response to treatment during the first course of radiationtherapy. Then, the tumors grew in size until the second course of radiationwhen they again saw a dramatic decrease in tumor size. Figure 1c displays the patient’s weight over the course of tumor progressionand treatment. Note the weight loss (16 kg over 2 years), alongwith the weight gain (11 kg over 4 months) during and after the firstcourse of radiation therapy. Figure 1d shows the patient’s immunecells throughout treatment.
A gastric tube was placed for nutrition. He was considering hospice or a course of palliative radiation therapy. He wastreated with a dose of 50 Gy in 20 fractions to all visible tumors from 6/30/14 to 7/29/14, using 6MV photons and intensitymodulated radiation therapy technique (IMRT). He tolerated the treatment well, with improvement of dysphagia. As shown on Figure-1, the subcarinal node decreased in volume by 88%,and the paratracheal node decreased by 86% (Figure-1). After treatment, the patient no longer needed his gastric tube,and was able to eat and function normally until spring 2015. A chest CT on March 16th, 2015 revealed tumor progression(Figure 1). A bronchoscopy on March 26th, 2015 revealed a 70-80% obstruction of the left main bronchus (Figure 2).
Figure 2. Endobronchial tumor response after second line of radiation therapy (36 Gray concurrent with Taxol).
This figure shows the left main bronchus, imaged endobronchially, before and after the second line of radiation therapy (36 Gray [Gy] with Taxol).
Due to extensiveness of the disease, he was not considered tobe a candidate for surgical resection. His mediastinal lesion was negative for PD-L1 expression, thus not eligible for an active trial. There were no treatment options available at thattime. The case was discussed in tumor board, and the patient was given a month to live and recommended to enter hospice.Palliative radiation was discussed with the patient as a very high risk option. The patient was consented for serious complications including treated-related death. A dose of 32 Gy radiation was delivered to the obstructive subcarinal tumor, using MRT technique, from 3/23/2015-4/17/2015. Low doseof Taxol was given concurrently for radiation sensitization. The patient tolerated the treatment without any notable sideeffects. The obstruction of the left main bronchus was 10%in May 2015 (Figure 2). PET scan showed a great response to treatment with little residual tumor with minimum FDG activity of radiated subcarinal tumor. The FDG avid upper mediastinalmass (not re-irradiated) was slightly smaller in size. His overall performance improved; the patient started Nivolumabat end of May, 2015. PET scan on August 7, 2015 showed almost complete response with minimal residual disease.The non-radiated upper mediastinal tumors also had almostcomplete response (Figure 3).
Figure 3. Potential radiation abscopal effect.
This figure shows remarkable response of subcarinal tumor after 36 Gy re-irradiation, and stable disease of upper mediastinum tumor. After re-irradiation to the subcarinal tumor, the non-irradiated upper mediastinal tumor also showed a modest response. Most interestingly,the upper mediastinum tumors also achieved complete response to immunotherapy. The patient is currently on his 15th cycle of Nivolumab,and is alive and well without evidence of tumor progression at12 months after the second course of radiotherapy.
This case is unique as palliative radiation remarkably prolonged survival, low dose of re-irradiation with sensitizingdose of chemotherapy generated a great local tumor response and stabilized diseases, and after re-irradiation the patient responded to immunotherapy that he failed previously. Thepatient had over 6 months of tumor progression free survival after the 1st course of radiation without any systemic therapy.
he second course of radiation, low dose to part of progressed tumors, relieved the bronchial obstruction. This stabilized thedisease outside of radiation field and almost complete responseto Nivolumab (anti-PD-L1 treatment) may contribute to radiation abscopal effect, similar to that reported in melanoma .It is interesting to note that PD-L1 inhibitors without radiation often have limited response. In a study of 30 bladder cancer patients positive for the PD-L1 receptor, 47% (N=14) experiencedan objective response, while 26% (N=8) of patients experienced stable disease and 25.6% (N=8) experienced progressivedisease, but only 7% (2 patients) were seen to have a complete response . The lack of PD-L1 expression in thispatient’s tumor, along with the complete response was alsovery interesting. In melanoma clinical trials with Nivolumab, the response rate was 17% in PD-L1 negative patients, compared with 44% in PD-L1 positive patients, however in the PD-L1 negative patients that do respond, the radiographic response is often dramatic (75-100% reduction in tumor burden),very similar to that of our case. The fact our patient experienced a complete response to the Nivolumab (especially with the tumor’s PD-L1 negative status), may have been impactedby the abscopal effect.
In previous studies, involving both humans and murine models, a halting of distant tumor progress associated with local radiation therapy (known as the abscopal effect) has been observed [4,7-9]. A murine model study found that the abscopal effect is mediated through p53 . Another murine model found that in some cases when immunotherapy alone is noteffective in inducing an immune effect on the tumor and neither is low dose radiation therapy to a distant target, the combination can be effective in halting distant tumor growth8. In aprevious case report, radiation therapy was shown to increase CD4+ ICOShigh. This is important, because high CD4+ ICOShigh is associated with improved clinical benefit and overall survival in melanoma patients receiving iplimumab. Furthermore, utilizationof local ablation combined with immunomodulation has also been described by electrochemotherapy with adjuvantimmunogene electrotransfer . A well-designed prospective study is needed to determine the potential role of radiationabscopal effect in metastatic bladder cancer.