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<h3 class=”bodytextnoindentMIstyles”>Case report</h3> <p class=”bodytextnoindentMIstyles”>A 38-year-old-man presented to his local hospital in July 2015 with a three-day history of urinary retention, right leg weakness for the previous six weeks, and severe radicular right leg pain. Spinal cord compression was suspected and he was transferred to the National Spinal Unit in the Mater Hospital. MRI of his spine showed a large right pelvic mass however, not a cord compression. He went on to have a CT thorax, abdomen, and pelvis (CT TAP). This revealed multiple pulmonary metastases, extensive adenopathy, the previously seen right pelvic mass, and an 8x9cm left-sided testicular mass. He also had a large right common iliac vein thrombus and multiple bilateral pulmonary emboli. Differential diagnosis at this point included a metastatic testicular germ cell tumour (GCT) or a lymphoma.
Haematological investigations revealed a normal beta-human chorionic gonadotropin (β-hCG) of <1.2, but an elevated lactate dehydrogenase (LDH) at 1,790IU/l (Normal range: 140-280 IU/l) and elevated alpha-fetoprotein (AFP) at 1,766IU/l (Normal range: 0-9IU/l). The elevated AFP ruled out a pure seminoma or a lymphoma and he was diagnosed with a non-seminomatous germ cell tumour (NSGCT). Staging for advanced NSGCTs is carried out based on post-orchidectomy tumour marker levels (AFP, LDH, and β-hCG). However, non-pulmonary visceral metastases (as in this case with the right pelvic mass lesion with bone invasion) or a mediastinal primary immediately stratify a patient into the poor risk classification. Thus, our patient was staged as stage 3C, poor risk NSGCT.
He commenced etoposide and cisplatin (EP) combination chemotherapy. Bleomycin was omitted from his first cycle due to the extent and volume of his pulmonary metastases and pulmonary emboli. His AFP had dropped to 1,007IU/l on day one of his second cycle of chemotherapy and his condition had now stabilised significantly so bleomycin was added (BEP regimen) at that point. He completed two cycles of BEP chemotherapy, but had a persistently elevated AFP at 89IU/l, indicating residual active tumour cells. Restaging CT TAP revealed a mixed response compared to his scan at diagnosis. There was a decrease in the number and size of pulmonary nodules, his right pelvic mass was stable in size but he had developed a new bone lesion.
At this point his case was discussed at the oncology multidisciplinary meeting (MDM) and change of treatment to the second-line regimen TIP (paclitaxel, ifosfamide, and cisplatin) was recommended given his incomplete response to first-line treatment. He completed four cycles of TIP chemotherapy, with his AFP normalising between the second and third cycles on his 82nd day in hospital. He developed haemorrhagic cystitis but otherwise tolerated TIP relatively well, with some episodes of neutropaenia, but did not require a dose reduction. Physically, he was making slow gains with intensive physiotherapy and occupational therapy input, but was still heavily dependent on assistance for all activities of daily living (ADLs).
He went on to have a PET-CT after his four cycles of TIP chemotherapy. This showed a decrease in the size of all the previously identified lesions, but low-grade standard uptake value (SUV) uptake at multiple sites with persistent disease in the lungs and the right pelvic mass. His case was again discussed at the oncology MDM and given his normalised AFP and the very low uptake of fludeoxyglucose (FDG), the consensus was to closely observe him and proceed to orchidectomy. Orchidectomy at this point was indicated to surgically resect the potential sanctuary site of the testicle. His orchidectomy histology showed predominantly necrotic tissue but residual foci of both choriocarcinoma and embryonal components. Clinically, he was making steady if slow progress with regards his rehabilitation.
Unfortunately, at this point his AFP tumour marker was noted to be rising. On the morning of his orchidectomy it had risen to 33IU/l and a week later it had more than doubled to 69IU/l. Unfortunately it continued to rise and when his case was discussed again at the oncology MDM the decision was made to refer him for high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) rescue.
The work-up prior to ASCT is extensive. During the work-up, our patient developed sepsis. He had recurrent temperature spikes, with tachycardia and hypotension at times, despite escalating antibiotic therapy. Chest x-ray and urine samples were negative. Initial blood cultures were negative for any growth from both his recently inserted portacath and peripheral samples. At this point he had been accepted for an ASCT in St James’s Hospital, Dublin. He was due to start his HDCT in preparation for stem cell harvest and while he had stabilised from a sepsis point of view, he still had recurrent pyrexia of unknown origin. The decision was made to defer his stem cell harvest, which meant losing a slot in St James’s. Meanwhile, his AFP was ominously rising quickly, now at 850IU/l.
His portacath was removed after consultation with the infectious diseases team and he completed a further 10 days of vancomycin and meropenem antibiotics for presumed line sepsis without any further pyrexia or evidence of infection. An isolate was never identified. At this point his AFP had climbed to a peak of 3,071IU/l on day 200 of his admission.
He was re-referred to St James’s and a Hickman line was inserted to facilitate his first dose of paclitaxel and ifosfamide chemotherapy before transfer to St James’s for planned stem cell harvest. Midway through the second ifosfamide infusion he was suspected of becoming confused. Ifosfamide-induced encephalopathy was suspected and his ifosfamide infusion was stopped. He went on to stem cell harvest on day 10 and luckily he mobilised enough stem cells in a single harvest and did not require a second cycle of paclitaxel/ifosfamide. He was transferred to St James’s for the harvest and remained an inpatient there, completing three cycles of CE (carboplatin/etoposide) before his stem cells were re-transplanted.
Just over two months later he was transferred back to our unit and his AFP was in the normal range (8IU/l, normal: 0-9IU/l). It declined to 4IU/l and then rose to 8IU/l again over two weeks. He continued his rehabilitation and was now mobilising with a rollator zimmer frame. Discharge planning was initiated as he still required significant assistance with ADL and was not yet fit for discharge home.
Unfortunately, this was not the end of his story. His AFP began to climb again. It rose to 50IU/l, then 277IU/l and 671IU/l over three subsequent weeks. PET-CT after it rose to 50IU/l showed stable pulmonary nodules and lymph nodes from the previous CT, which were not FDG-avid. There was, however, a new FDG-avid T3 vertebral lesion. Given this appeared to be a solitary FDG-avid lesion, with the suspicion being that it might be the only source of the AFP rise, curative dose external beam radiotherapy (EBRT) was commenced to the T3 lesion, split over five fractions. He has just completed this treatment and we await his AFP results to see if he has responded.
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The National Cancer Registry Ireland (NCRI) reports there are 167 cases of testicular cancer in Ireland per year, with 95.7 per cent five-year survival rates and only five deaths attributable to testicular cancer per year in Ireland. This low mortality rate is a combined analysis of all stages of disease, however, and while it shows the responsiveness of these tumour cells to the available treatment modalities, it does not take into account the differences in prognosis for the early-stage versus advanced disease groups. The International Germ Cell Cancer Collaborative Group (IGCCCG) classification, which was published in the <em>Journal of Clinical Oncology</em> (<em>JCO</em>) in 1997, originally defined the favourable, intermediate and poor risk groups for advanced GCTs and reported five-year overall survival (OS) of 91 per cent, 79 per cent, and 48 per cent, respectively. Importantly, this risk group classification is predominantly based on post-orchidectomy tumour marker levels only, not pre-orchidectomy values. We were able to stage our patient pre-orchidectomy due to the non-pulmonary visceral organ involvement at diagnosis, which immediately stratified him into the poor risk group.
A more recent 942-patient observational study, presented at the ASCO Genitourinary Cancers Symposium 2016, showed five-year OS rates of 95 per cent, 93 per cent, and 64 per cent, respectively, for favourable, intermediate, and poor risk groups of advanced GCTs. This study gives a more modern prognosis for these patients given the advent of better therapeutic and supportive care options including HDCT with stem cell transplant (SCT) rescue and granulocyte-colony stimulating factor (G-CSF). By this estimate, our patient has a 64 per cent chance of being alive at five years from diagnosis. However, given the short time to biochemical progression after his HDCT and ASCT, his prognosis is most likely to be lower than that. We remain hopeful that radiotherapy to his solitary FDG-avid T3 lesion will eliminate his last site of active disease.
<h3 class=”bodytextMIstyles”> <span style=”font-size: 1.17em;”>Summary</span></h3>
Metastatic testicular GCTs are one of the more treatable forms of metastatic cancer, with a much better prognosis than most. However, when first-line chemotherapy regimens fail, the patient’s prognosis is significantly reduced. When second-line regimens also fail, therapeutic options are limited. The patients involved are predominantly young males in their 30s or 40s, given the age-profile of GCTs, and failure of these regimens can be devastating. One remaining therapeutic option at this point is HDCT, with stem cell transplant rescue in the salvage setting.
Stem cell transplantation allows for high dose chemotherapy regimens to be administered with curative intent and with low treatment-related mortality (<3 per cent). It can be used in the second-line or third-line setting for relapsed or platinum-refractory relapsed GCTs. The case report in this article highlights the challenges and difficulties in treating poor risk GCTs that relapse.
<p class=”referencesonrequestMIstyles”><strong>References on request</strong>
