A 46-year-old male with advanced nonseminomatous testicular cancer, renal and lung impairment
A 46-year-old male with a past history of hypertension initially presented to a urologist with a left-sided testicular mass.
The urologist ordered an ultrasound of the mass; however, the patient chose not to pursue further workup at that time and had no follow-up for approximately 4 months. He then presented to an ophthalmologist for complaints of decreased visual acuity. On examination, the ophthalmologist found him to have retinal hemorrhages and hypertension with blood pressure measured at 220 mm Hg/110 mm Hg.
He was sent to a local hospital and was found to have anemia, hypercalcemia with a level of 15.7 mg/dL, and acute renal failure with a creatinine of 3.5 mg/dL. His baseline creatinine before this was unknown. In addition, he had a large left-sided scrotal mass that he reported had continued to enlarge during the previous several months.
CT scans showed a large left-sided testicular mass measuring approximately 15 cm, as well as a 19 cm × 10 cm × 8 cm retroperitoneal mass that was causing obstruction to the left kidney, resulting in moderate to severe left-sided and right-sided hydronephrosis.
He was noted to have retrocrural and celiac adenopathy, as well as a 10 cm ×12 cm large calcified pelvic mass. Chest CT showed significant mediastinal adenopathy and a 1 cm right upper lobe pulmonary nodule. He underwent bilateral percutaneous nephrostomy tube drainage for the hydronephrosis that was noted on imaging studies. Tumor markers were obtained and revealed lactic dehydrogenase (LDH) of 637 IU/L, alpha fetoprotein (AFP) of 7392 ng/mL and beta-human chorionic gonadotropin (B-hCG) of 66 mIU/mL.
Fine needle aspiration of this retroperitoneal mass was positive for malignant cells and consistent with germ cell tumor etiology. The report stated that the findings were consistent with a seminoma.
Bone scan showed no evidence of osseous metastatic disease. Given the high risk of brain metastasis, an MRI of the brain was obtained and was negative for metastatic disease.
He was transferred to another hospital for further management of his advanced testicular cancer. Repeat LDH was 782 IU/L, AFP was 8,992 ng/mL and B-hCG was 53 mIU/mL, confirming the tumor to be a nonseminomatous germ cell tumor. Pulmonary function testing was performed and showed decreased diffusion capacity.
After staging, it was determined that he had advanced-stage testicular cancer with intermediate risk. Physical exam on presentation was significant for BP (184 mm Hg/118 mm Hg), with vitals otherwise within normal limits. Exam revealed a systolic ejection murmur and 20 cm hard scrotal mass with loss of anatomical differentiation between the scrotum and the penis with 3+ bilateral lower extremity pitting edema.
Urology was consulted and recommended induction chemotherapy and consideration of surgical consolidation after chemotherapy. The case was discussed extensively at tumor board. The consensus was that cisplatin-based chemotherapy is an essential component of potentially curative treatment, so the planned treatment included reduced-dose etoposide and cisplatin with aggressive IV hydration along with renally dosed allopurinol given the bulk of the tumor.
This case presented a challenge involving the initial management and treatment of a male with advanced-stage nonseminomatous testicular cancer with intermediate risk.
Potentially curative chemotherapy typically includes cisplatin, which is nephrotoxic, and bleomycin, which may cause pulmonary interstitial fibrosis. This patient’s presentation with a large tumor burden, as well as renal impairment and lung impairment in the form of decreased diffusion capacity of unknown etiology, potentially limited the options available to him for chemotherapy.
Treatment for this patient typically would involve four cycles of bleomycin, etoposide and cisplatin (BEP). Given this patient’s decreased lung diffusion capacity, bleomycin was not an option. Also, given the nephrotoxic effects of cisplatin, the issue arises how to best treat patients with renal insufficiency using this drug.
Testicular cancer has become one of the most curable solid neoplasms, with the current 5-year survival rate more than 95%. This is in large part due to the effective chemotherapeutic regimens available. A mainstay of this treatment in germ-cell tumors is cisplatin-based chemotherapy, which has been shown to offer cure, even in patients with advanced-stage disease, including visceral metastasis and elevated tumor markers.
The use of cisplatin in patients with renal impairment is complex. Cisplatin offers substantial opportunity for cure in testicular cancer; however, it also is one of the most nephrotoxic drugs. The nephrotoxicity from cisplatin is due to damage to renal tubules, and the toxicity appears to be related to the unbound plasma compound. Factors contributing to the likelihood of cisplatin-induced nephrotoxicity are high-peak plasma-free platinum concentrations, previous cisplatin therapy, renal impairment and use of other nephrotoxic drugs. Impaired renal function can result in delayed drug excretion, which may result in increased rates of systemic toxicity.
Unfortunately, there is no definitive approach to the use of cisplatin in patients with underlying renal insufficiency, as most clinical trials typically exclude patients with significant renal failure. There are many different approaches to this problem.
One of the main strategies to prevent nephrotoxicity relies on adequate sodium chloride hydration. This is essential for all patients treated with cisplatin. The optimal hydration solution and regimen to prevent cisplatin-induced nephrotoxicity is still unclear, however. No studies have directly compared different regimens or types of IV fluids in a prospective, randomized fashion. Standard practices often include saline infusion before and after the cisplatin to maintain a urine flow of at least 100 mL/hour for the 2 hours before and 2 hours after the infusion. Diuretics such as furosemide also may be used during this time to ensure adequate urine output.
Another option to prevent nephrotoxicity, especially in a patient with pre-existing renal impairment, is dose reduction. Similar to IV hydration, there are no definitive guidelines and no FDA-approved dosing reduction guidelines for cisplatin. There are limited data that suggest cisplatin can be given to patients with renal impairment in reduced dosing.
These recommendations vary. Some include a dose reduction of 50% for a creatinine clearance of 10 mL/minute to 50 mL/minute, whereas others have used a 25% dose reduction for a creatinine clearance of 46 mL/minute to 60 mL/min and a 50% dose reduction for a creatinine clearance of 31 mL/minute to 45 mL/minute. There also are reports of cisplatin being successfully used in patients who are undergoing dialysis treatment.
Besides adequate hydration and dose reduction, many other drugs have been evaluated to investigate potential protection from nephrotoxicity. Despite this, there still are no recommended agents.
One agent that has been used, amifostine, is an organic thiophosphate that may provide some protection from cisplatin-induced nephrotoxicity due to the donation of a protective thiol group. Treatment with amifostine before cisplatin administration decreased nephrotoxicity in animal models and preliminary clinical studies. In clinical practice, however, it is not commonly used due to its potential for negative side effects, including nausea, vomiting and hypotension, reports of Stevens-Johnson syndrome and toxic epidermal necrolysis, and the costs associated with its administration. There also are concerns about possible interference with the antitumor efficacy of cisplatin.
Other chemopreventive agents that have been investigated but are not commonly used include sodium thiosulfate, N-acetylcysteine and theophylline.
There is hope that promising new drugs with reduced nephrotoxicity may become available soon. One such example is liposomal cisplatin, which in clinical trials appears to have reduced nephrotoxicity.
As can be demonstrated from this case, current chemotherapeutic regimens offer significant opportunity for cure in a number of cancers. These treatments, however, inherently carry their own toxicities, which must be weighed against the individual patient and any coexisting medical problems they may have. As always, the risk vs. benefit of a treatment compared with potential toxicities must be evaluated. In this case, the chance for cure that cisplatin offers was significant enough that it was deemed an essential component of treatment, despite this patient’s pre-existing renal impairment.
Tim McCarthy, MD, is an internal medicine resident physician at Robert Wood Johnson Medical School in New Brunswick, N.J. He will be starting his fellowship in hematology/oncology this summer at the University of North Carolina at Chapel Hill. Disclosure: Dr. McCarthy reports no relevant financial disclosures.
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