Managing renal cell carcinoma

Dr Christian Kollmannsberger from the Vancouver Cancer Centre and British Columbia Cancer Agency recently visited Australia. He reviewed the current therapeutic options for renal cell carcinoma and provided a perspective on new and emerging therapies. Dr Kollmannsberger made particular mention of strategies to optimise patient management by managing treatment toxicity and by avoiding unnecessary dose reductions or early treatment termination.

A Canadian perspective

Reviewing the latest sunitinib data, Dr Kollmannsberger reported that the objective response rate in the first line setting was 47% with approximately 90% of patients gaining some form of tumour control.¹ "This translates into a significant progression free survival benefit and a median overall survival of more than two years and as a consequence has changed the treatment paradigm for metastatic renal cell carcinoma," he said.¹

Further, the safety profile of sunitinib has been reinforced by the sunitinib expanded access program of almost 4,000 patients with metastatic renal cell carcinoma.¹

The incidence and type of adverse events were consistent with those reported in the Phase III trial and there was no evidence of cumulative toxicity.⁵ Factors maximising patient outcomes on sunitinib are managing dosing, treatment duration and side effect management.

"Unlike the case of chemotherapy given over relatively short periods, sunitinib is given as continuous ongoing therapy. This means that managing adverse events is critical. The aim is to strive for continued treatment on sunitinib to optimise the chance for improved survival."⁶

Evaluating the side effect profile for sunitinib in the phase II and III studies shows the number of patients with severe side effects was low with the more clinically relevant adverse events being fatigue, gastrointestinal side effects, skin toxicity, hypertension and hypothyroidism.¹

Cardiotoxicity, extensively discussed in the recent literature, appears to occur infrequently and in most cases does not translate into clinically relevant heart failure.²

"While between 50% and 70% of patients complain about fatigue, actually only 7% to 11% experience severe fatigue.² It’s important oncologists rule out other causes of fatigue including dehydration, anaemia, depression, hypercalcaemia and hypothyroidism. Treatment is symptom oriented and includes nutritional support and encouragement of patient activity.^1,2

"Hypothyroidism is an important side effect," he said. "85% of patients had abnormal results on one or more thyroid function tests. This can range from elevated thyroid stimulating hormone (TSH) to full-blown thyrotoxicosis.² Approximately 50% of patients treated with hormone replacement therapy may experience an improvement of symptoms and in general hypothyroidism does not limit sunitinib therapy.^2,7

"With skin rash, my approach is usually to interrupt treatment in severe cases but continue with the same dose level once the rash has improved. Many patients seem to adapt to the drug and the skin rash gradually subsides. In terms of overall toxicity it’s important to include patients in the side effect management process. This way they can actively avoid factors linked to specific adverse effects. When patients are counselled to recognise side effects and alert the oncologist, we can step onto the front foot and intervene early,"² Dr Kollmannsberger said.

In terms of cardiovascular effects, hypertension is a class effect of antiangiogenic agents. "While it can occur within days of initiating treatment, it is easily managed with antihypertensive agents in the vast majority of cases. Sunitinib has also been found to cause a decrease in left ventricular ejection-fraction. It is mostly reversible, treatable and so far has rarely been reported to be life-threatening."²

Sunitinib dose response does impact patient survival.^1,3 "We know that in order to achieve target inhibition we need certain plasma concentrations of sunitinib and the probability of response increases with the higher the level of dose given. Patients who can tolerate higher doses have higher plasma levels and better outcomes than those patients on lesser doses of sunitinib.²

"The relationship between sunitinib and efficacy demonstrates it is important to maintain a good dose level over a prolonged period of time and not make dose reductions lightly. Stopping sunitinib therapy may cause significant tumour regrowth and lowering a dose too far can mean there is not enough drug onboard to achieve complete receptor inhibition."²

In terms of accumulation of particular side effects, Dr Kollmannsberger says there is no evidence over the time the drug has been studied to show side effect accumulation and instead the problem is managing the coexistence of several different side effects that all impact together can make life difficult for the patient.^1,2

"The key to managing and preventing side effects is to screen for early signs, initiate treatment early on in order to optimise outcomes and educate and involve patients so they may participate in their own treatment management.

"Optimal management of renal cell carcinoma is to start sunitinib at 50 mg/day using a 4 week on and 2 week off drug schedule and maintain therapy as long as clinical benefit is observed. Sunitinib is an active agent that has significantly changed the way we treat kidney cancer and has opened up a new dimension in the lives of these patients."^1,2

References

1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27(22):3584-90.
2. Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R, Bjarnason G. Sunitinib therapy for metastatic renal cell carcinoma: Recommendations for management of side effects. Can Urol Assoc J. 2007; 1(2 Suppl):S41-54.
3. Houk BE, Bello CL, Michaelson MD, Bukowski RM, Redman BG, Hudes GR, et al. Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol. 2007; 25:(18 Suppl):5027.
4. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Eng J Med. 2007; 356(2):115-24.
5. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: An expanded-access trial. Lancet Oncol. 2009; 10(8):757-63.
6. Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008; 13(9):1001-11.
7. Desai J, Gurney H, Pavlakis N, McArthur G, Davis I. Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor. Asia Pac J Clin Oncol. 2007; 3:167-76.
8. Rixe O, Billemont B, Izzedine H. Hypertension as a predictive factor of sunitinib activity. Ann Oncol. 2007; 18(6):1117.

(Source: Pfizer: Pfizer Oncology Update: March 2010)