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PRIORITY PRESS - 15th European Cancer Conference and 34th ESMO Multidisciplinary Congress

Berlin, Germany / September 20-24, 2009

Key growth factors involved in the pathogenesis of renal cell carcinoma (RCC) include vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). According to Dr. Bernard Escudier, Head of Immunology, Institut Gustave-Roussy, Villejuif, France, several antiangiogenic agents including the tyrosine kinase inhibitors (TKIs) target the VEGF family of receptors as well as the PDGF receptor, and this is believed to be important for the maintenance and survival of new blood vessels. Located downstream of VEGF activity is the mTOR enzyme, critical to relaying the angiogenic message. “The mTOR inhibitors, including temsirolimus and everolimus, bind to intracellular mTOR and inhibit its activity, thereby turning down cell growth, proliferation, metabolism and cell survival, so it is a very good target in RCC,” Dr. Escudier stated.

The pivotal phase III trial comparing temsirolimus to interferon-alpha (IFN-a) indicated that patients with metastatic RCC had a median progression-free survival (PFS) of 5.5 months on mTOR inhibitor therapy compared with a median PFS of 3.1 months for the IFN-a arm (P<0.001). Median overall survival (OS) was 10.9 months and 7.3 months for the two arms, respectively (P=0.008), for a 49% improvement in OS in favour of the mTOR inhibitor arm (Hudes et al. N Engl J Med 2007;356:2271-81). Based on these findings, temsirolimus is now recommended in Canada as first-line treatment for metastatic RCC in poor-risk patients. In the US, the mTOR inhibitor everolimus is indicated for advanced RCC in patients whose disease has progressed on or after treatment with VEGF-targeted therapy.

Management of Treatment-emergent Adverse Events

If the therapeutic armamentarium has greatly expanded for metastatic RCC in the past decade, physicians are still learning how best to maximize treatment response and minimize treatment-related toxicities. The most predominant adverse events (AEs) in clinical trials of temsirolimus include asthenia, fatigue, dyspnea, rash, facial and peripheral edema, mucositis and nail problems. Patients on mTOR inhibitor therapy can also develop certain metabolic abnormalities, most notably hyperglycemia. Conversely, significant hematologic toxicity is relatively rare with mTOR inhibitor therapy. As Dr. Escudier indicated, these AEs are essentially a class effect and need to be both anticipated and dealt with promptly if they occur.

When caring for patients receiving mTOR inhibitor therapy, oncology nurse Clementine Molin, Karolinska University Hospital, Stockholm, Sweden, reminded delegates that patients first need to be assessed for their ability to receive intravenous (i.v.) treatment peripherally as many may require central i.v. access. An in-line filter should be used during administration and an infusion pump is recommended. “One of the important side effects [during infusion] is a hypersensitivity reaction, which is mostly grade 1 and 2,” she explained. In anticipation of this reaction, patients should be made aware that they may experience flushing or a sensation of warmth, headache, chest pain, cough, shortness of breath or rash during infusion. Emergency equipment should be kept ready in case the reaction is severe and antihistamines (diphenhydramine 25 to 50 mg) should also be given prophylactically 30 minutes prior to administering temsirolimus.

Ms. Molin also reminded delegates that asthenia and fatigue can be caused by both the disease and the treatment. To minimize these, patients should be counselled to adjust their activities to allow for adequate rest, to maximize fluid and caloric intake, and to use enteral supplements if caloric intake from the diet is inadequate. They need to know that eating little but often can help counter nausea or taste changes as well. Hemoglobin (Hb) levels should also be monitored throughout treatment, as Ms. Molin noted, and any sign of anemia corrected.

Delegates generally agreed that rash, typically on the thorax and neck, is usually fairly mild with mTOR inhibitor therapy. Nevertheless, patients can be bothered by it, as Ms. Molin observed, and daily use of unscented moisturizers starting with the first infusion may help prevent or lessen rash. “Patients also need to be educated about the potential for facial or peripheral edema,” she noted. A short course of corticosteroids may be required to resolve the edema.

Mucositis, again mostly low grade, can also occur with targeted therapies. Here, preventive strategies including avoidance of spicy food, the use of antiseptic (though not astringent) mouthwash or topical treatment with lidocaine or xylocaine may lessen the discomfort. The Karolinska University Hospital also recommends patients use a mouthwash with bicarbonate and some patients report relief when they hold cold milk or cream in their mouths for brief intervals of time.

In the Global ARCC trial, 11% of patients who received temsirolimus developed grade 3 to 4 hyperglycemia, so blood glucose levels should be monitored throughout treatment and antihyperglycemic agents initiated if blood glucose levels become significantly elevated. Elevated lipids also can occur with mTOR inhibitor therapy.

While in theory, elevated cholesterol levels are less of a concern in the setting of metastatic disease, some patients do develop exceptionally high cholesterol levels on mTOR inhibitor therapy and require treatment, as Ms. Molin indicated. “In general, temsirolimus has a manageable side-effect profile and most side effects can be medically managed or addressed with supportive measures,” she remarked. She concluded that the weekly i.v. dosing regimen for temsirolimus allows oncology nurses to serve as the patient’s primary point of contact and educational resource while undergoing treatment for advanced RCC.

Quality-of-Life Assessment

According to a quality-of-life (QoL) analysis, IFN-a AEs are harder for patients to tolerate than those associated with mTOR inhibitor therapy. As presented by clinical investigator Dr. Joseph Purvis, Collegeville, Pennsylvania, 270 patients out of a total of 416 randomized into the comparative trial between temsirolimus and IFN-a were evaluable for QoL measures, as assessed by the EQ5D index. The EQ5D score reflects symptoms from both treatment and disease, both of which affect QoL. To be eligible, patients were required to have an EQ5D assessment at baseline, at week 12 and at last visit after week 12. Some 95% of patients in the study had at least three adverse prognostic factors and their mean EQ5D score at baseline was 0.62.

Controlling for baseline co-variates, the analysis indicated that the least square means for on-treatment EQ5D in the IFN-a arm was 0.492 vs. 0.590 for the mTOR inhibitor arm—a difference between the two considered both clinically and statistically significant (P=0.0022).

“We already know that temsirolimus provides a survival and PFS advantage over IFN-a in this patient population so the question was, was that difference obtained at a price of increased toxicity?” Dr. Purvis said in an interview. The answer, based on EQ5D measurements, was that treatment with this particular mTOR inhibitor was associated with a significantly better QoL than the cytokine-based treatment.

In a related analysis presented here at ECCO-ESMO, Rajagopalan et al. reanalyzed patients in the Global ARCC trial who required hospitalization due to an AE. A total of 144 AE-related hospitalizations were observed in the trial—80 in the IFN-a arm and 64 in the mTOR inhibitor arm, or a 44% lower risk of hospitalization for an AE in favour of the mTOR inhibitor arm (P=0.0005). The mean time to first hospitalization was also significantly longer for mTOR inhibitor patients at 97.6 days vs. 48.4 days for the IFN-a arm. As investigators noted, the median time to first hospitalization for mTOR inhibitor patients could not be calculated because more than 50% of them were not hospitalized during the follow-up interval. In contrast, the median time to first hospitalization for those randomized to the cytokine arm was 266 days.

Summary

Targeted agents including the TKIs and mTOR inhibitors have dramatically changed the outlook for patients with metastastic RCC in terms of overall response rates, PFS and OS. At the same time, good management dictates that physicians possess a thorough understanding of how these agents can adversely affect patients and try to anticipate and minimize the risk of unwanted AEs. As experience with these novel agents grows, it can be expected that patients with metastatic RCC will enjoy not only prolonged survival but a better QoL than was previously possible with cytokine-based therapies, both important considerations in the setting of metastatic disease.