Written Summary: Urology, 32:07 - RENAL CANCER: CURRENT DATA AND CONCEPTS

Main Written Summaries Listing | Urology: 2009 Listings

Volume 32, Issue 07

July 1, 2009

The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program. If, after reviewing this written summary, you would like to hear the contents and/or earn CME/CE credit, simply visit the Audio-Digest Foundation website

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Renal Cancer: Current Data and Concepts

Educational Objectives

The goal of this program is to improve the treatment of renal cell carcinoma (RCC). After hearing and assimilating this program, the clinician will be better able to:

1. Cite recent data documenting an increase over time of the percentage of newly diagnosed RCC patients who present with stage I disease.

2. State the overall therapeutic goal in the management of advanced RCC.

3. Discuss data on targeted therapy in RCC with regard to objective response rates (ORR), progression-free survival (PFS) and overall survival (OS).

4. Explain the rationale for considering initial observation of patients with advanced RCC and identify those who are appropriate candidates for this approach.

5. Describe the evidence supporting the use of cytoreductive nephrectomy before systemic therapy in advanced RCC and explain the advantages of laparoscopic vs open procedures.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Kane is on the Speaker’s Bureau of Boehringer Ingelheim Pharmaceuticals, and has received honoraria from Intuitive Surgical. Dr. Rini is a consultant for and has received research funding from Pfizer, Wyeth, Genentech, and Bayer HealthCare. Dr. Rini presents information related to off-label or investigational use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Kane was recorded at the University of California, San Diego, School of Medicine Urology Postgraduate Course, held February 20-21, 2009, in La Jolla, CA. Dr. Rini spoke at the 8th Annual Multidisciplinary Genitourinary Oncology Course, held November 13, 2008, in Cleveland, OH, and presented by the Cleveland Clinic Taussig Cancer Institute and Glickman Urological and Kidney Institute. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Stage Migration and Practice Trends

Christopher J. Kane, MD, Professor, Department of Surgery and Chief, Division of Urology, University of California, San Diego, School of Medicine

Epidemiology of kidney cancer: ≈50,000 new cases and ≈12,000 deaths/yr; incidence higher in blacks and in men (twice as common as in women); study by Katz et al (1994) reported “dramatic” increase in incidence from 1930s to 1980s; study by Hock et al (2002), which analyzed stage migration and incidence of kidney cancer from 1985 to 1998, first appeared to show increase in localized disease and decrease in advanced disease; however, more careful analysis of Surveillance Epidemiology and End Results (SEER) database shows that although localized disease increasing fastest, regional disease increasing also, and advanced disease remaining stable or increasing slightly (ie, increase in diagnosis of small renal masses not diminishing increased incidence of regional and advanced disease); some data indicate increase in kidney cancer mortality over last 20 yr

Analysis of National Cancer Data Base (NCDB): study by speaker et al looked at diagnostic and surgical stage migration of renal cell carcinoma (RCC) over 12-yr period; NCDB queried for adults diagnosed with RCC between 1993 and 2004; comparison of 1993 and 2004 data showed dramatic increase in newly diagnosed stage I disease, and decrease in stage IV and III disease (stage II relatively constant); mean size of stage I tumors decreased from ≈4.2 cm in 1993 to ≈3.4 cm in 2003; data also showed that percentage of stage I tumors <3 cm increased (>40% in 2003), and 25% of these were <2.0 cm; stage and survival data — 5-yr relative survival rate ≈92% for stage I disease, ≈85% for stage II, ≈78% for stage III, and ≈10% for stage IV; in multivariate analysis of data (looking at stage, histology, and age), stage, but not histology, strongly predicted relative survival; 3.3% improvement in overall relative survival found for patients diagnosed in 1998 vs 1993

Utilization of nephron-sparing surgery: analysis of NCDB data showed increasing use of partial nephrectomy in management of stage I disease; however, this type of surgery still significantly underutilized nationally; interstitial therapy also not highly utilized; speaker feels that stage and size migration should drive more liberal use of nephron-sparing surgery

Managing Renal Cell Carcinoma

Brian I. Rini, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Staff Member, Department of Solid Tumor Oncology and Associate Director for Clinical Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Overall therapeutic goal: to optimize timing and type of therapy so that lethal tumor burden delayed as long as possible while patient has maximal quality of life and convenience

Role of debulking nephrectomy: in 2 large prospective randomized trials, patients with metastatic clear-cell RCC randomized to radical nephrectomy plus low-dose interferon-alpha (IFN-a) or IFN-a alone; nephrectomy associated with ≈6 mo improvement in overall survival; speaker suggests that, in appropriately selected patients, nephrectomy should be standard of care; criteria for cytoreductive nephrectomy —>75% debulking of tumor burden possible; no metastases in central nervous system (CNS) or liver; adequate pulmonary and cardiac function; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; predominantly clear cell histology; the more tumor removed with debulking, the better the outcomes

Molecular biology of RCC: normal physiology consists of normal oxygen concentration and normal Von Hippel-Lindau (VHL) tumor suppression gene; in 60% to 80% of sporadic cancers (or in inherited cancers), VHL tumor suppressor gene inactivated; this results in accumulation of hypoxia-inducible factor (HIF) in nucleus of cell, causing upregulation of HIF target genes (eg, vascular endothelial growth factor [VEGF]; platelet-derived growth factor [PDGF]); overproduction of VEGF characteristic feature of RCC; drugs that combat this include VEGF ligand-binding agents (eg, bevacizumab) and small molecules (eg, sunitinib, sorafenib); mammalian target of rapamycin (mTOR) pathway — also important in RCC; activated by variety of cellular stimuli; downstream events include overproduction of HIF

Targeted systemic therapies: immunotherapy — includes cytokines (eg, high-dose interleukin [IL]-2; low-dose IL-2, or IFN-a; associated with modest objective response rates (ORR), progression-free survival (PFS; 3-5 mo) and overall survival (OS; »1 yr); little data on tumor burden reduction; reasons for patients to get cytokines include small complete remission (CR) rate with IL-2 in highly selected patients; enrollment in clinical trial recommended; small-molecule inhibitors of VEGF and related receptors — sunitinib has highest ORR (≈47% in recent phase III trial); sorafenib has much lower ORR; each causes some tumor burden reduction in 70% to 75% of patients; recent data suggest that treatment with either agent improves OS; bevacizumab — modest ORR as single agent; much higher ORR when combined with IFN-a; tumor burden reduction consistent with other agents; PFS in more recent trials similar to sunitinib in front-line patients; data on OS not yet available); mTOR inhibiting agents — temsirolimus, everolimus; very modest ORR; not much data on tumor burden reduction; temsirolimus only mTOR inhibitor to show OS benefit (in modified poor-risk patients); everolimus tested in highly treatment-refractory population showed PFS benefit compared to placebo

When to start therapy: most patients who present with metastatic RCC require therapy in relatively near future; however, ≈5% to 10% of patients have indolent disease (RCC extremely biologically diverse); these patients have inherent control of tumor burden and do not require immediate systemic treatment; possibly best served in long run with initial period of observation; data from randomized discontinuation trial of sorafenib suggests that clinical benefit of targeted therapy same if delayed for period of observation

Which patients should be observed: limited modern data; patients with good PS and “low volume,” slow growing, asymptomatic disease are candidates (after discussion of risk and benefits) for period of initial observation; patients with bulky symptomatic disease not candidates for observation; retrospective and prospective studies under way looking at tumor burden and at progression of disease in patients placed on uniform observation protocol

Management strategies in advanced RCC: major trials have looked at bevacizumab plus IFN-a vs IFN-a alone, sorafenib vs placebo, sunitinib vs IFN-a, and temsirolimus vs IFN-a; studies done in different patient populations; most for first-line therapy; most patients had previous nephrectomy; Memorial Sloan-Kettering Cancer Center risk group stratification varied widely between studies; studies had differing histology requirements

Choosing therapy based on response rate: sunitinib has highest ORR; all other agents tested have had ORR in range of ≈10% when given as monotherapy; tumor shrinkage rate relatively uniform across studies; for those patients who require immediate treatment, and as much tumor burden shrinkage as possible, sunitinib most reasonable initial choice

Choosing therapy based on histology: clear cell biology supports VEGF-targeted therapy; clinical trials almost entirely restricted to clear cell cancers (very limited data on non-clear cell histologies); data from retrospective single-institution study — patients with metastatic papillary or chromophobe RCC received either sunitinib or sorafenib as initial treatment; results showed very modest ORR (slightly better response with sunitinib)

Optimizing therapies: 30% to 40% of patients experience significant drug-induced toxicities, including fatigue, hand-foot skin reaction, diarrhea, mucositis, and hypertension; important to educate medical team on how to manage toxicities and help get patients through treatment; many toxicities unique and mandate unique management (eg, hypothyroidism seen with sunitinib does not occur as often with sorafenib but easily managed and must be recognized; interstitial pneumonitis with mTOR inhibitors needs better description); cytopenias usually not major problem (thrombocytopenia can be dose limiting; requires dose interruption if severe)

When to stop therapy and what to do next: maximize each individual treatment (ie, avoid giving up too soon if there is benefit remaining, but do not continue therapy if only result is toxicity); Response Evaluation Criteria in Solid Tumors (RECIST) wholly inadequate in categorizing response or progression; RECIST uses arbitrary thresholds, eg, ≈30% tumor reduction to designate partial responders; response on continuum, and little difference between patients on either side of threshold; recent study of sorafenib found no correlation between amount of tumor reduction and PFS; patterns of tumor response (examples from original bevacizumab trial) and challenges they present to treatment

Reasons for drug failure: physiologic resistance — (eg, reduced absorption, increased clearance), indicating need for dose modification (eg, dose escalation, re-escalation) or rechallenge with same drug after holiday; pharmacodynamic problem — fundamental shift to alternative tumor-promoting pathway, which would require change in agents and/or change in target

Prospective trials of sequential targeted agents: phase II trials have reported reasonable (≈20%) ORR with sunitinib (for bevacizumab-refractory patients) and axitinib (for sorafenib-refractory patients); tumor shrinkage has varied in studies; recent phase III trial reported relatively large benefit with everolimus (in patients refractory to sunitinib, sorafenib, and other agents); 2 large phase III trials have started globally (temsirolimus vs sorafenib in sunitinib-refractory patients; axitinib vs sorafenib in front-line refractory patients)

RCC treatment algorithm: untreated patients — level 1 evidence (from phase III trials) supports use of sunitinib and bevacizumab plus IFN-a in low- to intermediate-risk patients, temsirolimus in poor-risk patients; other options (based on level 2 evidence) include observation or clinical trial; refractory patients — rarely see cytokine refractory patients now, but do see VEGF- and mTOR-refractory patients; everolimus only drug for which level 1 evidence supports its therapeutic use; tumor burden — sunitinib most effective at reducing tumor burden

Conclusions: overall goal in RCC to prevent patients from dying from their cancer, which translates into optimal control of tumor burden; debulking nephrectomy standard of care until proven otherwise (appropriate patient selection key); VEGF and mTOR pathways biologically relevant in RCC; optimal timing of systemic therapy in advanced RCC unknown and should be studied prospectively; decisions about resistance and next therapy largely empiric (based on limited data); clinical trials remain priority

Questions from audience: does speaker prefer administering sunitinib intermittently or on low-dose daily basis?, do patients better tolerate continuous sunitinib therapy?, relative merits of bevacizumab-INF vs sunitinib; possible randomized trial of bevacizumab-INF vs sunitinib

Laparoscopic Nephrectomy: High Risk and Advanced Disease

Dr. Kane

Introductory remarks: current controversy about timing and utility of nephrectomy; major objections to initial cytoreductive nephrectomy in patients with advanced RCC is significant perioperative morbidity and possible delay in induction of systemic therapy (largely based on small studies from mid 1990s in which significant percentage of patients did not go on to systemic therapy and had rapid tumor progression)

Clinical trials: 2 large prospective randomized trials supporting cytoreduction (2004) — ≈331 patients with metastatic RCC randomized to cytoreductive nephrectomy plus IFN-a vs IFN-a alone; median survival ≈13.6 mo for nephrectomy plus IFN-a vs ≈7.8 mo for IFN-a alone; nephrectomy appeared to improve OS independently of patient PS, site of metastasis, and measurability of disease; combined analysis of studies concluded that cytoreductive nephrectomy before systemic therapy beneficial for patients with good ECOG PS [defined as <2] and with resectable primary tumor with limited morbidity; recent single-institution study suggests that patients with better ECOG PS do best after cytoreduction

Role of laparoscopic nephrectomy (speaker’s experience): has used laparoscopic nephrectomy for cytoreduction of large lesions with vascular or regional spread; 4-port transperitoneal technique; also used approach with curative intent in 45 patients who had larger renal masses, but did not have advanced cancer; in higher-stage cohort, mean diameter of tumor ≈9 cm, patient age ≈62 yr, operative time >4 hr, and blood loss ≈200 mL; 1 open conversion early in series; in curative intent group, ≈3 patients with disease recurrence, no isolated local recurrence, ≈1 cancer-specific death, and ≈93% cancer free survival with mean follow up of ≈47 wk; comparison of laparoscopic vs open cytoreduction — done in patients with known metastases, and performed without curative intent; performed ≈12 open vs ≈16 laparoscopic procedures during period of review; operative time slightly shorter, and blood loss significantly less in laparoscopic group; percentage receiving transfusions, amount of blood transfused, pain, and number of hospital days all significantly favored laparoscopic cohort; no difference in patient survival

Comments: similar data reported in studies from MD Anderson Center (found laparoscopic nephrectomy could be done safely and was reasonable approach in well-selected patients with good PS); and from Cleveland Clinic group (found laparoscopic nephrectomy associated with lower blood loss, shorter length of stay, and earlier systemic therapy than open procedure)

Conclusions: cytoreductive nephrectomy prior to systemic therapy is appropriate and beneficial for majority of patients with advanced RCC; most nephrectomies can be performed laparoscopically with less morbidity; indications for open radical nephrectomy are midline encroachment of mass, extensive regional adenopathy and inferior vena cava thrombus