Evidence-Based Clinical Practice Guideline for Renal Cell Carcinoma: The Japanese Urological Association 2011 update

Abstract

Remarkable advances have been made in medical practice in relation to renal cell carcinoma in recent years, and a large amount of new evidence has been accumulated. In keeping with the plan at the time the first version of the “Evidence-Based Clinical Practice Guideline for Renal Cell Carcinoma” compiled by the Japanese Urological Association was published in 2007, the Japanese Urological Association has just published a revised 2011 version. The main revisions regard the selection of treatment methods according to prognostic factors, reconsideration of treatment methods for small-diameter renal cell carcinoma and selection criteria for medical treatment of advanced renal cell carcinoma, including selection of neoadjuvant treatment with molecular targeted medicines. This Guideline presents clinical practice methods that are thought to be the most standard methods in Japan at the present time. In this English translation of a shortened version of the original Guideline, we cited particularly important clinical questions and references.

Abbreviations & Acronyms

CQ =

clinical questions

CRP =

C-reactive protein

CT =

computed tomography

ESR =

erythrocyte sedimentation rate

IFN-α =

interferon-α

IL-2 =

interleukin-2

JUA =

Japanese Urological Association

MSKKC =

Memorial Sloan-Kettering Cancer Center

mTOR =

mammalian target of rapamycin

PET =

positron emission tomography

RCC =

renal cell carcinoma

RFA =

radiofrequency ablation

TKI =

tyrosine-kinase inhibitor

Introduction

There have been remarkable advances in clinical practice in regard to RCC, and this situation has made it difficult for healthcare providers and patients to continually keep apprised of the latest and best clinical practice. The purpose of the “Clinical Practice Guideline” is to support healthcare practitioners engaged in practice in the field and patients, and revisions at relatively short intervals are desirable. A summary of the “Evidence-Based Clinical Practice Guideline for Renal Cell Carcinoma, 2007” was published in 2009.¹ As a great deal of evidence was accumulated in Europe, the USA and Japan after the publication of the 2007 version, we revised the original Japanese version. We describe the main revision points in the present article.

1. Background and methods used to draft the revised Guideline

Our application to the JUA to undertake the project of revising the “Evidence-Based Clinical Practice Guideline for Renal Cell Carcinoma, 2007” was approved in 2010. The members of the committee to draft the revised Guideline were selected and the number was increased, and the “Committee to Draft of the Evidence-Based Clinical Practice Guideline for Renal Cell Carcinoma, 2011,” which included medical oncologists and radiologists, in addition to urologists, was formed (Table 1).

Table 1.  Committee members of the Clinical Practice Guideline for Renal Cell Carcinoma – JUA 2011

Chairperson	Tomoaki Fujioka (Professor, Department of Urology, Iwate Medical University)
Vice-chairperson	Tsuneharu Miki (Professor, Department of Urology, Kyoto Prefectural University of Medicine)
Committee members	Hideyuki Akaza (Professor, Department of Strategic Investigation on Comprehensive Center Network Research Center for Advanced Science and Technology, the University of Tokyo)
	Masatoshi Eto (Professor, Department of Urology, Graduate School of Medical Sciences, Kumamoto University)
	Seiichiro Ozono (Professor, Department of Urology, Hamamatsu University School of Medicine)
	Yoshihiro Ogawa (Chief director, SENDAI Radiation Oncology & Imaging Clinic)
	Yoshiyuki Kakehi (Professor, Department of Urology, Kagawa University School of Medicine)
	Hiroomi Kanayama (Professor, Department of Urology, Institute of Health Biosciences, Tokushima University Graduate School of Medicine)
	Nobuo Shinohara (Associate Professor, Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University)
	Taro Shuin (Professor, Department of Urology, Kochi University School of Medicine)
	Shunji Takahashi (Director, Department of Medical Oncology and Hematology, Cancer Institute Hospital of Japanese Foundation for Cancer Research)
	Yoshihiko Tomita (Professor, Department of Urology, Yamagata University Graduate School of Medicine)
	Seiji Naito (Professor, Department of Urology, Graduate School of Medical Sciences, Kyusyu University, Chairman of Japanese Society of Renal Cancer)
	Norio Nonomura (Professor, The Department of Urology, Osaka University Graduate School of Medicine)
	Isao Hara (Professor, Department of Urology, Wakayama Medical University)
	Yoshihiko Hirao (Professor, Department of Urology, Nara Medical University)
Supporting committee members	Takashige Abe (Assistant Professor, Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University)
	Tomoyuki Kato (Associate Professor, Department of Urology, Yamagata University Graduate School of Medicine)
	Katsunori Tatsugami (Associate Professor, Department of Urology, Graduate School of Medical Science, Kyushu University)
	Fumiya Hongo (Associate Professor, Department of Urology, Kyoto Prefectural University of Medicine)
	Souichi Mugiya (Associate Professor, Department of Urology, Hamamatsu University School of Medicine)
	Takeshi Yuasa (Director, Department of Urology Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research)
	Takahiro Wada (Associate Professor, Department of Urology, Graduate School of Medical Sciences, Kumamoto University)
Evaluation committee members	Kenjiro Kohri (Professor, Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences)
	Taiji Tsukamoto (Professor, Department of Urology, Sapporo Medical University School of Medicine)
Document retrieval	Shiro Hinotsu (Associate Professor, Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
Executive Office	Wataru Obara (Associate Professor, Department of Urology, Iwate Medical University)

The first step in drafting the revised Guideline was to review the CQ in the 2007 Guideline, and make changes and additions. As a result, a total of 24 CQ were reworded: two related to risk factors and prevention, five to diagnosis, nine to surgical treatment and local treatment, seven to systemic therapy, and one to follow up (Table 2). Key words to use for literature searches in regard to each CQ were also specified, and the 1996-to-2005 literature search period of the old version was extended to 2009. PubMed and Japana Centra Revuo Medicina Web were used to carry out the searches, and a structured abstract was prepared for each reference that was selected. If any of the most recent documents in the literature – that is, those published after the end of the search period – were judged to be essential to the Guideline, they were added at the discretion of the members of the drafting committee.

Table 2.  Clinical questions

Risk factors/prevention	CQ1: Is it recommended to call attention to obesity, occupations, lifestyle habits, environment and genetic factors with respect to development of RCC?
	CQ2: What are the types of examinations that are useful for early detection of RCC?
Diagnosis	CQ3: Are screening tests for RCC recommended in dialysis patients?
	CQ4: What should the next examination be when any renal tumor is detected during a routine medical examination or complete medical check?
	CQ5: Are chest CT, bone scintigraphy and PET recommended for the staging of RCC?
	CQ6: Are measurements of the ESR and CRP as prognostic factors recommended in cases of RCC?
	CQ7: Is it recommended that the treatment method for metastatic advanced renal cell carcinoma be selected on the basis of prognostic factors?
Surgical treatment/local treatment	CQ8: Is laparoscopic nephrectomy recommended for stage I or II RCC?
	CQ9: Is partial nephrectomy recommended in patients with RCC measuring up to 4 cm in diameter (T1a)?
	CQ10: Is nephrectomy recommended in patients with metastatic RCC?
	CQ11: Is lymph node dissection recommended during radical nephrectomy?
	CQ12: Is resection of the adrenal on the affected side recommended during nephrectomy in RCC patients?
	CQ13: Is tumor thrombectomy recommended in RCC patients with an inferior vena cava thrombus?
	CQ14: Are surgical treatments recommended for metastatic foci?
	CQ15: Is percutaneous local treatment recommended for small renal cell carcinomas?
	CQ16: Is radiation therapy recommended for the treatment of metastatic loci?
Systemic treatment	CQ17: Is monotherapy with cytokines, including IFN-α or IL-2, recommended for treatment of patients with advanced RCC?
	CQ18: Is combined therapy with IFN-α + IL-2 or cytokine + molecular targeted medicine recommended for patients with advanced RCC?
	CQ19: Is neoadjuvant therapy with a molecularly targeted therapy recommended for renal cell carcinoma?
	CQ20: Are adjuvant cytokine therapies recommended for preventing tumor recurrence in patients who have undergone radical nephrectomy for the treatment of stage I or II RCC?
	CQ21: Is molecular targeted therapy recommended for patients with advanced renal cell carcinoma?
	CQ22: Is molecular targeted therapy recommended for cases of advanced renal cell carcinoma in which cytokine therapy is ineffective?
	CQ23: Is there any treatment that shows promise of being effective in cases of advanced renal cell carcinoma in which molecular targeted therapy is ineffective?
	CQ24: What is the appropriate protocol for follow up after radical nephrectomy?

The text of the Guideline was drafted in relation to each CQ, based on the structured abstracts, and the grade of recommendation was decided (Table 3). If the characteristics and so on of Japanese people are to be taken into consideration, literature from Japan should constitute the core of the evidence that forms the foundation for the recommendations. However, few large-scale randomized comparisons have been carried out in Japan, and, in view of its evidence level, literature from Western countries was used as the core. Thus, the possibility that this Guideline does not always reflect information from Japan cannot be denied.

Table 3.  Recommendation grade

	Five grades of recommendations from A to D were set based on agreement among the members of the committee for establishment of Clinical Practice Guidelines for the Management of Renal Carcinoma
A	Strongly recommended for implementation in routine clinical practice, because there is sufficient evidence.
B	Recommended for implementation in routine clinical practice, because there is some evidence.
C 1	Might be implemented in routine clinical practice, although there is insufficient evidence.
C 2	Not recommended for implementation in routine clinical practice, because there is insufficient evidence.
D	Not recommended for implementation in routine clinical practice, because there is evidence that it might be harmful to patients.

2. Principal revisions and the clinical questions

1) Reconsideration of prognostic factors, and treatment selection

Because opportunities to measure the ESR have decreased dramatically at many institutions, the ESR has not been used as a prognostic factor in the 2011 version. There have been many reports in regard to CRP in Japan,^2–5 and as there is evidence from many patients of the importance of preoperative CRP values as a prognostic factor and that the CRP value at the time metastasis is diagnosed is a significant prognostic factor in relation to overall survival rate, measurement of CRP is now recommended as an important examination before treatment. In addition, the 2011 version proposes that risk classification based on prognostic factors be taken into consideration when selecting medical treatment for advanced RCC.

CQ6: Are the ESR and CRP recommended as prognostic factors for RCC?

[Recommendation grade B] The ESR and CRP are important as prognostic factors for RCC, but in recent years there are many institutions that no longer measure ESR, therefore CRP is recommended as an examination before treatment.

CQ7: Is it recommended that the treatment method for metastatic advanced RCC be selected on the basis of prognostic factors?

[Recommendation grade B] There have been many reports in relation to prognostic factors for metastatic RCC, but few have mentioned them in relation to treatment selection. In view of a report on a risk factor classification that was devised based on a retrospective study in the cytokine era,^5–7 selection of the treatment based on prognostic factors is recommended.

2) Reconsideration of treatment methods for small-diameter renal tumors

The grade of recommendation of partial nephrectomy for small-diameter renal tumors is the same as in the 2007 version, but in the 2011 version it was decided to use the evidence of higher level for recommending partial nephrectomy as the standard treatment.^8–10 In addition, taking into account the medium-term results of treatment with RFA and cryoablation, and the clinical practice situation in Japan, in the 2011 version, RFA and cryoablation have been made the choices of treatment for cases in which curative treatment would be difficult.^11–17 In Japan, the cryosurgery was approved the insurance in July, 2011.

CQ9: Is partial nephrectomy recommended for the treatment of RCC patients whose tumor diameter is ≤4 cm (T1a)?

[Recommendation grade B] As its anticancer ability is equivalent to that of radical nephrectomy, and it is useful in terms of preserving of renal function and capable of reducing both the overall mortality rate and the non-cancer mortality rate, partial nephrectomy is recommended.

CQ15: Is percutaneous local treatment recommended for small RCC?

[Recommendation grade C1] RFA and cryoablation are recommended as percutaneous local treatments for small RCC when curative treatment would be impossible because of the patient's general condition or complications.

3) Place of cytokine therapy in the treatment of advanced RCC

In Western countries, where molecular targeted medicines are the mainstay of treatment for advanced RCC, the efficacy of cytokine therapy has been limited.¹⁸ In Japan, in contrast, long-term survival can be expected using cytokine therapy,⁴ and there have been reports of the efficacy of cytokine combination therapy with IFN-α and IL-2 against pulmonary metastasis after nephrectomy,^19,20 and even a report on STAT3 polymorphism analysis that can predict the therapeutic efficacy of IFN-α therapy.²¹ Therefore IFN-α has been left as a choice of treatment for Japanese RCC patients. However, the recommendation grade has been reduced from A in the 2007 version to B in the 2011 version. There have been some reports from Western countries in regard to combination therapy consisting of cytokine therapy and a molecular targeted medicine excluding bevacizumab; no efficacy and even worsening of adverse events has been seen, but the results of a clinical trial that is under way in Japan are being awaited.

CQ17: Is cytokine monotherapy with IFN-α, IL-2 and so on recommended for advanced RCC?

[Recommendation grade B] IFN-α or IL-2 monotherapy is recommended for advanced RCC.

4) Role of molecular targeted medicine

The greatest advances have been made in recent years is treatment methods for advanced RCC. Recently, neoadjuvant therapy using molecular targeted medicines has been reported.^22–24 Large-scale randomized controlled trials comparing a molecular targeted medicine with a placebo or cytokine have reported an objective tumor response and a progression-free survival or overall survival prolonging effect.^25–28 Furthermore, treatment effects and an adverse event for molecular targeted medicines have been reported in Japan.^29–32

CQ19: Is neoadjuvant therapy with molecular targeted medicines recommended for RCC?

[Recommendation grade C1] Neoadjuvant therapy with a molecular targeted medicine on the presumption of surgery might be a safe and effective treatment for the primary RCC lesion.

CQ21: Is molecular targeted therapy recommended for patients with advanced RCC?

[Recommendation grade B] An objective tumor response and prolongation of survival time are expected when patients with advanced RCC are treated with a molecular targeted medicine.

CQ22: Is molecular targeted therapy recommended for cases of advanced RCC in which cytokine therapy is ineffective?

[Recommendation grade A] Prolongation of progression-free survival can be expected of molecular targeted medicine in cases where cytokine therapy is ineffective.

CQ23: Is there any treatment that shows promise of being effective in cases of advanced RCC in which molecular targeted therapy is ineffective?

[Recommendation grade B] Prolongation of progression-free survival can be expected of second-line treatment with a mTOR inhibitor in cases where an angiogenesis inhibitor has been ineffective.

[Recommendation grade C1] Responses are seen even when a switch is made to another angiogenesis inhibitor.

3. Criteria for selecting medical treatment for advanced RCC

The selection criteria proposed in this clinical practice Guideline are based on medicines approved by the national health insurance system in Japan at the time the Guideline was drafted. The treatments are classified into first-line and second-line, and the recommended therapeutic agents are suggested based on the MSKCC risk classification or prior treatment (Table 4).

Table 4.  Criteria for selecting medical treatment for the advanced RCC

Setting	MSKCC criteria or prior treatment	Recommendation
First-line treatment	Favorable or intermediate	IFN-α (+ low dose IL-2) – lung metastasis
		IL-2
		Sunitinib
		Sorafenib
	Poor	Temsirolimus
		Sunitinib
Second-line treatment	Cytokine refractory	Sorafenib
		Sunitinib
	TKI refractory	Everolimus
	mTOR inhibitor refractory	Clinical trial

In favorable or intermediate risk cases according to the MSKCC risk classification, IFN-α (+low-dose IL-2) therapy is recommended for only lung metastasis. IL-2 therapy, sunitinib and sorafenib are also recommended in this category. In contrast, temsirolimus and sunitinib are recommended in poor-risk cases. Sorafenib and sunitinib are recommended for cytokine-resistant cases, and everolimus is recommended for tyrosine kinase inhibitor-resistant cases.

Caution is required in regard to the fact that the contents of the recommendations made here are definitely selection criteria, and they in no way compel their use. It is greatly important to evaluate host factors (age, past medical history), tumor-related factors (histological type, metastatic sites, etc.), characteristics of the drugs, and to select therapeutic agents that are suitable for each case.

4. Revision of the diagnostic and treatment algorithm (Fig. 1)

Figure 1. Diagnostic and treatment algorithm of RCC.

RFA or cryoablation has been made an option for T1a RCC. Neoadjuvant therapy with a molecular targeted medicine has been made an option for the treatment of T3b-c RCC. A risk classification based on prognostic factors has been suggested for stage IV RCC cases, and depending on the individual case, neoadjuvant therapy with a molecular targeted medicine has also been made an option. In addition, nephrectomy is impossible even in some cases in which there are no distant metastases. Immunotherapy and molecular targeted medicines are each clearly specified.

Conclusion

We described a summary of the JUA RCC Guideline 2011 version. After receiving evaluations from the parties concerned, primarily the JUA, this guideline is scheduled to be revised based on the latest information early.

Conflict of interest

None declared.