Renal Cell Carcinoma Guidelines

Renal Cancer Facts

• Most renal cancers arise from the epithelial tubules of the nephron.
• Adenocarcinomas account for the majority of the 79,000 cases and 14,000 deaths from renal cell carcinoma (RCC) reported annually in the US.
• The overall lifetime risk of RCC is 1 in 46 men (2.02%) and 1 in 80 women (1.03%).¹
• Approximately 5% of kidney are associated with inherited syndromes while the remaining 95% are sporadic, the cause of which remains unknown.²
• There are no screening recommendations except in high-risk familial syndromes. It is not believed kidney cancer is a preventable disease.
• Detection of most kidney tumors is incidental. Signs and symptoms therefore mostly often occur later in the disease evolution.³

Renal Cancer Risk Factors

• Age (median at diagnosis = 65)
• Gender (male: female 2:1)
• Smoking
• Obesity
• Hypertension (to lesser degree) ²

Renal Cancer Testing

• Contrast CT or MRI of the abdomen (Pre and Post)
  • Use of iodinated contrast acceptable with GFRs >= 45
  • Use of appropriate gadolinium agents acceptable at any GFR (FN ACR guidelines)
• Chest Imaging
• Complete Blood Counts
• Metabolic profiles
• Urinalysis
• Core Needle or Excisional Biopsy*⁴

*Treatment of a suspicious renal mass is sometimes undertaken without a preoperative tissue diagnosis.

Renal Cancer Prognosis

As with nearly all solid tumors, prognosis is driven primarily by tumor histology, stage, and grade.

Tumor Histology

RCC is a biologically heterogeneous disease with more than a dozen recognized histologic types described. These basically fall into two categories, clear cell RCC and non-clear cell RCC.

Staging

Staging describes the size and shape of the tumor. The 3 aspects used in determining stage are:

1. Tumor size (T)
2. Spread to lymph nodes (N)
3. Spread to distant organs or lymph nodes (M)

Table 1: Kidney Cancer Stages

Stage	Stage Grouping	Stage Descriptor
I	T1 N0 M0	– Tumor is 7cm across or less – No spread to lymph nodes – No spread to distant organs or distant lymph nodes
II	T2 N0 M0	– Tumor is larger than 7cm across – No spread to lymph nodes – No spread to distant organs or distant lymph nodes
III	T3 N0 M0 OR T1-T3 N1 M0	– Tumor growing in kidney tissue or major vein – No spread to lymph nodes – No spread to distant organs or distant lymph nodes OR – Tumor any size but may have grown outside kidney but hasn’t reached Gerota’s fascia – Spread to nearby lymph nodes – No spread to distant organs or distant lymph nodes
IV	T4 N (Any number) M0 OR T (Any number) N (Any number) M1	– Tumor growing in kidney tissue or major vein – May have spread to nearby lymph nodes – No spread to distant organs or distant lymph nodes OR – Tumor any size but may have grown outside kidney anywhere – May have spread to nearby lymph nodes – Spread to distant organs and/or distant lymph nodes

Grade

Describes cellular features and tumor architecture which reflect potential tumor aggressiveness. Tumor grade measures nuclear pleomorphism and is also important in prognosis.

Renal Cancer Survival Rates

Survival rates are well discriminated by histology, stage, and grade. However, more sophisticated nomograms and models are available following treatment of localized disease, or prior to treatment for metastatic disease. ⁶

• ASSURE nomogram.⁷ This is the most robust predictive model to estimate recurrence following treatment for localized RCC. It can provide patients and clinicians with an accurate assessment of recurrence rates, guide the selection of patients for adjuvant therapy, and inform surveillance protocols.
• IMDC¹¹ (International Metastatic RCC Database Consortium) and MSKCC¹⁰ (Memorial Sloan-Kettering Cancer Center) model. These models are very similar and are used interchangeably.

Management of RCC

Management depends on a constellation of:

• tumor related factors (stage, grade, type, other)
• patient related factors (age, renal function, competing risks, and co-morbidities)
• provider experience

Treatment of Localized Renal Cancer

Stage I and II RCC is considered localized disease, the difference being only in the size of the tumor.⁸ 

Treatment Options Include:

• Excision via partial or radical nephrectomy, which can be performed via open or laparoscopic/robotic approaches. Most patients with localized RCC are candidates for partial nephrectomy with equivalent oncologic outcomes as radical nephrectomy when done by technically proficient surgeons.
• Ablation, which is ordinarily performed percutaneously using cryoablation, radiofrequency ablation or microwave thermal therapy
• Active surveillance, which is typically preserved for patients with small masses (<2cm) who are elderly, infirmed, or at risk for dialysis

Treatment of Locally Advanced Renal Cancer

Locally advanced RCC includes stage III disease where the tumor extends beyond the renal capsule to involve nearby fat, veins, or regional lymph nodes.

Treatment Options Include:

• Up-front surgery remains the standard of care for locally advanced RCC with long survival rates in the 50-70% range depending on other tumor and host factors. 
• Surgery most often includes radical nephrectomy unless renal function would render the patient in CKD IV or V (in need of dialysis)
• Neoadjuvant systemic therapy is occasionally used to downsize a locally advanced tumor if renal function is at significant risk, patient has poor operative risks or suspicion that metastatic disease is present.
• Tumor ablation and active surveillance have limited roles for those with locally advanced disease.

Adjuvant therapy options for high risk, fully resected, locally advanced RCC include:

• Clinical trial
• Close surveillance
• Adjuvant Sunitinb or Pembrolizumab, two FDA approved therapies with level 1 evidence demonstrating improved disease-free survival following approximately 1 year worth of treatment

Treatment of Metastatic Renal Cancer

Approximately 20% of patients with RCC present with metastatic disease. Stage IV RCC is incurable in the majority of patients.

Detecting Treatment

Before determining treatment, patients are first stratified into favorable, intermediate or poor risk groups using IMDC and MSKCC criteria.

• Clear cell histologies. Level 1 evidence exists for multiple combinations which currently largely mean a tyrosine kinase inhibitor given orally with a checkpoint inhibitor given intravenously.
• Non-clear cell metastatic RCC. Preferred regimens usually start with a tyrosine kinase inhibitor alone or a clinical trial.
• Evidence blocks. The NCCN uses “evidence blocks” to estimate a specific drug or combinations of drugs for:
  • Tradeoffs of efficacy
  • Safety
  • Quality Consistency of the evidence
  • Affordability

Current 1^st line treatment options for Stage IV include:**

• Tyrosine kinase inhibitors and immunotherapies. While stage IV is resistant to standard chemotherapies, it is quite responsive to various tyrosine kinase inhibitors and immunotherapies given in sequence or combination. Also, first line systemic therapies for kidney cancer are in rapid evolution as new trial data emerge.
• Cytoreductive surgery. The role of surgery to remove (cytoreduce) the primary renal tumor is controversial. In well selected patients who are young, healthy and have a majority of their tumor burden in their primary renal tumor, removal of the kidney is offered.
• Neoadjuvant therapy. Increasingly, patients with stage IV RCC start with tissue sampling, a workup for extent of disease and neoadjuvant therapy.
• Metastasectomy. Surgery to remove metastases (metastasectomy) is performed occasionally and primarily to remove lung, adrenal or regional lymph node metastases in appropriately selected circumstances. 
• Stereotactic body radiotherapy (SBRT). SBRT can also be used to target metastases, especially if symptomatic or those in surgically difficult locations.

**Second and third-line therapies depend on which first line therapies are used and how active they have been.

Considerations of Specific Treatment Modalities

Surgery

• Resection remains the mainstay treatment for localized and locally advanced RCC and in some cases of recurrent or metastatic disease. Data support equivalent oncologic outcomes for open, laparoscopic, and robotic techniques when performed with technical proficiency.
• Adrenalectomy and lymphadenectomy are not routinely performed unless radiographically abnormal.

Radiation

SBRT strategies are most often employed. The role of radiation in the management of RCC is currently limited to symptomatic metastases or lesions that are:

• Low volume
• Isolated
• Hard to manage surgically

These typically include those in the bone, lung, and soft tissues.

Systemic Therapies

• Systemic therapies have revolutionized the management of RCC.
• They are infrequently used in the neoadjuvant setting other than in a clinical trial or occasionally to downstage a large, localized tumor in patients with an imperative need for a partial nephrectomy.
• Data in the adjuvant setting following full surgical resection are emerging although none have yet shown an improvement in overall survival compared to placebo.
• In the metastatic setting, tyrosine kinase inhibitors alone may be used for indolent metastatic disease. Far more common are combinations of TKIs and immunotherapies. These therapies have led to 4-5x improvements in OS over the last two decades. Most are well tolerated although immune related toxicities may limit their use.

To learn more about systemic treatments, read Kidney Cancer Treatment Regimens.

Surveillance Following Therapy

Imaging remains the mainstay to detect recurrence following therapy. The principles and algorithms for surveillance are summarized in the AUA guidelines.

Table 2. Follow-Up After Intervention

• Follow-up timeline is approximate and allows flexibility to accommodate reasonable patient, caregiver, and institutional needs.
• Each follow-up visit should include:
  • relevant history
  • physical examination
  • laboratory testing
  • abdominal and chest imaging
• Overall, 30% of renal cancer recurrences after surgery are diagnosed beyond 60 months. Informed/shared decision-making should guide surveillance decisions beyond 60 months.

References

1. Key Statistics About Kidney Cancer: How common is kidney cancer? American Cancer Society. Update January 12, 2022. Accessed August 25, 2022.
2. Risk Factors for Kidney Cancer American Cancer Society. Update February 1, 2020. Accessed August 27, 2022.
3. Kidney Cancer Signs and Symptoms American Cancer Society. Update February 1, 2020. Accessed September 1, 2022.
4. NCCN Guidelines for Kidney Cancer Update April 2020.
5. Kidney Cancer Stages American Cancer Society. Update February 1, 2020. Accessed September 1, 2022.
6. Survival Rates for Kidney Cancer American Cancer Society. Update March 1, 2022. Accessed September 1, 2022.
7. Assure RCC Prognostic Nomogram Eur Urol. 2021 Jul;80(1):20-31. doi: 10.1016/j.eururo.2021.02.025. Epub 2021 Mar 9.
8. Renal Mass and Localized Renal Cancer Eur Urol. 2021 Jul;80(1):20-31doi: 10.1016/j.eururo.2021.02.025. Epub 2021 Mar 9.
9. Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-up: AUA Guideline: Part II  J Urol. 2021 Aug;206(2):209-218. doi: 10.1097/JU.0000000000001912. Epub 2021 Jul 11.
10. A simple prognostic model for overall survival in metastatic renal cell carcinoma Can Urol Assoc J. 2016 Mar-Apr; 10(3-4): 113–119. doi: 10.5489/cuaj.3351.
11. Novel risk scoring system for metastatic renal cell carcinoma patients treated with cabozantinib Cancer Treat Res Commun. 2021;28:100393. doi: 10.1016/j.ctarc.2021.100393. Epub 2021 May 9.