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KIDNEY CANCER: MANAGEMENT OF LOCALIZED AND LOCALLY ADVANCED DISEASE

INCLUDES 2014 CUA Surgical Management of RCC Consensus Statement, 2021 AUA Renal Mass and Localized RCC Guidelines, 2018 CUA Adjuvant Therapy After Nephrectomy Consensus Statement, 2018 CUA Guidelines on Follow-up After Treatment of Non-metastatic RCC, 2019 CUA Advanced Kidney Cancer Consensus Statement

Management of Localized (cT1-2) Renal Cell Carcinoma

Options:
1. Active surveillance (AS)/expectant management
2. Thermal ablation (TA)
3. Partial nephrectomy (PN)
4. Radical nephrectomy (RN)
Patient counseling
- Review the most common and serious urologic and non-urologic morbidities of each treatment pathway.
- Discuss potential effect of intervention on risk of chronic kidney disease (CKD), dialysis, and survival.
  - Patients with renal masses often have a high burden of CKD to begin with because of the shared risk factors with RCC and CKD, such as hypertension.
  - Predictive factors for post-operative development of CKD or progression of pre-existing CKD (8):
    1. Older age
    2. Diabetes
    3. Hypertension
    4. Male sex
    5. Obesity
    6. Tobacco use
    7. Larger tumour size
    8. Post-operative acute kidney injury
  - Optimizing glycemic and blood pressure control, smoking cessation and minimizing risk of acute kidney injury (with avoidance of hypotension and nephrotoxic agents such as intravenous contrast or non-steroidal anti-inflammatory drugs) should reduce the degree of renal dysfunction in the perioperative period.

Active surveillance

Advantage
1. Least invasive
Disadvantages
1. Patient anxiety
2. Oncologic risks

Many small renal masses grow relatively slowly (median growth rate 0.12-0.34 cm/yr) and have a relatively low rate of metastasis (1-2% during 2-4 years of follow-up)
- Results should be interpreted with caution since many masses were not biopsied and there is limited follow-up.

Indications
- 2021 AUA Localized RCC Guidelines
  - Absolute (1):
    1. Risk of intervention/competing risks of death outweighs the potential benefits of intervention
  - Relative (9):
    - Tumour factors (2)
    - Patient factors (7)
Contraindications
- In general, AS is not appropriate
  - Larger (>3-4 cm), poorly marginated, or nonhomogeneous solid renal lesions
  - Biopsy indicates a potentially aggressive RCC, except in patients with limited life expectancy
- AS is also not advisable in younger, otherwise healthy, patients with small, solid tumors that have radiographic characteristics consistent with RCC
Indications for intervention (treatment or AS intensity)
- 2021 AUA (5)§:
  1. Tumour size >3cm
  2. Growth kinetics (>5mm/year)
  3. Stage progression
  4. Clinical changes in patient/tumour factors (e.g. infiltrative on imaging, suspicion of advanced T stage)
  5. Additional biopsy results (e.g. unfavourable histology)
Follow-up
- Optimal regimen is unclear

Prior abdominal imaging should be evaluated to assess growth rate or changes in clinical stage
2021 AUA
- Patients with no prior imaging should have surveillance imaging initially every 3 to 6 months
- Preferred modality is not well established, but initial imaging should preferably consist of contrast-enhanced cross-sectional imaging.
- Frequency and intensity are tailored to patient-risk, based on tumour size, tumor complexity, infiltrative appearance and median growth
- Chest x-ray is warranted annually or if intervention triggers are encountered or symptoms arise.
- Due to the imperfect nature of renal mass biopsy, patients with benign renal mass biopsy may warrant follow-up.

Expectant management (observation)
- Appropriate in patients in whom treatment poses an unacceptably higher risk than surveillance
- Yearly abdominal US including images of the retroperitoneal and intraperitoneal organs can be performed to screen for stage progression which may trigger systemic therapy in the appropriately selected patient

Thermal ablation (TA)

Options: radiofrequency ablation (RFA) and cryoablation

Experience with renal cryosurgery predates that of RFA and has been more extensive
No randomized trials directly compare cryoablation to RFA
Meta-analyses have shown no significant differences between cryoablation and RFA in outcomes as defined by complications, metastatic progression, or cancer-specific survival.

Advantages (2):
1. Low morbidity
  - In the Agency for Healthcare Research and Quality (AHRQ) analysis, TA had the most favorable perioperative outcome profile and a similar low risk of harms when compared to other strategies
2. Comparable cancer-specific and overall survial outcomes to partial nephrectomy, in select patients
Disadvantage
1. Risk of local recurrence after primary treament is higher with TA (3-10% cryoablation and 5-20% RFA) than partial (0-3%) or radical nephrectomy (0%)
Indications
- Alternative approach for management of cT1a solid renal masses <3cm
  - Current technology does not allow for reliable treatment of lesions >4.0 cm, and success rates appear to be highest for tumors <2.5-3.0 cm
- Relative (4):
  1. Advanced age
  2. Significant comorbidities
  3. Local recurrence after previous nephron-sparing surgery
  4. Hereditary renal cancer who present with multifocal lesions for which multiple PNs might be cumbersome
- 2021 AUA
  - Alternative approach for management of cT1a solid renal masses <3cm
    - PN seems preferred over TA for cT1a: "PN should be prioritized in the management of patients with clinical T1a renal mass".
Contraindications

Absolute
- Inaccessible tumour
- Large tumour
Relative
- Completely intrarenal lesions or those immediately adjacent to the sinus or hilum are more difficult to treat effectively by TA

Technology§
- RFA
  - Utilizes high frequency alternating current (460-500 kHz) to induce ion agitation and frictional heating in adjacent tissue
    - Can be achieved through 2 types of radiofrequency generator systems:
      1. Temperature-based system: drives the current to reach a target temperature
      2. Impedance-based systems: continue ablation until a predetermined impedance level is reached.
  - Cryoablation
    - Generates lethal temperatures below -20 to -40 °C, resulting in coagulative tissue necrosis
    - Volume of lethal temperature generated during cryoablation is regulated by (4):
      1. Duration of freezing
      2. Number of freeze cycles
      3. Size and number of cryoprobes
      4. Local tissue interactions
    - Complete treatment of a tumour requires that the iceball extend beyond the tumor because the peripheral leading edge of the iceball is at sub-lethal temperatures
      - Lethal temperatures are reached approximately 5 mm from the periphery of the iceball; the ice-ball is usually extended ≈1 cm beyond the edge of the tumor
Technique
- TA for cystic lesions requires further investigation.
- A renal mass biopsy should be performed prior to ablation to provide pathologic diagnosis and guide subsequent surveillance
- Percutaneous approach is preferred over a surgical approach whenever feasible to minimize morbidity.
  - Percutaneous displacement techniques such as the use of fluid (hydro-dissection), carbon dioxide, or spacer balloons frequently enable separation of adjacent structures from the anticipated zone of ablation, rendering many cases suitable for percutaneous TA.
  - A laparoscopic approach is seldom needed except for occasional cases in which adhesions prevent displacement of adjacent structures or when the collecting system is at risk for serious injury even with thermo-protective maneuvers such as pyeloperfusion.
Complications
- Cryoablation:
  1. Renal fracture
  2. Hemorrhage
  3. Adjacent organ injury
  4. Ileus
  5. Wound infection
- RFA (uncommon):
  1. Acute renal failure
  2. Stricture of the ureteropelvic junction
  3. Necrotizing pancreatitis
  4. Lumbar radiculopathy
Post-treatment imaging
- Immediate post-procedural imaging of the ablated tumor generally shows the treatment bed to be larger than the pre-treatment tumor size for RFA due to ablation of a peripheral margin of normal tissue, and for cryoablation due to extension of the iceball beyond the original tumor margin.
- Renal tumours successfully treated with
  - RFA demonstrate no contrast enhancement. However, they do not regress significantly in size.
    - Residual enhancement is considered suggestive of residual or recurrent disease
  - Cryoablation may demonstrate reduction in size or complete resolution or scar formation
- On MRI, the imaging hallmark of successful renal tumor ablation is lack of tumor enhancement with gadolinium-enhanced imaging.
- Rim enhancement, believed to represent reactive change, may occasionally be seen at early postprocedural MR scanning after RFA or cryoablation, which later resolves.
Recurrence following treatment
- Diagnosis of local recurrence after TA can be challenging because evolving fibrosis within the tumor bed can be difficult to differentiate from residual cancer.
- Findings suggestive of local recurrence (5):
  1. Enhancement within the tumor bed beyond 6 months
  2. Progressive increase in size of an ablated neoplasm
  3. New nodularity in or around the treated zone
  4. Failure of the treated lesion to regress over time
  5. Satellite or port site lesions
- Most local recurrences can be salvaged with repeat ablation
  - Some patients with progressive disease eventually require conventional surgery.
    - PN and minimally invasive approaches are occasionally precluded in this setting because of the extensive fibrotic reaction induced by TA, necessitating RN.
Other new technologies, such as high-intensity focused ultrasound and image-guided radiosurgical treatments (SBRT), are under development and may allow extracorporeal treatment of small renal tumors in the future

Partial nephrectomy (PN)

Advantages (2):
1. Preserved renal function compared to RN
2. Oncologic efficacy
Disadvantages
1. Higher rsk of blood transfusions and urologic complications (e.g. urine leak) than TA or RN
2. Potential for hyperfiltration renal injury

Patients who undergo nephron-sparing surgery for RCC may be left with a relatively small amount of renal tissue and are at risk for development of long-term renal functional impairment from hyperfiltration renal injury
- Proteinuria is the initial manifestation
  - A 24-hour urinary protein measurement should be obtained yearly in patients with a solitary remnant kidney to screen for hyperfiltration nephropathy
- Efforts to prevent or to ameliorate the damaging effects of hyperfiltration have focused on dietary and pharmacologic interventions, primarily the use of ACE-inhibitors combined with a low-protein diet

Indications
- 2021 AUA
  - Absolute (3):
    1. Anatomic or functionally solitary kidney
    2. Bilateral tumors
    3. Known familial RCC syndrome
  - Relative (4):
    1. cT1a renal masses (preferred over TA and RN), not managed with active surveillance
    2. Pre-existing CKD
    3. Pre-existing proteinuria
    4. Young age
    5. Multifocal masses
    6. Comorbidities that are likely to impact future renal function, including (4):
      1. Moderate to severe hypertension
      2. Diabetes mellitus
      3. Recurrent urolithiasis
      4. Morbid obesity
Approach
- Can be done via open/laparoscopic/robotic approach
  - Pure or robot-assisted laparoscopic PN should be done by experienced surgeons
Technique
- The extent of normal parenchyma removed should be determined by surgeon discretion taking into account the clinical situation, tumor characteristics including growth pattern, and interface with normal tissue.
- Margin width is not important as long as final margins are negative.
  - While positive surgical margin during PN has not definitively been shown to adversely affect survival outcomes (recurrence-free, metastasis-free, cancer-specific, or overall survival), a negative surgical margin is always the goal; close surveillance is recommended in patients with a positive surgical margin
    - Cohort study of 1,344 PN patients from MSK found that compared to negative margins, positive margins was not associated with worse recurrence-free or metastasis-free survival. J Urol 2008.
    - Multi-centre cohort study of 775 patients from Europe found that compared to negative margins, positive margins was not associated with worse recurrence-free, cancer-specific, or overall-survival. Eur Urol 2010.
  - Management of positive surgical margins after PN or tumor enucleation
    - Controversial
    - A variety of factors should be taken into account during counseling including the extent of the margin (microscopic versus extensive), tumor histology and grade, and other indicators of tumor biology such as locally invasive phenotype.
  - PN in patients with absolute indications should focus on preservation of renal parenchymal volume and functional nephrons with margin width being a less relevant consideration
Local recurrence in the remnant kidney after PN for RCC
- Occurs in 0-3% of patients
- Main risk factor is advanced T stage
- Most ipsilateral recurrences are distant from the tumor bed and are therefore likely a result of unrecognized tumor multicentricity or de novo occurrence rather than true treatment failure

Radical nephrectomy (RN)

Advantages
1. Favorable perioperative outcomes compared to PN
  - May reflect the high proportion of RN performed via the laparoscopic approach
2. Oncologic efficacy
Disadvantage
- Associated with the greatest decrease in GFR and highest risk of de novo CKD stage 3 or higher.
  - While these changes in GFR may be clinically insignificant in patients with a normal contralateral kidney, they warrant consideration in certain patients
  - In general, median loss of global renal function with PN is ≈10%, while RN is typically associated with ≈35-40% loss of global function, although this can vary substantially for RN based on uneven split renal function, and for PN based on tumor complexity
Indications
- 2021 AUA (2):
  1. Increased oncologic potential is suggested by tumor size, biopsy, and/or imaging characteristics
  2. If ALL criteria are met (3):
Approach
- Can be done via open/laparoscopic/robotic approach
- See Open Kidney Surgery Chapter Notes
2017 AUA Localized RCC Guideline: If final pathology shows locally advanced features, adjuvant therapy or clinical trials should be considered

Partial vs. radical nephrectomy

Studies show that CKD increases risk of cardiovascular events and death
In observational studies, RN has been associated with increased CKD, worse overall survival, and cancer-specific survival compared to PN. The association with worse cancer-specific survival raises concerns about selection bias since PN should not theoretically be a more effective oncologic intervention than RN
EORTC 30904

Population: 541 patients with tumours <5cm suspicious for RCC (and normal contralateral kidney)
Randomized to RN vs. PN
Primary outcome: OS
Secondary outcomes: CSS, cardiovascular events, renal function outcomes
Results:

RN significantly improved OS
No difference in CSS (only 2% of patients died of cancer)
Cardiovascular deaths were less common in the RN group
RN favorable in terms of lower perioperative morbidity, while PN provided better renal functional outcomes
In the subgroup analysis of patients with RCC histology, association for OS was extinguished

Trial criticisms: premature study closure, trial designed as non-inferiority design but OS significance is based on superiority, patient comorbidity imbalances, cross-over, low statistical power, variable surgical technique and parenchymal sparing

Further studies have suggested that there may be a difference between CKD resulting from medical (CKD-M) and surgical (CKD-S) causes.
- Patients with CKD caused by hypertension or diabetes will continue to suffer from these comorbidities, and will likely experience progressive decline in renal function, eventually affecting survival.
- Patients with CKD primarily resulting from surgical removal of nephrons typically do not need further surgery, and might stabilize
Despite the above, the following recommendations are made:

PN is preferred over RN for small renal masses (T1a, <4.0 cm) whenever feasible when intervention is indicated, because PN minimizes the risk of CKD or CKD progression and is associated with favorable oncologic outcomes, including excellent local control and RN represents gross overtreatment for most such lesions, which tend to have limited biologic potential
Larger renal tumors (clinical stages T1b and T2) have increased oncologic potential and have often already replaced a substantial portion of the parenchyma, leaving less to be saved by PN. In the setting of a normal contralateral kidney, the relative merits of PN versus RN can be debated in this population.

Locally Advanced Renal Cell Carcinoma (cT3+)

Differential diagnosis of a large, invasive upper quadrant abdominal masses (10):
1. Lymphoma
2. Urothelial carcinoma
3. Sarcomatoid differentiation (chromophobe is the most prone one to have this)
4. Collecting duct carcinoma
5. Renal medullary carcinoma
6. Locally invasive RCC
7. Xanthogranulomatous pyelonephritis (XGP)
8. Metastasis (occasionally)
9. Sarcoma
10. Adrenocortical carcinoma

IVC involvement

See Open Kidney Surgery Chapter Notes
A venous tumour thrombus is an intraluminal growth of RCC into the renal venous circulation.
- There can be a tumour and benign portion to the thrombus.
Diagnosis and evaluation
- IVC tumour thrombus should be suspected in patients with a renal tumour and (7):
  1. Lower extremity edema
  2. Isolated right-sided varicocele or one that does not collapse with recumbency
  3. Dilated superficial abdominal veins
  4. Proteinuria
  5. Pulmonary embolism
  6. Right atrial mass
  7. Non-function of the involved kidney
- MRI is the preferred imaging to characterize the extent of the thrombus, though CT may be adequate
  - Prognostic significance of IVC thrombus level has been controversial. Even patients with level IV IVC thrombi can be cured with surgical resection
  - Imaging should be obtained as close as possible to the date of surgery because progression of the tumor thrombus may mandate important changes in intraoperative management
  - Although MRI has been recommended as the test of choice at most centers, several recent studies have demonstrated that multiplanar CT also provides sufficient information for surgical planning, and it has become the preferred diagnostic study at many centers.
  - See Open Kidney Surgery Chapter Notes for staging of the level of IVC thrombus
Prognosis
- 45-70% of patients with RCC and IVC thrombus can be cured with an aggressive surgical approach including RN and IVC thrombectomy
Management
- Preoperative renal artery embolization can be considered to attempt to shrink the thrombus and facilitate surgery
- See Open Kidney Surgery Chapter Notes

Locally invasive RCC (T4N0M0 (Local tumour extension to adjacent organs without metastatic disease))

Management
- Complete resection of disease through RN with resection of adjacent organs, if feasible
  - Because surgical therapy is the only potentially curative management for RCC, extended operations with en bloc resection of adjacent organs are occasionally indicated.
    - Removing all known disease, with possible concomitant resection of involved organs, such as the adrenal gland, liver, pancreas, diaphragm, and bowel is the aim of therapy.
    - Incomplete excision of a large primary tumor, or debulking, is rarely indicated as survival estimates are only 10-20% at 12 months
    - Vaccination against Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitides should be performed preoperatively in those without previous vaccination when splenectomy is likely during nephrectomy
  - Even with an aggressive surgical approach the prognosis remains poor and the oncological benefits of surgery should be carefully considered in the context of surgical morbidity
  - Regional lymphadenectomy should be considered for adequate pathologic staging

Special considerations

Renal Cell Carcinoma in Pregnancy
- RCC is the most common renal tumour in pregnancy§
- It has been suggested that surgery should not be delayed in the first and third trimesters. However, if a mass is diagnosed in the second trimester then it is reasonable to wait until fetal viability before proceeding to surgery§
  - However, these recommendations are based on a tumour doubling time of 300 days from a report published in 1980
Pre-existing renal dysfunction
- Patients undergoing surgical intervention (RN or PN) for RCC involving a functionally or anatomically solitary kidney must be advised about the potential need for temporary or permanent dialysis postoperatively.
  - A functioning renal remnant of at least 20-30% of one kidney is necessary to avoid ESRD, although this presumes good functional status of the remaining parenchyma.
    - Overall preservation of renal function is achievable in most patients with absolute indications for PN.
Patients with VHL or other familial syndromes

Appropriate surgical treatment of RCC in VHL requires excision of all solid and cystic renal lesions.
Nephron-sparing strategies, including tumor enucleation when feasible, should be pursued whenever possible, given the multifocal nature of the disease, even for centrally located tumors.
- For PN, an enucleative approach is often preferred rather than wide resection.
The National Cancer Institute have defined a 3-cm threshold for intervention in patients with VHL disease.
- 3-cm threshold also applies to patients with HPRCC and Birt-Hogg-Dubé syndromes. However, HLRCC and SDH-RCC are exceptions in that tumors in these syndromes are typically more aggressive and should be managed accordingly, even when <3 cm
After initial management, patients with VHL disease are at much higher risk for local recurrence than patients with sporadic RCC and must be observed closely.
If needing another intervention for recurrence, repeat PN can be challenging because of postoperative fibrosis, and TA may be preferred for local control

Lymphadenectomy
- Main landing zones for RCC:
- Indications
  - No randomized trials assessing the effect of lymphadenectomy for patients with cN+ disease.
    - However, a subset of patients with regional lymph node metastases will be cured, or experience prolonged survival following surgery
  - 2014 CUA
    - cN1M0 disease
    - Lymphadenectomy may be performed for diagnostic purposes in patients with cN1M1 disease
  - 2021 AUA
    - Clinically concerning regional lymphadenopathy (for staging purposes)
  - Other sources (8):
  - Regional lymphadenectomy should be considered in those patients who may have a reasonable chance of benefiting from the added surgery.
    - Bulky lymphadenopathy carries a poor prognosis similar to metastatic disease, although surgical resection should be considered if feasible and if appropriate, given careful assessment of disease burden and patient age/comorbidities.
  - CUA/AUA: Routine lymphadenectomy at the time of RN or PN is not routinely recommended in patients with clinical N0 disease.
    - Reasons for limited benefit of routine lymphadenectomy (3):
      1. RCC metastasizes through the bloodstream independent of the lymphatic system in many patients
      2. Lymphatic drainage of the kidney is highly variable.
        
        Even an extensive retroperitoneal dissection may not remove all possible sites of metastasis.
      3. Low overall incidence of lymph node disease (5%)

If lymph node involvement is confirmed on pathology, consider referral to medical oncology

Adrenalectomy

The ipsilateral adrenal gland should be preserved at the time of the nephrectomy provided it appears normal on imaging and there is no sign of direct tumour invasion

Traditionally, radical nephrectomy included the ipsilateral adrenal gland and complete regional lymphadenectomy from the crus of the diaphragm to the aortic bifurcation, as described by Robson and colleagues in 1969 for management of renal malignancy.
Overall incidence of adrenal metastasis is <5% and removal of the adrenal gland, when not involved by tumor, has not been shown to improve survival of patients with renal cancer.
CT has 99.4% specificity and 99.4% negative predictive value for detecting adrenal involvement

Indications
- 2021 AUA (2):
  - Absolute (1):
    1. If preoperative imaging or intraoperative inspection suggests metastasis or adrenal enlargement
      - One exception is when patient has a well-characterized adenoma, which may not mandate surgical excision
  - Relative (1):
    1. Locally advanced features are identified preoperatively or during exploration and the gland is in close proximity to the tumour
      - Adrenal may be spared in this setting if the contralateral adrenal gland is absent and the ipsilateral gland demonstrates normal morphology and no malignant involvement.
- Other sources (7):
If adrenal involvement is confirmed on final pathology, consider referral to medical oncology

Minimally invasive approach

Should be considered when it would not compromise oncologic, functional and perioperative outcomes

Pathologic evaluation of the adjacent renal parenchyma should be performed after PN or RN to assess for possible intrinsic renal disease, particularly for patients with CKD or risk factors for developing CKD.
- Given that diabetes and hypertension are independent risk factors for RCC, diabetic nephropathy and hypertensive nephropathy are found in 8-20% and at least 14% of tumor nephrectomies, respectively.
- College of American Pathologists established a requirement that pathologic evaluation of the renal parenchyma for possible nephrologic disease should be included in all synoptic reports for kidney cancer.

Management summary (as per 2014 CUA Surgical Management of RCC Consensus Statement):

cT1a disease

PN recommended
Consider laparoscopic RN for tumours not amenable to PN
Consider TA (RFA or cryotherapy) in patients with high surgical risk.
- A biopsy should be obtained before or at the time of ablation
Consider active surveillance in the elderly or infirm

Not yet recommended for the young and fit
Patients must be counselled on the potential of systemic (1.1%) or local progression (12%)
Follow-up must include serial imaging

cT1b disease

PN when technically feasible
Laparoscopic RN should be offered if a PN is not feasible; open RN if laparoscopic surgery not feasible.
Ablative modalities are not recommended for these tumours due to the high rate of incomplete ablation in lesions > 4 cm

cT2

RN; PN in highly selected cases

The role of extended PN for tumours > 7 cm is controversial, and the consideration of such highly selected cases should be limited to experienced surgeons

cT3

RN – open, laparoscopic or robotic assisted

Resection of vascular thrombus when applicable (usually open)
Resection of all gross disease including hilar or retroperitoneal extension
Patients with tumours > 7 cm should raise suspicion of involvement of peri-renal tissues, such as Gerota’s fascia or renal sinus fat

PN may be attempted in highly selected cases by experienced surgeons.

cT4

RN with resection of adjacent organs, such as the adrenal gland, liver, pancreas, diaphragm, and bowel, if feasible
Regional lymphadenectomy should be considered for adequate pathologic staging

IVC and renal vein thrombus

In the presence or absence of distant metastases, tumour thrombus should be resected if technically feasible in appropriately selected patients
It is recommended that these operations be performed in a centre with experience and with an availability of a multidisciplinary team as these complex procedures have significant risk of morbidity and mortality.
Tumour thrombectomy with cytoreductive nephrectomy in the metastatic setting should be considered for all patients secondary to the poor outcome associated with untreated intravascular disease.

M+

See Advanced Kidney Cancer Chapter Notes

Prognosistic factors in Localized Disease

Pathological risk factors for ipsilateral renal recurrence include (4):
1. T stage
2. Grade
3. Multifocality
4. Positive surgical margins (controversial)
Pathological risk factors for disease relapse include (4):
- Pathologic stage (most important)
  - Most patients with direct or metastatic ipsilateral adrenal involvement, found in 1-2% of cases, eventually die due to systemic disease progression
  - 5-year OS by pT stage
    - pT1a: 90-100%
    - pT1b: 80-90%
    - pT2a: 65-80%
    - pT2b: 50-70%
    - pT3a: 40-70%
    - pT3b: 30-50%
    - pT3c: 20-40%
    - pT4: 0-30%
  - The presence of lymph node or distant metastases is associated with dismal prognosis
    - Median cancer-specific survival for pN1: 2.8 years
- Histological subtype
- Grade
  - See Grade in Kidney Cancer: Pathology and Familial Syndromes
  - Higher Fuhrman grade is an independent prognostic factor for RCC generally and for ccRCC in particular
- Other prognostic factors:
  - Tumour size (independent prognostic factor, despite its correlation with stage)
  - Necrosis
  - Microvascular invasion
  - Sarcomatoid features
  - DNA ploidy
  - Collecting system invasion
Clinical factors associated with prognosis:
1. Performance status (Eastern Cooperative Oncology Group [ECOG])
2. Presence of symptoms (localized or systemic)
3. Cachexia
4. Laboratory: anemia, platelet count, elevated erythrocyte sedimentation rate

Although patient age and comorbidity are important predictors of overall survival in patients with RCC and strongly affect the choice of treatment in these patients, they have no effect on the likelihood of dying of cancer-specific causes.

Prognostic Nomograms in Localized Kidney Cancer

Developed to predict survival
Stage, Size, Grade, and Necrosis (SSIGN) score: tumour stage, size (≥5 cm), grade, and presence of necrosis
University of California Los Angeles Integrated Staging System (UISS): tumour stage, grade, and Eastern Cooperative Oncology Group performance status
Karakiewicz: tumour stage, grade, and symptom classification (systemic vs. local vs. no symptoms at diagnosis)

Molecular markers are not recommended in the routine clinical setting
See prognostic factors for advanced disease in Advanced Kidney Cancer Chapter Notes

Neoadjuvant/pre-surgical therapy for RCC

Neoadjuvant therapy is defined as pre-operative medical treatment for patients undergoing definitive surgical resection of their kidney cancer with curative intent (i.e., non-metastatic disease).
- Aims of neoadjuvant therapy for locally advanced disease (5):

Reduce the risk of recurrence
Reduce the size of tumours to make unresectable tumours resectable
Make PN more feasible
Reduce the rate of positive surgical margins
Simplify the resection of venous thrombus

Indications

2019 CUA Management of Advanced Kidney Cancer Consensus Statement: currently there is no role for neoadjuvant therapy or pre-surgical therapy outside of a clinical trial

Adjuvant therapy for RCC

Adjuvant therapy is defined as post-operative medical therapy after surgical resection with definitive curative intent.
Aim of adjuvant therapy is to decrease the risk of cancer recurrence in patients with features indicative of intermediate- or high-risk for recurrence.
- In patients with kidney cancer, high-risk features for recurrence include (4):
  1. High grade (Fuhrman’s Grade 3 or 4)
  2. High T-stage (>T2b)
  3. Unfavourable histology
  4. Nodal involvement
Indications
- 2019 CUA: adjuvant therapy is not currently recommended outside of a clinical trial
- 2021 AUA: standard of care for patients with fully resected renal cancers remains close clinical and radiographic observation. Patients with a high risk of recurrence should be counseled regarding systemic adjuvant options and/or considered for enrollment into adjuvant clinical trials
Treatments
- Despite demonstrable anti-tumor effects in patients with metastatic disease, one RCT with IL-2 and 3 RCTs with interferon alfa did not prove to be beneficial in the adjuvant setting.
- A variety of autologous tumor vaccine–based approaches have been used in the postoperative setting with negative results
- S-TRAC
  - Population: 615 nephrectomy patients with either ccRCC and non-ccRCC, high-risk according to modified UISS (≥T3, regional lymph-node metastasis, or both)
    - Higher risk than ASSURE
  - Randomized to sunitnib vs. placebo.
    - Sunitnib started within 3 months of nephrectomy
  - Results:
    - Adjuvant sunitnib significantly improved DFS (improvement comparable to time on therapy) but not OS
    - Adjuvant sunitnib FDA approved in 2017, not approved in Canada
  - Ravaud, Alain, et al."Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy." New england journal of medicine 375.23 (2016): 2246-2254.
  ASSURE
  - Population: 1934 nephrectomy patients with ccRCC, pT1b G3−4 N0 (or pNX where clinically N0) M0 to T (any) G (any) N + (fully resected)
  - Randomized to sunitinib vs. sorafenib vs. placebo
  - Results:
    - No significant difference in DFS or OS between the 3 treatment arms
    - Dose reductions were necessary during study due to a high attrition rate from treatment intolerability
  - Haas, Naomi B., et al."Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial." The Lancet 387.10032 (2016): 2008-2016.
- PROTECT
  - Population: 1500 nephrectomy patients with intermediate and high-risk disease
  - Randomized to pazopanib vs. placebo
  - Results:
    - No significant difference in DFS or OS
    - Many required dose reduction due to high attrition rates
  - Motzer, Robert J., et al."Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma." Journal of Clinical Oncology 35.35 (2017): 3916.
- SORCE
  - A phase III randomized double-blind study comparing sorafenib to placebo in patients with resected intermediate- to high-risk RCC
- EVEREST
  - Randomizing nephrectomy patients to everolimus vs. placebo
- ATLAS
  - Population: 724 nephrectomy patients with ≥pT2 and/or N+, any Fuhrman grade RCC
  - Randomized to adjuvant to axitnib vs. placebo
  - Results:
    - Trial was stopped due to futility at the prespecified interim analysis, with no significant difference in DFS observed at that time
- ARIZER
  - Population: 864 nephrectomy patients with ccRCC, pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater
  - Randomized to girentuximab vs. placebo
- PROSPER
  - Randomizing nephrectomy patients to nivolumab vs. placebo
- IMotion
  - Randomizing nephrectomy patients to atezolizumab vs. placebo
- KEYNOTE-564
  - Population: 496 patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy
  - Randomized to pembrolizumab vs. placebo
  - Primary outcome: disease-free survival
  - Results:
    - Disease-free survival significantly improved with pembrolizumab
    - Absolute survival benefit at 24 months: 3.1% (96.6% pembrolizumab vs. 93.5% placebo)
  - Choueiri, Toni K., et al."Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma." The New England Journal of Medicine 385.8 (2021): 683-694.

Follow-up After Treatment of Non-metastatic RCC

Discuss patient's risk of recurrence based on tumour histology, stage, grade, and surgical margin status
Rationale for surveillance

Monitor for (3):
1. Post-operative complications
2. Renal function
3. Recurrence
  1. Local
  2. Contralateral kidney
  3. Distant
Renal function
- Decreases postoperatively and usually improves over time until a new baseline is achieved in ≈3–6 months.

Long-term monitoring of serum creatinine, eGFR, and proteinuria is recommended.
- The aim of renal function surveillance is to prevent or delay CKD and avoid dialysis.
Consider nephrology referral if eGFR <45 ml/min/1.73m2 or progressive CKD develops after surgery, especially if associated with proteinuria

Recurrence
- Most common locations of the first recurrence (4):
- Metastases to the
Early diagnosis of local and contralateral kidney recurrence (incidence <2%) is useful, since the majority can be cured with treatment

Surveillance

Risk-stratified
- 2021 AUA Guidelines (4):
  1. Low-risk: pT1 and Grade 1/2
  2. Intermediate-risk: pT1 and Grade 3/4, or pT2 any Grade
  3. High-risk: pT3 any Grade
  4. Very high-risk: pT4 or pN1, or sarcomatoid/rhabdoid dedifferentiation, or macroscopic positive margin
  - If final microscopic surgical margins are positive for cancer, the risk category should be considered at least one level higher, and increased clinical vigilance should be exercised.
- 2018 CUA Guidelines (4):
  1. Low-risk: pT1
  2. Intermediate-risk: pT2
  3. High-risk: pT3-4
  4. Very high-risk: N+
Investigations
- History and physical exam
  - Signs and symptoms of disease recurrence/progression: weight loss, night sweats, shortness of breath, pleuritic chest pain, hemoptysis, epistaxis, dermatologic involvement, musculoskeletal pain, weakness, or focal neurological deficits
  - Physical exam should assess for
    - Masses in the abdomen/abdominal wall
    - Lymphadenopathy (supraclavicular, axiallary, groin)
    - Lower extremity edema that might suggest recurrence with IVC involvement
- Laboratory
  - 2018 CUA (4):
    1. Serum creatinine, eGFR
    2. Serum chemistries
    3. CBC
    4. LFTs
  - 2021 AUA (2):
    1. Serum creatinine, eGFR
    2. Urinalysis
    - Other laboratory evaluations (e.g., complete blood count, lactate dehydrogenase, liver function tests, alkaline phosphatase and calcium level) may be obtained at the discretion of the clinician or if advanced disease is suspected.
    - With significant nephron mass loss, hyperfiltration can occur resulting in glomerular damage, exacerbation of proteinuria and progressive sclerosis with further decline in GFR., Therefore, repeat assessment of blood pressure, eGFR, and proteinuria should be performed soon after nephrectomy then again in 3-6 months to assess for development or progression of CKD
    - Patients found to have progressive renal insufficiency or proteinuria should be referred to nephrology
- Imaging
  - Regional
    - Abdominal imaging
      - CT or MRI pre- and post-intravenous contrast preferred
        
        MRI has acceptable accuracy to detect musculoskeletal and lymph node metastases, but lower sensitivity to detect pulmonary metastases when compared to CT
      - See schedule below
  - Distant
    - Chest
      - See schedule below
    - Bone scan
      - Not indicated in routine follow-up of treated malignant renal mass
        
        These metastases are usually symptomatic
      - Indications
        
        2021 AUA (3):
        
        Bone pain
        
        Elevated alkaline phosphatase
        
        Radiographic findings suggestive of a bony neoplasm
    - CT/MRI brain and/or spine
      - Not indicated in routine follow-up of treated malignant renal mass
        
        These metastases are usually symptomatic
      - Indication (1):
        
        Acute neurological signs or symptoms
      - Modality
        
        MRI is the most sensitive and specific imaging test for detection of metastatic neoplasms to the brain
  - Other
    - Additional site-specific imaging can be ordered as warranted by clinical symptoms suggestive of recurrence or metastatic spread
    - Positron emission tomography (PET) scan should not be obtained routinely but may be considered selectively.
      - Fluoride PET-CT is more sensitive at detecting RCC skeletal metastases than bone scintigraphy or CT.
      - Currently, PET-CT is not a standard exam for diagnosis, staging, or surveillance in RCC.
Schedule
- 2021 AUA
  - See Table 1 from original 2021 AUA Guidelines
  - Imaging for at least 5 years:
    - Abdominal
      - After 2 years, abdominal ultrasound (US) alternating with cross-sectional imaging may be considered in the low- and intermediate-risk groups at physician discretion.
      - After 5 years, informed/shared decision-making should dictate further abdominal imaging.
        
        The option to use abdominal US instead of CT or MRI s intended to allow continuous monitoring after 5 years, while minimizing radiation exposure/cost in the LR and IR groups.
    - Chest
      - Modality
        
        Chest x-ray low- and intermediate-risk groups
        
        CT chest for high and very high-risk groups.
      - After 5 years, informed/shared decision-making discussion should dictate further chest imaging and chest x-ray may be utilized instead of chest CT for high and very high-risk groups.
- 2018 CUA
  - See Table 1 from Original Guideline for Surveillance Schedule
  - If patient is symptomatic or has an abnormal blood test, earlier radiological investigations may be indicated
  - Low-risk (pT1)
    - Abdominal imaging (CT/MRI/US) is recommended at 24 and 60 months
      - US is less sensitive than CT, however, its use is justifiable and cost-effective in patients with a minimal risk of abdominal recurrence and lower BMI
    - Follow-up is the same for PN for lesions <4 cm, since local recurrence rates in this population are similar to RN
      - Postoperative CT abdomen at 3–12 months is optional for patients treated with PN to evaluate the residual baseline renal appearance
    - Routine imaging beyond 5 years is optional and can be risk-adapted
  - Intermediate-risk (pT2)
    - Abdominal imaging (CT/MRI/US) recommended at 12, 24, 36, and 60 months
    - Routine imaging beyond 5 years is at the discretion of the treating physician
  - High-risk (pT3-4)
    - Abdominal CT or MRI is recommended every 6 months for 2 years, then at 36 and 60 months, then every 2 years
  - Very high-risk (N+)
    - Abdominal CT or MRI is recommended at 3 and 6 months, then every 6 months for 3 years, then yearly
  - Imaging
    - Abdomen
      - CT abdomen/pelvis recommended, particularly in cases of tumour-associated symptoms
        
        Abdominal US may be performed for lower-risk patients (pT1 and pT2)
    - Chest
      - Modality
        
        CXR recommended
        
        CT chest in higher-risk patients due to the higher sensitivity of this test compared to CXR
        
        Can consider alternating CT chest with CXR

Follow-up after ablation
- Patients who have undergone ablation should be followed with contrast-enhanced imaging (MRI or CT) to assess for residual enhancing disease and post-procedure complications.
  - Ultrasound should not be used for post-ablation surveillance
- Schedule
  - 2021 AUA
    - If biopsy confirmed malignancy or was non-diagnostic, pre- and post-contrast cross-sectional abdominal imaging should be done within 6 months after TA.
    - Subsequent follow-up should be according to the intermediate-risk recommendations (see Table 1 from original guidelines)
  - 2018 CUA
    - Surveillance is similar to low-risk except for abdominal imaging (CT or MRI) at 3, 6, and 12 months, then annually thereafter for up to 5 years.
      - CXR is recommended annually during follow-up
    - If pre-treatment biopsy demonstrated oncocytoma and imaging post-ablation shows treatment success, routine imaging beyond one year is not recommended
Follow-up after surgical treatment of benign renal mass
- 2021 AUA:
  - Should undergo at least one postoperative visit to assess patient recovery and laboratory testing to assess renal function.
  - Further surveillance for adverse sequelae of treatment, such as progressive decline in renal function, may also be required selectively.
- Patients who have only had a biopsy without definitive management, may carry a small risk of a missed malignancy and should be considered for surveillance.

Local Recurrence after Radical Nephrectomy or Nephron-Sparing Surgery

Local recurrence is defined as any persistent or recurrent disease present in the treated kidney or associated renal fossa after initial treatment.
- Includes recurrence in the renal fossa, ipsilateral adrenal gland, or ipsilateral retroperitoneal lymph nodes
Uncommon, occurs in 2-4% of cases
Risk factors include locally advanced or node-positive disease and adverse histopathologic features
Associated with a poor prognosis
Management
- Patients who are found to have a new renal primary tumor, or a local recurrence above should undergo a metastatic evaluation (CT chest and either CT or MRI abdomen are preferable).
- 2021 AUA: For appropriately selected patients with good performance status and an isolated new renal primary tumor or a local recurrence, surgery or ablation should be considered for definitive management.
  - Can provide long-term cancer-free status for 30-40% of patients
  - Patients with local recurrence treated non-surgically have a low survival rate
  - The best outcomes are reported in those patients treated with surgical resection for isolated local recurrence only
    - The presence of synchronous metastasis (e.g. lung metastasis) is associated with a significantly lower survival rate.
    - Other factors, including time to local recurrence, location in the ipsilateral adrenal or renal fossa, and size of local recurrence are NOT independently associated with a worse outcome.
Patients with isolated local recurrence after PN can be considered for repeat PN, completion nephrectomy, TA, or AS
See Metastectomy for Distant Recurrence Section in Advanced Kidney Cancer Chapter Notes

Questions

What are the treatment options for a patient with localized kidney cancer?
Which patients should be preferentially treated with partial over radical nephrectomy?
When should nephrology referral be considered prior to surgical management of RCC?
What are the indications of intervention in a patient on surveillance for a small renal mass?
What clinical findings are suggestive of IVC involvement of a renal malignancy?
What is the differential diagnosis of a large, invasive upper quadrant abdominal mass?
As per the CUA guidelines on follow-up after treatment for RCC, when is abdominal imaging indicated in a patient with pT1a disease?

Answers

What are the treatment options for a patient with localized kidney cancer?
1. Radical nephrectomy
2. Partial nephrectomy
3. Thermal ablation
4. Surveillance
Which patients should be preferentially treated with partial over radical nephrectomy?
1. Clinical T1a when technically feasible
2. Solitary kidney (functional or anatomical)
3. Bilateral tumours
4. Multiple tumours
5. Familial RCC syndrome
6. Pre-existing CKD
7. Risk of ESRD after RN
8. Proteinuria
When should nephrology referral be considered prior to surgical management of RCC?
1. Confirmed proteinuria
2. Diabetes with pre-existing CKD
3. eGFR < 45
4. Expected eGFR < 30 after intervention
What are the indications of intervention in a patient on surveillance for a small renal mass?
1. Tumour size >3cm
2. Stage progression
3. Growth kinetics (>5mm/year)
4. Patient preference
What clinical findings are suggestive of IVC involvement of a renal malignancy?
1. Lower extremity edema
2. Non-reducing or right-sided varicocele
3. Dilated superficial abdominal veins
4. Right atrial mass
5. Proteinuria
6. Pulmonary embolus
7. Non function of the involved kidney
What is the differential diagnosis of a large, invasive upper quadrant abdominal mass?
1. Locally advanced RCC
2. Urothelial Ca
3. Adrenal Ca
4. Sarcoma
5. Lymphoma
As per the CUA guidelines on follow-up after treatment for RCC, when is abdominal imaging indicated in a patient with pT1a disease?

24 and 60 months

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 57
Campbell, Steven C., et al. "Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-Up: AUA Guideline Part I." The Journal of urology (2021): 10-1097.