Role of surgery in metastatic renal cell carcinoma,Role of metastatectomy, Role of lymphadenectomy, Literature review,CARMENA Trial

1. CYTOREDUCTIVE
NEPHRECTOMY
Dr.Bhavin
Vadodariya

2. •Metastatic renal-cell carcinoma has diverse clinical presentations
ranging from incidental detection to a highly symptomatic systemic
illness.
•Patients with metastatic renal-cell carcinoma are assigned a risk
category — favorable, intermediate, or poor — on the basis of two
published models containing five or six pretreatment selection
factors, including source of immunosuppressive or tumor-promoting
growth factor.

3. Comparison of Risk Factor Criteria for RCC:
Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic
Foundation (CCF)
Risk groups are defined as follows:
Favorable: 0 risk factors present
Intermediate: 1 or 2 risk factors
Poor: 3,4, or 5 risk factors
Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.
mRCC Database Consortium 2013
Factor Poor Prognostic
Factor
Karnofsky Performance
Status
<80
Time from diagnosis to
Treatment
< 12 months
Anemia Hb below normal
Hypercalcemia Corrected serum Ca
above normal
Neutrophilia ANC above normal
Thrombocytosis Platelet count above
normal
MSKCC Criteria 2002
Factor Poor Prognostic
Factor
Time from diagnosis to
treatment with IFN-alfa
< 12 months
Hemoglobin < lower limit of
laboratory’s reference
range
Lactate dehydrogenase > 1.5 X the upper limit
of laboratory’s range
Corrected serum
calcium
> 10.0 mg/dL
Karnofsky Performance
Status
< 80

4. PARTS
Nephrectomy may be performed as part of a combined modality
approach in order to decrease the bulk of the tumor prior to systemic
therapy.
●Metastasectomy may be performed in patients with one or a very
limited number of metastases.
●Palliative nephrectomy may be performed to control severe local
and systemic symptoms from the primary tumor.

5. WHY TO DO
Nephrectomy for stage IV disease removes the primary kidney tumor
and its potential for bleeding and pain during subsequent systemic
therapy for metastases.
In addition, nephrectomy could possibly eliminate the primary tumor
as a potential , source of immunosuppressive or tumor-promoting
growth factors.

6. WHY NOT TO DO
Avoiding surgery can provide other benefits for patients.
Initial nephrectomy can delay the start of systemic targeted therapies
that have shown a survival benefit, and patients may die before
receiving such therapies.
Avoiding nephrectomy also avoids surgical complications involving
blood transfusions, further operations, or intensive care, which may
also delay systemic therapy.
In addition, there is uncertainty about which patients are appropriate

8. THE SOUTHWEST ONCOLOGY
GROUP (SWOG)
Randomly assigned 246 patients presenting with RCC to
treatment with nephrectomy followed by interferon alfa (IFNa; 5
million units/m2 three times weekly) versus immediate
treatment with IFNa .
Compared with IFNa alone, nephrectomy before treatment
resulted in a statistically significant improvement in overall
survival (median 11 versus 8 months, respectively).
Among those who underwent nephrectomy plus IFNa, patients
with a performance status (PS) of 0 survived longer than those

9. EORTC LANCET 2001 :RCT

10. EORTC LANCET 2001 :RCT
•83 Patients with metastatic RCC were randomly assigned to the same
treatment arms as in the SWOG study above .
•Both time to progression (median five versus three months) and
overall survival duration (median 17 versus 7 months) significantly
favored cytoreductive nephrectomy prior to immunotherapy.

11. In 2001, two randomized, phase 3 trials showed a survival advantage
with nephrectomy plus interferon over interferon alone and
nephrectomy became the accepted first step in management.
With the addition of sunitinib and similar drugs targeting
angiogenesis, nephrectomy continued to be used, under the
assumption that the therapeutic benefit was unchanged.

12. However, concerns were raised that the operation, particularly in
poor-risk patients, could lead to perioperative complications coupled
with disease progression during surgical recovery, thus preventing
patients from receiving sunitinib and hindering the potential for
longer survival.
Also, the observation that sunitinib (unlike interferon) could cause
regression of the primary renal tumor deterred many oncologists
from recommending routine nephrectomy, thus decreasing its use.

13. PATIENT SELECTION
•There is no universal approach to selection of the appropriate patient
with metastatic RCC who should be offered cytoreductive
nephrectomy.
•In general, the selection of patients should be done with considerable
care so that appropriate patients can proceed with systemic therapy.

15. ●Greater than 75 percent tumor debulking possible
●Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
●Adequate organ function
●No evidence of extensive liver or bone metastases or any central
nervous system involvement

16. Overall Survival
Cytoreductive nephrectomy
Median OS 20.6 vs 9.5 months (p<0.0001)
Adjusted HR 0.60 (95%CI 0.52-0.69, p<0.0001)
OverallSurvival
No Cytoreductive nephrectomy
Months Since Initiation of Targeted Therapy

17. Using IMDC Prognostic Factors
# of IMDC
Criteria
Met
No CN OS
months
(N)
CN OS
month
s (N)
P value
0 92% (65/71) patients had CN, insufficientnumber to
compare
1 22.5 (n=72) 30.4 (n=178) 0.0024
2 10.2 (n=143) 20.2 (n=253) <0.0001
3 10.0 (n=113) 15.9 (n=106) <0.0001
4 5.4 (n=103) 6.0 (n=67) 0.1664
5 3.6 (n=36) 2.8 (n=14) 0.5044
6 25% (3/12) patients had CN, insufficient number to
compare

18. JOURNAL OF UROLOGY 2011 IMDC
The study by the International Metastatic Database Consortium (IMDC), patients with
estimated overall survival <12 months or four or more of the prognostic factors
identified by the IMDC did not benefit from nephrectomy
•Anemia
●Thrombocytosis
●Neutrophilia
●Karnofsky Performance Status (KPS) <80 percent
●<1 year from diagnosis to treatment

19. CARMENA

20. METHODS
In this phase 3 trial, they andomly assigned, in a 1:1 ratio, patients
with confirmed metastatic clear-cell renal-cell carcinoma at
presentation who were suitable candidates for nephrectomy to
undergo nephrectomy and then receive sunitinib (standard therapy)
or to receive sunitinib alone.
Randomization was stratified according to prognostic risk
(intermediate or poor) in the Memorial Sloan Kettering Cancer Center
prognostic model

21. INCLUSION CRITERIA
Adults (≥18 years of age) with clear-cell renal-cell carcinoma
confirmed on mandatory biopsy and documented metastatic
disease.
 Patients were required to have an Eastern Cooperative
Oncology Group (ECOG)
Performance-status score of 0 or 1,
An absence of brain metastases or treated brain metastases
without recurrence 3 weeks after treatment,
Acceptable organ function.

22. EXCLUSION CRITERIA
Previous systemic treatment for kidney cancer (including VEGF-
targeted therapy) or
Anticoagulants
Any medical condition, including cardiovascular disease,

23. Nephrectomy was performed within 28 days after randomization,
according to the normal procedures of the institute.
In the sunitinib-only group, sunitinib treatment was initiated within
21 days after randomization and was given at an initial dose of 50
mg daily in cycles of 28 days on followed by 14 days off every 6
weeks.

24. In the nephrectomy–sunitinib group, sunitinib treatment was initiated
between 3 and 6 weeks after nephrectomy.
Dose reductions or interruptions of sunitinib treatment were
permitted to manage
adverse events.
After recruitment and randomization, each patient was followed for a
minimum

27. RESULTS
The median follow-up of the patients was 50.9 months overall.
In both the intermediate-risk and poor-risk groups of patients, the
median overall survival was longer in the sunitinib-alone group than
in the nephrectomy– sunitinib group (23.4 vs. 19.0 months in the
intermediate-risk subgroup and 13.3 vs. 10.2 months in the poor-
risk group).

28. In the intermediate-risk population, the hazard ratio for death in the
sunitinib-alone group, as compared with the nephrectomy–sunitinib
group, was 0.92 (95% CI, 0.68 to 1.24), and in the poor-risk
population, the hazard ratio was 0.86 (95% CI, 0.62 to 1.17).

29. The median progression-free survival was longer among patients in
the sunitinib-alone group than among those in the nephrectomy–
sunitinib group (8.3 months [95% CI, 6.2 to 9.9] vs. 7.2 months [95%
CI, 6.7 to 8.5]) .
The hazard ratio for progression or death, stratified according to risk
group, was 0.82 (95% CI, 0.67 to1.00).

30. LIMITATIONS
Enrolled patients were appropriate candidates for nephrectomy in the
opinion of the treating urologist; therefore, the results are not
generally applicable to patients with a poor performance status,
minimal primary tumor burden, and high volumes of metastatic
disease, because these patients are not generally recommended to
undergo nephrectomy

31. The use of MSKCC risk groups, which were the risk groups in
common use at the time the trial was launched, is an unavoidable
limitation of this analysis, since these are not as relevant as IMDC risk
groups in the era of targeted therapy.
In addition, the inclusion of patients with minimal tumor burden
could have resulted in different survival outcomes. more likely to
have T3 or T4 disease (conferring higher risk) than the sunitinib alone

32. Because this was a noninferiority trial, the results may underestimate
the benefit of nephrectomy.
Another imitation of this trial is the recruitment of fewer patients
than planned (450 patients rather than 576), which reduced the
statistical power.
However, the trend in longer overall survival and progression-free
survival among patients who did not undergo nephrectomy suggests
that their conclusion is correct

33. Finally, the exclusion, at the investigator’s discretion, of patients with
low metastatic burden could be considered to result in a potential
bias, and this situation may have contributed to the high proportion
of patients with features indicating poor prognostic risk and the
relatively short overall survival that was observed in the trial.
These patients are usually considered to be good candidates for
nephrectomy followed by surveillance.

34. In the cytoreductive nephrectomy arm, 18% of patients did not receive
sunitinib and 7% of patients did not receive nephrectomy.
Furthermore, in the sunitinib alone arm, 17% of patients underwent
cytoreductive nephrectomy.
Per- protocol analyses attempt to account for this attrition with
censoring,but the inevitable biases resulting from these deviations pose a
substantial challenge for the interpretation of the CARMENA results.

35. CONCLUSION,
in this trial, sunitinib alone was not inferior to nephrectomy followed
by sunitinib in patients with metastatic renal-cell carcinoma who were
in the MSKCC intermediaterisk or poor-risk groups.

38. SURTIME
The SURTIME trial randomized patients with de novo mRCC to either
upfront surgery followed by sunitinib, or sunitinib followed by a
delayed nephrectomy.
After nearly 6 years, the study accrued only 99 patients across 19
institutions.

40. Although SURTIME was severely underpowered to draw definitive
conclusions, an analysis stratified by World Health Organization
(WHO) performance status identified a trend towards improved overall
survival (OS) in patients who received deferred compared with
immediate nephrectomy (32.4 versus 15.1 months; HR 0.57, 95% CI
0.34–0.95, P = 0.032).
.

41. Substantial attrition from the prescribed study therapy in SURTIME
(for example, surgery or sunitinib) further clouds the interpretation of
these results
The study closed after 5.7 years with 99 patients entered by 19
institutions.
As of May 5, 2017, median follow-up is 3.3 years.
In the immediate CN arm, 46 of 50 patients had CN, 40 of 46 had
post-CN sunitinib. In the deferred CN arm, 48 of 49 patients had

42. PFR was 42.0% (CI: 28.2 – 56.8) and 42.9% (28.8 – 57.8) in the
immediate and deferred arms, resp (p > 0.99).
The OS HR (stratified by WHO PS) of intention to treat (ITT) with
deferred versus immediate CN in all patients was 0.57 (CI: 0.34 –
0.95, p = 0.032) with a median OS of 32.4 (14.5-65.3) and 15.1
months (CI: 9.3, 29.5), respectively.

45. CONCLUSION-SURTIME
The sequence of CN and sunitinib did not affect the PFR at 28 weeks.
The sample size precludes definitive conclusions from other
endpoints.
Although an OS signal was seen for deferred CN. CN after sunitinib
appears safe.

46. JOURNAL OF UROLOGY 2017

47. LYMPHADENECTOMY SHOULD BE
DONE OR NOT?

48. A possible benefit of retroperitoneal lymphadenectomy in the context
of nephrectomy and systemic therapy for patients presenting with
stage IV disease has not been well studied (but at least one report
suggests that there is no advantage to this approach and suggest that
the presence of retroperitoneal nodes is a strong predictor of
systemic treatment failure.

49. 305 patients treated with cytoreductive nephrectomy for metastatic
renal cell carcinoma between 1990 and 2010, of whom 188 (62%)
underwent lymph node dissection.
In this study author did not identify an oncologic benefit to LND in
the overall cohort of patients with M1 RCC, nor among high risk
subgroups, including patients with preoperative lymphadenopathy or
across increasing threshold probabilities for pN1 disease.

50. On the contrary, pN1 status was associated with an increased
incidence of more aggressive primary tumor features and poor
survival.
These findings suggest that nodal metastases may reflect a more
aggressive disease biology, which may in part explain the absence of
a therapeutic benefit to LND.
Elimination of LND from CN would allow greater use of a minimally
invasive surgical approach,

51. LND in Metastatic RCC
• Why?
– May be prognostic in the
setting of M1 disease
– Might be therapeutic
– May guide subsequent
therapy decisions
– No added morbidity
• WhyNot?
– May add morbidity and
delay therapy
– How can it be therapeutic in
the setting of distant mets?
– Information gained is not
worth the effort; Doesn’t
guide therapy decisions

52. LND in Metastatic RCC
• Is definitely prognostic!
• May be therapeutic, especially in the setting of clinically or
pathologicallypositivelymph nodes
• Informationgained from LND may guide subsequent therapy
decisions
• Metastasectomy versus systemic therapy
• What type of systemic therapy?
• Little to no added morbidity associatedwith a limited template
dissection

53. Resection Of Retroperitoneal Nodal Metastases In
Patients With Metastatic Conventional Renal Cell
Carcinoma: The MDACC Experience
• 1990 to 2007
• 322 - TanyN0M1
• 55 - TanyN1-2M1
• Clear cell histology
• Retroperitoneal adenopathy only

54. Hazard Ratio(95%
CI) P
Median Survival
(mos)
N0M1 Referent -- 28.4
N1-2M1 + LND
1.53
(1.04, 2.25)
0.03 18.3
N1-2M1
No LND
3.10
(1.95, 4.91)
<0.001 9.8

55. METASTASECTOMY
Resection of metastatic disease (metastasectomy) has been
performed in several situations:
●Patients with stage IV disease at presentation, where it is performed
with nephrectomy
●Patients who develop metastatic disease following nephrectomy
●Patients who have persistent disease despite systemic therapy

56. JCO 1998

57. In selected patients with metastatic renal cell carcinoma (RCC),
surgical resection of metastatic foci, known as metastasectomy, is a
treatment option that can yield long-term disease-free survival
The potential role of surgery is illustrated by the results from a series
of 278 patients with recurrent RCC in which
 51 percent underwent removal of all of their metastatic disease with
curative intent
, 25 percent underwent partial resection of their metastatic disease,
 24 percent were treated without surgery

58. The five-year overall survival rate was highest in patients treated with
curative-intent metastasectomy (44 versus 14 and 11 percent,
respectively).
Survival rates after complete resection of a second and third
metastasis were not different from those after initial metastasectomy.

59. THE STRONGEST PREDICTORS OF
PROLONGED SURVIVAL
Disease-free interval from nephrectomy to detection of metastases
of greater than one year (55 versus 9 percent five-year overall
survival),
A single site versus multiple sites of metastases (54 versus 29
percent five-year survival),
If the site was the lung, an Eastern Cooperative Oncology Group
(ECOG) performance status of 0 or 1
The absence of prior cytotoxic chemotherapy or of significant recent

60. LUNG METASTASES: CANCER 2011

61. Surgical resection of isolated lung metastases in carefully selected
patients has been associated with a 20 to 50 percent five-year
survival.
Complete resection of lung-only metastases is associated with
markedly improved survival as compared with incomplete resection
(five-year cancer-specific survival 73.6 versus 19 percent,
respectively)
PS [0,1],Complete resection , localized primary,Synchronous

62. ISOLATED BONE METASTASES
J

63. Excision of bone metastases may be considered in carefully selected
patients for both pain relief and tumor control
295 consecutive patients with metastatic RCC who had a solitary
lesion, intractable pain, or impending fracture underwent resection
Overall, the one- and five-year survival rates were 47 and 11 percent.
Stereotactic radiosurgery (SRS) is increasingly being used to treat
oligometastatic bony disease and may extend targeted-therapy
treatment

64. BRAIN METASTASIS ,CLIN GU
CANCER SEP 2013

65. BRAIN METASTASIS
Brain lesions have been traditionally treated with surgical resection,
whole-brain irradiation, or SRS.
SRS alone may be an attractive therapeutic option for patients with
incidentally identified brain metastases from RCC
However, regardless of the treatment approach, the prognosis is
poor, and median survival in patients with brain metastases is
approximately nine months.

66. POOR PROGNOSIS-BRAIN
METASTASIS
●Performance status at the start of therapy <80 percent
●Diagnosis to treatment time <12 months
●>3 sites of brain metastases

67. LIVER METASTASES

68. LIVER METASTASES
Despite the negative impact of liver metastases on survival ,
resections of solitary metachronous liver metastases are possible,
although the morbidity may be high .
Contemporary reports suggest that with careful patient selection,
two-year survival is greater than 50 percent.

69. LIVER METASTASES
Factors that may identify appropriate patients for hepatic
metastasectomy include those in whom surgery is being performed
with curative intent,
An interval of more than 24 months from RCC diagnosis to
development of liver metastases,
Tumor size less than 5 cm,
the feasibility of repeat hepatectomy if necessary

70. THYROID METASTASES
American Journal of clinical oncology 2009

71. THYROID METASTASES
RCC commonly metastasizes to the thyroid gland .
 Fine needle aspiration is essential to make this diagnosis.
Limited data suggest that metastasectomy may confer a survival
advantage.
 In this study of 97 patients with thyroid metastases (22 percent
from a renal primary), median survival time was 30 and 12 months
for those who underwent metastasectomy compared with those who
did not .

72. THYROID METS
Poor prognostic indicators were patient age >70 years and prior
nephrectomy for contralateral renal metastases.

73. PANCREATIC METASTASIS
BJS 2009

74. PANCREATIC METASTASIS
Patients with pancreatic metastases seem to have a better prognosis,
which may be a result of a more indolent biology.
In addition, patients who present with pancreatic metastases also
respond better to targeted agents , although the reason for this is
unknown.

75. PANCREATIC METASTASIS
A systematic literature review of 384 patients with RCC metastases to the
pancreas managed with (n = 321) or without (n = 73) metastasectomy
revealed five-year overall survivals of 73 and 14 percent, respectively .
The postoperative in-hospital mortality associated with pancreatic resection
was 2.8 percent.
The presence of extrapancreatic RCC metastases was associated with worse
disease-free survival, and symptomatic metastases were associated with
worse overall survival.
Surprisingly, the size of the largest tumor resected, number of pancreatic
metastases, type of pancreatic resection, and interval from diagnosis of RCC

76. PALLIATIVE NEPHRECTOMY
Local symtomps- Hematuria, Clot colic
Systemic Paraneoplastic Syndromes, ypercalcemia, fatigue, fever,

77. LOCAL RECURRENCE
Although the majority of patients who develop a local soft tissue
recurrence die of metastatic disease, the limited data suggest that
resection of the recurrence may prolong survival in carefully selected
patients
As with metastatic disease, patients with a longer time to recurrence
following nephrectomy and with small-volume recurrent disease tend
to do better.

78. TAKE HOME-CARMENA
Cytoreductive surgery should be offered to favourable risk according
to MSKCC or IMDC criteria.
For patients who have metastatic RCC at presentation, a good
performance status, and a resectable primary tumor with low tumor
burden outside the kidney, upfront debulking (cytoreductive)
nephrectomy as the preferred initial approach

79. TAKE HOME- SURTIME
For patients with limited tumor burden, we suggest metastasectomy
rather than immediate treatment with systemic therapy .
This approach has been associated with prolonged disease-free
survival in selected patients.

80. For patients with one to three readily resectable metastases at
presentation or who relapse following initial surgical treatment and
have a disease-free interval >1 year, we suggest metastasectomy
rather than immediate initiation of systemic therapy

81. THANK YOU