Endometrial Cancer: More Surgery, Less Radiation

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Endometrial CancerMore Surgery, Less Radiation
Korean Society of Gynecologic Oncology and
Colposcopy May 3, 2002 Larry J. Copeland,
M.D. James Cancer Hospital Ohio State University
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Endometrial Cancer
An Overview

• 39,300 new diagnosis annually (US)
• 6,600 deaths annually
• most common female genital tract
• malignancy
• (Jemal et al CA Cancer J Clin, 5223-47, 2002)

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Endometrial Cancer

• Pelvic and Aortic Nodes are at risk
• for metastatic disease
• Adjuvant treatment planning has
• relied heavily on prognostic profiling
• of the uterus in an attempt to risk for
• the presence of regional disease.
• Why risk profiling when more
• accurate information is available?

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Endometrial Cancer Risk ProfilingCervical
Cancer Corollary
The Cervical Cancer corollary would be to omit
therapeutic lymphadenectomy, evaluate the
surgical specimen (uterus/cervix) for prognostic
factors (depth of invasion, size and LVS
involvement, etc.) and decide on adjuvant
radiation. We do not consider that to be
acceptable therapy for cervical cancer - nor
should we accept a similar treatment plan for
endometrial cancer.
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Endometrial Cancer Risk Profiling
Correlation of Grade and MI with Nodal
Involvement

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Endometrial Cancer
Correlation of Grade and MI with Nodal Involvement

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Node Sampling Unreliable for Diagnosis

• Less than 30 of nodes are palpable
• (Creasman et al, Cancer 602035, 1987)
• 37 of nodal metastasis are lt 2 mm
• (Girardi et al, Gynecol Oncol 49177, 1993)
• Intraoperative prediction by Gyn Onc
• 36 false negative rate, sensitivity of 72
• (Arango et al, Obstet Gynecol 9529, 2000)

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Lymph Node Dissection versus Lymph Node
Sampling
Extent of lymphadenectomy correlates with
survival (Kilgore et al, Gynecol Oncol 5629,
1995) (COSA-NZ-UK, Int J Gynecol Cancer 6102,
1996) Lymphadenectomy is the standard of care
and decreases the need for external radiation
therapy (Orr et al, Am J Obstet Gynecol
176777, 1997) (Podratz et al, Gynecol
Oncol 70163, 1998)
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Lymph Node Dissection versus Lymph Node
Sampling
Pelvic and Aortic node dissections ? improved
survival and fewer retroperitoneal recurrences
(Chuang et al, Gynecol Oncol 58189, 1995)
(Mohan et al, Gynecol Oncol 70165, 1998)
(Mariani et al, Gynecol Oncol 76348, 2000) If
Pelvic and Aortic nodes negative - no XRT
(Gretz et al, Gynecol Oncol 61409, 1996)
(Orr et al, Am J Obstet Gynecol 176777, 1997)
(Berclaz et al, Int J Gynecol Cancer 9322,
1999)
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Adjuvant Radiation TherapyExternal Pelvic
Radiation

• Postoperative radiotherapy in stage I
• endometrial carcinoma reduces local
• recurrences but has no impact on overall
• survival
• 3 Prospective randomized trials
• Aalders et al Obstet Gynecol 56419, 1980
• Roberts et al (GOG) Abstr. Gynecol Oncol
  68135, 1998
• Creutzberg et al (PORTEC) Lancet 3551404,
  2000

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Adjuvant Radiation Therapy No Evidence of
Survival Benefit

• Aalders et al Obstet Gynecol 56419, 1980
• Pelvic XRT 5-Yr Surv. Death Rec. Vag/PV
  Rec
• Yes 89 12.5 2
• No 91 12.3 7
• _________________________________
• Issues
• No lymph node surgery, also vaginal cuff XRT
  given
• 91 survival suggests selection of low risk
  population
• High of vaginal recurrences treated for cure

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Adjuvant Radiation Therapy No Evidence of
Survival Benefit
Roberts et al (GOG 99) Gynecol Oncol 68135,
1998 Pelvic XRT 5-Yr Surv. Vag/PV Rec
Comp. Rate Yes 94 2 15
No 89 (NS) 12
6 _______________________________________________
__________________________________________________
___ Issues Lymph node sampling, not
lymphadenectomy (PLND) Intended to be
intermediate risk - actually low risk
population (18 grade 3) Prognostic subset
analysis XRT 87 vs 73 (Plt0.01) (No
surprise - High risk patients without PLND)
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Adjuvant Radiation Therapy No Evidence of
Survival Benefit
Creutzberg et al (PORTEC) Lancet 3551404,
2000 Pelvic XRT 5-Yr Surv. Vag/PV Rec
Comp. Rate(G3/4) Yes 81 4
25 No 85 (NS) 14
6 _______________________________________________
__________________________________________________
___ Issues Without routine LND, Bx
suspicious nodes Vag recurrence 21 of XRT
patients NED _at_ 2yrs 79 of no XRT patients
NED _at_ 2yrs
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Stage I with PLND and no EBRT Evidence of
Excellent Outcome

• Orr et al, Am J Obstet Gynecol 176777, 1997
• 444 patients TAH/BSO/PVPA LND
• No teletherapy (EBRT)
• Complications Blood loss, infection, DVT
• and surgical mortality similar to lesser Sx
• Late complications Lymphocele (1.2),
• leg edema (1.8), hernia (2.9)
• Survivals Stage IA 100, IB 97, IC 93
• Omission of XRT in SX Staged Good Results

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Pelvic Recurrences
Vaginal recurrence Prevented by brachytherapy,
but 75 cured (Akerman et al Gynecol Oncol
60177, 1999) (Nag et al, 2002 - peer
review) Pelvic sidewall recurrences
Prevented with lymphadenectomy
possibly decreased by external beam radiation in
unstaged patients but costly and complications
high
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Extrauterine Disease Important to Identify
Disease
Significant percentage benefit from
disease-directed local, systemic or combined
therapy (15 - 50 extended survival) (Corn et
al, Gynecol Oncol 5629, 1995) (Gabriel et al,
Int J Gynecol Cancer 8397, 1998) (Selman et al,
Int J Gynecol Cancer 8423, 1998) (49 5 yr
survival stage IIIC with Chemo) (Katz et al, Am J
Obstet Gynecol 1841071, 2001) (McMeekin et al,
Gynecol Oncol 81273, 2001) (77 3 yr survival
stage IIIC with XRT, Chemo)
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GOG122 Endometrial (Stage III/IV)
Whole Abdomen Radiation Therapy
I

• Endometrial Cancer
• Stage III/IV
• No distant mets
• Aortic nodes negative
• Aortic nodes unknown
• Aortic nodes positive
• with neg. scalene
• neg. CXR

Cisplatin 50 mg/m2 Doxorubicin 60 mg/m2
II
x 8
Open 04-May-92 Closed 25-Feb-98 Accrual 389
pts
Conclusions Too early
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Grade 1 Disease Potential Trapfor Under
Staging and Under Treatment

• Thought to be a disease likely to be
• treated satisfactorily with only
• TAH/BSO
• Reliability of assessment of grade and
• myometrial invasion based on
• preoperative and intraoperative
• information is poor

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Grade 1 Disease Under Staging and Under
Treating

• Numerous studies support that at least
• 20 of these patients are under staged
• and under treated by surgery alone
• Malviya et al, Gynecol Oncol 34299, 1989
• Goff et al, Gynecol Oncol 3846, 1990
• Kucera et al, Gynecol Obstet Invest 4962,
  2000
• Petersen et al, Aust NZ J Obstet Gynecol
  40191,2000
• Mariana et al, Am J Obstet Gynecol 1821506,
  2000
• Orr et al, Current Opinion Oncology, 2001

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Grade 1 Disease Under Staging and Under
Treating

• Clear cell and serous variants may be at
• increased risk for nodal disease in the
• absence of myometrial invasion
• Takeshima et al J Obstet Gynecol 88280, 1996
• Cirisano et al, Gynecol Oncol 7755, 2000
• Gehrig et al, Obstet Gynecol 97153, 2001
• Clear cell and serous component often
• not diagnosed until postop path review

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Correlation of Grade DC versus
HysterectomySant Cassia et al, Gynecol Oncol
35,362, 1989

• Hysterectomy
  Grade DC Grade 1 2 3
• 1 75 20
  5
• 2 23 65
  11
• 3 20 35 50

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Cost Considerations

• Lymphadenectomy adds little to cost
• (neither ? hospital stay nor morbidity)
• Radiation therapy External beam therapy
• with or without brachytherapy expensive
• (Konski et al, Int. J Radiat Oncol Biol Phys
  37367, 1997)

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Cost ConsiderationsRadiation Therapy
(Konski et al, Int. J Radiat Oncol Biol Phys
37367, 1997) Radiation Rx Approx. Payor
Cost LD Brachy (Cuff) 3500 Ext Beam (Whole
pelvis) 4100 EBRT Cuff 7200 High Dose Rate
(Cuff) 5400 EBRT HDR Cuff 9200
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How Did We Get to This State of Affairs?
(Compromised Treatment Plan)

• Compare to Cervical Cancer - we do not accept
  avoidance of LND or sampling
• Yet the risk and pathophysiology is similar to
  endometrial cancer
• History Evolution of Gyn Oncologist based on
  the radical procedures - radical hysterectomy
  and radical vulvectomy
• Therapeutic management of regional nodes were a
  component of standard therapy for Cx Vulva

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How Did We Get to This State of Affairs?
(Compromised Treatment Plan)

• There is no controversy about the regional
  disease management for Cervix Vulva - Radiation
  is reserved for clearly defined high risk
  metastatic disease or recurrence
• How did we succumb to a distorted approach
  Endometrial Cancer?

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How Did We Get to This State of Affairs?
(Compromised Treatment Plan)

• During the evolution of the discipline of
  Gynecologic Oncology, endometrial cancer required
  a primary surgical procedure (simple TAH/BSO),
  and radiation was an ingrained and accepted
  component of primary therapy.
• Actually for years the primary therapy was
  preoperative radiation with surgery as the
  adjuvant therapy!

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How Did We Get to This State of Affairs?
(Compromised Treatment Plan)

• It took decades to get over the problem of
  preoperative radiation - it was not until 1988
  that the surgical staging of endometrial cancer
  was adopted.
• Why did we change to surgical staging?
• We had no idea as to the disease extent we were
  treating. Preoperative radiation was distorting
  - down staging - the disease features

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How Did We Get to This State of Affairs?
(Compromised Treatment Plan)

• So how did we enter the process of lymph node
  sampling? This was evolving in the late 70s
  early 80s and it was the gynecologic
  oncologists idea!
• What was the motivation - possibly debulking
  clinically suspect nodes
• Why was lymph node dissection avoided - possibly
  to avoid the recognized complications of
  combining radiation with extensive surgery

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Why Not Move On and Do It Correctly?

• The data has evolved to support that every
  patient with endometrial cancer should undergo a
  pelvic and aortic lymphadenectomy and radiation
  should not be used in any surgically staged
  patient with disease limited to the uterus,
  regardless of prognostic profile of grade, MI,
  age, etc.

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Why Did it Take So Long toFigure This Out?

• The understanding of this disease, both the
  biology (risk of metastatic disease) and the role
  of adjuvant therapy has been compromised by
  incomplete data based upon incomplete surgical
  staging

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We Need to Move Along!

• But the data are now there and the modality of
  optimal treatment is not the issue now
• The challenge now is the institution of the
  correct treatment
• Turf is an inhibitor. Who does the surgery is
  not as important as to how well it is done!

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We Need to Move Along!

• Quality of lymphadenectomy Honesty is needed.
  Pathology reports reflecting 1 or 2 nodes per
  pelvic or aortic node dissection is not a
  satisfactory surgical intervention.
• Worse yet, nodules of fat do not constitute a
  lymphadenectomy

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A Rad Onc Speaks!

• Adjuvant XRT in EC least satisfying
• most patients do not benefit from XRT
• Historic selection inadequate - unnecessary XRT
  treatment for many
• Women in my family treated with comprehensive
  surgical staging unless disease beyond uterus
  adjuvant teletherapy would not be administered
• Russell - Editorial, Gyn Oncol 84,191, 2002

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Conclusions

• 1) All EC patients are at risk for nodal dz
• 2) Preop and intraoperative assessment of
• prognostic features are unreliable
• 3) All patients should have therapeutic pelvic
• and aortic lymphadenectomy
• 4) LND reduces need for adjuvant radiation
• 5) It is a serious challenge to our discipline to
• correct the current practice patterns

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