A brief overview of radiotherapy practices and practical guidelines in the management of Gynecological malignancies

1. Radiotherapy Practices in Gynecological malignancies
DR AJEET KUMAR GANDHI
MD (AIIMS), DNB (GOLD MEDALIST)
UICCF (MSKCC,USA)
ASSISTANT PROFESSOR, RADIATION ONCOLOGY
DR RMLIMS, LUCKNOW

2. Optimum radiotherapy utilization rates:
Gynecological cancer
Delaney G. Cancer 2004;101:671–92
Tumor Site Optimal utilization rate
Carcinoma uterine cervix 55-60%
Carcinoma endometrium 35-46%
Carcinoma Vagina 90-100%
Carcinoma Vulva 60%

3. Carcinoma Cervix

4. FIGO STAGING (2009)

5. Staging work up
 Clinical examination including detailed Pelvic examination [under
sedation/Anesthesia]
 HMG/LFT/KFT
 Chest X-Ray
 Biopsy from the cervical growth
 CECT Abdomen/Pelvis or CEMRI Abdomen/Pelvis
 Cystoscopy and Sigmoidoscopy: Only in case of clinical or radiological
suspicion of involvement
 Bone Scan/CECT Chest [Optional]
 Whole body PET-CT [Optional]

6. Management options: Early Cervical Cancers
[Stage I-IIA]
 Radical Surgery*
 Radical RT
 Radical CTRT
 NACT  Radical Surgery*
 BRT  Radical Surgery*
 Concomitant Chemoradiation Adjuvant Hysterectomy
* Adjuvant RT+/- CT

7. Management options: Early Cervical Cancers
[Stage IA 1-2]
 Surgery mainstay of treatment
 Carcinoma in situ: [Multifocal CIS, CIS involving cervix and vagina,
Recurrent CIS]
 Equivalent LDR doses of 45-50 Gray at point A
 Invasive [Medically In-operable patients/ Refusal to surgery]
 Equivalent LDR doses of 60-75 Gray at Point A
 HDR Brachytherapy alone :5- 7 Gray per # in 5-8#

8. Study Design Result Remarks
Landoni F. Lancet
1997
IB-IIA (Surgery vs. RT)
PORT added for high risk
patients
RCT
5 year DFS (83%),OS (74%)
and recurrence rates (25-
26%) identical in both arms
Increased morbidity
in surgery arm
[28% vs. 14%]
Piver MS. Am J Clin
Oncol 1988
IB (Surgery vs. RT)
Non-RCT
5 Year DFS for Surgery vs.
RT [92.3% vs. 91.1%]
5 Year OS rates
equivalent
Perez CA. IJROBP
1987
IB-IIA (RT vs. RT +
Surgery)
Stage IB: 5 Year DFS 80%
vs. 82%
Stage IIA: 5 year DFS 56%
vs. 79%
No difference in
grade 2-3
complications
NO study till date compares Surgery to CTRT (considered the
standard of care now)!!!
Management options: Early Cervical Cancers
[Stage IB-IIA]

9. Management options: Early Cervical Cancers
[Stage IB-IIA]
 Usually a combined decision [Institutional policy, Waiting lists]
 Surgery:
 Young age
 Not suitable for Chemotherapy
 Anticipation for the need of PORT
 Adenocarcinoma histology
 Others: Pregnancy, associated uterine pathologies (pyometra, fibroid, pyosalpinx)
 Chemoradiation:
 Medically inoperable patients
 Imaging s/o pelvic lymphadenopathy
 Postmenopausal patients
 Parametrium borderline positivity on clinical/imaging

10. Study Design Result Remarks
Rotman M. IJROBP 2006
Sedlis A. Gynecol Oncol
1999
IB (Surgery f/b RT versus
Observation) in intermediate
risk patients (2 or more of
DSI,LVSI, >4 cm)
RCT
Recurrence rates: 17% vs. 30.7% No difference in OS
Song S. Gynecol Oncol
2012
Retrospective analysis of RT
vs. CTRT in intermediate risk
patients (n=110)
5 year RFS: 85% vs. 93.8%
Significant decrease in pelvic
recurrence (p=0.012); distant
mets (p=0.027)
Acute grade ¾ GI &
Chronic toxicity not
different
Okazawa M. Int J
Gynecol Cancer 2013
316 patients (stage IB1-IIB)
124: RT
192: CCRT
High risk group: RT vs. CCRT
5 year PFS: 44.3% vs. 72%; 5 year OS: 59.1 vs. 78.2%
(P=0.005)
Intermediate risk:
5 year PFS: 77.5% vs. 90.2% (P=0.049); No difference in
OS
Management options: Early Cervical Cancers
[Adjuvant treatment]

11. Adjuvant treatment: Early Cervical Cancer
 Adjuvant RT:
 Any 2 of the risk factors (Intermediate group): Deep stromal invasion, LVSI,
Large tumor size >4 cm
 Adjuvant CTRT:
 Pelvic lymph node +ve, parametrial +ve, margin +ve
 Radiation dose:
 EBRT: 50.4 Gray/28#/5.5 weeks
 Brachytherapy: Intra Vaginal Brachytherapy 8 Gray/ 2#

12. Carcinoma cervix following Inadvertent
simple hysterectomy
 Inadvertent versus Intentional
 30% of patients with SH presents with gross residual disease*
 Invasive tumor, gross residual tumor:
 EBRT (50.4 Gray) preferably with Chemotherapy
 f/b brachytherapy : Interstitial or Intravaginal
*Sharma DN et al. Asian Pac J Cancer Prev 2011;12:1537–1541
**Saibish kumar et al. Int J Radiat Oncol Biol Phys 2005;63:828–833

13. Management options: Advanced Cervical
Cancers [Stage IIB-IVA]
 Concomitant Chemoradiation +BRT
 Radical RT(EBRT + BRT)
 NACT Concomitant Chemoradiation +BRT
 Concomitant Chemoradiation +BRT  Adjuvant CT

14. Concurrent CRT Results of Meta-analyses
 Vale et al ; JCO : 2008
 18 trials, 4818 pts
 CRT vs RT –
 19% reduction in risk of death
 absolute surv. benefit -6% at 5 yrs
 absolute DFS benefit of 8% at 5 yrs
 5yr loco-regional DFS – 9% benefit
 5 yr survival benefit –
 stage Ib –IIa – 10%
 stage IIb – 7%
 stage III-IVa – 3%
 CRT (platinum vs non-platinum)
– no difference
 Cycle length or dose intensity
of cisplatin – no difference

15. Definitive Extended field irradiation
Author N Study Design Clinical Outcome Acute Toxicity
(Grade 3-4)
Varia MA et al*
[GOG Study]
95 Pelvic + Para-Aortic Irradiation
with concurrent Cisplatin + 5 FU
The 3-year OS and
PFI rate were 39%
and 34%,
Gastrointestinal:
18.6% &
Hematological
:15.1%
William Small Jr et
al #[RTOG 0116
Study]
26 Pelvic + Para-Aortic Irradiation
with concurrent Cisplatin weekly
Estimated disease-
free and overall
survival at 18
months are 46%
and 60%.
The acute Grade
3/4 toxicity rate,
excluding Grade 3
leukopenia was
81%. Late Grade
3/4 toxicity was
40%.
*Int. J. Radiation Oncology Biol. Phys., Vol. 42, No. 5, pp. 1015–1023, 1998
#Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 4, pp. 1081–1087, 2007

17. Dose and fractionation: EBRT
 EBRT:
 50.40 Gy/28#/5.5 weeks [No MLS]
 Concurrent chemotherapy* (Cisplatin 40
mg/m2)
*Avoid in selected cases (non functioning kidney, poor
PS)

18. Dose and fractionation: Brachytherapy
 Brachytherapy:
 ICRT: 7 Gy/3#/3 weeks
 ISBT: 8-10 Gray/2#/2 weeks
 Indications of ISBT:
• Distorted anatomy/non-negotiable OS
• Distal vaginal involvement
• Bulky parametrial disease
• Cervical stump carcinoma and vault
recurrence

19. Definitive extended field CTRT
 45 Gray/25#/5 weeks with concurrent
cisplatin*
 Boost (10 Gray) to pelvic or para-
aortic lymph nodes as required
 Brachytherapy:
ICRT: 7 Gy/3#/3 weeks
ISBT: 8-10 Gray/2#/2 weeks
*Selected patients

20. Recurrent carcinoma cervix
 Loco-regional failure after previous surgery (no radiotherapy):
 EBRT (45-50 Gray) with concurrent chemotherapy->BRT
 After definitive radiotherapy:
 Surgery (central recurrences) +/- IORT
 Re-irradiation: EBRT 36-45 Gray-> BRT (ISBT 15-20 Gray in 3-5#)
 Chemotherapy f/b Reirradiation
 Isolated Para-aortic recurrences:
 EBRT 45-50 Gray with/without concurrent chemotherapy

21. Haemostatic & Palliative RT in carcinoma
cervix
 EBRT
 20-30 Gray in 5-10 fractions
 Brachytherapy
 Haemostatic ICRT/ Ovoid: 8-10 Gray

22. Treatment Overview
Early Stage Carcinoma Cervix
Stage I A1-2
Stage I B-IIA
Surgery
Brachytherapy+/- EBRT
Surgery (Adjuvant RT/CTRT)
CTRT (50.4 Gray/28#/5.5 weeks-> BRT)

23. Treatment Overview
Late stage Ca Cervix
Stage IIB-IIIB Stage IV
Radiotherapy ± Chemo *Stage IVA Stage IVB
EBRT + Brachytherapy (ICRT/ISBT)
[50.4 Gray/28#/5.5 weeks with concurrent cisplatin 40 mg/m2]
*Selected cases
Palliative RT
Palliative CT

24. Carcinoma Endometrium

25. FIGO STAGING 2009

26. WORK-UP
 Hemogram, LFT, KFT
 Chest X-ray
 Endometrial biopsy or aspiration curettage
 Imaging: TVS/ CT scan/ MRI of abdomen & pelvis
 Optional
 Cystoscopy , procto-sigmoidoscopy
 Whole body PET CT

27. EARLY ENDOMETRIAL CANCER-RISK
STRATIFICATION
 FIGO 2009 Stage I EC
 Risk factors for cancer recurrence in Stage I
 >1/2 myometrial invasion
 Grade 3
 Risk grouping
 High (both risk factors)
 Intermediate (any one risk factor)
 Low (grade1/2 with <50% myoinvasion)
Other risk factors:
Age >60 years
LVSI

28. Adjuvant RT: Stage I Endometrial Carcinoma

29. Current Protocol: Operated
G I G II G III
IA Observation Observation Observation or
IVBT*
IB IVBT EBRT+ IVBT EBRT+ IVBT
II EBRT + IVBT
III EBRT + IVBT + Chemotherapy
*Adverse risk Factors [Myoinvasion, Age >60 years, LVSI]
** Stage IV: Palliative RT/ Chemotherapy

30. Dose Practices: Post -op
EBRT doses
 45 Gray in 25# over 5 weeks (stage I)
 50.4 Gray in 28# over 5.5 weeks (stage II-III)
 45-50.4 Gray (Medically in-operable case)
Brachytherapy alone
 7 Gy X 3 sessions, each 1 week apart.
Brachytherapy in Combination with EBRT
 6 Gy X 2 sessions 1 week apart
Chemotherapy (Stage III)
 Sandwich/Sequential 6 cycles of
chemotherapy (Paclitaxel/Carboplatin)

31. Uterine Sarcomas

32. FIGO 2009 Staging for LMS and ESS
FIGO staging for uterine sarcoma. Int J Gynaecol Obstet 2009;104:179

33. FIGO 2009 Staging Adenosarcoma
FIGO staging for uterine sarcoma. Int J Gynaecol Obstet 2009;104:179
Carcinosarcoma is staged according to the FIGO staging
for endometrial adenocarcinoma

34.  Adjuvant radiotherapy
 Carcinosarcoma ( staged and treated as endometrial adenocarcinoma)
 Leiomyosarcoma: Stage II-IVA
 ESS: Stage II-IVA
 Undifferentiated endometrial sarcoma: stage I-IVA
Reed N.S et al, European J of Cancer 44(2008) 808-818
Sampath S et al, Int J Rad Oncol Bio. Phys,76;3:728
Role of pelvic radiotherapy

35.  Not well defined
 Our practice: IVBT (same as endometrial cancers)
Brachytherapy in uterine sarcoma

36. Follow up policy: Cervix & Endometrium
 First visit : 1 months after completion of brachytherapy [Clinical
examination]
 Second visit: 3 months [Clinical examination + pap smear]
 Third visit: 6 months [Clinical + CECT abdomen/pelvis]
 6 monthly till 2 years
 Yearly follow up thereafter

37. Carcinoma Vulva

38. STAGING :FIGO 2009

39. WORK UP AND EVALUATION
 Pelvic Examination preferably under GA.
 Biopsy from primary vulval lesion and also from the
nodes if clinically or radiologically visible.
 Hemogram/LFTs/KFTs/HIV serology
 Chest X-Ray
 CECT Abdomen and Pelvis/MRI Pelvis
 Cystoscopy and proctosigmoidoscopy (Optional)
 PET/CT(Optional).

40. SURGERY
o Radical wide local excision with 1 cm* margin all around with or with I/L or
C/L groin dissection: Current standard of practice
o Radical vulvectomy:
 Multifocal Invasive cancers
 Invasive cancers with extensive VIN
 Extensive vulvular dystrophy
*Heaps J M et al, Obste Gyanacol 38:1990

41. RADIATION THERAPY
 Currently used in variety of settings:
 Radical Brachytherapy (Stage IA/B)
 Postoperative RT/CTRT(?)
 Preoperative RT/CTRT
 Definitive CTRT
 Salvage RT/CTRT
 Palliative RT

42. Post-operative Radiotherapy
 Close (<8-10 mm),positive margins*
 Depth of invasion >5 mm
 LVSI
 More than equal to 2 regional nodes
 Extracapsular perinodal spread

43. Pre-operative RT/CTRT
 An anticipated clinical margin of <1 cm*
 Tumor abutting Pubic arch, anal sphincter or >1.5 cm of distal urethra
 Tumor involving clitoris/vaginal intraoitus(Sexual preservation)
 Extensive (matted, fixed, ulcerated) or unresectable groin metastasis.**
**Gustavo M et al, a GOG study ,IJROBP 48:2000
*GOG protocol 101 study

44. DOSE AND FRACTIONATION: EBRT
Post-operative RT: 50.4 Gray
Pre-operative RT: 45-50.4 Gray
Definitive RT: 45-50.4 Gray (boost 10-15 Gray)

45. Brachytherapy
Brachytherapy:
Alone: 45-50 Gray/15-18#
Boost:18-21 Gray/6-7#
Recurrent: Individualized

46. Carcinoma Vagina

47. FIGO STAGING 2002/2009
• Stage I Confined to Vaginal Wall
• Stage II Invades paravaginal tissues but not pelvic wall.
• Stage IIA Subvaginal infiltration (not PM)
• Stage IIB PM infiltration not upto LPW
• Stage III Extended to pelvic sidewall
• Stage IVA Bowel or Bladder
• Stage IVB Distant mets

48. WORK UP AND EVALUATION
History and clinical examination
Colposcopy
Biopsy/Cervical cytology
CECT Abdomen/Pelvis
Chest X-ray
Cystoscopy/Urethroscopy (ant)
Sigmoidoscopy (post)

49.  RT is the preferred Rx for most patients.
 Ca-in-situ: local surgical excision/RT
 Early stage: surgery or RT (mostly RT)
 Locally advanced: definitive RT
 Distant mets: Pall RT +/- chemo

50. Surgery: Indication
 Stage I disease in the upper posterior vagina/distal vagina
 Stage IVa disease, particularly in the presence of a rectovaginal or
vesicovaginal fistula
 Central recurrence after radiotherapy

51.  Intracavitary RT or Interstitial BT alone
 EBRT + ICRT
 EBRT + Interstitial BT
RADIOTHERAPY

52. Radiotherapy practices: Stage 0-1
 Vaginal intra-epithelial neoplasia:
 Brachytherapy alone (30 Gray in 5#; 60 Gray LDR equivalent)
 Stage I:
 Brachytherapy alone (60-70 Gray equivalent)
 EBRT (45-50.4 Gray) f/b Brachytherapy* (7-10 Gray in 2-3#)
*For more infiltrative and poorly differentiated lesions

53. Radiotherapy practices: Stage II-IVA
 Stage II:
 EBRT (45-50.4 Gray) f/b Brachytherapy (7-10
Gray in 2-3#)
 Stage III-IVA (selected cases)
 EBRT (45-50.4 Gray) with concurrent
chemotherapy**
 Interstitial Brachytherapy (7-10 Gray in 2-3#)
* No randomized data (Extrapolation)
oLesions <0.5 cm:
Intravaginal
brachytherapy
oLesions >0.5 cm thick
or lateral extension:
Interstitial
brachytherapy

54. Brachytherapy in carcinoma Vagina

55. Carcinoma Ovary

56. Whole abdominal radiotherapy: IMRT

57. Current role of radiotherapy
 Salvage radiotherapy: isolated pelvic recurrences
 Palliative radiotherapy
 Intra-operative RT for recurrent cancers
 Consolidative radiotherapy after adjuvant chemotherapy
 Risk stratifications of abdomino-pelvic failures [J Gynecol Oncol 2013; 24:146-53]
 WAR 30 Gray/20# (IMRT) well tolerated
 Ongoing OVAR-IMRT-02 [Rochet N. BMC Cancer 2011; 11:41]

58. Conclusion
 Radiotherapy plays an important and vital role in the management of
gynecological malignancies
 Carcinoma cervix: Radical, Adjuvant [RT for all stages!!]
 Carcinoma endometrium: Adjuvant, Radical
 Carcinoma Vulva: Pre-operative, Adjuvant, Radical
 Carcinoma Vagina: Radical, Adjuvant
 Palliation and haemostatic for all gynecological malignancies
Multidisciplinary decision making and individualization of treatment for
each case is the key to success!!

59. Thanks for your kind attention!!