Radiotherapy uterine carcinoma cervix carcinoma brachytherapy in uterine carcinoma brachytherapy in cervical carcinoma detailed decription explanation about recent recommendations explanations about landmark trials one shot whole ppt for learning about EBRT and brachytherapy in cervical and uterine carcinoma

1. Radiotherapy in Uterine & Cervical Carcinoma
Dr Atul Gupta
DM Resident
Radiotherapy & Oncology
AIIMS Jodhpur

2. Role of Radiotherapy in Uterine Carcinoma

4. Endometrial Cancer : Basic Management Principles-
• Work-up & Diagnosis – Imaging, Biopsy/Curettage/Histology type
• Mostly present in Early stage due to early symptoms
• Surgery- Mainstay of treatment
• Detailed Histopathology – Mandatory
• Surgical – Pathological FIGO staging---- helps in tailoring adjuvant treatment
• Adjuvant Therapy –
1. RT---well established modality
2. Chemotherapy/CTRT--- attempted in high risk and ongoing RCTs

5. Quick Recap of Surgical Aspect –
 Mainstay of treatment – Surgery (Hysterectomy with BSO with peritoneal cytology with some form of LN assessment)
 BSO is recommended- d/t ~10% patients may have adnexal involvement
Synchronous cancer can be ruled out (<5% in <50 yrs of age)
ovarian mets vs synchronous primary
 Open vs Minimal- 5 yrs OS similar
Post Op complications- less in minimally invasive (less hospital stay, less moderate to severe postop
events)
 In Clinical stage-I endometrial carcinoma- Pelvic Lymphadenectomy didn’t improve OS .
 Stage II Endometrioid Adenocarcinoma – Radical Hysterectomy not recommended.
Total Hysterectomy + BSO and LN staging---- SOC
 Stage III/IV Endometrioid Adenocarcinoma- Complete macroscopic cyto-reduction and comprehensive staging
recommended.
 Non-EEC (apparent stage I)- Lymphadenectomy is recommended.
 Staging Omentectomy- should be considered in serous carcinoma.

6. Prognostic Factors in Endometrial Cancer-
Adverse Prognostic Factors-
1. Depth of myometrial invasion
2. Cervical stroma involvement
3. Adnexal Involvement
4. Pelvic/Para-aortic LN
5. Extension into bladder/rectum
6. Distant spread
Does Stage Matter ? Stage- correlates directly with risk of recurrence (NRG/GOG study- Stage I- ~9.8% , Stage II-
~21.6%, Stage III ~ 38.9%)
Does Age Matter ? Older Age- Adverse impact (>60yrs- shown to be predictive of loco-regional recurrence)
Does Grade Matter ? Grade 1/2- no significant difference in prognosis-- low grade
Grade 3- clearly worse outcome ---- high grade
Does Histology Matter ? NRG/GOG study- Survival and recurrence rates for patients with clear cell carcinoma similar to
endometrioid Grade III disease but were significantly better that serous endometrial carcinoma
LVI- prognostic significance depends on its extent and presence of other prognostic factors.

7. Molecular Subtypes-
1. POLEmutant--- most favorable
outcome
2. p53 mut--- poorest prognosis
3. MSI group--- 1.5 to 2 fold higher
risk of death compared to p53
wild type

8. Low Risk (IA G1-2 LVSI negative)
 For patients with low-risk endometrial carcinoma, no adjuvant treatment is recommended (I, A).
 When molecular classification is known:-
• For patients with endometrial carcinoma stage I–II, low-risk based on pathogenic POLE-mutation, omission of
adjuvant treatment should be considered (III, A).
• For the rare patients with endometrial carcinoma stage III–IVA and pathogenic POLE-mutation, there are no
outcome data with the omission of the adjuvant treatment. Prospective registration is recommended (IV, C).
 Surgery alone--- Total hysterectomy + BSO
 No Lymphadenectomy, no RT
 95% relapse free survival
 No Vaginal Brachytherapy recommended

9. Intermediate Risk
• Stage IB endometrioid + low-grade‡ + LVSI negative or focal
• Stage IA endometrioid + high-grade‡ + LVSI negative or focal
• Stage IA non-endometrioid (serous, clear cell, undifferentiared carcinoma, carcinosarcoma, mixed) without myometrial
invasion
 Adjuvant RT to be given
 IVBT vs Pelvic RT ? ------- Addressed by two RCTs
 Omission of Pelvic RT in favor of IVBT does not significantly increase risk of
vaginal recurrence.
 Neither Pelvic RT nor Pelvic Lymphadenectomy has been shown to improve
survival in pts with early stage endometrial cancer.
 No adjuvant treatment is an option, especially for patients <60yrs age (II,C)
1. PORTEC-2 trial---
• 10 yr update (2018)
• EBRT vs IVBT was compared
• 10 yrs vaginal recurrence- 3.4% versus 2.4% for IVBT vs. EBRT
• No significant difference in OS/DFS
• 10 yrs isolated pelvic recurrence- not statistically different
• More GI and GU toxicity with EBRT---- deteriorates QOL
2. Sorbe et al(2012)---
• Five-year locoregional relapse rates were 1.5% after EBRT plus IVBT and 5% after IVBT alone (P =
0.013)
• 5-year overall survival (OS) rates were 89% and 90%, respectively.
• More GI and GU toxicity with EBRT combination---- deteriorates QOL

10. In Nutshell- (For Early Stage Endometrial Cancer)-
• If Post-op RT is required--- IVBT preferred option
• ~80% recurrences-- vaginal
• And better toxicity profile

11. High-Intermediate Risk
► Stage I endometrioid + substantial LVSI regardless of grade and depth of invasion
► Stage IB endometrioid high-grade‡ regardless of LVSI status
► Stage II
If pN0 after surgical staging-
 In view of the higher risk of recurrence in this newly classified group (even with negative nodes), adjuvant
brachytherapy can be recommended to decrease vaginal recurrence.
 In the case of substantial LVSI and/or stage II, EBRT can be considered as it has been shown to reduce the risk of
pelvic and para-aortic nodal relapse.¹
1. Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus
paclitaxel/carboplatin in high-intermediate and high-risk early-stage endometrial cancer. JCO 2019;37:1810–8.
► Adjuvant brachytherapy can be recommended to decrease vaginal recurrence (II, B).
► EBRT can be considered for substantial LVSI and for stage II (I, B).
► Adjuvant chemotherapy can be considered, especially for high-grade and/or substantial LVSI (II, C).
► Omission of any adjuvant treatment is an option (IV, C).

12. If cN0/pNx (LN staging not done)-
Recommendations -
► Adjuvant EBRT is recommended, especially for substantial LVSI and/or for stage II (I, A).
► Additional adjuvant chemotherapy can be considered, especially for high-grade and/or
substantial LVSI (II, B).
► Adjuvant brachytherapy alone can be considered for high-grade LVSI negative and for stage
II grade 1 endometrioid carcinomas (II, B).
*PORTEC III, GOG 249, GOG 99

13. High Risk Endometrial Cancer
► Stage III–IVA with no residual disease
► Stage I–IVA non-endometrioid (serous, clear cell, undifferentiated carcinoma, carcinosarcoma, mixed) with myometrial
invasion, and with no residual disease
1. PORTEC III Trial – (Update 2019)-
• With a longer median follow-up of 72 months and with 75% of participants having reached 5 years of follow-up, were
published.
• Compared Combined chemotherapy and radiotherapy (two cycles of cisplatin during radiotherapy followed by four
cycles of carboplatin-paclitaxel) with radiotherapy alone.
• A statistically significant 5% overall survival benefit at 5 years and a 7% failure-free survival benefit was seen in the
combined therapy group compared with radiotherapy alone.
• The greatest overall survival difference was seen in stage III carcinomas and in serous carcinomas regardless of stage.

14. 2. GOG-258 Trial – (Phase III RCT)-
• Compared CTRT to Chemo alone
• 736 patients with Stage III & IVA, Stage I/II Serous or clear cell endometrial ca with positive cytology
• Adj Chemotherapy ( 6 cycles of Pacli + Carbo) vs CTRT f/b 4 cycles of Pacli + Carbo
• Median follow-up of 47 months
• No difference in 5 yr RFS
• CTRT-- a/w lower rates of vaginal and pelvic/para-aortic recurrence but more distant recurrence
Recommendations-
► EBRT with concurrent and adjuvant chemotherapy (I, A) or alternatively sequential
chemotherapy and radiotherapy is recommended (I, B).
► Chemotherapy alone is an alternative option (I, B).
► Carcinosarcomas should be treated as high-risk carcinomas (not as sarcomas) (IV, B).

15. Principles of Radiation Therapy for Uterine Neoplasms
General Principles-
• RT is directed at sites of known or suspected tumor involvement and may include EBRT and/or brachytherapy.
• Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT.
• In general, EBRT is directed to the pelvis with or without the para-aortic region.
Target Volumes-
• Target Volumes Pelvic radiotherapy should target the gross disease (if present), the lower common iliacs, external iliacs,
internal iliacs, obturators, parametria, upper vagina/para-vaginal tissue, and presacral lymph nodes (in patients with
cervical involvement).
• Extended-field radiotherapy should include the pelvic volume and also target the entire common iliac chain and para-
aortic lymph node region. The upper border of the extended field depends on the clinical situation but should at least
be 1–2 cm above the level of the renal vessels.
• Pelvic tissues at risk, especially in the post-hysterectomy setting, can be highly variable depending on bowel and
bladder filling. In this situation, the internal target volume (ITV), which encompasses the range of organ movement and
deformation, is considered the clinical target volume (CTV), and should be fully covered in the treatment volume.

16. Dosing Prescription-
1. EBRT –
• External-beam doses for microscopic disease should be 45–50 Gy. CT treatment planning should be
utilized, and intensity-modulated RT (IMRT) for normal tissue sparing should be considered.
• Treating with IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with
or without para-aortic treatment.
• Postoperatively, if there is gross residual disease and the area(s) can be sufficiently localized, a boost can
be added to a total dose of 60–70 Gy, respecting normal tissue sensitivity.
• For gross nodal disease, consider boost to 60–65 Gy while respecting normal tissue constraints.
2. Brachytherapy –
• Initiate brachytherapy as soon as the vaginal cuff is healed, preferably 6–8 weeks after surgery but in
general initiation of brachytherapy should not exceed 12 weeks.
• For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5 cm
from the vaginal surface; the dose depends on the use of EBRT.
• The target for vaginal brachytherapy after hysterectomy should be no more than the upper two-thirds of
the vagina; in cases of extensive LVSI or positive margins, a longer segment of the vagina may be treated.
• Dose Regimens- 6Gy*5#
7Gy*3#---- More commonly used
5.5Gy*4#

20. Role of Radiotherapy in Carcinoma Cervix

40. *Till date, there is no evidence of prophylactic para-aortic LN irradiation.

47. *Role of IMRT in Post Op Cases

50. Principles of Radiation Therapy in Cervical Cancer
General Principles-
• The use of CT-based treatment planning and conformal blocking is considered the standard of care for EBRT.
• MRI is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced
tumors.
• IMRT is helpful in minimizing the dose to the bowel and other critical structures in the post-hysterectomy setting and in
treating the paraaortic nodes when necessary.
Target Volumes-
• The volume of EBRT should cover the gross disease (if present), parametria, uterosacral ligaments, sufficient vaginal
margin from the gross disease (at least 3 cm), presacral nodes, and other nodal volumes at risk.
• For patients with negative nodes on surgical or radiologic imaging, the radiation volume should include the entirety of
the external iliac, internal iliac, obturator, and presacral nodal basins.
• For patients deemed at higher risk of lymph node involvement (eg, bulkier tumors; suspected or confirmed nodes
confined to the low true pelvis), the radiation volume should be increased to cover the common iliacs as well.
• In patients with documented common iliac and/or para-aortic nodal involvement, extended-field pelvic and para-aortic
radiotherapy is recommended, up to the level of the renal vessels (or even more cephalad as directed by involved nodal
distribution).
• For patients with lower 1/3 vaginal involvement, the bilateral groins should be covered as well.

51. Dose Prescription-
• Coverage of microscopic nodal disease requires an EBRT dose of approximately 40–45 Gy (in conventional fractionation
of 1.8–2.0 Gy daily possibly with an SIB if IMRT is used), and highly conformal boosts of an additional 10–20 Gy may be
considered for limited volumes of gross unresected adenopathy, with consideration of the dose given by brachytherapy.
• For the majority of patients who receive EBRT for cervical cancer, concurrent platinum-containing chemotherapy is given
during the time of EBRT.
For Post Hysterectomy patients –
• At a minimum, the following should be covered: upper 3 to 4 cm of the vaginal cuff, the parametria, and immediately
adjacent nodal basins (such as the external and internal iliac, obturator, and presacral nodes).
• For documented nodal metastasis, the superior border of the radiation field should be appropriately increased
• A dose of 45 to 50 Gy in standard fractionation with IMRT is generally recommended.
• Grossly involved unresected nodes may be evaluated for boosting with an additional 10 to 20 Gy of highly conformal
(and reduced-volume) EBRT.

53. Role of Brachytherapy in Carcinoma Cervix

68. *Easy application in patients with effaced fornices, Intact cervix /
cervix not flushed

83. Principles of Brachytherapy
• Brachytherapy is a critical component of definitive RT for patients with primary cervical cancer. This is usually performed
using an intracavitary approach, with an intrauterine tandem and vaginal colpo-stats.
• The goals of care would include an equivalent dose at 2 Gy (EQD2) to the HR-CTV with a D90 of 80–85 Gy; however, with
large disease or poor response dose goals should be HR-CTV D90 ≥87 Gy.
• Normal tissues should be limited according to published guidelines with 2-cc rectal dose ≤65–75 Gy, sigmoid 2-cc dose
≤70–75 Gy, and 2-cc bladder dose ≤80–90 Gy.