Introduction to the role of radiation therapy in gynecologic cancer management

1. RADIATION THERAPY IN
GYNECOLOGIC CANCER
K.S.Reddy
Professor of Radiation Oncology
MGMC & RI, Pondicherry

2. Radiation Therapy in Gynecologic Cancer
Radiotherapy plays a major role
in the treatment of patients with
Gynecological malignancies.
 Discovery of X-rays & Radioactivity
during the waning years
of 19th Century
 Radium, Artificial radionuclides
 Biological effects of RT
 Radiation therapy was used for
treatment of Various Malignancies
Wilhelm Roentgen
(1845-1923)
Marie Curie
(1867-1934)

3. Radiotherapy Machines

4. Modern Linear Accelerators

5. Brachytherapy Machines

6. Radiation therapy is delivered
in three ways
1.Teletherapy: X-rays are
delivered from a source at
distance from the
body(External beam radiation
therapy)
2.Brachytherapy: Radiation
sources are put within OR
adjacent to the target to be
irradiated.(Intra cavitary
/interstitial)
3.Radioactive Solution: solution
that contains isotopes
(radioactive colloidal Gold-198
or Phosphorus-32) are instilled
in the peritoneal cavity to treat
intra peritoneal metastatic
nodules/malignant ascitis

7. The Goal of Radiation Therapy
Maximize tumor cell death while minimizing
damage to healthy cells
This goal hasn’t changed in over 50 years!
“There is never any reason to give any dose to
uninvolved normal tissue. An increase in dose to the
tumor will, to a point, improve local control.
Achieving these objectives is self-evidently true and
does not require randomized prospective trials.”

8. External Beam Radiotherapy
Simple 2-dimentional Radiotherapy
3-D Conformal Radiotherapy
Immobilization devices
Simulators
2-D simulators
CT- Simulator
MRI – Simulator
PET-CT- Simulator
Treatment Planning Systems

9. Intensity Modulated Radiotherapy
(IMRT)
Pelvic RT - treatment of large volumes of
the rectum and small bowel, exposing pts
to gastrointestinal (GI) toxicity
IMRT overcomes this problem by
reducing the dose to the small bowel and
rectum

10. Intensity Modulated RT (IMRT)
• Novel approach to the planning and
delivery of RT
• Unlike conventional CRT, IMRT conforms
the dose to the shape of the target
tissues in 3D, sparing normal tissues
• Normal tissue Sparing
- ⇓ toxicities ( ⇑ patient quality of life)
- ⇑ Ability to escalate dose
(⇑ tumor control)
• Rapid Arc, VMAT

11. Emil Grubbe (1875-1960)
Better sparing of small bowel,
bladder and rectum
IMRT
4 Field

12. Acute GI toxicity
IMRT vs. Conventional RT
100
90
80
70
60
50
40
30
20
10
0
Grade 0 Grade 1 Grade 2 Grade 3
IMRT
CRT
Mundt et al. Int J Radiat Oncol Biol Phys 52:1330-1337, 2002

13. Chronic GI Toxicity
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 1 2 3
IMRT
CRT
Mundt AJ, Int J Radiat Oncol Biol Phys 56:1354, 2003

14. X-ray Mania
Recently developed a "Bone Marrow Sparing" IMRT
approach
Lujan AE, Mundt AJ. Int J Radiat Oncol Biol Phys 2003;57:516-521, 2003

15. Public Demonstration 1902100% 95% 90% 70% 50%
Isodose lines bend away from BM (crests)

16. Grade  2 WBC Toxicity
CRT versus IMRT Patients
60%
50%
40%
30%
20%
10%
0%
RT Alone
p = 0.82
RT + Chemo
p = 0.08
Brixey et al. Int J Radiat Oncol Biol Phys 52:1388-93, 2002
CRT
IMRT

17. LIMITATIONS
Significantly increased expenditure:
– Machine with treatment capability
– Imaging equipment: Planning and Verification
– Software and Computer hardware
Extensive physics-manpower and time required.
Conformal nature – highly susceptible to motion and setup
related errors
Target delineation remains problematic: Interpersonal,
Intrapersonal and Inter-specialists variation in PTV
delineation
Treatment and Planning time both significantly increased
Radiobiological disadvantage:
– Decreased “dose-rate” to the tumor
– Increased integral dose

18. with good vision todayAn Important Concern
While IMRT reduces the volume of normal
tissues receiving high doses, it increases the
volume of normal tissues receiving low doses
Raises concern about potential induction of 2nd
cancers
In over a decade of use, however, no
increased rate observed
But all patients need to be carefully followed up

19. Modern Computer-Controlled
But the revolution continues…IGRT

20. What is IGRT?
Image Guided RT (IGRT) is the use of
real-time imaging to guide RT
Imaging of the patient on the treatment table in
the treatment position
IGRT can be used to:
- Improve setup accuracy of patients
- Manage internal organ motion
- Adapt treatment to changes in patient
anatomy and/or tumor response

21. multiple electron energies)Why IGRT?
Reason 1
Fields are large and
difficult to set up
Accurate setup is
essential due to
proximity of normal
tissues
Cone Beam CT could
improve daily setup
Schefter T et al.
Cervical Cancer: Case Study
IMRT: A Clinical Perspective 2005

22. 1990s
Why IGRT?
Reason 2
Organ motion issues
exist, particularly in pts
with an intact uterus
Large CTV-PTV margins
are thus used
IGRT could reduce these
margins, improving
sparing of normal
tissues
Huh et al. (Korea)
Radiother Oncol 2004;71:73

23. Why IGRT?
Reason 3
Changes occur during
treatment
Treatment plan needs to be
adapted to these changes
Dynamic Adaptive RT (DART)

24. Radiation Oncology
46% ⇓GTV, 18% ⇓ CTV, 9% ⇓ PTV
Re-planning improved rectal sparing
If >30cc GTV reduction, re-planning
improved sparing of the small bowel
Supports for DART concept
GTV
Pre-RT 30 Gy

25. • Most exciting use of IGRT is the ability to
adapt treatment to changes in the patient
and/or tumor
• Although many tumors shrink over the
course of treatment, it is common to largely
ignore these changes and use a single
treatment plan
• At best, patients are re-planned once
midway through treatment if large changes
occur
Dynamic Adaptive RT (DART)

26. Brachytherapy
Radioactive isotopes placed close to or with
in the tumor volume
 Intra cavitary
 Interstitial
 Internal : Instillation
Brachytherapy is an integral part of
Radiotherapy in Gynecologic cancer

27. Different methods of Brachytherapy in
Cancer of Cervix

28. Technique Amount and type of
Radium
No of app-
lications
Duration
Paris Intra uterine tube:
33.3 mg,
Two vaginal ovoids:
13.3 mg each
One 5-7 days, Daily
radium is removed,
cleaned and
reapplied
Stokholm Intra uterine tube:
50 mg
vaginal box: 50-60 mg
Three 48 hrs. each
Gap of 1-2 weeks
between each
Manchester Intra uterine tube:
35-40 mg
Vaginal Ovoids:
20-22.5 mg each
Two 72 hrs. each
Gap of 1 week

29. Pre-loaded
After loaded
Manual
Remote
-Low dose rate
40-200 cGy/hr
-High dose rate
>1200 cGy/hr

31. Intracavitary application
Isodose distribution

32. Interstitial implantation
Cervix Vagina

33. Carcinoma of the Uterine Cervix
•For stage IA1, simple type 1 extrafascial
hysterectomy is potentially curative.
•For stage IB1, the procedure of choice is a
radical hysterectomy with resection of the
parametria and dissection of the pelvic
lymph nodes. Para-aortic lymph nodes
should be examined and sampled if findings
are suggestive of metastatic disease.
•If parametrial extension or regional nodal
metastasis is identified intraoperatively,
many gynecologic oncologists abort
hysterectomy and proceed to pelvic
radiotherapy.

34. Post-op Radiotherapy
In a study by the Gynecology Oncology Group (GOG)
•277 patients had 2 or more of the following risk
factors identified after surgery:
Greater than one third cervical stromal invasion,
Capillary/lymphatic space invasion, and
Large clinical tumor diameter.
•Patients were randomized to receive 46-50Gy
of whole-pelvic radiotherapy postoperatively
versus no further treatment.

35. • Statistically significant (47%) reduction in local recurrence
of cervical cancer
• Prolongation in recurrence-free survival.
• However, this occurred at the cost of a 4% increase in grade
3/4 (6% vs 2.1%) toxicity, including 1 patient death.
• Statistically significant improvement in overall survival was
not observed.
• Interestingly, much of the benefit of postoperative radiation
seemed to be confined to non-squamous histologies.
Rotman,Sedlis et al IJROBP, 2006. 65(1):169

36. Treatment combining chemotherapy with
radiotherapy
•Traditionally, whole-pelvic radiotherapy alone was
offered in this setting, but a randomized trial by
GOG, reported by Peters et al. demonstrated a
survival advantage for patients who received
chemoradiation as compared with radiation
therapy alone.
•Post-operative pelvic chemoradiation is
recommended for patients with cancers of stage
IB1 or higher that are incidentally found after
simple hysterectomy for presumed benign disease.

37. •The addition of concurrent chemotherapy to
radiation in the treatment of cervical cancer, both
in the postoperative adjuvant setting for early
stage disease and as definitive primary therapy
for advanced disease, emerged as one of the
major breakthroughs in the treatment of
gynecologic cancer in the last decade.
•The results of a number of randomized trials
showed dramatic survival advantages for
chemoradiotherapy versus radiotherapy alone.
Meta-analysis would indicate a survival
advantage of approximately 30% when
chemotherapy is incorporated into treatment.

38. 5 Trials Demonstrating Improved Survival with
Chemo-Radiation compared to Radiation Alone
Adapted from: Thomas. NEJM,1999. 340: 1198-1200

39. •Given these findings, in 1999 the (NCI)
National Cancer Institute issued a rare
clinical announcement that
“Strong consideration should be given to
the incorporation of concurrent cisplatin-
based chemotherapy with radiation
therapy in women who require radiation
therapy for treatment of cervical cancer."

40. •Treatment of bulky stage I (stage IB2, clinical tumor
diameter >4 cm) cervical cancer remains
controversial.
•Common treatment strategies consist of
primary radical hysterectomy, with postoperative
adjuvant chemoirradiation administration tailored to
histopathologic findings, or
definitive primary chemoradiotherapy.
Proponents of definitive primary chemoradiation point
to the fact that many (or in some series, most) patients
undergoing radical surgery demonstrate surgical-
pathologic risk factors that may ultimately require
them to receive adjunctive postoperative
chemoradiation, with an attendant increase in
morbidity.

41. •Neoadjuvant chemotherapy administration (to
reduce tumor volume preoperatively) followed by
radical hysterectomy and
•Chemoradiotherapy followed by type I extrafascial
hysterectomy are additional treatment strategies
that are less-commonly used (endocervical –
adeno carcinoma).
•Randomized trials defining the optimal treatment
strategy of bulky cervical cancer are not available.
• Regardless of treatment, patients with bulky
stage I cervical cancers have significantly higher
rates of regional lymph node metastases,
locoregional and distant-site relapse, and poor
outcome.

42. Primary chemo-
radiotherapy is
generally indicated for
the management of
stage IIB-IVA locally
advanced cervical
cancer.
Surgical treatment is
usually reserved for
patients with isolated
central pelvic disease
that persists or recurs
after definitive chemo-
radiotherapy.

43. Treatment combining
XRT and brachytherapy
• Comprehensive radiotherapy
for stage IB-IVA cervical cancer
involves both XRT and
brachytherapy. Initial external-
beam fields encompass a
clinical target volume including
the primary tumor and the
adjacent areas at risk for direct
occult invasion or regional
lymph-node metastases.
• For patients with gross disease
in the para-aortic nodal region,
some believe retroperitoneal
lymphadenectomy before XRT
can improve the likelihood of
disease control.

44. Cancer of Uterine cervix
Early stage cancer
• Stage I-A1: Two intracavitary treatments 65-75 Gy to Point A
Stage I-A2: EBRT 40-45 Gy + ICRT 30-35 GY to Pt A
Survivals are similar to surgery (95-100%)
• Stage I-B1, Non bulky stage II A: EBRT 40-45 Gy + ICRT 40-45
Gy
Survivals are similar to surgery (85-90%)
(Alternative to surgery in early stage lesions)
Adjuvant RT: Post op- High risk group
(Ly nodes, Parametria, margins are +ve)
EBRT 46-50 Gy + Brachytherapy to proximal 3rd vagina 15 Gy at
0.5 cm
Significant reduction risk of recurrence/progression
Significant improvement in overall survival
Rotman et al. IJROBP. 2006, 65:169-176

45. Cancer Cervix-Bulky and advanced cancers
Stage IB2 to IV A
Concurrent Chemo Radiation
•EBRT 45-50 Gy + ICRT 40-45 Gy to Pt.A(total dose
85-90 Gy to PtA)
•Weekly Cisplatin 40 mg/m2 X 6 or
3 weekly Cisplatin+5-FU X 2
•5 yr survivals reported are
80-85% - Stage I B2/II A
70-80% - Stage II B
50 % - Stage III B
15-20% - Stage IV A
Peters et al.JCO,2000,18:1606-1613;
Randal et al. IN Principles & Practice of Gynecologic Oncology 4th ed, 2005

46. Carcinoma of the Uterine Corpus
•When hysterectomy is medically contraindicated,
primary radiotherapy can offer 5-year disease-
specific survival rates of 80-90%, approaching
those achieved with surgery.
•Indications for adjuvant radiation after surgery for
endometrial cancer are somewhat controversial.
•Whole-pelvis external-beam radiotherapy (EBRT)
and intravaginal brachytherapy are potential
adjuvant postoperative therapies for patients with
stage I disease.
•Recommendations are based on the stage and
grade of disease.

47. American Brachytherapy Society Guidelines for the
Postoperative Treatment of Pathologic Stage I
Endometrial Carcinoma
Stage
Grade
1 2 3
IA Observation only Observation only Observation, intravaginal
brachytherapy, or intravaginal
brachytherapy plus pelvic XRT
IB Observation or
brachytherapy
Observation, intravaginal
brachytherapy, or intravaginal
brachytherapy plus pelvic XRT
Intravaginal brachytherapy or
intravaginal brachytherapy plus
pelvic XRT
IC Observation or
intravaginal
brachytherapy plus
pelvic XRT
Intravaginal brachytherapy plus
pelvic XRT
Intravaginal brachytherapy plus
pelvic XRT

48. Several randomized trials have now examined the
role of postoperative adjuvant radiation in
endometrial cancer.
• The first, a randomized study conducted at the Norwegian
Radium Hospital,
• In the study, 540 patients with stage I endometrial cancer
were treated between 1968 and 1974 with 6000 cGy of
vaginal radium. These patients were then randomized to
receive no further treatment versus an additional 4000 cGy
of XRT.
• demonstrated a statistically significant reduction in the risk
of vaginal and pelvic recurrence in patients external radiation
treatment compared with those who did not (1.9% vs 6.9%,
respectively)
• No difference in overall 5-year survival.
Alders et al. Obstet Gynecol 56:419-427,1980

49. Postoperative Radiotherapy in Endometrial Cancer
[PORTEC]
•conducted in the Netherlands at numerous radiation
oncology centers between 1990 and 1997
•In the study, 715 patients who had undergone
hysterectomy for intermediate-risk endometrial cancer
were randomized to receive 46 Gy of XRT versus no
further treatment. No vaginal brachytherapy was used
and routine surgical staging was not performed.
•Radiation reduced locoregional recurrence (4% vs 14%),
•5-year overall survival and cancer-specific death rates
were not statistically different in the 2 treatment
groups.
Creutzberg et al.:Lancet 355:1404-1411, 2000

50. Gynecologic Oncology Group, GOG 99
conducted between 1987 and 1995, in which 448
patients with intermediate-risk endometrial cancer
were randomized to receive postoperative XRT (50.4Gy)
versus no further therapy, the cancer recurrence rate
was lower (3% vs 12%)in the radiation group.
•Unlike the PORTEC trial, in which patients with deeply
invasive grade 3 tumors were excluded, the definition
of intermediate risk for enrollment into the GOG trial
included any degree of myometrial invasion of any
grade in the absence of lymph node metastases.
Patients in the GOG trial underwent routine surgical
staging with lymphadenectomy.
Keys et al.:Gynecol Oncol 92:744-751,2004

51. Brachytherapy
•Although neither GOG 99 nor the PORTEC study
incorporated intravaginal brachytherapy, the
vaginal cuff is well recognized to be a common
site of recurrence in many patients with early
stage disease. Therefore, one can extrapolate
from these trials when considering adjuvant
intravaginal brachytherapy in lieu of whole-
pelvis irradiation. Intravaginal brachytherapy
may be administered with an after loading
device (LDR) or (HDR).

52. •The HDR technique has become popular
because of its convenience as a well-
tolerated outpatient regimen.
•When intravaginal brachytherapy is given
after pelvic XRT, a typical dosage schedule for
intravaginal brachytherapy is 15 Gy
prescribed to a depth of 0.5 cm over 3-4 cm
of the upper vagina, given in 3 weekly
fractions of 5 Gy each.
•When intravaginal brachytherapy is
administered without pelvic XRT, a dose of 21
Gy to a depth of 0.5cm given in 3 fractions is
commonly prescribed.

53. Additional considerations
• Two important pathologic findings not specifically addressed in
the FIGO/AJCC staging system are extensive invasion of the
lymphovascular space and a close (less than a few millimeters)
margin of resection. When either feature is found, consideration
of postoperative radiotherapy is warranted. Also, adjuvant
treatment should be considered in certain patients with
pathologic stage I disease in whom surgical staging was
incomplete.
• For stage II endometrial carcinoma, preoperative or
postoperative radiotherapy may be administered. The goals of
preoperative treatment are to facilitate hysterectomy by
reducing tumor bulk, by clearing microscopic infiltration from
the upper vaginal mucosa, or by rendering cells incapable of
local implantation. Pelvic XRT may be combined with
brachytherapy in this setting.
• For stage II disease recognized during postoperative
histopathologic analysis, pelvic XRT and intravaginal
brachytherapy may be indicated.

54. Stage III-IV endometrial cancer
• For stage III-IV disease, numerous institutions have reported
outcomes for patients treated with combinations of pelvic XRT,
whole-abdomen radiotherapy (WAR), intravaginal brachytherapy,
and chemotherapy; however, no clear consensus has emerged.
• A study (GOG 122) comparing WAR with combination
chemotherapy involving doxorubicin and cisplatin to treat
advanced endometrial carcinoma found that chemotherapy was
apparently the more effective treatment.
• Of 396 assessable patients, 202 were randomized to receive WAR
and 194 to receive chemotherapy. At 60 months, 50% of patients
who received chemotherapy were predicted to be alive and
disease-free as compared with 38% of patients who received
radiotherapy, a survival advantage that reached statistical
significance.
• Treatment was thought to have contributed to the death of 8
patients (4%) treated with chemotherapy and 5 patients (2%)
treated with radiation.
Randall et al.: J Clin Oncol 24: 36-44, 2006

55. Histological variants of Endometrial carcinoma
•Uterine papillary serous cancer (UPSC) is
characterized by a propensity for local and
distant recurrence.
•Carcinosarcoma, formerly called Malignant
Mixed Müllerian Tumor (MMMT), is
associated with a particularly high rate of
pelvic failure after hysterectomy.
•Patients may benefit from postoperative
pelvic XRT in all stages of disease.

56. Vaginal Cancer
•Primary nonsurgical treatment is usually preferable for
stage I or II vaginal lesions, partial or total vaginectomy
followed by postoperative radiotherapy is sometimes
feasible for these.
•Combined treatment with RT+Cisplatin is likely to be more
beneficial than RT alone because the biologic behavior of
vaginal cancer is expected to be similar to that of cervical
cancer.
•After EBRT is administered to fields in doses of 45-50 Gy
•Tailored interstitial brachytherapy is generally necessary to
deliver potentially curative doses of radiation to the
primary site.

57. Vulvar cancer
•The aim of integrated multimodality therapy including
surgery, chemo-radiotherapy is to reduce the risk of
local, regional failure in patients with advanced primary
or distant nodal involvement.
•To obviate the need of exenteration in women having
urethra , anal extension of cancer.
•The dose of radiation given is 45-50Gy with microscopic
and 60-64Gy with macroscopic disease.
•Pre operative Interstitial implant(60 Gy in 6 days) shrinks
the tumor and facilitates extirpation of tumor at later
date .
•Post operative radiotherapy is preferred in women with
+ve inguinal nodes.

58. Ovarian Cancer
•Whole-abdomen radiation (WAR) was used, but its
popularity has waned because of the favorable toxicity
profiles of current chemotherapeutic regimens.
•Techniques for WAR have included AP-PA field treatment
to the entire peritoneal cavity at doses of 25-30Gy given
in fractions of 1-1.5 Gy.
•Renal doses of less than 20Gy and whole-liver doses of
less than 30Gy were advisable using shielding
techniques.
•Boost treatment to the pelvis and para-aortic lymph
nodes may be combined with WAR for total doses of 45-
50 Gy to these regions. Unfortunately, small bowel
obstruction several years following WAR was a common
complication.

59. Palliative radiotherapy
•Palliative radiotherapy is frequently offered to
patients who have focally symptomatic recurrences
of ovarian cancer.
•For patients with painful or hemorrhagic pelvic
masses refractory to chemotherapy, a
hypofractionated schedule of 14.8Gy given in 4
fractions within 2 days may be administered by
using AP-PA fields and then repeated once or twice
at 2- to 4-week intervals.
•Three monthly fractions of 10Gy are also
reasonable, especially in patients with poor
performance and a limited life expectancy in whom
convenience and expediency are paramount.

60. Radiotherapy in choriocarcinoma
Though the tumor is radiosensitive, RT is
usually not used in the management as
Chemotherapy is highly effective
Radiation is reserved for
Metastases to CNS, Spinal Cord or Liver

61. Radiotherapy in hormonal ablation
•Tamoxifen is widely given to premenopausal
women with estrogen receptor–positive breast
cancer.
•However, low-dose radiotherapy is sometimes
administered.
•Radiotherapy can be highly effective and cost-
effective.
•A dose of 10-20Gy in 5-10 fractions is usually
sufficient to eliminate ovarian hormone production.
•To limit the size of the radiotherapeutic field, the
location of the ovaries is ideally verified by
performing Ultrasound/CT scanning.