1. Radiotherapy and Chemotherapy in Cervical Cancer Dr. K. S
Radiotherapy and Chemotherapy in Cervical Cancer Dr. K.S.Reddy MGMC & RI

2. Cervical cancer is the third most common cancer in women worldwide
Fourth highest mortality rate among cancers in women.
Most cases of cervical cancer are preventable by routine screening and by treatment of precancerous lesions.
Most of the cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols
More than 1/5 th of all new cases are diagnosed in India.
Frequently presents as large tumors and in advanced stage
Over 80% of patients reported to FIGO with invasive
cancer were treated by radiotherapy

3. Treatment recommendations for early stage disease
Stage IA1,A2,B1,IIA1
Primary treatment of early stage cervical cancer is surgery or radiation therapy
Treatment recommendations include extra fascial hysterectomy, modified radical trachelectomy, or hysterectomy with pelvic node dissection
Alternative options include brachytherapy
with or without pelvic radiation therapy
And Chemotherapy ?

4. When is RT or Chemo/RT Indicated After Radical Hysterectomy?
Radiation if two of the following:
Deep invasion, large tumor or vascular invasion
GOG 92 (Sedlis A et. al. Gyn Onc 73: , 1999)
Chemo-RT if one of the following:
Positive margin, parametrial extension, positive node
GOG 109 (Peters WA et. al. J Clinic Oncol 18: , 2000)

5. Treatment recommendations for advanced stage disease
Stage IIB, IIIA, IIIB, and IVA:
Traditionally, advanced disease includes stages IIB-IVA
Many oncologists now also include patients with IB2 and IIA2 in the advanced disease category
Treatment recommendations for advanced disease include
Concomitant chemoradiation and brachytherapy

6. Risk of lymph node metastases
Stage 5 yr survival %+ Pelvic LN %+ PA LN I II
III
Prophylaxis of para-aortic LN?
Not standardized
If + pelvic LN, large tumor
size, LVI - prophylactic PAN RT
Resect or boost LNs >3cm

7. Chemoradiation Therapy
Between 1998 and 2000, the initial results of six RCTs were published, which showed benefit for concomitant cytotoxic chemotherapy with radiation (chemo radiotherapy)
The patient populations in these studies included
women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy,
women with FIGO stages I to IIA disease who, at the time of primary surgery, who were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.

8. Although the positive trials vary somewhat in terms of
the stage of disease,
dose of radiation, and
schedule of cisplatin and radiation,
the trials demonstrated significant survival benefit for this combined approach.
The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

9. Based on these results, concurrent cisplatin-based chemotherapy with radiation therapy is the standard of care for women who require radiation therapy for treatment of cervical cancer.
In February 1999, the National Cancer Institute (USA) issued an alert that this management should be considered for all patients with cervical cancer.
(Eifel 2004; Keys 1999; Peters 2000;
Rose 1999;Whitney 1999;Wong 1999).

10. Subsequently based on the data analyzed which included twenty four trials (21 published, 3 unpublished) and 4921 patients,
Potential absolute survival benefit of 12% is attributable to the use of chemo radiotherapy,
Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer.
It also appears to reduce local and distant recurrence
Radiosensitisation and systemic cytotoxic effects.
Some acute toxicity is increased, but the long-term side effects are still not clear.
The Cochrane Library 2015, Issue 2

11. What is the Global Standard Therapy for Stage IB2 - IVA?
External beam pelvic radiation (40 to 60 Gy)
Brachytherapy
(8,000 to 8,500 cGy to Point A)
I.V. Cisplatin chemotherapy
Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks)
GOG 120 (Rose PG et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. NEJM 340(15):1144, 1999
Monk et al J Clin Oncol 25:

12. The use of linear accelerators, CT-based treatment planning and conformal blocking is considered the standard of care for EBRT.
These technological advances have enabled precise dose delivery of radiation doses.
MRI is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced tumors.
In patients who are not surgically staged PET imaging is useful to help define nodal volume for coverage.

14. CT vs MRI vs PET-CT for determination of nodal disease: Meta-analysis
41 studies
PET or PET-CT showed highest sensitivity (82%) and specificity (95%)
CT sensitivity 50% and specificity 92%
MRI sensitivity 56% and specificity 91%
Choi et al. Cancer Science (2010)

16. Standard Anterior and Lateral External-beam Irradiation Ports Used to Treat Locally Advanced Cervical Carcinoma Limited to the Pelvis
Monk et al J Clin Oncol 25:

17. 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 ( Pt. quality of life)
- Ability to escalate dose
( Tumor control)
Rapid Arc, VMAT

18. IMRT may be reasonable, but must consider
Contouring
Organ motion/ margins
Image guidance
Daily IGRT
Time and cost

19. ROLE OF 3-D CRT & IMRT
Ensures better tumor control.
Lesser dose to normal tissue resulting in less late term complications.
Potential reduction in acute toxicity & better radiation tolerance.

20. BRACHYTHERAPY
Brachytherapy is a type of radiation treatment in which small, encapsulated radioactive sources are arranged in a geometric fashion in & around tumour
Advantages:
It delivers very high dose of radiation to tumour
Sparing normal tissue
Dose delivered in short duration.
Manchester, Paris, Stockholm Systems, Interstitial
After loading – Manual/Remote –LDR/HDR

21. Intracavitary Brachytherapy
Point A is a point 2cm. lateral to the center of the uterine canal and 2 cm. superior to the mucosa of the lateral fornix, in the plane of the uterus.
Represents paracervical triangle where the uterine vessels cross the ureter
Point B is a point 2cm above external os & 5 cm lateral to midline
Represents dose to the pelvic wall, obturator L.N.

22. INTERSTITIAL IMPLANTATION
The aim of this technique is to tailor the dose of irradiation to the anatomy of the patient with a better target volume coverage.
Originally, interstitial implants were performed with free-hand placement of the radioactive needles.
The development of transperineal or transvaginal templates resulted in a better needle positioning.

23. Modern after loading HDR applicators

24. Treatment recommendations for Metastatic disease
Stage IVB:
• Patients with metastatic disease are primarily treated with cisplatin-based chemotherapy
• In addition, individualized radiation therapy should be considered for control of pelvic disease and other symptoms

25. Radiotherapy for Cervix Cancer: An Important Paradigm
Local control remains a clinical problem (ASTRO 2006)
RTOG 0128: 2 yr DFS is 69%
2 yr Local Regional Failure is 26%
55% of first sites of recurrence included a local-regional component

26. Add-ons for Concurrent Chemoradiation
Para aortic nodal irradiation
Outback chemotherapy
(after CCRT)

27. Picking up PA nodes N=237, IB-IVA disease, SCC/adeno /adenosquamous
All patients underwent PET scan followed by laparoscopic para-aortic lymphadenectomy
The false negativity rate for PET was 12%

28. Addressing PA nodes Patients went on to receive radical CT-RT
Patients with documented PA nodal involvement received EFRT & conc chemotherapy
Event-free survival rates of patients with PA node <5mm and without PA node were similar
Event free survival rates of patients with PA node>5mm were significantly worse than patients without PA node/ with PA node<5mm, despite EFRT & conc chemotherapy

29. Prophylactic PA nodal irradiation: RTOG 79-20
Bulky IB-IIA & IIB disease
Pelvic only OR pelvic+para-aortic RT
10-yr OS 44% vs 55% (p=0.02)
Similar local control & DFS rates
Significantly increased incidence of grade 4-5 toxcities at 10 years for pelvic+PA RT
Higher OS with similar DFS can be explained by lower incidence of distant failure & better salvage for pelvic+PA vs pelvic RT
Rotman et al. JAMA 1995

31. Adjuvant chemotherapy for early stage disease: Meta-analysis (2012)
Stage I-IIA disease (including bulky)
RT +/- Adjuvant chemotherapy
3 trials
N=368
Adjuvant chemotherapy significantly reduces risk of death (HR=0.56) & disease progression (HR=0.47)
No trials have till date assessed adjuvant chemotherapy after surgery
Rosa et al. Cochrane Library Issue 6

32. THE OUTBACK TRIAL/GOG 0274 A Phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone
Linda Mileshkin on behalf of ANZGOG
Kathleen Moore on behalf of the GOG
ClinicalTrials.gov Identifier: NCT

33. Design Stage IB2-IVa Cervical cancer: Stratify for FIGO stage
Pelvic nodal involvement
Uterine +ve on MRI
4 cycles
Carboplatin + Paclitaxel
Standard
chemoXRT
Standard
chemoXRT
ClinicalTrials.gov Identifier: NCT

34. Summary of Primary Treatment
Early stage cervical cancer usually cured with radical local excision
Randomized trials have established role of adjuvant CCRT
CCRT used to treat locally advanced disease
Extending the RT fields in treatment of PA nodes in high-risk disease is important
Demand yet something more, possibly outback chemotherapy

35. Chemotherapy for Recurrent Cervical Cancer - Lessons Learned in the 80’s and 90’s
Platinum-based therapies most effective
Cisplatin more active than carboplatin
Two ways to increase response without prolongation in Survival
Increase platinum dose / add other drugs
Single agent cisplatin became standard
Addition of Paclitaxel improves response
Other drug combinations with Gemcite/Vinorelbine/ Topotecan did not show any added benefit

36. Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD.
GOG 227-C
Persistent or recurrent squamous cervical cancer
1-2 prior cytotoxic regimens (not including initial chemo-RT)
Measurable disease
GOG PS ≤ 2
Bevacizumab 15 mg/kg IV
q 21 days until disease
progression or
prohibitive toxicity
Bevacizumab
GOG Historical Database) (Failing one or two cytotoxic
regimens, not including
chemo-RT
Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD.
J Clin Oncol Mar 1;27(7):

37. GOG 240 – Bevacizumab Objective
Cisplatin + Paclitaxel Cohort N=229
Cis + Pac
(n=114)
Events, n (%)
69 (60.5)
Median OS, mos
14.3
17.5
Cis + Pac + Bev
(n=115)
67 (58.3)
HR=0.68 (95% CI, )
P=0.0348
1.0
0.9
0.8
0.7
RR, %
45 (CR, n=9)
50 (CR, n=17)
2-sided P=0.5090
0.6
0.5
Proportion Surviving
0.4
0.3
0.2
0.1
0.0 12 24 36
Months on Study
Tewari KS et al N Engl J Med Feb 20;370(8):
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

38. Progress in Survival in Advanced and Recurrent Cervical Cancer
GOG 240 Cisplatin + Palcitaxel + Bevacizumab
Months    
GOG 64 Cisplatin
Year
Adding Bevacizumab to Chemotherapy Improves Survival

40. SUMMARY
Cervical cancer accounts for deaths every year in low resource countries
Surgery and chemoradiation can yield cure rates of around 80% and 60% in early-stage and advanced cancers respectively
Immunization with HPV vaccine and screening are essential if one has to improve the outcome in women

41. Thank you