Cervix carcinoma, HIV and Radiotherapy

1. Cervix carcinoma, HIV and Radiotherapy The Challenges and the Rewards Hannah Simonds Tygerberg Hospital/University of Stellenbosch SASGO November 2008

2. Introduction • Background • Treatment and outcomes • Principles of Radiotherapy • HAART and Radiotherapy • Case • Conclusions

3. Background - Impact of HAART • Cervix carcinoma is an AIDS-defining illness • Evidence points to women presenting at a younger age and more ‘advanced’ stage if co-existent HIV • Prior to HAART (and where not available), HIV/AIDS priority illness with a shortened life-expectancy , effective palliation is the main aim of treatment • With life-expectancy beyond 10 years on HAART the challenge is to treat Ca Cx with curative intent

4. Treatment • Chemoradiation • Weekly Cisplatin 4-6 cycles • External Beam Radiotherapy (45-50Gy over 5 weeks) • Brachytherapy • OR Consider high dose palliation in a shortened regimen without chemo.

5. Outcomes • Shrivastava et al (Rad and Onc 2005) Mumbai • 42 patient cohort (5-10 years younger than median age) • 50% IIIb-IVa • 76% Radical intent • 24% discontinued treatment • Grade III-IV GI toxicity 14% (Diarrhoea 7-9 x day) • Grade III skin toxicity 27% (desquamation) • 50% CR • NB Radiation fields large/no shielding used

6. Gichangi et al (Gyn Onc 2006) Nairobi • 208pts • 20% positive (38 vs 50 yr) • Skin toxicity 39% vs 32% • GI toxicity 34% vs 41% • GU toxicity 19% vs 5% • Overall increased toxicity in HIV group • Increased interruptions • High incidence of PD (41 vs 16%) • NB only EBRT and very low energy (Co60)

7. Increased toxicity? • Inherent cellular radiosensitivity (fibroblasts in skin biopsies) (Formenti et al) • Glutathione deficiency (found to be low in HIV+ patients) increases radiosensitivity • Published literature on Anal Ca Chemoradiation increased toxicity and poorer long term outcomes for local control, not improved with introduction of HAART • However, NHL HAART+Chemo better outcome without increased toxicity

8. Principles of Radiation • Give a high enough dose to cure but low enough to avoid toxicity. • Total dose (50 Gy EBRT + Equivalent 30Gy HDR) = 75Gy + needed to eradicate squamous cell carcinoma cell lines • Treatment time (less than 6 weeks) – not allow repopulation of cells • Dose per fraction (2Gy or less) minimise toxicity • Additional radiosensitisers (Cisplatin) increase efficacy and toxicity

9. Aim to treat conformal fields • Shield organs at risk • Bone marrow • Small bowel • Treat high energy reduces toxicity (esp. skin) Monk, B. J. et al. J Clin Oncol; 25:2952-2965 2007

10. IMRT • More radiation fields = more conformal • Minimise acute and late effects • Chemoradiation toxicity exacerbated by large volumes of marrow irradiation

11. ORGANS AT RISK • V40 Bone Marrow • 21% IMRT • 50% 4 field • 98% AP/PA

12. RT +HIV • No change to total dose • Conformal fields • Dose per fraction can be reduced to 1.8Gy to reduce toxicity • Caution with radiosensitisers (additive risk of neutropaenia) • Treatment time may need to be extended due to toxicity or intercurrent infection • HAART and RT?

13. HIV+RT • Traditionally if CD4 >200 treat • Refer to start HAART after RT • If less, start HAART and delay 3 months • However …..

14. HAART + Radiosensitisation • HAART (protease inhibitors) found to induce insulin resistance and diabetes • Insulin signals through the Akt pathway • HAART inhibit this pathway • In tumour cells mutations cause activation of the PI3-kinase/Akt pathway • Theoretically HAART would down-regulate this pathway

15. (Gupta et al Cancer Res 2005 ) showed 15% reduction in surviving fraction of tumour cells after RT and HAART (nelfinavir/amprevavir) use vs. RT alone • Potential for use as a radiosensitiser even in an HIV negative population • First Phase I study in pancreatic cancer combining chemoradiation and Nelfinavir promising activity (Brunner et al JCO 2008)

17. (Gupta et al Cancer Res 2005 ) showed 15% reduction in surviving fraction of tumour cells after RT and HAART (nelfinavir/amprevavir) use vs. RT alone • Potential for use as a radiosensitiser even in an HIV negative population • First Phase I study in pancreatic cancer combining chemoradiation and Nelfinavir promising activity (Brunner et al JCO 2008)

18. Recommendations • Consider starting ALL patients on HAART at diagnosis • As Cervix Ca AIDS-defining illness patients will qualify irrespective of CD4 count • This is current management for Kaposi’s sarcoma and NHL • CD4 count will fall during treatment • HAART may protect against opportunistic infection

19. Case • 38 year old lady • HIV positive Sept 2007/CD4 <200 • Started on ARVs • Pap showed CIN III/ ?infiltration initially not followed up • Dec 2007 CD4 160 • Presented PV bleeding Feb 2008 • Biopsy confirmed infiltrating Squamous Cell Ca

20. Clinical stage IIIb (8cm primary/extending to bilateral side walls) • PS 1 • Hb 7.3 / Cr 72 • CXR/ USS/ Cystoscopy Normal • CD4 136 (March 2008)

21. Reasons for low CD4 on HAART • Primary drug resistance • Non compliance • Lab variance • Co-existent factors (e.g.) • Slow responders

22. May 2008 CD4 114 • Patient consented for risks of treatment • Planning scan no nodes/hydronephrosis • Radical RT – conformal planning • 50.4Gy/28#

23. No treatment breaks • Grade II GI toxicity • Received 3 separate transfusions to keep Hb>10 (lowest 9.2) • Week 6 Hb 12.3/WCC 2.79/Neuts 2.19/Plts 182

24. At EUA parametria clear/<2cm on cervix • 20Gy/ 4# HDR brachytherapy • 6 week check • No toxicity reported • No sign of residual disease • Continues under care of Infectious diseases • Due 4 month check on Monday

25. Conclusions • In SA access to HAART • Treat the patient as you would any other immunocompetent patient • BUT be aware of risks of increased toxicity • Risk of falling CD4 • Use Cisplatin with caution • HAART additional benefit as a chemosensitiser…consider starting prior to RT • COLLECT YOUR DATA!