# Presentation: 527186

## NCI Workshop on Advanced Technologies in Radiation Oncology: Cervix

- December 1, 2006
- David Gaffney MDPhD
- Huntsman Cancer Hospital
- University of Utah

## Radiotherapy for Cervix Cancer: An Important Paradigm 

- Cure very large tumors with RT alone
- Local control correlates with survival
- Brachytherapy permits very high dose to tumor
- Requisite component of successful treatment
- Morbidity is high (dose to bladder and rectum)
- Concurrent Chemotherapy improves LC and DMFS
- Modern Imaging (MRI and PET ) provides superior pre-Tx evaluation and treatment

## Radiotherapy for Cervix Cancer: An Important Paradigm 

*Cure very large tumors with RT alone*
**Eifel PJ, *****et al*****  Time course and outcome of central recurrence after radiation therapy for carcinoma of the cervix. *****Int J Gynecol Cancer***** 2006;16:1106–1111.**

- 5% of patients received chemotherapy

## 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

*Brachytherapy permits very high dose to tumor, and minimized complications*
- FIGO IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy
- 	Logsdon and Eifel  IJROBP 43(4):763, 1999.

- Pt A 85 Gy,
- VSD 110 Gy,
- Cervical os 150-200 Gy

## Radiotherapy for Cervix Cancer: An Important Paradigm 

*Dose Limiting toxicity*
- Small Bowel: < 45 Gy
- Rectum: < 75 Gy
- Bladder: < 75 Gy

## Chemo?

- Chemotherapy improves DMFS and **LC!**
- Neoadjuvant chemo has not worked in multiple randomised trials
- NCI 1999: 5 randomised trials
- All improved local control
- 2 improved DMFS
- Other chemo showed same benefit as CDDP                         (IPD Meta-analysis Tierney IGCS 2006)
- Extended adjuvant chemo may have benefit                            (IPD Meta-analysis Tierney IGCS 2006)

## Radiotherapy for Cervix Cancer: An Important Paradigm 

*Imaging is better now: PET*
- 		Grigsby *et al* IJROBP 59(3):706, 2004

- Pelvic Nodes

- Para-aortic nodes

## Imaging is better now: PET

- 5/132 with PET + Pelvic LN’s failed.           1/33 with PET + PA LN’s failed.

- “Lymph node recurrence as the only site of failure occurred in <2% of our patients...To resect or not to resect enlarged lymph nodes or to increase the irradiation dose to toxic levels in all patients is not the clinically relevant issue.“

## Radiotherapy for Cervix Cancer: An Important Paradigm 

- Tumors regress rapidly: shrinking GTV, poorly defined CTV---effect of endometrial extension is not clear

- SUV t1/2 20 days or 25 Gy

- t1/2 21 days or 31 Gy

**Rapid involution and mobility of carcinoma **
**of the cervix, Lee *****et al***** IJROBP 58(2):625, 2004**

**Sequential FDG-PET brachytherapy **
**treatment planning in carcinoma of the cervix**
**Lin *****et al***** IJROBP 63:1494, 2005**

## Radiotherapy for Cervix Cancer: An Important Paradigm 

- FDG-PET imaging for the assessment of physiologic volume response during radiotherapy in cervix cancer    Lin *et al* IJROBP 65(1):177, 2006

- RFS by PET

## Cervix Cancer

- Cervix/Vagina is mobile
- Variable filling of bowel and bladder
- ITV used in post hysterectomy setting in RTOG 0418

- Lee et al IJROBP 2004

## Cervix: Stereotactic RT

- No Randomized Trials!

## 		Cervix: IMRT/IGRT 	   No Randomized Trials!1. Promising Single Institutional Data	-AJ Mundt MD U of Chicago/UCSD	-bone marrow sparing	-less GI and hemetologic toxicity2. Prospective RTOG phase II trial: 0418

## Cervix: Image Guided BrachytherapyRX to HR-CTV by MR, not point ANo Randomized Trials!

- Single Institution Experience: Univ of Vienna
- RTOG 0417 -secondary endpoint: develop dose volume library to correlate with toxicity

## Cervix: ProtonsNo Randomized Trials!

**High-energy proton beam radiation therapy for gynecologic malignancies. Potential of proton beam as an alternative to brachytherapy. ****Arimoto et al Cancer 68:79-83, 1991.**
- N=15, 1983 to 1987
- Particle Radiation Medical Science Center
- Local Control 14/15.
- Radiation-induced proctitis (n=2, neither of which required surgical treatment) were the only complications despite a dose > 80 Gy in most cases.
- “The results suggest that sharply localized, high-dose proton beam RT can produce an antitumor effect equivalent to that of conventional brachytherapy.”

## Cervix: NeutronsYes! Randomized Trials!

**Neutron therapy in cervical cancer: results of a phase III RTOG Study. **_[Maor ](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Maor+MH%22%5BAuthor%5D)__[MH](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Maor+MH%22%5BAuthor%5D)_** et al IJROBP 14:885, 1988**
- 	-n=156 patients
- 	-(50 Gy in 25 fractions over 5 weeks plus intracavitary applications or external-beam boost) or mixed-beam radiotherapy (2 fractions a week of neutrons, 3 fractions a week of photons to a total RBE-adjusted dose of 50 Gy plus intracavitary applications or external mixed-beam boost).
- 	-The % of patients undergoing intracavitary applications was 50% on mixed beam and 75% on photons (p < 0.01).
- 	-Tumor clearance was 52% and 72% for mixed beam and photons, respectively (p<0.03).
- 	-Median survivals were 1.9 years on mixed beam and 2.3 years on photons.
- 	*-Severe complications occurred in 19% and 11% in mixed beam and photons respectively (p<0.13). The inferior outcome with neutron therapy in this study may have resulted from the use of horizontal neutron beams of varying energy and penetration. *

## Neutrons: Randomized Brachy Trial

- 252Cf vs conventional gamma radiation in the brachytherapy of advanced cervical carcinoma long-term treatment results of a randomized study. *Tacev et al Strahlenther Onkol 179:377, 2003*
- N=227, 40 Gy-eq via brachy in first week, 16 Gy photon brachy week 5, ext beam 40 Gy/20 fractions, pt A 85 Gy
- 19% increase in OS and LC for 252Cf, p<0.003

- Promising phase II experience at Univ of Kentucky by
- Maruyama *et al.*
- Sources now at Tufts.

## Neutrons/Photons vs Photons

## Neutrons/Photons vs Photons

## Slide 21

## Hyperthermia: Two Ongoing Randomized Trials

- Dutch Trial
- RT and hyperthermia +/- chemo
- Ellen Jones MDPhD Duke PI
- ChemoRT +/- hyperthermia (q week)

## Promising Technologies in Cervix Cancer

- Image Guided Brachy: MR-Based (RTOG 0417)
- Point A was not designed for dose prescription

- Dimoupoulos *et al* IJROBP
- 66(1):83, 2006

## Promising Technologies in Cervix Cancer

- Improved imaging (ACRIN/GOG study: Correlate surgical findings with MR and PET)
- Improved imaging (ACRIN/RTOG proposed study: MR and PET; Correlate imaging with response, pre, during and post Tx, identify poor responders)
- GOG/RTOG have performed trials previously in Cervix and Endometrium successfully +/- RT: GOG 92 and 99 (Reminiscent of success of RTOG 0413/NSABP B39)
- IMRT (RTOG 0418) Stratification factor in GOG trials
- Image Guided Brachytherapy (MRI)

## Promising Technologies in Cervix Cancer 

- Better Radiosensitizers: In Meta-analysis: other chemo had same survival benefit as CDDP (Tierney *et al* IGCS 2006)
- Extended Adjuvant chemo in LN + patients
- Personalized Tx eg microarray gene expression analysis (permit dose escalation, choice of chemo?)

## Promising Technologies in Cervix Cancer

- Hyperthermia (mult adv may make this more attractive)
- High LET Brachytherapy program
- Positive trial with Cf252
- Limited institution
- Proton beam
- For Intact Cervix: Adaptive RT and IGRT required
- Lymph node boosts
- Recurrent disease
- Poorly responding advanced stage disease