HYPERTHERMIA in CERVIX and VAGINA CANCER. J. van der Zee

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1 HYPERTHERMIA in CERVIX and VAGINA CANCER J. van der Zee ESTRO 2006

2 Deep hyperthermia in Rotterdam

3 HYPERTHERMIA in CERVIX and VAGINA CANCER ESTRO 2006 Hyperthermia and radiotherapy in primary advanced cervix cancer Hyperthermia and cisplatin in recurrent cervix cancer, after previous radiotherapy Hyperthermia and radiotherapy in primary advanced vaginal cancer

4 DUTCH DEEP HYPERTHERMIA TRIAL Lancet 2000;355: Pooled data from 2 similar studies on advanced pelvic tumours: bladder cancer T3 (>5 cm), T4, N0M0 cervix cancer IIb-distal, IIIb, IVa, N0-1, M0 rectal cancer irresectable primary or recurrent M0-1 Randomised to RT +/- HT primary objective: local control 1990 start of studies in Amsterdam and Rotterdam 1996 studies closed 1998 analysis on 360 pts, median follow-up 38 months. All patients evaluated, intention to treat principle.

5 DDHT CERVIX PATIENT AND TUMOUR CHARACTERISTICS RT+HT RT Number of patients Age median (range) 51 (26-75) 50 (30-82) WHO performance 0 / 1 45 / / 17 FIGO stage IIB-lateral IIIA - 1 IIIB % IVA 7 4 Nodal status N0 / N1/ Nx 9 / 16 / / 19 / 31 Histology SCC / adeno 51 / 4 46 / 7 Tumour maximum diameter (mm) < % >

6 DDHT CERVIX TREATMENT CHARACTERISTICS RT+HT RT Radiotherapy (n) # Dose (Gy) median; range 68; ; mean; s.d. 67.2; ; 7.2 Overall treatment time (days) median; range 48; ; Number of hyperthermia treatments # restricted to patients with a total dose of 49 Gy or higher.

7 Analysis according to intention to treat

8 LATE TOXICITY (%) Dutch Deep Hyperthermia Trial RT+HT (n=148) RT (n=129) F.U duration (days) skin gr subcutis gr bladder gr 2 / 3 / 4 7 / 5 / 1 7 / 3 / 1 small intestine gr 2 / 3 / 4 1 / 4 / 1 2 / 2 / 2 large intestine gr 2 / 3 / 4 / 5 3 / 4 / 1 / 1 3 / 4 / 2 / 1 bone gr joint gr nerve gr yrs actuarial cumulative incidence of gr 3-4 toxicity: 12% in both treatment arms

9 Dutch Deep Hyperthermia Trial: Addition of hyperthermia to radiotherapy results in higher complete response rate: 83% vs 57% better pelvic tumour control: 61% vs 41% at 3 yrs better overall survival: 51% vs 27% at 3 yrs no change in acute or late radiation morbidity Similar large differences in other trials

10 Hyperthermia and cispt in recurrent cervix ca HTNR 722, born cervix ca Ib, N+, postoperative RT Feb 1995 PAO N+, RT Nov 1995 PAO recurrence; severe pain This patient: cispt and HT twice (Dec 95 and Sept 97) HTNR : NED

11 Hyperthermia and cispt in cervix cancer Two published phase I/II studies on HT/cisPt in cervix cancer after previous radiotherapy: ~ 50% objective response (with cispt alone expected : <15%), 4/40 long term disease free Amsterdam update of results, 54 pts 45% objective response, 4 pts alive/ned Rotterdam update of results, 47 pts 57% objective response, 2 pts alive/ned 83% palliative effect

12 For patients with recurrent cervix cancer after radiotherapy, the combination of hyperthermia and cisplatin is a therapeutic option palliation when resulting in resectability (observed in 5-10% of patients), possibly curative (NL: offered as standard care)

13 Concomitant radiotherapy and hyperthermia for primary carcinoma of the vagina: a cohort study Aktas et al., Eur J Obstet Gynecol Reprod Biol 2006, June 13 (Epub) : all 39 patients with histologically confirmed primary cancer of the vagina and treated with radiotherapy NCDB report (Creasman et al.,cancer 1998;83: ) 5-yr overall survival Stage II (664 pts) 58% Stage III-IV (773 pts) 36%

14 Vaginal carcinoma Procedure Erasmus MC Histologic confirmation of malignancy Pelvic examination under general anaesthesia Staging Treatment options: Local exision, radical surgery Chemotherapy (1) Radiotherapy Monotherapy (29) FIGO III and tumour >4 cm: radiotherapy and hyperthermia (6; and 1 pt with FIGO II and tumour >4 cm) Chemoradiation (3)

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16 THERAPY radiotherapy 29 radiotherapy + hyperthermia 7 (radiotherapy + cisplatin/ifosfamide 3) RT: external beam dose median 47, range Gy brachytherapy dose median 17, range Gy

17 RESULTS Toxicity diarrhea and cystitis; no major long-term side-effects Overall survival at 5 yrs All patients: 63% Stage I 83% Histological grade % Stage II 59% Histological grade 3 25% Stage III 56% Tumour < 4 cm 60% Stage IV 50% Tumour >4 cm 63% Radiotherapy alone 57% Radiotherapy + hyperthermia (poor prognostic group) 68%

18 Vaginal carcinoma cohort study: results Low grade High grade

19 Vaginal carcinoma cohort study: results All FIGO stages FIGO II FIGO III

20 Vaginal carcinoma cohort study: results Radiotherapy + hyperthermia Radiotherapy

21 Vaginal carcinoma cohort study: conclusions 5-yrs overall survival comparable to other studies Poorly differentiated tumours have a worse prognosis No significant survival differences between FIGO stages No significant survival differences between tumour sizes No difference in 5-yrs OS for FIGO II/III - thanks to hyperthermia? NCDB 1998: FIGO II 58% versus FIGO III-IV 36% Results of radiotherapy with or without hyperthermia are comparable, while Hyperthermia given only to tumours > 4 cm Almost all patients with FIGO stage III cancers received RT + HT

22 Hyperthermia in cervix and vagina cancer CONCLUSIONS Cervix cancer: worthwhile in combination with radiotherapy (instead of cisplatin) or chemotherapy (salvage treatment after radiotherapy) Vagina cancer: promising in combination with radiotherapy phase III study? registration study?