Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

Richard Pötter, Petra Georg, Johannes C A Dimopoulos, Magdalena Grimm, Daniel Berger, Nicole Nesvacil, Dietmar Georg, Maximilian P Schmid, Alexander Reinthaller, Alina Sturdza, Christian Kirisits, Richard Pötter, Petra Georg, Johannes C A Dimopoulos, Magdalena Grimm, Daniel Berger, Nicole Nesvacil, Dietmar Georg, Maximilian P Schmid, Alexander Reinthaller, Alina Sturdza, Christian Kirisits

Abstract

Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT).

Methods: Treatment schedule was EBRT with 45-50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the "protocol period" (2001-2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D(2cc)) were 70-75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis.

Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB-IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D(2cc) 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2-5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2-5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2-5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n=32/3, for rectum n=14/5, for bowel (including sigmoid) n=3/0, for vagina n=128/2, respectively.

Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95-100% at 3years in limited/favourable (IB/IIB) and 85-90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65-70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Figures

Fig. 1
Fig. 1
Outcome after radiotherapy ± chemotherapy and image-guided adaptive brachytherapy. (a) Local control, cancer specific survival and overall survival for all 156 patients. (b) Local control and tumour size. (c) Cancer specific survival for FIGO stages IB, IIB, IIIB. (d) Local control for FIGO stages IB, IIB, IIIB.

References

    1. Bentzen S.M. Radiation oncology health technology assessment: the best is the enemy of the good. Nat Clin Pract Oncol. 2008;5:563.
    1. Thwaites D.I., Verellen D. Vorsprung durch Technik: evolution, implementation, QA and safety of new technology in radiotherapy. Radiother Oncol. 2010;94:125–128.
    1. Verellen D., De Ridder M., Linthout N., Tournel K., Soete G., Storme G. Innovations in image-guided radiotherapy. Nat Rev Cancer. 2007;7:949–960.
    1. Bortfeld T., Schmidt-Ullrich R., DeNeve W., Wazer D. Springer; 2005. Image-Guided IMRT.
    1. Webb S. Institute of Physics Publishing; Bristol: 2004. Contemporary IMRT: Developing Physics and Clinical Implementation.
    1. Haie-Meder C., Pötter R., Van Limbergen E. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235–245.
    1. Potter R., Haie-Meder C., Van Limbergen E. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006;78:67–77.
    1. Dimopoulos J.C., Schard G., Berger D. Systematic evaluation of MRI findings in different stages of treatment of cervical cancer: potential of MRI on delineation of target, pathoanatomic structures, and organs at risk. Int J Radiat Oncol Biol Phys. 2006;64:1380–1388.
    1. Viswanathan A.N., Dimopoulos J., Kirisits C., Berger D., Pötter R. Computed tomography versus magnetic resonance imaging-based contouring in cervical cancer brachytherapy: results of a prospective trial and preliminary guidelines for standardized contours. Int J Radiat Oncol Biol Phys. 2007;68:491–498.
    1. Kirisits C., Pötter R., Lang S., Dimopoulos J., Wachter-Gerstner N., Georg D. Dose and volume parameters for MRI-based treatment planning in intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys. 2005;62:901–911.
    1. Dimopoulos J.C., Kirisits C., Petric P. The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: clinical feasibility and preliminary results. Int J Radiat Oncol Biol Phys. 2006;66:83–90.
    1. Jurgenliemk-Schulz I.M., Tersteeg R.J., Roesink J.M. MRI-guided treatment-planning optimisation in intracavitary or combined intracavitary/interstitial PDR brachytherapy using tandem ovoid applicators in locally advanced cervical cancer. Radiother Oncol. 2009;93:322–330.
    1. Pötter R., Dimopoulos J., Georg P. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol. 2007;83:148–155.
    1. Keys H.M., Bundy B.N., Stehman F.B. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340:1154–1161.
    1. Morris M., Eifel P.J., Lu J. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340:1137–1143.
    1. Peters W.A. 3rd, Liu, PY, Barrett, RJ, 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18:1606–1613.
    1. Rose P.G., Bundy B.N., Watkins E.B. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144–1153.
    1. Whitney C.W., Sause W., Bundy B.N. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17:1339–1348.
    1. Vale C., Thierny J.F., Stewart L.A. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008;26:5802–5812.
    1. Michiels S., Le Maitre A., Buyse M. Surrogate endpoints for overall survival in locally advanced head and neck cancer: meta-analyses of individual patient data. Lancet Oncol. 2009;10:341–350.
    1. Duenas-Gonzalez A., Zarba J.J., Patel F. Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. J Clin Oncol. 2011;29:1678–1685.
    1. Quinn M.A., Benedet J.L., Odicino F. Carcinoma of the cervix uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95:S43–103.
    1. Hunter, RD, Davidson, SE. Low dose-rate brachytherapy for treating cervix cancer: changing dose rate. In: Joslin CAF FA, Hall E, editor. Principles and practice of brachytherapy using afterloading systems, London: Arnold. 2001;343–353.
    1. Meredith W.J. Livingstone; Edinburgh: 1967. Radium Dosage: The Manchester System.
    1. Perez C.A., Grigsby P.W., Chao K.S., Mutch D.G., Lockett M.A. Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix. Int J Radiat Oncol Biol Phys. 1998;41:307–317.
    1. Fletcher G.H., Hamburger A.D. Female Pelvis. Squamos cell carcinoma of the Uterine Cervix. In: Fletcher G.H., editor. Textbook of Radiotherapy. Lea and Febiger; Philadelphia: 1980. pp. 720–789. third edition.
    1. Perez C.A., Breaux S., Bedwinek J.M. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer. 1984;54:235–246.
    1. Eifel P.J., Moughan J., Owen J., Katz A., Mahon I., Hanks G.E. Patterns of radiotherapy practice for patients with squamous carcinoma of the uterine cervix: patterns of care study. Int J Radiat Oncol Biol Phys. 1999;43:351–358.
    1. Gerbaulet A., Michel G., Haie-Meder C. The role of low dose rate brachytherapy in the treatment of cervix carcinoma. Experience of the Gustave-Roussy Institute on 1245 patients. Eur J Gynaecol Oncol. 1995;16:461–475.
    1. Haie-Meder C., Chargari C., Rey A., Dumas I., Morice P., Magne N. DVH parameters and outcome for patients with early-stage cervical cancer treated with preoperative MRI-based low dose rate brachytherapy followed by surgery. Radiother Oncol. 2009;93:316–321.
    1. Tan L.T., Coles C.E., Hart C., Tait E. Clinical impact of computed tomography-based image-guided brachytherapy for cervix cancer using the tandem-ring applicator - the Addenbrooke’s experience. Clin Oncol (R Coll Radiol) 2009;21:175–182.
    1. Narayan K., van Dyk S., Bernshaw D., Rajasooriyar C., Kondalsamy-Chennakesavan S. Comparative study of LDR (Manchester system) and HDR image-guided conformal brachytherapy of cervical cancer: patterns of failure, late complications, and survival. Int J Radiat Oncol Biol Phys. 2009;74:1529–1535.
    1. Kang H.C., Shin K.H., Park S.Y., Kim J.Y. 3D CT-based high-dose-rate brachytherapy for cervical cancer: clinical impact on late rectal bleeding and local control. Radiother Oncol. 2010;97:507–513.
    1. Wittekind C., HMeyer H-J. Springer; Berlin Heidelberg New York: 2002. UICC: TNM Klassifikation maligner Tumoren.
    1. Kirisits C., Lang S., Dimopoulos J., Berger D., Georg D., Pötter R. The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: design, application, treatment planning, and dosimetric results. Int J Radiat Oncol Biol Phys. 2006;65:624–630.
    1. Dimopoulos J.C., Pötter R., Lang S. Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy. Radiother Oncol. 2009;93:311–315.
    1. Dimopoulos J.C., Lang S., Kirisits C. Dose-volume histogram parameters and local tumor control in magnetic resonance image-guided cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2009;75:56–63.
    1. Lang S., Kirisits C., Dimopoulos J., Georg D., Pötter R. Treatment planning for MRI assisted brachytherapy of gynecologic malignancies based on total dose constraints. Int J Radiat Oncol Biol Phys. 2007;69:619–627.
    1. Georg P., Lang S., Dimopoulos J.C. Dose-volume histogram parameters and late side effects in magnetic resonance image-guided adaptive cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2011;79:356–362.
    1. Georg, P, Potter, R, Georg, D, et al. Dose Effect Relationship for Late Side Effects of the Rectum and Urinary Bladder in Magnetic Resonance Image-Guided Adaptive Cervix Cancer Brachytherapy. Int J Radiat Oncol Biol Phys, in press, .
    1. Chargari C., Magne N., Dumas I. Physics Contributions and Clinical Outcome with 3D-MRI-Based Pulsed-Dose-Rate Intracavitary Brachytherapy in Cervical Cancer Patients. Int J Radiat Oncol Biol Phys. 2009;74:185–193.
    1. Mahantshetty U., Banerjee S., Chopra S., Engineer R., Shrivastava S.K. Clincal outcome of patients treated with template based high dose rate (HDR) interstitial brachytherapy boost in gynecological malignancies. Radiother Oncol. 2011;99:S117.
    1. Beriwal S., Bhatnagar A., Heron D.E. High-dose-rate interstitial brachytherapy for gynecologic malignancies. Brachytherapy. 2006;5:218–222.
    1. Charra-Brunaud C., Levitchi M., Delannes M. Dosimetric, clinical results of a French prospective study of 3D brachytherapy for cervix carcinoma. Radiother Oncol. 2011;99:S57.
    1. Pötter R., Knocke T.H., Fellner C., Baldass M., Reinthaller A., Kucera H. Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: report on the Vienna University Hospital findings (1993–1997) compared to the preceding period in the context of ICRU 38 recommendations. Cancer Radiother. 2000;4:159–172.
    1. Pötter R., Dimopoulos J., Bachtiary B. 3D conformal HDR-brachy- and external beam therapy plus simultaneous cisplatin for high-risk cervical cancer: clinical experience with 3 year follow-up. Radiother Oncol. 2006;79:80–86.
    1. Lee C.B., Stinchcombe T.E., Rosenman J.G., Socinski M.A. Therapeutic advances in local-regional therapy for stage III non-small-cell lung cancer: evolving role of dose-escalated conformal (3-dimensional) radiation therapy. Clin Lung Cancer. 2006;8:195–202.
    1. Duprez F., Bonte K., De Neve W., Boterberg T., De Gersem W., Madani I. Regional relapse after intensity-modulated radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2011;79:450–458.
    1. Deutsch I., Zelefsky M.J., Zhang Z. Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT. Brachytherapy. 2010;9:313–318.
    1. Lang S., Nulens A., Briot E. Intercomparison of treatment concepts for MR image assisted brachytherapy of cervical carcinoma based on GYN GEC-ESTRO recommendations. Radiother Oncol. 2006;78:185–193.
    1. Jurgenliemk-Schulz I.M., Lang S., Tanderup K. Variation of treatment planning parameters (D90 HR-CTV, D 2cc for OAR) for cervical cancer tandem ring brachytherapy in a multicentre setting: comparison of standard planning and 3D image guided optimisation based on a joint protocol for dose-volume constraints. Radiother Oncol. 2009;94:339–345.
    1. De Brabandere M., Mousa A.G., Nulens A., Swinnen A., Van Limbergen E. Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma. Radiother Oncol. 2008;88:217–226.
    1. Lindegaard J.C., Tanderup K., Nielsen S.K., Haack S., Gelineck J. MRI-guided 3D optimization significantly improves DVH parameters of pulsed-dose-rate brachytherapy in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2008;71:756–764.
    1. Pötter R., Kirisits C., Fidarova E.F. Present status and future of high-precision image guided adaptive brachytherapy for cervix carcinoma. Acta Oncol. 2008;47:1325–1336.
    1. Tanderup K., Lindegaard J.C., Kirisits C. EMBRACE. Radiother Oncol. 2011;99:S22.
    1. Sturdza A., Lindegaard J.C., Fokdal L.U. Retro-EMBRACE: Preliminary results of image guided BT for cervical cancer in the last years of the 20st century. Radiother Oncol. 2011;99:S22.
    1. Dimopoulos J.C., De Vos V., Berger D. Inter-observer comparison of target delineation for MRI-assisted cervical cancer brachytherapy: application of the GYN GEC-ESTRO recommendations. Radiother Oncol. 2009;91:166–172.
    1. Dimopoulos J.C., Schirl G., Baldinger A., Helbich T.H., Pötter R. MRI assessment of cervical cancer for adaptive radiotherapy. Strahlenther Onkol. 2009;185:282–287.
    1. Hellebust T.P., Kirisits C., Berger D. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy. Radiother Oncol. 2010;96:153–160.
    1. Trnkova P., Potter R., Baltas D. New inverse planning technology for image-guided cervical cancer brachytherapy: description and evaluation within a clinical frame. Radiother Oncol. 2009;93:331–340.
    1. Jurgenliemk-Schulz I.M., Lang S., Tanderup K. Variation of treatment planning parameters (D90 HR-CTV, D 2cc for OAR) for cervical cancer tandem ring brachytherapy in a multicentre setting: comparison of standard planning and 3D image guided optimisation based on a joint protocol for dose-volume constraints. Radiother Oncol. 2010;94:339–345.
    1. Tanderup K., Potter R., Lindegaard J.C., Berger D., Wambersie A., Kirisits C. PTV margins should not be used to compensate for uncertainties in 3D image guided intracavitary brachytherapy. Radiother Oncol. 2010;97:495–500.
    1. Viswanathan A.N. The Frank Ellis memorial lecture: the use of three-dimensional imaging in gynaecological radiation therapy. Clin Oncol (R Coll Radiol) 2008;20:1–5.
    1. Lee L.J., Sadow C.A., Russell A., Viswanathan A.N. Correlation of point B and lymph node dose in 3D-planned high-dose-rate cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2009;75:803–809.
    1. Tanderup K., Nielsen S., Nyvang G. From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing organs at risk in brachytherapy of cervical cancer. Radiother Oncol. 2010;94:173–180.
    1. Koom W.S., Sohn D.K., Kim J.Y. Computed tomography-based high-dose-rate intracavitary brachytherapy for uterine cervical cancer: preliminary demonstration of correlation between dose-volume parameters and rectal mucosal changes observed by flexible sigmoidoscopy. Int J Radiat Oncol Biol Phys. 2007;68:1446–1454.
    1. Fidarova E.F., Berger D., Schussler S. Dose volume parameter D2cc does not correlate with vaginal side effects in individual patients with cervical cancer treated within a defined treatment protocol with very high brachytherapy doses. Radiother Oncol. 2010;97:76–79.
    1. Georg P., Kirisits C., Goldner G. Correlation of dose-volume parameters, endoscopic and clinical rectal side effects in cervix cancer patients treated with definitive radiotherapy including MRI-based brachytherapy. Radiother Oncol. 2009;91:173–180.
    1. Van de Kamer, JB, De Leeuw, AA, Moerland, MA, Jurgenliemk-Schulz, IM. Determining DVH parameters for combined external beam and brachytherapy treatment: 3D biological dose adding for patients with cervical cancer. Radiother Oncol 2010;94:248–253.
    1. Lorvidhaya V., Chitapanarux I., Sangruchi S. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys. 2003;55:1226–1232.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren