Robert Wade
Case history
A 35-year-old woman presented to the gynaecology department with post-coital bleeding. At colposcopy she was found to have an exophytic tumour arising from her cervix. She underwent an EUA, staging MRI scan of the pelvis, and CT scans of the chest and the abdomen. The MRI showed a 4cm tumour centred on the cervix with parametrial extension (Fig. 18.1) with no evidence of nodal spread. Biopsy revealed a poorly differentiated squamous cell carcinoma. Blood tests showed a mild anaemia (haemoglobin 11.5g/dl, normal 13.0–17.0) but normal renal and liver function.
Fig. 18.1
Questions
1. What stage disease does this patient have?
2. Outline your treatment approach.
Answers
1. What stage disease does this patient have?
The patient has a FIGO (International Federation of Gynecology and Obstetrics) stage IIb TNM stage T2bN0M0 squamous cell carcinoma of the cervix. T1 disease is confined the cervix, T2 disease invades beyond the uterus but not to the pelvic side-wall or lower third of the vagina (T2a involves the upper two-thirds of the vagina; T2b involves parametria), T3 disease extends to the pelvic sidewall or lower third of the vagina and/or causes hydronephrosis (T3a involves the lower third of the vagina, T3b extends to the pelvic sidewall/causes hydronephrosis), and T4 disease involves mucosa of the rectum or the bladder or extends beyond the true pelvis.
2. Outline your treatment approach.
In stage IIB, stage III, and selected stage IV patients the standard treatment is chemoradiotherapy followed by brachytherapy. Concurrent cisplatin 40mg/m2 once weekly for 5 weeks is given concomitantly with external beam radiotherapy Based on 13 trials, the addition of chemotherapy improved 5-year survival by 6% with an absolute improvement in PFS of 13% (Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration 2010).
At the MDT meeting treatment with chemoradiotherapy and brachytherapy is recommended.
Question
3. Describe your radiotherapy clinical target volume (CTV) and planning target volume (PTV) in detail. What dose would you prescribe?
Answer
3. Describe your radiotherapy clinical target volume (CTV) and planning target volume (PTV) in detail. What dose would you prescribe?
The structures that need to be treated with external beam radiotherapy include the primary tumour, vagina, uterus, parametria, pelvic sidewalls, and draining pelvic nodes. A contrast-enhanced planning CT with slice thickness ≤3mm should be performed. For node-negative disease the nodal CTV starts at the level of the junction of 4th and 5th lumbar vertebrae. The pelvic lymph nodes with a 7mm margin are outlined by following the course of the major pelvic arteries and veins. Taylor et al. (2005) and Small (2008) describe the appropriate structures that need to be included. The nodal CTV is grown a further 7mm to derive the nodal PTV. The uterus, parametria, cervix, and vagina are defined as the tumour CTV. A 15mm expansion of the tumour CTV to the PTV is required to ensure adequate tumour coverage. The nodal and tumour PTVs are then added together. The lower border of the treatment field tends to be at the level of the bottom of the obturator foramen or the inferior extent of vaginal involvement with a margin of 15mm. A dose of 45Gy in 25 fractions is prescribed to the International Commission on Radiation Units and Measurements (ICRU) reference point.
She is treated with 45Gy in 25 fractions with concomitant cisplatin.
Question
4. What clinical factors should be monitored during treatment?
Answer
4. What clinical factors should be monitored during treatment?
The main issues to watch out for apart from the direct side-effects of chemotherapy are haemoglobin levels and renal function. It is important to maintain haemoglobin levels above 12g/dl throughout treatment. A haemoglobin level below 12g/dl is recognized as a poor prognostic indicator and correction to 12g/dl may negate this factor. Overall treatment time is also important: the whole treatment from the start of external beam radiotherapy to the completion of brachytherapy should take no longer than 50 days, otherwise treatment becomes less effective. In the case of unexpected delays, Royal College of Radiologists guidelines for category 1 (patients with a tumour types for which there is evidence that prolongation of treatment affects outcome, and who are being treated with radical curative intent; see <https://www.rcr.ac.uk/docs/oncology/pdf/BFCO(08)6_Interruptions.pdf>) treatments should be followed. Two external beam fractions in a day with at least 6h between treatments need to be given to compensate for delays so that overall length of treatment stays within 50 days.
In the last week of external beam treatment the patient had a repeat MRI scan which showed a reduction in the size of her primary tumour. She underwent image-guided [high-dose-rate (HDR)] brachytherapy (IGBT) delivering four fractions of 7Gy each (over a period of 3 days with at least 6h between each fraction). She had a ring and tandem inserted in theatre but no interstitial needles were required. A MRI scan was performed with the applicator in situ.
Questions
5. Define high-risk CTV, intermediate-risk CTV, and point A.
6. What organs at risk (OARs) are important in IGBT and what are the accepted dose limits?
7. Which dosimetric parameters are important? How do you improve coverage to the high risk-CTV?
8. What outcome would you expect following treatment?
Answers
5. Define high-risk CTV, intermediate-risk CTV, and point A.
The principles behind IGBT are similar to those of external beam conformal planning. The basic technique requires placement of an intrauterine tube and ring in theatre under general anaesthetic with or without interstitial needles. In order to determine the optimal tandem/ring/needle combination the patient is anaesthetized and a ring and tandem are inserted, imaged, and planned prior to applicator removal. This allows the oncologist to determine whether interstitial needles are likely to be required, and their optimal placement. While CT localization is good enough to determine the OARs, a MRI scan is required to accurately define the high-risk CTV (HR-CTV) and to allow dose escalation. Ideally CT and MRI should be performed and fused on the treatment planning system. The HR-CTV includes residual tumour at the time of brachytherapy, the whole cervix, and any parametrial spread including gray zones (high-risk areas for micrometastatic disease which appear gray on T2-weighted MRI sequences) and clinical findings from EUA. The location of the lower uterine arteries is helpful in defining the extent of the cervix. The intermediate-risk CTV (IR-CTV) reflects the extent of the tumour at initial presentation and takes into account tumour regression. In practice the IR-CTV is grown from the HR-CTV using a margin of between 5 and 15mm, editing out the OARs. The aim is to deliver four fractions of 7Gy each to the HR-CTV. Point A is the dose delivered to a point 2cm lateral to and 2cm superior to the cervical os. Figure 18.2 (See also colour plate section) shows the principal volumes of interest.
Fig. 18.2 (See also colour plate section)
6. What organs at risk (OARs) are important in IGBT and what are the accepted dose limits?
Four OARs are recognized—rectum, sigmoid colon, urinary bladder, and small bowel. The dose received by 2cm3 of an OAR is the dose-limiting constraint. The acceptable 2Gy equivalent doses (EQD2) by 2cm3 of OARs are: rectum 70–75Gy, sigmoid colon 70–75Gy, bladder 90–95Gy, and small bowel 70–75Gy. (Acceptable dose limits combine external beam and brachytherapy doses expressed as EQD2.)
7. Which dosimetric parameters are important? How do you improve coverage to the high-risk CTV?
The important dosimetric parameters are V100, D90, and EQD2 and physical dose to point A (V100 is the volume receiving 100% of the prescribed dose; D90 is the minimum dose delivered to 90% of the tumour target volume).
Optimization in IGBT is the process by which coverage to the HR-CTV is improved. With a ring and applicator the only way this can be done is by increasing the dwell times in the tandem, but this will increase toxicity to the anterior and posterior OARs. Interstitial needles allow the lateral dose to be increased without overdosing bladder, bowel, and rectum, thus improving tumour coverage and hopefully reducing morbidity. The dwell times in the intrauterine tube, ring, and interstitial needles can then be altered in order to maximize the D90 dose and the V100. A D90 of >75Gy to the HR-CTV according to the Royal College of Radiologists’ guidance should achieve similar outcomes to historical series. Three-dimensional IGBT should achieve HR-CTVs of the order of 85–90Gy. Although in practice it is only really possible to optimize dose to one volume, a D90 of 60Gy to the IR-CTV should also be possible. Four fractions are delivered over 3 days with a minimum of 6h between each fraction with the applicator remaining in situ for all of that time.
8. What outcome would you expect following treatment?
Local control rates at 3 years from the Vienna group are 98% for tumours of 2–5cm and 92% for tumours >5cm (96% IIB; 86% IIIB). The expected 3-year cancer-specific survival is 83% for tumours of 2–5cm and 70% for tumours >5cm (84% IIB; 52% IIIB) (Potter et al. 2011). Other published series show similar results (e.g. Tan et al. 2009).
Further reading
Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. The Cochrane Database of Systematic Reviews 2010; Jan 20 (1): CD008285.
Haie Meder C, Potter R, Van Limbergen E, et al. 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. Radiotherapy and Oncology 2005; 74: 235–245.
Potter R, Haie Meder C, Van Limbergen E, et al. 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. Radiotherapy and Oncology 2006; 78: 67–77.
Potter R, Georg P Dimopoulos JC, et al. 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. Radiotherapy and Oncology 2011; 100/1: 116–123.
Small W Jr, Mell LK, Anderson P, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. International Journal of Radiation Oncology Biology Physics 2008; 71: 428–434.
Tan LT, Coles CE, Hart C, et al. Clinical impact of computerised tomography-based image-guided brachytherapy for cervix cancer using the tandem-ring applicator—the Addenbrooke’s experience. Clinical Oncology 2009; 21: 175–182.
The Royal College of Radiologists. Implementing image guided brachytherapy for cervix cancer in the UK. London: Royal College of Radiologists, 2009.
Taylor A, Rockall AG, Reznek RH, et al. Mapping pelvic lymph nodes: guidelines for delineation in intensity modulated radiotherapy. International Journal of Radiation Oncology Biology Physics 2005; 63: 1604–1612.