Abstract
Objective:
Pelvic side wall dose in locally advanced cervical carcinoma treated with definitive chemoradiation has been debated. The present study investigated relationship of disease recurrence with dose for the pelvic side wall. It also attempted to identify minimal dose that significantly reduced recurrence.
Methods:
Pelvic side wall recurrence at median 24 months was assessed clinically and radiologically across three groups of patients receiving variable pelvic wall doses using no parametrial boost, external beam or interstitial boost, or dose escalated combined external beam with interstitial boost.
Results:
At 24 months, recurrence occurred in 3/155 boost vs 40/130 no boost patients. (p < 0.0001). Receiver operating characteristic curve analysis demonstrated cut-off pelvic wall dose to be 58.9 Gy (p < 0.0001). Dose escalated combined boost showed no significant benefit compared to single modality parametrial boost (p = 0. 0.553).
Conclusion:
Mean pelvic wall dose of at least 58.9 Gy offers clinically significant benefit in pelvic wall control. Doses recommended by guidelines should be adhered to in the patients’ best interests.
Advances in knowledge:
This preliminary study determined a relationship between recurrence rates and dose to the pelvic side wall and also a cut-off dose that significantly improved pelvic wall control in locally advanced cervical cancer.
Introduction
The gold-standard for treatment in locally advanced cervical carcinoma is definitive chemoradiation.1,2 Recurrence rates following definitive chemoradiation are higher for locally advanced tumours as compared to early stages with higher locoregional relapse than distant metastases in patients having larger tumour volumes at initiation of radiotherapy.3
Patients with pelvic recurrence may either have central disease, involving the bladder and rectum, or recurrence involving the distal parametria and pelvic side wall. The management of pelvic wall recurrence is particularly challenging. Unlike central disease, which is usually managed with pelvic exenteration surgery or in selected instances re-irradiation, the management of pelvic wall recurrence necessitates multimodality treatments utilising a combination of surgery, radiotherapy, and occasionally chemotherapy. Lateral extended endopelvic resection (LEER) is a complex surgery associated with considerable perioperative morbidity that requires long hospital stays and adequate availability of skilled personnel and resources. Additionally, all cases of pelvic wall recurrence are not suitable for LEER. As a result, pelvic side wall recurrence often confers poorer outcomes, despite being biologically similar to central relapse.4 Unsuccessful salvage leads to a poorer quality of life and increases the dependence on palliative care and patient support services. Overall, pelvic side wall relapse has a considerable impact on patients’ lives and healthcare services.
The recommended dose prescription guidelines for high risk clinical target volume (HRCTV) and intermediate risk clinical target volumes (IRCTVs) for improving treatment outcomes in patients with locally advanced cervical cancer are well established. The recommended doses account for a considerably higher tumour burden in the distal parametria and near the pelvic walls as opposed to earlier stages.5,6
However, reports suggest that satisfactory loco regional control can be achieved with doses considerably lower than those recommended in these guidelines, in the context of clinically involved parametria.7 Some studies utilising parametrial boost have reported higher organ at risk doses and toxicity with external beam boost fields. Dosimetry with interstitial brachytherapy boosts have been reported to be more favourable.8–10 Investigators have also reported satisfactory dosimetry with advanced radiotherapy techniques such as IMRT.11
Low resource regions such as India are major contributors to the global cervical cancer burden every year, and most patients continue to present at locally advanced stages.12,13 Numerous centres treating such patients in our setting, lack the facilities for interstitial brachytherapy, which is more cost and resource intensive compared to intracavitary applications. Additionally, a large proportion of patients continue to have restricted access to intensity modulated radiotherapy (IMRT) or other advanced radiotherapy technologies. Consequently, a boost to the distal parametria and pelvic wall is often compromised due to concerns about excessive toxicity. Sub optimal doses increase the risk of pelvic side wall recurrence, which is challenging to treat in the setting of limited resources. The present study investigated the impact of variable pelvic side wall dose on recurrence in the clinics, in addition to determining a cut-off dose that can significantly improve pelvic side wall control.
Patients and methods
In this study, 285 female patients with histologically proven locally advanced carcinoma cervix (FIGO Stage IIB–IVA), from two different cancer centres, were compared for pelvic side wall recurrence during a median duration of 24 months follow-up. The study duration extended from April 2007 to February 2014. All the patients received telecobalt external beam pelvic radiotherapy with weekly concomitant Cisplatin at doses of 40 mg/m2 followed by high dose rate (HDR) brachytherapy with Ir192 sources. The study cohort comprised of three groups based on the total mean pelvic side wall dose administered. One group received intracavitary brachytherapy with no parametrial boost, the second group received parametrial boost with either external beam radiotherapy or interstitial brachytherapy, and the third group received dose escalated parametrial boost with combined external beam and interstitial brachytherapy.
Patients receiving parametrial boost (n=155)
These patients received pelvic chemoradiation with telecobalt up to a dose of 50 Gy/ 25 fractions in 5 weeks, with weekly concomitant Cisplatin at a dose of 40 mg/m2 ; all individuals subsequently received image-guided HDR brachytherapy. The patients were randomly allocated to receive HDR brachytherapy with either interstitial (ISBT) or intracavitary (ICRT) technique. For patient convenience and higher turnover, the brachytherapy schedule chosen was 9 Gy per fraction weekly for two weeks. Those receiving ICRT additionally received an external beam parametrial boost (PMB) using a midline shield that was individually customised according to the width of the brachytherapy prescription isodose.14 The dose for the PMB was 9 Gy/5 fractions in 1 week. Those receiving ISBT were randomly allocated to either receive additional PMB or no further treatment. The borders for the PMB fields were as follows: superior border: L5–S1 junction to include parametrium only excluding nodes, and inferior and lateral borders: as for the whole pelvic fields. The measurement of the shield was customised according to the needs of the particular case. The height of the shield was the same as that of the boost field. The width of the shield depended on the width of the brachytherapy reference isodose, as documented during brachytherapy planning.
Patients receiving no boost (n=130)
All the patients received pelvic chemoradiation as per the institutional protocol, with telecobalt, up to a dose of 50 Gy/25 fractions in 5 weeks with weekly concomitant Cisplatin at a dose of 40 mg/m2. Subsequent HDR brachytherapy was delivered by ICRT. The dose of brachytherapy for all the patients was 7 Gy per fraction weekly for three weeks. No additional PMB was delivered after brachytherapy.
Calculation of mean pelvic side wall dose
The pelvic side wall dose was measured bilaterally at a point on the pelvic side wall at the level of the external os. A representative CT image is shown in Figure 1. Mean pelvic side wall 2 Gy equivalent doses (EQD2) were individually calculated for the external beam and brachytherapy contributions, and were summated. The HDR brachytherapy doses were converted using a dedicated Microsoft spreadsheet program.14 The α/ β values for the tumour and normal tissues were considered to be 10 and 3, respectively. The mean pelvic side wall dose and pelvic side wall recurrence during the median duration of 24 months follow-up was individually recorded and compared between the group receiving boost and the group that did not receive boost. Pelvic side wall recurrence was also compared between the subgroups receiving parametrial boost at different pelvic side wall doses. One subgroup received ISBT boost (n = 43), while the second subgroup (n = 57) received ICRT with PMB (ICRT/PMB). The third subgroup (n = 55) received a dose escalated combined modality parametrial boost with ISBT and external beam (ISBT/PMB).
Figure 1.
CT image at the level of the external os showing the measurement of the point dose on the pelvic side wall. The point doses from external beam radiotherapy and brachytherapy were summated after converting them to EQD2.
The receiver operating characteristics (ROC) curve of pelvic side wall dose and recurrence at 24 months was analyzed to identify a cut-off dose that had a clinically significant impact on pelvic side wall recurrence in this cohort. All patients were followed up at 1 month after treatment and 3 monthly thereafter for 2 years. Patients subsequently visited every 6 months for the next 5 years, and annually thereafter. History taking and clinical examination were performed at each visit. Contrast-enhanced CT scans were performed at 3, 6, and 12 months after treatment unless otherwise indicated.
Results
In this study, 285 patients with locally advanced cervical cancer were investigated. Among them, 278 (97.5%) had non-keratinizing squamous cell carcinoma, while the remainder had other histologies. Among 285 patients, 231 (81.1%) had Stage IIIB disease at presentation. The median age of this cohort was 36 years (ranging from 24 to 69 years); 227 (79.6%) patients had completed at least 4 weeks of concomitant chemotherapy. The median duration of follow up was 24 months (ranging from 20 to 29 months) (Table 1).
Table 1.
Patient characteristics
| Patient characteristics (n = 285) | |||||
|---|---|---|---|---|---|
| Overall | ISBT/PMB (n = 55) | ICRT/PMB (n = 57) | ISBT (n = 43) | No boost (n = 130) | |
| Age | 25–69 years (median 39 years) | 28–57 years (median 42 years) | 33–69 years (median 38 years) | 36–58 years (median 44 years) | 25–53 years (median 41 years) |
| Stage | |||||
| IIB | 24 | 7 | 3 | 2 | 12 |
| IIIA | 4 | 0 | 1 | 2 | 1 |
| IIIB | 231 | 44 | 48 | 32 | 107 |
| IVA | 26 | 4 | 5 | 7 | 10 |
| Histological diagnosis | |||||
| Squamous cell carcinoma | 278 | 54 | 55 | 42 | 127 |
| Adenocarcinoma | 6 | 1 | 2 | 1 | 2 |
| Small cell carcinoma | 1 | 0 | 0 | 0 | 1 |
ICRT, intracavitary brachytherapy; ISBT, interstitial brachytherapy; PMB, parametrial boost.
The mean pelvic wall doses (EQD2) among the three subgroups receiving parametrial boost were 68.1 Gy (62.3–70.7 Gy) for those receiving external beam PMB (ICRT/PMB), 69.6 Gy (65.3–73.3 Gy) for those receiving ISBT, and 72.9 Gy (68.7–78.2 Gy) for those receiving dose escalated combined ISBT/PMB. In patients who received no boost, the mean pelvic wall dose was 57.4 Gy (55.2–58.6 Gy) (Table 2).
Table 2.
Mean pelvic wall dose in each treatment grouP
| Total population (n = 285) | |
|---|---|
| Treatment group | Mean pelvic wall dose (EQD2) |
| Parametrial boost | |
| Combined ISBT/PMB (n = 55) | 72.9 Gy (68.7–78.2 Gy) |
| ISBT (n = 43) | 69.6 Gy (65.3–73.3 Gy) |
| ICRT/PMB (n = 57) | 68.1 Gy (62.3–70.7 Gy) |
| No boost (n = 130) | 57.4 Gy (55.2–58.6 Gy) |
ICRT, intracavitary brachytherapy; ISBT, interstitial brachytherapy; PMB, parametrial boost.
Statistical analyses
All the statistical analyses were performed using MedCalc Statistical Software, v. 18.6 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018). The level of significance in the difference of recurrence rates between the different groups was analysed using the Fisher’s two tailed t-test.
At the end of 24 months, pelvic side wall recurrence was recorded in 3/155 patients who received any parametrial boost and 40/130 patients who received no boost (p-value as calculated by Fisher’s exact two tailed t-test <0.0001). No significant difference was found between the groups receiving ISBT and external beam boost (p = 1.000). Comparison between the escalated dose parametrial boost and single modality boost showed no significant difference in pelvic side wall recurrence rates (p-value as calculated by Fisher’s exact two tailed t-test = 0.553).
The analysis of the ROC curve demonstrated that the cut-off dose to the pelvic wall to be 58.9 Gy for significant clinical benefit. The area under the ROC curve (AUC) was 0.806 (p-value < 0.0001). The Youden Index J for the analysis was 0.65 (Figure 2). The incidence of persistent disease (no response), partial response, and recurrence within 24 months have been summarised in Table 3.
Figure 2.
ROC curve demonstrating the optimal pelvic wall dose that significantly reduced recurrence. ROC, receiver operating characteristics.
Table 3.
The incidence of persistent disease, partial response, recurrence, and disease free survival in the cohort
| Total number of patients including partial responders and those with persistent disease (n = 285) | ||||
|---|---|---|---|---|
| Disease status | Patients who received pelvic wall boost doses by modality | Patients who did not receive any pelvic wall boost (n = 130) | ||
| ICRT/PMB (n = 57) | ISBT (n = 43) | Combined ISBT/PMB (n = 55) | ||
| Persistent disease | 1 | 0 | 0 | 1 |
| Partial response | 2 | 1 | 4 | 12 |
| Overall recurrence (including central, pelvic wall, and distant recurrence) | 11 | 7 | 9 | 26 |
| Disease free survival (median) | 18.3 months | 19.1 months | 18.7 months | 14.3 months |
ICRT, intracavitary brachytherapy; ISBT, interstitial brachytherapy; PMB, parametrial boost.
Discussion
The pelvic side wall constitutes the peripheral boundary of the IRCTV in locally advanced cervical cancer. Parametrial boosts using external beam radiotherapy with midline blocks or ISBT have been traditionally used to achieve pelvic wall doses recommended by international guidelines. The adequate dose to the parametria, however, is debated. Rajasooriyar et al observed satisfactory locoregional control in patients with clinically involved parametria without additional parametrial boosts.7 On the contrary, Perez et al reported higher rates of local recurrence in patients who received less than 50 Gy to the lateral parametria.15 In the absence of widespread facilities for ISBT and IMRT, the need for a parametrial boost is often questioned in our setting owing to concerns regarding the toxicity associated with it; additionally, reports suggest that it is unnecessary.7,9,10 However, the individual customisation of midline blocks according to the width of the brachytherapy prescription isodose has been found to make parametrial boosts safer in our practice. It is a widely available and cost-effective method for achieving recommended IRCTV doses.16
In this study, lower pelvic side wall recurrence was noted at median 24 months follow-up in patients who received any form of parametrial boost compared with those who did not. Significant benefit in local control was noted irrespective of the parametrial boost technique employed, i.e. external beam radiotherapy or ISBT (p < 0.0001). No significant benefit was achieved from escalated dose parametrial boost using combined ISBT and external beam radiotherapy, compared to single modality parametrial boost (p = 0.553). The results demonstrate that the administration of parametrial boosts by any technique offers significantly better pelvic wall control than no boost. However, the escalation of pelvic wall dose beyond recommended doses is clearly unnecessary.
Analysis of the ROC curve in this cohort demonstrated that the optimal pelvic side wall dose that significantly improved pelvic wall control was 58.9 Gy, which is in agreement with the doses recommended by international guidelines. Our study had a limited number of patients since many patients failed to attend for follow-up. However, this study is instructive in demonstrating that it is in the patients’ best interests not to treat the pelvic side wall in locally advanced cervical cancer with doses lower than those recommended by guidelines. In settings where advanced radiotherapy techniques are not available, the customised parametrial boost is necessary to boost pelvic side wall doses. This will serve to improve patient outcomes.
Conclusions
Recurrence at the pelvic side wall in locally advanced cervical cancer treated with definitive chemoradiation is related to total pelvic wall doses, and administering at least 58.9 Gy has a clinically significant impact on recurrence.
Footnotes
Acknowledgment: The authors would like to thank the Institutional Ethical Committee, Medical College Hospitals, Kolkata for kindly approving the study. The authors are also particularly grateful to Mr Surojit Maity, Department of Medical Records, Chittaranjan National Cancer Institute, Kolkata for his invaluable assistance during data collection
Contributor Information
Aparna Gangopadhyay, Email: mails7778@gmail.com.
Subrata Saha, Email: saha1958@yahoo.co.in.
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