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Image-guided adaptive brachytherapy in cervical cancer: Patterns of relapse by brachytherapy planning parameters
Brachytherapy
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Image-guided adaptive brachytherapy in cervical cancer: Patterns of relapse by brachytherapy planning parameters Cyrus Chargari1,2,3,4,5,*, Renaud Mazeron1,2,3, Alexandre Escande1,3, Pierre Maroun1,3, Isabelle Dumas1,3, Florent Martinetti1,3, Alain Tafo-Guemnie1,3, Eric Deutsch2,3,5, Philippe Morice5,6, Christine Haie-Meder1,3 1
Brachytherapy Unit, Department of Radiotherapy, Gustave Roussy, Villejuif, France 2 INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France 3 Radiotherapy Department, Gustave Roussy, Villejuif, France 4 Effets biologiques des rayonnements, Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France 5 Department of Surgery, Gustave Roussy, Villejuif, France 6 University Paris-Sud, SIRIC SOCRATES, Faculte de Medecine, Le Kremlin-Bic^etre, France
ABSTRACT
PURPOSE: Cervical cancer patients with a bulky high-risk clinical target volume (HR-CTV) get the largest benefit of dose escalation in terms of local control. However, the expected survival benefit could be lessened by a higher metastatic risk. We examined the patterns of relapse according to major prognostic factors: the HR-CTV volume and to the D90 HR-CTV. METHODS AND MATERIALS: The clinical records of patients treated with pulsed-dose-rate image-guided adaptive brachytherapy after concurrent pelvic chemoradiation were reviewed. All patients had an optimal workup before treatment comprising a 18-fluorodeoxyglucose positron emission tomography/computed tomography and a para-aortic lymph node dissection. Patients with initial extrapelvic disease were excluded. RESULTS: A total of 109 patients fulfilled inclusion criteria. Median followup was 39 months. An HR-CTV volume $40 cm3 was associated with a poorer local failure-free survival. There was a strong inverse correlation between the HR-CTV volume and the D90 of the HR-CTV (correlation coefficient r 5 0.696; p ! 0.001) with increasing HR-CTV volume being associated with a decreasing D90 HR-CTV. A D90 HR-CTV !85 Gy and an HR-CTV volume $40 cm3 were significant univariate factors for experiencing nonlocal failure ( p 5 0.002 and 0.035, respectively), even after exclusion of local relapses. CONCLUSION: A lower ability to reach the target D90 HR-CTV planning and an HR-CTV volume $ 40 cm3 correlated with a high propensity of relapsing at distance, these factors being interrelated. Next step of treatment personalization should design strategies integrating this risk, which is now the main cause of failure. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Image-guided adaptive brachytherapy; Dose escalation; High-risk clinical target volume; Planning aim
Introduction The implementation of image-guided adaptive brachytherapy (IGABT) has allowed dose escalation without Received 16 January 2016; received in revised form 31 March 2016; accepted 12 April 2016. Conflict of interest: No conflict of interest relative to this work. * Corresponding author. Brachytherapy Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Tel.: þ33-1-42-11-45-66; fax: þ33-1-42-11-52-08. E-mail address: [email protected] (C. Chargari).
increasing toxicity, translating into a meaningful improvement in local control rates in cervical cancer patients (1e9). Based on retrospective data showing a clear doseeeffect relationship in cervical cancer, dose escalation has a sound rationale and should be encouraged for patients presenting a bulky residual disease at time of brachytherapy to optimize the probability of local control (10, 11). Thus, a recent analysis of predictive factors for local control has shown that the volume of the high-risk clinical target volume (HR-CTV), which reflects the residual tumor bulk at time of IGABT and the response to external beam
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.04.006
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radiotherapy (EBRT), was an independent major factor inversely correlated with the probability of achieving local control. Moreover, higher doses were required to reach the same probability of local control in patients with larger HR-CTV volumes (9). The persistence of a bulky residual disease after 45 Gy of pelvic chemoradiation illustrated by a large HR-CTV is a surrogate of a poor sensitivity to radiotherapy and therefore a potential pejorative factor of local control. At the same time, the inability to deliver an adequate dose to the HR-CTV because of its bulk could be also a marker of a high metastatic risk that would lessen the benefit of improving local control. An alternative explanation would be that larger tumors with a poor response to chemoradiation are predictive of the distant metastatic risk. Actually, the HR-CTV volume and the D90 HR-CTV are entangled parameters, as D90 HR-CTV tends to be higher in small HR-CTV and lower in large HR-CTV. We examined the impact of the HR-CTV volume and of the dose achieved to the HR-CTV on local and distant failures rates after chemoradiation and IGABT for a locally advanced cervical cancer. Potential relationships could suggest on the need for further local or systemic intensification in these patients.
Patients and methods Patients and tumors We reviewed the clinical records of consecutive patients with histologically confirmed primary locally advanced cervical cancer treated in our institution with pulsed-dose-rate (PDR) IGABT after initial concurrent chemoradiation between April 2007 and February 2012. Patients’ outcome was prospectively documented. They were eligible in case of disease limited to the pelvis after an exhaustive primary staging including a 18-fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) and a systematic primary laparoscopic para-aortic lymphaden-ectomy. Treatment characteristics Patients received pelvic EBRT, 45 Gy in 25 fractions of 1.8 Gy through a 3D conformal technique with high megavoltage photons of a linear accelerator. Only patients receiving concurrent chemotherapy were analyzed, to minimize any bias related to systemic agents. Concurrent weekly cisplatin 40 mg/m2 was delivered. Weekly carboplatin area under curve 2 was preferred in case of contraindication to cisplatin. If no hematological contraindication, an additional cycle of chemotherapy could be delivered at time of IGABT. Patients received a PDR brachytherapy boost based on a 3D computerized assisted treatment planning through the PDR Selectron seed projector (Nucletron, an Elekta
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Company, Stockholm, Sweden) or Varian afterloader (Varian Medical System, Palo Alto, CA) and using the vaginal mold technique (12, 13). Definitions of volumes followed the guidelines of the Groupe Europeen de Curietherapiee European Society for Radiotherapy & Oncology (10, 11). Brachytherapy irradiation aimed at delivering at least 60 Gy to 90% of the intermediate-risk clinical target volume, taking into account the contribution of EBRT after converting doses into biological effective doses normalized to a radiobiologically weighted dose equivalent of 2 Gy/ fraction (a/b 5 10 Gy) and 85 Gy to the D90 of the HR-CTV. Dose constraints to the rectum, bladder, and sigmoid colon were, respectively, 75, 85, and 75 Gy (a/b 5 3 Gy). Irradiation was delivered through continuous hourly pulses, without exceeding the limit of 0.6 Gy per hour to the organs at risk. The brachytherapy was delivered through one single application per patient. However, when the endocavitary implantation did not allow an adequate coverage of HR-CTV volume because of distal parametrial extension, an additional implantation could be performed with interstitial needles. Further details on the brachytherapy procedure and on the dosimetric process have been previously published (9,12e14). Thereafter, patients received a pelvic sequential fractionated boost for delivering 60 Gy to PET-positive pelvic lymph node, taking into account the contribution of IGABT. The overall treatment time was aimed at not exceeding 55 days.
Followup and statistical analysis Followup was scheduled at 6 weeks, then every 3 months during 2 years. A systematic MRI of the pelvis and paraaortic area was performed 6e8 weeks after IGABT, then every 6 months. Hysterectomy was kept for isolated local failure. Patients were completely restaged through PET/ CT when local recurrence was detected. Only first sites of relapse were considered and classified as local (failure within the true pelvis), pelvic nodal, or distant (including para-aortic). The factors associated with local and nonlocal failure (defined as pelvic nodal or distant failure) were examined. Risk factors for nonlocal failures were examined after exclusion of patients with local failure to minimize the effect of local failure on secondary distant events. Survival times were calculated from the time of histological diagnosis, and survival rates were estimated using the KaplaneMeier method. Only first relapses were examined. Univariate analyses were carried out using log-rank tests. Multivariate analysis was not performed because of a low number of events and because of potential interactions between factors. Statistical analyses were performed using SPSS statistics 20.0 (Statistical Package for Social Science) for windows (an IBM company software, Chicago, IL).
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Results Patients, tumors, and treatments delivered A total of 109 patients fulfilled inclusion criteria. Median age was 44 years (range: 26e69). Median hemoglobin level was 12.5 g/dL (range: 8.5e14.6 g/dL). Median tumor width was 45 mm (range: 10e100 mm). Initial median tumor volume was 34 cm3 (range: 1.1e183.4 cm3). All patients had a disease limited to the pelvis after undergoing a para-aortic lymph node dissection as part of the primary staging. Median number of lymph nodes removed at primary para-aortic lymphadenectomy was 14 (range: 0e 43). Concurrent chemotherapy was cisplatin in 98 patients (90.0%) and carboplatin for the 11 remaining patients (10%). Forty-five patients (45.3%) had pelvic nodal uptakes at PET/CT and received a sequential boost to a median dose of 9 Gy (range: 8e12 Gy; 1.8e2 Gy per fraction). The brachytherapy dosimetry was based on MRI in 100 patients (91.7%) and the rest on CT (n 5 9). The median HR-CTV volume was 21 cm3 (range: 6e76 cm3). Sixteen patients (14.7%) had an HR-CTV volume $ 40 cm3 classified as bulky HR-CTV. The median initial tumor volume was 55 cm3 among patients with an HR-CTV $ 40 cm3 vs. 28 cm3 in patients with an HR-CTV ! 40 cm3 ( p ! 0.001). Eight patients (7.3%) received a parametrial boost using interstitial needles. Median overall treatment time was 47 days (range: 38e80 days). The median D90 HR-CTV was 83 Gy (range: 53e108 Gy). Forty-seven patients (43.1%) had a D90 HRCTV $ 85 Gy, and 62 patients (56.9%) had a D90 HRCTV ! 85 Gy. The median D90 HR-CTV was 70 Gy (range: 52.9e78.1 Gy) in patients with an HR-CTV $ 40 cm3 and 85.1 Gy (range: 65.7e107.6 Gy) in patients with an HRCTV ! 40 cm3 ( p ! 0.001). Characteristics of patients, tumors, and treatments are shown in Table 1. Patterns of relapse Median followup was 39 months. At last followup, a total of 25 patients (22.9%) experienced tumor relapse. First failures were local in 11 patients (10.1%), pelvic nodal in 7 patients (6.4%), and distant in 17 patients (15.6%). Isolated local relapses occurred in 5 patients (4.6%). Nonlocal failures were reported in 20 patients (18.3%). Six patients (5.5%) presented both local and nonlocal failure. Fourteen patients (12.8%) presented nonlocal failure as the only pattern of relapse. Patients with a bulky HR-CTV $40 cm3 experienced local failure in 4/16 (25.0%) vs. 7/93 (7.5%) in case of a nonbulky HR-CTV ( p 5 0.05). There was no isolated local relapse in patients with a bulky HR-CTV vs. 5/93 (5.4%) in case of not bulky HR-CTV (not significant). Patients with a bulky HR-CTV volume experienced more frequent nonlocal failures than those with an HR-CTV !40 cm3: 8/16 (50.0%) vs. 12/93 (12.9%) ( p 5 0.002). Patterns of relapse according to the volume of the HR-CTV are detailed in Fig. 1.
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Table 1 Patients and treatments characteristics Characteristics
Total
Number of patients Median age (range) Median hemoglobin level in g/dL (range) Tumor stage (%) IB1 IB2 IIA IIB IIIA IIIB IVA Pelvic lymph node uptake (%) Histology (%) Squamous cell carcinoma Adenocarcinoma Other Differentiation (%) Well Intermediate Poor Not determined Median tumor volume in cm3 (range) Risk groups (%) Low risk High riska Pelvic irradiation (%) Para-aortic irradiation (%) Pelvic dose (Gy) Concurrent chemotherapy (%) Cisplatin based Carboplatin based Image-guided adaptive brachytherapy (%) MRI based Computed tomography guided Use of interstitial needles (%) Median HR-CTV volume in cm3 (range) Median D90 HR-CTV in Gy (range) Number of patients with an HR-CTV volume $ 40 cm3 Median D90 IR-CTV in Gy (range) Median total reference air Kerma in cGy.m2 (range)
109 44 (26e69) 12.5 (8.5e14.6) 5 41 9 47 0 6 1 45
(4.6) (37.6) (8.3) (43.1) (0) (5.5) (0.9) (41.3)
85 (78.0) 21 (19.3) 3 (2.7) 36 39 14 20 34 44 65 109 0 45 109 98 11 109 100 9 8 21 83 16
(33.0) (35.8) (12.8) (18.3) (1.1e183.4) (40.4) (59.6) (100) (0) (100) (89.9) (10.1) (100) (91.7) (8.3) (7.3) (6e76). (53e108) (14.7)
69 (51e82) 1.8 (0.6e2.7)
D90 HR-CTV 5 dose delivered to D90 of the high-risk clinical target volume; D90 IR-CTV 5 dose delivered to D90 of the intermediate-risk clinical target volume; Gy 5 gray. a Patients with pelvic nodal metastases or with Stage IIIeIVA tumor classified as high risk.
Local failures were seen in 3/47 (6.4%) in patients with a D90 HR-CTV $ 85 Gy and in 8/62 (12.9%) in patients with a D90 HR-CTV ! 85 Gy, respectively (not significant). Nonlocal failures were seen in 2/47 (4.3%) and in 18/62 (29.0%), respectively ( p ! 0.001). Patterns of relapse according to the ability to deliver 85 Gy to 90% of the HRCTV are detailed in Fig. 2. Prognostic factors and patterns of relapse A combination of clinical factors (Stage: IeII vs. IIIe IV, positive vs. negative pelvic nodes, overall treatment
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Fig. 1. Patterns of relapse according to the HR-CTV volume. HR-CTV 5 high-risk clinical target volume.
time $ or ! 50 days, HR-CTV volume $ or ! 40 cm3, hemoglobin level $ or ! 11 g/dL, tumor width # or O 50 mm) and dosimetric parameters (D90 of the HRCTV: $ or !85 Gy (a/b 5 10 Gy)) was tested for survival without local failure and survival without nonlocal failure. In log-rank analysis, only an HR-CTV volume $40 cm3 was associated with a poorer local failure-free survival (Table 2). Three-year local failure-free survival rates were 93% (95% confidence interval [CI]: 88e99%) in patients with an HR-CTV volume!40 cm3 and 74% (95% CI: 52e96%) in case of an HR-CTV volume $40 cm3 ( p 5 0.025) (Fig. 3). After exclusion of patients with local failure, a D90 HR-CTV !85 Gy and an HR-CTV volume $40 cm3 were identified in log-rank analysis as significant univariate factors for experiencing nonlocal failure ( p 5 0.002 and p 5 0.035, respectively) (Table 2). Three-year estimated
survival without nonlocal failure was 98% (95% CI: 96e 100%) in patients with a D90 HR-CTV $ 85 Gy vs. 84% (95% CI: 79e89%) in those with a D90 HRCTV ! 85 Gy ( p 5 0.002) (Fig. 4). Three-year estimated survival without nonlocal failure was 91% (95% CI: 88e 94%) in patients with an HR-CTV volume !40 cm3 vs. 82% (95% CI: 81e83%) in those with an HR-CTV volume $40 cm3 ( p 5 0.035). There was a trend for more frequent nonlocal failures in patients with pelvic nodal metastases ( p 5 0.09). Interactions between factors We tested statistically for interaction between the D90 HR-CTV and the following factors: HR-CTV volume, tumor largest dimension, International Federation of
Fig. 2. Patterns of relapse according to the ability to deliver 85 Gy to 90% of the HR-CTV. HR-CTV 5 high-risk clinical target volume.
C. Chargari et al. / Brachytherapy
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Table 2 Results of log-rank analyses Factors tested
5
Survival without local failure Events/patients (n)
p-value
Factors tested for local failure D90 HR-CTV $85 Gy 0.526 Yes 3/39 No 8/70 OTT $49 days 0.601 Yes 4/31 No 7/78 Stage 0.669 III 10/102 IV 1/7 Hemoglobin level !11 g/dL 0.441 0 10/89 1 1/20 Tumor width O50 mm 0.585 0 8/86 1 3/23 HR-CTV volume $40 cm3 0.025 0 7/93 1 4/16 Presence of pelvic nodes 0.770 0 8/74 1 3/35 Factors tested for nonlocal failure (patients with local failure excluded) D90 HR-CTV $85 Gy 0.002 Yes 1/44 No 13/54 Stage 0.23 III 12/92 IV 2/6 Hemoglobin level !11 g/dL 0.30 0 10/79 1 4/19 Tumor width O50 mm 0.15 0 9/78 1 5/20 HR-CTV volume $40 cm3 0.035 0 10/86 1 4/12 Presence of pelvic nodes 0.09 0 7/66 1 7/32 D90 HR-CTV 5 dose delivered to D90 of the high-risk clinical target volume; OTT 5 overall treatment time; Gy 5 gray. Bold values are factors statistically significant.
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 P = 0.025
0.2 0.1 0 0
12
24
36 48 Survival Ɵme (months)
HR-CTV < 40 cm3
60
72
HR-CTV ≥ 40 cm3
Fig. 3. Correlation between the HR-CTV volume and the probability of survival without local failure. HR-CTV 5 high-risk clinical target volume.
( p ! 0.01). A bulky HR-CTV volume was associated with a more frequent use of interstitial parametrial boosts ( p 5 0.017) and with more frequent pelvic nodal metastases ( p 5 0.002).
Discussion The benefit of dose optimization in locally advanced cervical cancer patients is not disputable, and the increase of Survival without non-local failure 1 0.9 0.8 0.7 0.6 0.5
Gynecology and Obstetrics (FIGO) stage, brachytherapy technique (use of interstitial catheters), and patients’ age. There was a strong inverse correlation between the HRCTV volume and the D90 HR-CTV (correlation coefficient r 5 0.696; p ! 0.001) with an increasing HR-CTV volume being associated with a decreasing D90 HR-CTV. The mean D90 HR-CTV was 69.5 Gy for patients with an HR-CTV volume $40 cm3 vs. 85.2 Gy for patients with an HR-CTV !40 cm3 ( p ! 0.001). The mean HR-CTV volume was 17.1 cm3 for patients with a D90 HR-CTV $85 Gy vs. 31.5 cm3 for patients with a D90 HR-CTV ! 85 Gy ( p ! 0.001). A D90 HR-CTV !85 Gy also significantly correlated with a more advanced FIGO stage ( p 5 0.017) and with a larger tumor at diagnosis
0.4 P = 0.002
0.3 0.2 0.1 0 0
12
24
36 48 Survival Ɵme (months)
60
72
Fig. 4. Correlation between the inability to deliver 85 Gy to 90% of the HR-CTV and the probability of survival without nonlocal failure (patients with central failure excluded). HR-CTV 5 high-risk clinical target volume.
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local control is a major parameter for improving patients’ outcomes. The greatest impact of dose escalation was reported in bulky tumors (1e3,6). In the retrospective Vienna experience comparing 2D brachytherapy and IGABT, no impact of adaptive brachytherapy was reported in small tumors (2e5 cm). However, the 3-year local control rate increased from 64% to 82% for tumors O5 cm, in parallel to an increase in the mean D90 HR-CTV from 81 Gy to 90 Gy. Despite the lack of impact on distant progression, overall survival was significantly improved in patients with large tumors from 53% to 64% (3). The D90 HR-CTV was a major factor of local control, which was O95% for patients with a D90 HR-CTV $87 Gy (3, 4). In our previously published experience of IGABT, the target D90 HR-CTV to reach 90% of local control was 85 Gy, whereas the HRCTV volume was an independent factor for local control. Higher doses were required for locally advanced tumors or in case of HR-CTV volume O30 cm3 to warrant the same probability of local control (9). Although there is no demonstrated correlation between dosimetric parameters and survival in patients receiving IGABT, these data encourage dose escalation for a bulky disease. In the era of IGABT, the next step could be to better tailor treatment planning to tumor characteristics but also to take into account tumor response after chemoradiation. So far, significant tumors factors (FIGO stage, width at diagnosis, treatment time, HR-CTV volume) have been shown to impact the dose-volume effect for tumor control. A bulky HR-CTV is indicative of a large initial tumor (as clearly observed in this study), but also of a poor response to chemoradiation. Both factors are potentially associated with a higher risk for local relapse. Although dose escalation should be encouraged in these patients, patterns of relapse are now dominated by distant failures with a probability of developing distant metastases of 20e25% (2, 15). A multicenter nonrandomized prospective study showed that 3D treatment planning increased local control, but neither disease-free survival nor overall survival, probably because of a marginal impact on distant relapses (probably also partially because in this multicenter study only marginal dose escalation was performed) (16). Schmid et al. have investigated the patterns of distant relapse in patients receiving chemoradiotherapy and IGABT. After exclusion of local failures, three risk factors predicted distant metastases: FIGO stage, lymph node status, and the extent of tumor regression during treatment. The D90 HR-CTV was a significant factor for distant metastasis in the univariate analysis for high-risk patients (Stage IIIB-IVA or PET positive pelvic nodes) and the number of administrated chemotherapy cycles (15). Our results corroborate the pejorative impact of HR-CTV volume for local relapse. Although distinct biological patterns could partially explain the effect (e.g., hypoxia), this correlation also certainly relies on a lower ability to deliver an adequate dose. The effect of the D90 HR-CTV was not significant, but we have previously reported on the clear
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correlation between the D90 HR-CTV and the risk of local failure in a publication based on a larger cohort of 225 patients, with a higher statistical power to show this effect (9). In this series, we examined the patterns of relapse by brachytherapy parameters and observed a high frequency of distant relapses in patients with a D90 HR-CTV !85 Gy. However, the D90 HR-CTV volume could not be considered as an independent predictive factor for distant failures, as there was an inverse correlation between the HR-CTV volume and the D90 HR-CTV. The FIGO stage and a largest tumor dimension at diagnosis were also significantly correlated with the D90 HR-CTV. As the HR-CTV volume and the D90 HR-CTV are highly interrelated variables, any conclusion regarding the correlation between dosimetric parameters and distant failures should not be overstated. Tumor size and pelvic nodal metastases, which correlated with a larger HR-CTV volume in this series, are well-known prognostic factors, and it is impossible to draw definitive conclusions given the small number of events. Ideally, we would have performed a stratified analysis examining the rate of nonlocal failure for patients with bulky residual disease (HR-CTV $ 40 cm3) vs. nonbulky (HRCTV ! 40 cm3) who had a D90 ! 85 Gy vs. those with D90 $ 85 Gy. However, no patient with bulky residual disease (HR-CTV $ 40 cm3) received a D90 of greater than 85 Gy. Therefore, it is difficult to sort out which variable is predictive for distant failure: large residual tumor at the time of brachytherapy or the inability to achieve the planning aims. After taking into account these limitations, the main pattern of relapse in patients with a bulky HR-CTV and a low D90 HR-CTV was distant failure, even in patients who had not relapsed locally. The inability to deliver 85 Gy to 90% of the HR-CTV could potentially be a marker of a bulky residual disease and of a tumor poorly responding to chemoradiation. It is now well known that there are numerous common pathways between the mechanisms of radiation resistance and those involved in the metastatic process (17). This analysis of a homogeneous cohort of relatively young patients, all receiving chemoradiation plus IGABT after an exhaustive primary staging including a systematic para-aortic lymph node dissection suggests that dose escalation alone is not sufficient in bulky residual tumors to control the disease. For patients with a bulky HR-CTV, interstitial brachytherapy is frequently the best way to reach the threshold of 85 Gy for the D90 HR-CTV without exceeding doses to organs at risk. In our experience, there was a more frequent use of interstitial brachytherapy in patients with a bulky HR-CTV volume. Although this strategy could increase local control, it is uncertain whether it will improve survival. In our series, few interstitial procedures were used. Distant failure, however, was the main pattern of failure experienced by patients who did not receive the optimal dose because of the tumor volume. In the era of systematic IGABT, the probability of getting benefit from further dose optimization could be marginal if no effort is done for
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decreasing distant relapses, which account now for more than two-thirds of all relapses. The OUTBACK trial is investigating the benefit of an adjuvant chemotherapy based on carboplatin/paclitaxel after chemoradiation as primary treatment for locally advanced cervical cancer (NCT01414608), based on the finding that distant failure is the main pattern of relapse in these patients. Far from questioning the benefit of dose escalation, which is a major step for improving local control, the current results of IGABT and the increasing relative importance of distant failures should prompt radiation oncologists to look also at additional strategies, such as adjuvant or concurrent agents targeting molecular pathways involved in radiation resistance, in the metastatic cascade, or in the immune modulation of radiation therapy.
[8]
[9]
[10]
[11]
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Image-guided adaptive brachytherapy in cervical cancer: Patterns of relapse by brachytherapy planning parameters Cyrus Chargari1,2,3,4,5,*, Renaud Mazeron1,2,3, Alexandre Escande1,3, Pierre Maroun1,3, Isabelle Dumas1,3, Florent Martinetti1,3, Alain Tafo-Guemnie1,3, Eric Deutsch2,3,5, Philippe Morice5,6, Christine Haie-Meder1,3 1
Brachytherapy Unit, Department of Radiotherapy, Gustave Roussy, Villejuif, France 2 INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France 3 Radiotherapy Department, Gustave Roussy, Villejuif, France 4 Effets biologiques des rayonnements, Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France 5 Department of Surgery, Gustave Roussy, Villejuif, France 6 University Paris-Sud, SIRIC SOCRATES, Faculte de Medecine, Le Kremlin-Bic^etre, France
ABSTRACT
PURPOSE: Cervical cancer patients with a bulky high-risk clinical target volume (HR-CTV) get the largest benefit of dose escalation in terms of local control. However, the expected survival benefit could be lessened by a higher metastatic risk. We examined the patterns of relapse according to major prognostic factors: the HR-CTV volume and to the D90 HR-CTV. METHODS AND MATERIALS: The clinical records of patients treated with pulsed-dose-rate image-guided adaptive brachytherapy after concurrent pelvic chemoradiation were reviewed. All patients had an optimal workup before treatment comprising a 18-fluorodeoxyglucose positron emission tomography/computed tomography and a para-aortic lymph node dissection. Patients with initial extrapelvic disease were excluded. RESULTS: A total of 109 patients fulfilled inclusion criteria. Median followup was 39 months. An HR-CTV volume $40 cm3 was associated with a poorer local failure-free survival. There was a strong inverse correlation between the HR-CTV volume and the D90 of the HR-CTV (correlation coefficient r 5 0.696; p ! 0.001) with increasing HR-CTV volume being associated with a decreasing D90 HR-CTV. A D90 HR-CTV !85 Gy and an HR-CTV volume $40 cm3 were significant univariate factors for experiencing nonlocal failure ( p 5 0.002 and 0.035, respectively), even after exclusion of local relapses. CONCLUSION: A lower ability to reach the target D90 HR-CTV planning and an HR-CTV volume $ 40 cm3 correlated with a high propensity of relapsing at distance, these factors being interrelated. Next step of treatment personalization should design strategies integrating this risk, which is now the main cause of failure. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Image-guided adaptive brachytherapy; Dose escalation; High-risk clinical target volume; Planning aim
Introduction The implementation of image-guided adaptive brachytherapy (IGABT) has allowed dose escalation without Received 16 January 2016; received in revised form 31 March 2016; accepted 12 April 2016. Conflict of interest: No conflict of interest relative to this work. * Corresponding author. Brachytherapy Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Tel.: þ33-1-42-11-45-66; fax: þ33-1-42-11-52-08. E-mail address: [email protected] (C. Chargari).
increasing toxicity, translating into a meaningful improvement in local control rates in cervical cancer patients (1e9). Based on retrospective data showing a clear doseeeffect relationship in cervical cancer, dose escalation has a sound rationale and should be encouraged for patients presenting a bulky residual disease at time of brachytherapy to optimize the probability of local control (10, 11). Thus, a recent analysis of predictive factors for local control has shown that the volume of the high-risk clinical target volume (HR-CTV), which reflects the residual tumor bulk at time of IGABT and the response to external beam
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.04.006
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radiotherapy (EBRT), was an independent major factor inversely correlated with the probability of achieving local control. Moreover, higher doses were required to reach the same probability of local control in patients with larger HR-CTV volumes (9). The persistence of a bulky residual disease after 45 Gy of pelvic chemoradiation illustrated by a large HR-CTV is a surrogate of a poor sensitivity to radiotherapy and therefore a potential pejorative factor of local control. At the same time, the inability to deliver an adequate dose to the HR-CTV because of its bulk could be also a marker of a high metastatic risk that would lessen the benefit of improving local control. An alternative explanation would be that larger tumors with a poor response to chemoradiation are predictive of the distant metastatic risk. Actually, the HR-CTV volume and the D90 HR-CTV are entangled parameters, as D90 HR-CTV tends to be higher in small HR-CTV and lower in large HR-CTV. We examined the impact of the HR-CTV volume and of the dose achieved to the HR-CTV on local and distant failures rates after chemoradiation and IGABT for a locally advanced cervical cancer. Potential relationships could suggest on the need for further local or systemic intensification in these patients.
Patients and methods Patients and tumors We reviewed the clinical records of consecutive patients with histologically confirmed primary locally advanced cervical cancer treated in our institution with pulsed-dose-rate (PDR) IGABT after initial concurrent chemoradiation between April 2007 and February 2012. Patients’ outcome was prospectively documented. They were eligible in case of disease limited to the pelvis after an exhaustive primary staging including a 18-fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) and a systematic primary laparoscopic para-aortic lymphaden-ectomy. Treatment characteristics Patients received pelvic EBRT, 45 Gy in 25 fractions of 1.8 Gy through a 3D conformal technique with high megavoltage photons of a linear accelerator. Only patients receiving concurrent chemotherapy were analyzed, to minimize any bias related to systemic agents. Concurrent weekly cisplatin 40 mg/m2 was delivered. Weekly carboplatin area under curve 2 was preferred in case of contraindication to cisplatin. If no hematological contraindication, an additional cycle of chemotherapy could be delivered at time of IGABT. Patients received a PDR brachytherapy boost based on a 3D computerized assisted treatment planning through the PDR Selectron seed projector (Nucletron, an Elekta
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Company, Stockholm, Sweden) or Varian afterloader (Varian Medical System, Palo Alto, CA) and using the vaginal mold technique (12, 13). Definitions of volumes followed the guidelines of the Groupe Europeen de Curietherapiee European Society for Radiotherapy & Oncology (10, 11). Brachytherapy irradiation aimed at delivering at least 60 Gy to 90% of the intermediate-risk clinical target volume, taking into account the contribution of EBRT after converting doses into biological effective doses normalized to a radiobiologically weighted dose equivalent of 2 Gy/ fraction (a/b 5 10 Gy) and 85 Gy to the D90 of the HR-CTV. Dose constraints to the rectum, bladder, and sigmoid colon were, respectively, 75, 85, and 75 Gy (a/b 5 3 Gy). Irradiation was delivered through continuous hourly pulses, without exceeding the limit of 0.6 Gy per hour to the organs at risk. The brachytherapy was delivered through one single application per patient. However, when the endocavitary implantation did not allow an adequate coverage of HR-CTV volume because of distal parametrial extension, an additional implantation could be performed with interstitial needles. Further details on the brachytherapy procedure and on the dosimetric process have been previously published (9,12e14). Thereafter, patients received a pelvic sequential fractionated boost for delivering 60 Gy to PET-positive pelvic lymph node, taking into account the contribution of IGABT. The overall treatment time was aimed at not exceeding 55 days.
Followup and statistical analysis Followup was scheduled at 6 weeks, then every 3 months during 2 years. A systematic MRI of the pelvis and paraaortic area was performed 6e8 weeks after IGABT, then every 6 months. Hysterectomy was kept for isolated local failure. Patients were completely restaged through PET/ CT when local recurrence was detected. Only first sites of relapse were considered and classified as local (failure within the true pelvis), pelvic nodal, or distant (including para-aortic). The factors associated with local and nonlocal failure (defined as pelvic nodal or distant failure) were examined. Risk factors for nonlocal failures were examined after exclusion of patients with local failure to minimize the effect of local failure on secondary distant events. Survival times were calculated from the time of histological diagnosis, and survival rates were estimated using the KaplaneMeier method. Only first relapses were examined. Univariate analyses were carried out using log-rank tests. Multivariate analysis was not performed because of a low number of events and because of potential interactions between factors. Statistical analyses were performed using SPSS statistics 20.0 (Statistical Package for Social Science) for windows (an IBM company software, Chicago, IL).
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Results Patients, tumors, and treatments delivered A total of 109 patients fulfilled inclusion criteria. Median age was 44 years (range: 26e69). Median hemoglobin level was 12.5 g/dL (range: 8.5e14.6 g/dL). Median tumor width was 45 mm (range: 10e100 mm). Initial median tumor volume was 34 cm3 (range: 1.1e183.4 cm3). All patients had a disease limited to the pelvis after undergoing a para-aortic lymph node dissection as part of the primary staging. Median number of lymph nodes removed at primary para-aortic lymphadenectomy was 14 (range: 0e 43). Concurrent chemotherapy was cisplatin in 98 patients (90.0%) and carboplatin for the 11 remaining patients (10%). Forty-five patients (45.3%) had pelvic nodal uptakes at PET/CT and received a sequential boost to a median dose of 9 Gy (range: 8e12 Gy; 1.8e2 Gy per fraction). The brachytherapy dosimetry was based on MRI in 100 patients (91.7%) and the rest on CT (n 5 9). The median HR-CTV volume was 21 cm3 (range: 6e76 cm3). Sixteen patients (14.7%) had an HR-CTV volume $ 40 cm3 classified as bulky HR-CTV. The median initial tumor volume was 55 cm3 among patients with an HR-CTV $ 40 cm3 vs. 28 cm3 in patients with an HR-CTV ! 40 cm3 ( p ! 0.001). Eight patients (7.3%) received a parametrial boost using interstitial needles. Median overall treatment time was 47 days (range: 38e80 days). The median D90 HR-CTV was 83 Gy (range: 53e108 Gy). Forty-seven patients (43.1%) had a D90 HRCTV $ 85 Gy, and 62 patients (56.9%) had a D90 HRCTV ! 85 Gy. The median D90 HR-CTV was 70 Gy (range: 52.9e78.1 Gy) in patients with an HR-CTV $ 40 cm3 and 85.1 Gy (range: 65.7e107.6 Gy) in patients with an HRCTV ! 40 cm3 ( p ! 0.001). Characteristics of patients, tumors, and treatments are shown in Table 1. Patterns of relapse Median followup was 39 months. At last followup, a total of 25 patients (22.9%) experienced tumor relapse. First failures were local in 11 patients (10.1%), pelvic nodal in 7 patients (6.4%), and distant in 17 patients (15.6%). Isolated local relapses occurred in 5 patients (4.6%). Nonlocal failures were reported in 20 patients (18.3%). Six patients (5.5%) presented both local and nonlocal failure. Fourteen patients (12.8%) presented nonlocal failure as the only pattern of relapse. Patients with a bulky HR-CTV $40 cm3 experienced local failure in 4/16 (25.0%) vs. 7/93 (7.5%) in case of a nonbulky HR-CTV ( p 5 0.05). There was no isolated local relapse in patients with a bulky HR-CTV vs. 5/93 (5.4%) in case of not bulky HR-CTV (not significant). Patients with a bulky HR-CTV volume experienced more frequent nonlocal failures than those with an HR-CTV !40 cm3: 8/16 (50.0%) vs. 12/93 (12.9%) ( p 5 0.002). Patterns of relapse according to the volume of the HR-CTV are detailed in Fig. 1.
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Table 1 Patients and treatments characteristics Characteristics
Total
Number of patients Median age (range) Median hemoglobin level in g/dL (range) Tumor stage (%) IB1 IB2 IIA IIB IIIA IIIB IVA Pelvic lymph node uptake (%) Histology (%) Squamous cell carcinoma Adenocarcinoma Other Differentiation (%) Well Intermediate Poor Not determined Median tumor volume in cm3 (range) Risk groups (%) Low risk High riska Pelvic irradiation (%) Para-aortic irradiation (%) Pelvic dose (Gy) Concurrent chemotherapy (%) Cisplatin based Carboplatin based Image-guided adaptive brachytherapy (%) MRI based Computed tomography guided Use of interstitial needles (%) Median HR-CTV volume in cm3 (range) Median D90 HR-CTV in Gy (range) Number of patients with an HR-CTV volume $ 40 cm3 Median D90 IR-CTV in Gy (range) Median total reference air Kerma in cGy.m2 (range)
109 44 (26e69) 12.5 (8.5e14.6) 5 41 9 47 0 6 1 45
(4.6) (37.6) (8.3) (43.1) (0) (5.5) (0.9) (41.3)
85 (78.0) 21 (19.3) 3 (2.7) 36 39 14 20 34 44 65 109 0 45 109 98 11 109 100 9 8 21 83 16
(33.0) (35.8) (12.8) (18.3) (1.1e183.4) (40.4) (59.6) (100) (0) (100) (89.9) (10.1) (100) (91.7) (8.3) (7.3) (6e76). (53e108) (14.7)
69 (51e82) 1.8 (0.6e2.7)
D90 HR-CTV 5 dose delivered to D90 of the high-risk clinical target volume; D90 IR-CTV 5 dose delivered to D90 of the intermediate-risk clinical target volume; Gy 5 gray. a Patients with pelvic nodal metastases or with Stage IIIeIVA tumor classified as high risk.
Local failures were seen in 3/47 (6.4%) in patients with a D90 HR-CTV $ 85 Gy and in 8/62 (12.9%) in patients with a D90 HR-CTV ! 85 Gy, respectively (not significant). Nonlocal failures were seen in 2/47 (4.3%) and in 18/62 (29.0%), respectively ( p ! 0.001). Patterns of relapse according to the ability to deliver 85 Gy to 90% of the HRCTV are detailed in Fig. 2. Prognostic factors and patterns of relapse A combination of clinical factors (Stage: IeII vs. IIIe IV, positive vs. negative pelvic nodes, overall treatment
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Fig. 1. Patterns of relapse according to the HR-CTV volume. HR-CTV 5 high-risk clinical target volume.
time $ or ! 50 days, HR-CTV volume $ or ! 40 cm3, hemoglobin level $ or ! 11 g/dL, tumor width # or O 50 mm) and dosimetric parameters (D90 of the HRCTV: $ or !85 Gy (a/b 5 10 Gy)) was tested for survival without local failure and survival without nonlocal failure. In log-rank analysis, only an HR-CTV volume $40 cm3 was associated with a poorer local failure-free survival (Table 2). Three-year local failure-free survival rates were 93% (95% confidence interval [CI]: 88e99%) in patients with an HR-CTV volume!40 cm3 and 74% (95% CI: 52e96%) in case of an HR-CTV volume $40 cm3 ( p 5 0.025) (Fig. 3). After exclusion of patients with local failure, a D90 HR-CTV !85 Gy and an HR-CTV volume $40 cm3 were identified in log-rank analysis as significant univariate factors for experiencing nonlocal failure ( p 5 0.002 and p 5 0.035, respectively) (Table 2). Three-year estimated
survival without nonlocal failure was 98% (95% CI: 96e 100%) in patients with a D90 HR-CTV $ 85 Gy vs. 84% (95% CI: 79e89%) in those with a D90 HRCTV ! 85 Gy ( p 5 0.002) (Fig. 4). Three-year estimated survival without nonlocal failure was 91% (95% CI: 88e 94%) in patients with an HR-CTV volume !40 cm3 vs. 82% (95% CI: 81e83%) in those with an HR-CTV volume $40 cm3 ( p 5 0.035). There was a trend for more frequent nonlocal failures in patients with pelvic nodal metastases ( p 5 0.09). Interactions between factors We tested statistically for interaction between the D90 HR-CTV and the following factors: HR-CTV volume, tumor largest dimension, International Federation of
Fig. 2. Patterns of relapse according to the ability to deliver 85 Gy to 90% of the HR-CTV. HR-CTV 5 high-risk clinical target volume.
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Table 2 Results of log-rank analyses Factors tested
5
Survival without local failure Events/patients (n)
p-value
Factors tested for local failure D90 HR-CTV $85 Gy 0.526 Yes 3/39 No 8/70 OTT $49 days 0.601 Yes 4/31 No 7/78 Stage 0.669 III 10/102 IV 1/7 Hemoglobin level !11 g/dL 0.441 0 10/89 1 1/20 Tumor width O50 mm 0.585 0 8/86 1 3/23 HR-CTV volume $40 cm3 0.025 0 7/93 1 4/16 Presence of pelvic nodes 0.770 0 8/74 1 3/35 Factors tested for nonlocal failure (patients with local failure excluded) D90 HR-CTV $85 Gy 0.002 Yes 1/44 No 13/54 Stage 0.23 III 12/92 IV 2/6 Hemoglobin level !11 g/dL 0.30 0 10/79 1 4/19 Tumor width O50 mm 0.15 0 9/78 1 5/20 HR-CTV volume $40 cm3 0.035 0 10/86 1 4/12 Presence of pelvic nodes 0.09 0 7/66 1 7/32 D90 HR-CTV 5 dose delivered to D90 of the high-risk clinical target volume; OTT 5 overall treatment time; Gy 5 gray. Bold values are factors statistically significant.
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 P = 0.025
0.2 0.1 0 0
12
24
36 48 Survival Ɵme (months)
HR-CTV < 40 cm3
60
72
HR-CTV ≥ 40 cm3
Fig. 3. Correlation between the HR-CTV volume and the probability of survival without local failure. HR-CTV 5 high-risk clinical target volume.
( p ! 0.01). A bulky HR-CTV volume was associated with a more frequent use of interstitial parametrial boosts ( p 5 0.017) and with more frequent pelvic nodal metastases ( p 5 0.002).
Discussion The benefit of dose optimization in locally advanced cervical cancer patients is not disputable, and the increase of Survival without non-local failure 1 0.9 0.8 0.7 0.6 0.5
Gynecology and Obstetrics (FIGO) stage, brachytherapy technique (use of interstitial catheters), and patients’ age. There was a strong inverse correlation between the HRCTV volume and the D90 HR-CTV (correlation coefficient r 5 0.696; p ! 0.001) with an increasing HR-CTV volume being associated with a decreasing D90 HR-CTV. The mean D90 HR-CTV was 69.5 Gy for patients with an HR-CTV volume $40 cm3 vs. 85.2 Gy for patients with an HR-CTV !40 cm3 ( p ! 0.001). The mean HR-CTV volume was 17.1 cm3 for patients with a D90 HR-CTV $85 Gy vs. 31.5 cm3 for patients with a D90 HR-CTV ! 85 Gy ( p ! 0.001). A D90 HR-CTV !85 Gy also significantly correlated with a more advanced FIGO stage ( p 5 0.017) and with a larger tumor at diagnosis
0.4 P = 0.002
0.3 0.2 0.1 0 0
12
24
36 48 Survival Ɵme (months)
60
72
Fig. 4. Correlation between the inability to deliver 85 Gy to 90% of the HR-CTV and the probability of survival without nonlocal failure (patients with central failure excluded). HR-CTV 5 high-risk clinical target volume.
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local control is a major parameter for improving patients’ outcomes. The greatest impact of dose escalation was reported in bulky tumors (1e3,6). In the retrospective Vienna experience comparing 2D brachytherapy and IGABT, no impact of adaptive brachytherapy was reported in small tumors (2e5 cm). However, the 3-year local control rate increased from 64% to 82% for tumors O5 cm, in parallel to an increase in the mean D90 HR-CTV from 81 Gy to 90 Gy. Despite the lack of impact on distant progression, overall survival was significantly improved in patients with large tumors from 53% to 64% (3). The D90 HR-CTV was a major factor of local control, which was O95% for patients with a D90 HR-CTV $87 Gy (3, 4). In our previously published experience of IGABT, the target D90 HR-CTV to reach 90% of local control was 85 Gy, whereas the HRCTV volume was an independent factor for local control. Higher doses were required for locally advanced tumors or in case of HR-CTV volume O30 cm3 to warrant the same probability of local control (9). Although there is no demonstrated correlation between dosimetric parameters and survival in patients receiving IGABT, these data encourage dose escalation for a bulky disease. In the era of IGABT, the next step could be to better tailor treatment planning to tumor characteristics but also to take into account tumor response after chemoradiation. So far, significant tumors factors (FIGO stage, width at diagnosis, treatment time, HR-CTV volume) have been shown to impact the dose-volume effect for tumor control. A bulky HR-CTV is indicative of a large initial tumor (as clearly observed in this study), but also of a poor response to chemoradiation. Both factors are potentially associated with a higher risk for local relapse. Although dose escalation should be encouraged in these patients, patterns of relapse are now dominated by distant failures with a probability of developing distant metastases of 20e25% (2, 15). A multicenter nonrandomized prospective study showed that 3D treatment planning increased local control, but neither disease-free survival nor overall survival, probably because of a marginal impact on distant relapses (probably also partially because in this multicenter study only marginal dose escalation was performed) (16). Schmid et al. have investigated the patterns of distant relapse in patients receiving chemoradiotherapy and IGABT. After exclusion of local failures, three risk factors predicted distant metastases: FIGO stage, lymph node status, and the extent of tumor regression during treatment. The D90 HR-CTV was a significant factor for distant metastasis in the univariate analysis for high-risk patients (Stage IIIB-IVA or PET positive pelvic nodes) and the number of administrated chemotherapy cycles (15). Our results corroborate the pejorative impact of HR-CTV volume for local relapse. Although distinct biological patterns could partially explain the effect (e.g., hypoxia), this correlation also certainly relies on a lower ability to deliver an adequate dose. The effect of the D90 HR-CTV was not significant, but we have previously reported on the clear
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correlation between the D90 HR-CTV and the risk of local failure in a publication based on a larger cohort of 225 patients, with a higher statistical power to show this effect (9). In this series, we examined the patterns of relapse by brachytherapy parameters and observed a high frequency of distant relapses in patients with a D90 HR-CTV !85 Gy. However, the D90 HR-CTV volume could not be considered as an independent predictive factor for distant failures, as there was an inverse correlation between the HR-CTV volume and the D90 HR-CTV. The FIGO stage and a largest tumor dimension at diagnosis were also significantly correlated with the D90 HR-CTV. As the HR-CTV volume and the D90 HR-CTV are highly interrelated variables, any conclusion regarding the correlation between dosimetric parameters and distant failures should not be overstated. Tumor size and pelvic nodal metastases, which correlated with a larger HR-CTV volume in this series, are well-known prognostic factors, and it is impossible to draw definitive conclusions given the small number of events. Ideally, we would have performed a stratified analysis examining the rate of nonlocal failure for patients with bulky residual disease (HR-CTV $ 40 cm3) vs. nonbulky (HRCTV ! 40 cm3) who had a D90 ! 85 Gy vs. those with D90 $ 85 Gy. However, no patient with bulky residual disease (HR-CTV $ 40 cm3) received a D90 of greater than 85 Gy. Therefore, it is difficult to sort out which variable is predictive for distant failure: large residual tumor at the time of brachytherapy or the inability to achieve the planning aims. After taking into account these limitations, the main pattern of relapse in patients with a bulky HR-CTV and a low D90 HR-CTV was distant failure, even in patients who had not relapsed locally. The inability to deliver 85 Gy to 90% of the HR-CTV could potentially be a marker of a bulky residual disease and of a tumor poorly responding to chemoradiation. It is now well known that there are numerous common pathways between the mechanisms of radiation resistance and those involved in the metastatic process (17). This analysis of a homogeneous cohort of relatively young patients, all receiving chemoradiation plus IGABT after an exhaustive primary staging including a systematic para-aortic lymph node dissection suggests that dose escalation alone is not sufficient in bulky residual tumors to control the disease. For patients with a bulky HR-CTV, interstitial brachytherapy is frequently the best way to reach the threshold of 85 Gy for the D90 HR-CTV without exceeding doses to organs at risk. In our experience, there was a more frequent use of interstitial brachytherapy in patients with a bulky HR-CTV volume. Although this strategy could increase local control, it is uncertain whether it will improve survival. In our series, few interstitial procedures were used. Distant failure, however, was the main pattern of failure experienced by patients who did not receive the optimal dose because of the tumor volume. In the era of systematic IGABT, the probability of getting benefit from further dose optimization could be marginal if no effort is done for
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decreasing distant relapses, which account now for more than two-thirds of all relapses. The OUTBACK trial is investigating the benefit of an adjuvant chemotherapy based on carboplatin/paclitaxel after chemoradiation as primary treatment for locally advanced cervical cancer (NCT01414608), based on the finding that distant failure is the main pattern of relapse in these patients. Far from questioning the benefit of dose escalation, which is a major step for improving local control, the current results of IGABT and the increasing relative importance of distant failures should prompt radiation oncologists to look also at additional strategies, such as adjuvant or concurrent agents targeting molecular pathways involved in radiation resistance, in the metastatic cascade, or in the immune modulation of radiation therapy.
[8]
[9]
[10]
[11]
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