Image-guided high-dose rate brachytherapy: preliminary outcomes and toxicity of a joint interventional radiology and radiation oncology technique for achieving local control in challenging cases

Purpose

The multidisciplinary oncology team possesses a wide armamentarium of tools for achieving local tumor control, including thermal and other direct ablation techniques performed by interventional radiologists and external beam radiation therapy (EBRT) – based techniques delivered by the radiation oncologist [1, 2]. While these both offer excellent local control (LC) with acceptable toxicity for appropriately selected patients, there remain scenarios in which achieving LC is challenging. For IR-based ablative techniques these include lesions in close proximity to the vasculature and/or organs-at-risk (OARs) [3] and larger lesions [4, 5]. For EBRT-based ablative techniques, the main limitations are lesion size and proximity to critical OARs [6, 7, 8].
Image-guided interstitial high dose rate (IG-HDR) brachytherapy can overcome some of the limitations of both IR-based and EBRT-based ablative techniques [9]. With IG-HDR, a collaborative effort between interventional radiologists and radiation oncologists allows delivery of high doses of radiation via catheters placed directly into the target lesion. The sharp dose gradients and intra-tumoral heterogeneity provided by HDR allows for simultaneous dose-escalation and OAR sparing. There are multiple clinical reports using IG-HDR to treat hepatic lesions [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20], recurrent anorectal cancer [21, 22, 23, 24], lung [25], head/neck cancer [26, 27, 28, 29], and metastatic melanoma deposits in various locations [30]. Aside from the latter report, however, other reports on the use of IG-HDR to target a variety of locations in order to provide local control in patients with locally advanced or incurable disease are sparse. We describe the clinical outcomes of a series of 18 patients treated with IG-HDR in a wide variety of disease sites, either in combination with a course of EBRT or as monotherapy.

Material and methods

Brachytherapy planning and delivery

An institutional review board waiver was approved prior to conducting the present retrospective study. Eighteen patients treated at the Department of Radiation Oncology at the University of California Los Angeles between 2012 and 2014 were identified. All patients were deemed to be inappropriate candidates for a purely interventional radiology-based ablative approach or EBRT approach for the lesion in question. These other approaches were generally deemed inappropriate due to large size of disease and/or proximity to normal organs at risk with the small bowel being the most common limiting organ at risk. Briefly, a team of radiation oncologists and interventional radiologists performed the IG-HDR procedures. Patients were placed under sedation, and both physicians selected the number and trajectory of 15G flexi-guide catheters to be placed into the target under image-guidance (ultrasound, CT, or both). A pre-implantation plan was used for non-abdominal lesions; due to small bowel variation, pre-implantation plans were not used for abdominal lesions. Planning target volumes and OARs were contoured by the radiation oncologist using images obtained from a post-implantation CT simulation scan. Treatment planning was performed using the inverse planning simulation annealing algorithm from Oncentra Brachy Treatment Planning System Version 4.3 (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden). Manual graphical optimization was performed prior to final plan approval. Prescription doses were chosen conservatively on the basis of clinical judgment. Planning was performed with the goal of delivering a dose covering the target being greater than 90% of the prescription dose. Depending on the number of fractions prescribed, the patient either completed treatment later that day or was admitted to the hospital overnight for further fractions the following day. Patients receiving more than one fraction had at least six hours in between treatments. A repeat CT simulation scan was performed prior to each fraction and appropriate catheter adjustments were made as necessary. For the purposes of comparison, an equivalent dose in two Gy fractions (EQD2) was calculated for each patient, utilizing the formula EQD2 = (dose/fraction*number of fractions)*((dose/fraction + /)/(2 + /)), where / refers to tumor radiosensitivity and is set to 10 [31].

Toxicity and follow-up analysis

All patients had follow-up imaging with CT or MRI at least three months after treatment, were assessed by a clinician within 12-16 weeks and generally at three month intervals thereafter. Acute toxicity was graded utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 4 [32], and was derived from a retrospective review of follow-up notes. Chronic toxicities (defined as occurring > 90 days after IG-HDR) were also graded in this fashion. All follow-up dates were measured from the date of IG-HDR. Local control was determined on the basis of RECIST criteria [33] with progressive disease categorized as local failure and all other responses (stable disease and either partial or complete response) treated as LC. A Kaplan-Meier analysis was conducted to model LC and overall survival probability.

Results

Patient and treatment characteristics

The median clinical follow-up was 11.9 months (range: 4.0-28.5); the median imaging follow-up was 9.15 months (range: 3.5-28.5). Patient baseline characteristics are shown in Table 1. Detailed information on the dose/fractionation regimens for each patient are shown in Table 2 and clinical vignettes are provided in Table 3. Two patients presented for IG-HDR with primary locally advanced disease; the remaining 16 patients had locally recurrent and/or metastatic disease at presentation. Seven patients had prior EBRT that included the target lesion with a median EQD2 of 47.0 Gy and a median treatment interval of 17.2 months. Nine patients received IG-HDR in combination with a course of EBRT (median EQD2 of 49.6 Gy for concurrent EBRT doses).
Sample plans are shown in Figure 1, and average target dosimetry is shown in Table 4. The average number of catheters used per case ranged from 7 to 15, depending on site (averages of 15 for pelvis, 13 for extremity, 7 for abdomen/retroperitoneum, and 12 for head/neck). In general, the number of catheters used per case decreased over time as experience was accumulated. Dose fractionation schema varied but the overall average EQD2 delivered by IG-HDR was 34 Gy for patients treated with IG-HDR alone, and 16.7 Gy for patients who also received EBRT. The median total EQD2 for patients treated with combination IG-HDR and EBRT was 60.9 Gy. For the overall population, median EQD2 was 54.2 Gy.

Clinical outcomes

Six patients had local failures. The median time to local failure was 4.07 months (range: 1.0-23.2); among patients without local failure, the median imaging follow-up was 6.92 months (range: 3.47-28.47). Five patients had distant progression or developed new metastases after IG-HDR, at a median interval of 2.17 months (range: 1.03-11.67). Six patients died from their disease, with a median interval of 6.85 months (range: 4.50-23.17). Two of these patients had no metastases at the time of death, while three had metastatic disease at presentation and one developed metastatic disease after IG-HDR, Kaplan-Meier curves of LC and overall survival are shown in Figure 2, demonstrating a one-year LC rate of 59.3% and a one-year overall survival of 40.7%.
Two of the nine patients with abdominal/retroperitoneal lesions had local failures (22.2%), compared with neither of the two patients with extremity lesions (0%), one of two patients with head/neck lesions (50%), and three of five patients with pelvic lesions (60%). Four of seven patients who received a total EDQ2 < 45 Gy had local failures (57.1%), compared with two out of eleven treated with an EQD2 > 45 Gy (18.1%). Five out of nine patients treated with IG-HDR alone had local failures (55.6%), compared with one of nine patients (11.1%) treated with combination EBRT. Finally, four out of seven patients with prior EBRT had local failures (57.1%), compared with two out of eleven patients without prior EBRT (18.1%). Adjuvant chemotherapy did not appear to influence local control with local failures in one of six patients who did not receive adjuvant chemotherapy (16.7%) and five of 12 patients who did receive (41.7%).
Among patients who had LC, eight had stable disease and four had partial responses. Three of the patients who had local failures appear to have had “marginal misses”, wherein disease progressed towards the edge of the 100% isodose line (an example is shown in Figure 3). Times to local failure were 1.03 and 2.87 months, respectively; two of these patients had repeat IG-HDR. One patient had a local failure (third recurrence overall) in 2.57 months and was treated with systemic therapy; she remains alive. The second had a local failure (third recurrence overall) in 8.37 months and passed away 2.47 months later.

Organ-at-risk dosimetry and toxicity

Organ-at-risk dosimetric parameters are shown in Table 5. Acute toxicities were minimal with five instances of grade 1 skin toxicity, three instances of grade 1 nausea, four instances of grade 1 diarrhea, four instances of grade 1 fatigue, and two instances of grade 1 pain. One patient had grade 2 diarrhea, another had grade 2 urinary frequency, one had grade 2 fatigue, and three had grade 2 pain. Another patient endorsed grade 2 anxiety after his first fraction, secondary to catheter placement. He discontinued treatment before his second and final fraction could be delivered. Otherwise, all patients who needed an overnight stay in the hospital tolerated having the brachytherapy catheters left in place overnight. No acute grade 3 or higher toxicities were seen.
With regards to chronic toxicity, one patient developed pelvic-cutaneous and vesico-perineal fistulas. Before IG-HDR was performed, the patient had prior chemoradiation and an abdominoperineal resection procedure, followed by adjuvant chemotherapy; at the time of IG-HDR, he had a bulky, painful local recurrence (Figure 4A). Subsequent to IG-HDR, he had a significant clinical response, with improvement in pain and significant reduction in tumor burden (Figure 4B). Unfortunately, he subsequently developed a bulky, painful local recurrence after his initial response, and it was at this point that the fistulization manifested (Figure 4C). The patient also began to receive bevacizumab infusions as a component of systemic therapy one month after IG-HDR, which may have also contributed to his fistula formation [34]. Another patient developed chronic grade 1 lower extremity weakness as well as bone necrosis. She had a history of EBRT to the pelvis and due to progressive disease after IG-HDR, she underwent a second course 2.93 months later. Both patients had bulky local recurrences that likely contributed to these sequelae.

Discussion

Despite significant technological improvements in both interventional radiology and radiation oncology, achieving LC remains challenging in certain scenarios, whether due to lesion size, proximity to critical structures, prior treatments, or a combination of the above. While essential in the upfront treatment of localized disease, achieving LC is also important in the recurrent and/or metastatic settings for symptomatic improvement and, in the setting of oligometastatic disease, improved outcomes. Our data suggest that IG-HDR offers a nearly 60% chance of LC at one year in a heavily pre-treated population for whom neither a purely interventional radiology-based approach nor an EBRT approach were felt to be optimal. Of the eighteen patients treated, only two were treated for a localized primary, while the rest had recurrent lesions and/or systemic disease. Seven had prior EBRT and eight received EBRT in combination with IG-HDR. Acute toxicities were mild with no grade ≥ 3 toxicities noted, though one patient discontinued treatment halfway through due to anxiety. Two patients had grade 3 chronic toxicities; IG-HDR likely contributed but both patients also had bulky local recurrences contributing to their symptoms, and both had prior EBRT.
Several reports of outcomes following IG-HDR have been reported, primarily with regards to treating hepatic lesions [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20], recurrent anorectal cancer [21, 22, 23, 24], lung lesions [25], and head/neck cancer [26, 27, 28, 29]. Series including more heterogeneous populations are limited. Bretschneider et al. recently reported the outcomes of 14 patients who received IG-HDR for metastatic melanoma lesions located in the liver, lung, adrenals, lymph nodes, and kidneys [30]. The median lesion size was 1.5 cm, with a median dose of 19.9 Gy (EQD2 of 45.9 Gy). They reported a median LC rate of 90% at five months. Image-guided interstitial high dose rate was well-tolerated, with two patients developing small pneumothoraces and one patient developing cholangitis. In general, the average diameter of the lesions treated in our cohort was larger at 5.8 cm (corresponding to an average planning target volume of 93.8 ml), and the average EQD2 for lesions treated with IG-HDR monotherapy was 36 Gy. Despite these differences, our LC rate of 79% at five months is consistent with the results reported by Bretschneider et al. The generally large lesion size and high-risk composition of our cohort could also explain why our one-year LC rate of 59% is slightly lower than the reported results from the other aforementioned IG-HDR series. Our low toxicity rates, on the other hand, are comparable.
Despite its effectiveness and tolerability in a wide variety of anatomic locations, the optimal indication for IG-HDR remains unclear. Both EBRT and interventional radiology-ablation techniques have been well-studied and afford excellent probabilities of obtaining LC. However, many of the lesions in our series were either close to major vessels, close to other critical structures, and/or had a large diameter – all issues that can limit the appropriateness of either EBRT or interventional radiology- ablation techniques [3, 4, 5, 6, 7, 8]. In a recent dosimetric study comparing stereotactic body radiation therapy (SBRT) and IG-HDR plans for liver lesions, investigators found that IG-HDR could provide intra-tumoral dose escalation and decreased low dose spill to surrounding tissues [35]. On the other hand, for small lesions, SBRT may be preferred. For example, Rwigema et al. reported a one-year LC rate of 100% following the use of SBRT for 44 unresectable nodal and soft-tissue oligometatases [36]. The median gross tumor volume was 18.7 ml, considerably smaller than that in our study. Thus, IG-HDR may be most ideal in situations where other means of obtaining LC are relatively or absolutely contraindicated, as in the case of large lesion and/or lesions in close proximity to critical OARs.
Because of the small sample size, we did not attempt any statistical test to compare LC probabilities on the basis of anatomic site, EQD2, or combination with EBRT vs. IG-HDR alone. It is probable that the relatively improved LC with combination EBRT relates to the fact that most patients treated with IG-HDR alone had relative contraindications to combination EBRT. Further study will be needed to determine the adequate dose and fractionation for IG-HDR cases.
There are several limitations to this work. First, the treated population is heterogeneous, rendering it difficult to make firm conclusions about the efficacy of IG-HDR. The primary goal of this work was to determine the efficacy and safety of escalated doses of radiation in challenging treatment situations. Second, the employed definition of LC was based upon RECIST classification of treated lesions. Several patients had significant burden of disease and IG-HDR was performed with a goal of symptomatic relief. While at least one follow-up imaging study was required for inclusion in this report, several patients did not obtain further imaging, nor did we feel it was appropriate to request them to do so solely for this study. Thus, it is possible that some patients had LC for a longer interval than was reported here. Conversely, it is possible that post-treatment hyperemia could have obscured the clear identification of a local failure; however, all images were reviewed by radiologists trained in utilizing the RECIST criteria. Additionally, our data appear to show a strong dose-response relationship with higher EQD2 values associated with improved LC. As a result, one might argue that the patients who experienced poor LC in our study were underdosed. This may indeed be the case; as no clear OAR constraints and IG-HDR dosing guidelines were available for the relevant target locations at the time these patients were treated, doses were often chosen conservatively. Finally, the intention of IG-HDR as described herein is not to supplant other, more commonly used, and widely accessible ablative techniques but rather to provide an option in cases, for which those techniques may not be optimal.

Conclusions

In conclusion, IG-HDR appears to be an effective and safe joint interventional radiology/radiation oncology technique for achieving LC in patients with complex tumor masses, for which other ablative techniques are relatively contraindicated. Likely candidate lesions will be those that are large and/or in close proximity to critical structures or vessels.

Disclosure

Authors report no conflicts of interest.

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