Abstract
Background/Aim: Interstitial brachytherapy (iBT) seems to achieve higher local tumor control rates for lesions limited in size. The objective was to evaluate the efficacy and safety of iBT in the treatment of limited and large liver metastases from rare or less common cancers (RLCC). Patients and Methods: A total of 194 unresectable liver metastases categorized as limited (<4 cm, n=153, subgroup A) and large lesions (≥4 cm, n=41, subgroup B) were treated. Clinical and image-based follow-up was conducted every 3 months after iBT. Results: Cumulative local recurrence (CLR) rate was 9.8% (19 recurrences; A: n=16; B: n=3). No significant difference in CLR was noted between subgroup A and B (A:10.5%, B:7.3%, p=0.339). Median follow-up was 6.2 months (range=2.2-92.9 months). Complication assessment revealed 5 severe adverse events (grade 3: 4.3%, grade 4 and 5: 0%) with 4 events in A and 1 event in B. Conclusion: IBT is a feasible, effective, and safe minimally invasive treatment for small and large liver metastases from RLCC.
- Liver metastases
- oligometastases
- interventional oncology
- local ablation
- image-guided intervention
- interstitial brachytherapy
According to the RARECAREnet project, rare cancers belong to a defined group of diseases with an incidence rate of <6/100,000, whereas less common cancers could be defined by an incidence of ≥6/1,000,000 outside the common or frequent cancers, such as breast, colorectal, lung and prostate (1, 2). Taken together, these two groups of neoplasms add up to 47% of all newly diagnosed malignancies (2). Since treatment experience is limited even in major cancer centers, rare or less common cancers (RLCC) are a significant challenge to clinical practice with varying survival rates among European countries (3). In particular, developing adequately powered clinical trials for advanced-stage cancer is demanding due to the low number of patients; therefore, evidence for effectiveness of new therapeutic methods is difficult to provide, leading to limited therapy options. Hence, for advanced/metastasized RLCC, research is frequently confined to case reports or small retrospective series.
From a theoretical oncological perspective, metastases limited in number and distribution (i.e. oligometastases) are increasingly considered suitable for localized therapy aiming for disease control and prolongation of life in selected patients, as shown for colorectal cancer (CRC). In fact, for CRC patients with oligometastatic disease (OMD) confined to one organ, i.e. most commonly the liver, 5-year survival rates of 25-40% are reported after complete metastasectomy, furthermore, after a survival of 10 years post-surgery, patients are even considered cured (4-6). However, effective surgical resection is applicable to a limited number of cases, as the ability to perform complete macro- and microscopic resection of multiple liver metastases relies on the capacity of the future liver remnant to minimize the risk of post-hepatectomy liver failure. Resectability is limited by the distribution and accessibility of metastases, consequently, curative resection of liver metastases is not possible in up to 80% of CRC patients (7).
However, to overcome these issues, minimally invasive ablative treatments have been developed and the so-called ‘toolbox’ includes various image-guided local treatments such as radiofrequency ablation (RFA), microwave ablation, or high-dose-rate interstitial brachytherapy. Image-guided high-dose-rate interstitial brachytherapy (iBT) combines 192Iridium brachytherapy with computed tomography (CT) or magnetic resonance imaging (MRI) guidance for precise applicator implantation and 3D image-based adaptive treatment planning (8-10). More precisely, in a minimally invasive intervention, applicators are percutaneously implanted into the target volume under image guidance, followed by the insertion of an iridium-192 source via the applicators, thus, allowing a single high dose irradiation of the target volume. IBT has been shown to offer a safe, and effective treatment option for primary and secondary malignancies at various sites, and the method has been implemented in the ESMO guidelines for the management of metastasized CRC and also for hepatocellular carcinoma (11-13). However, several studies indicate that iBT seems to achieve better local tumor control (LTC) of lesions with a diameter smaller than 4 cm (14, 15).
With this study, we aimed to show that iBT is a feasible, effective, and safe therapeutic option in the treatment of oligometastatic liver disease in patients with RLCC independent of target size. Therefore, we retrospectively analyzed the radioablation of a total of 194 hepatic metastases, classified as limited (<4 cm) or large (≥4 cm).
Patients and Methods
Study design and eligibility criteria. In the primary analysis, local tumor control (LTC)/cumulative local recurrence (CLR) rate was evaluated (primary endpoint); secondary endpoint was safety of iBT as a radioablative approach.
We reviewed and collected the data from our institutional prospective database ASENA® (LoeScap Technology GmbH) and retrospectively analyzed patients who underwent iBT between February 2008 and March 2017 in our departments. Every case was individually determined for iBT by the consensus of an interdisciplinary tumor board after the careful assessment of alternative treatment options and the patient's informed choice. A positive vote of the institutional ethics committee for the analysis of the patient data was received and all patients gave oral and written informed consent prior to the procedure.
Inclusion criteria for this study were: i. surgical ineligibility (metastases ineligible for surgery: i.e. impossibility of R0 resection with ≥30% liver remnant or R0 resection only possible with complex procedure; too high risk for surgery) or refusal of surgery, ii. lack of acceptable chemotherapeutic options (progression under standard chemotherapeutic protocols; therapy discontinuation or termination of therapy due to toxicity; refusal of chemotherapy), iii. sufficient performance status to undergo iBT: East Coast Oncology Group (ECOG) performance status ≤2, iv. sufficient coagulation parameters/blood count (i.e. thrombocyte count >50 Gpt/l, Quick >50%, partial thromboplastin time <50 s, hemoglobin ≥6.0 mmol/l) and sufficient liver parameters (bilirubin <30 μmol/l), v. oligometastatic disease=OMD (≤5 metastatic lesions in ≤3 sites accessible for complete local ablation). No limitation was placed upon lesion size.
Exclusion criteria were: i. peritoneal carcinomatosis or widespread uncontrollable systemic disease, ii. estimated dose exposure to organs at risk (OAR) exceeding local clinical standards, iii. lack of consent.
Patient characteristics.
Patient cohort. With respect to these criteria we included all patients with complete electronic medical records and at least one follow-up visit. This retrospective study comprised 59 patients (42 males, 17 females; mean age: 63.9 years, range=39-78 years) with a total of 194 unresectable liver metastases treated with CT- or MRI-guided iBT at the Department of Radiology and the Department of Radiooncology. Histologically proven primary tumor entities included: pancreatic adenocarcinoma (PAC, n=15), renal cell carcinoma (RCC, n=14), gastric adenocarcinoma (GAC, n=11), gastroinstestinal stroma tumor (GIST, n=9), anal squamous cell carcinoma (ASCC, n=5) and esophageal squamous cell carcinoma (ESCC, n=5); for detailed patient characteristics see Table I.
Prior to iBT all patients underwent a full clinical status evaluation including a physical examination, blood test, as well as a whole-body contrast enhanced CT and a Gd-EOB-DTPA-enhanced MRI of the liver (Primovist®, Bayer, Pharma, Leverkusen, Germany) to detect hepatic and extrahepatic disease as accurate as possible.
Interventional procedure and irradiation. Under guidance of a fluoroscopy-CT (Aquillion, Canon Medical Systems, Neuss, Germany) or real-time MRI at 1.0 T (Panorama 1.0 T, open MR system, Philips Healthcare, Eindhoven, Netherland) the target lesion was punctured percutaneously with an 18-gauge needle. A stiff angiographic guide wire (Amplatz SuperStiff™, Boston Scientific, Marlborough, MA, USA) was then advanced through the needle and subsequently, a 6-F angiographic catheter sheath (Terumo Radifocus® Introducer II, Terumo Europe, Leuven, Belgium) was passed over the guidewire using Seldinger's-technique. Ultimately, a 6-F afterloading catheter (afterloading catheter, Primed® medical GmbH, Halberstadt, Germany) was inserted in the catheter sheath, which was transiently secured to the skin with a suture and covered with sterile bandages. The interventional radiologist and radiooncologist determined the number and arrangement of catheters used with regard to the complexity and location of the target lesion to achieve a sufficient coverage of the planning target volume (PTV). The procedure was performed under conscious sedation and analgesia using midazolam and fentanyl in combination with a local anesthesia (lidocaine). To prevent or minimize discomfort for the patient, an antiemetic prophylaxis consisting of dexamethasone and odansetron was administered intravenously prior to the procedure.
A contrast-enhanced multi-slice CT using the breath-holding technique or a Gadolinium-based MRI scan was obtained to verify correct catheter positioning. Additionally, the acquired imaging data were transferred to the irradiation planning system (Oncentra® Brachy treatment planning system, Elekta AB, Stockholm, Sweden). On this 3D dataset, the target volume was outlined precisely as gross tumor volume (GTV). For iBT, PTV is identical with the clinical target volume (CTV), known from external beam radiotherapy. As the sheaths were transiently sutured to the skin, the inaccuracy of respiratory movements could be excluded. PTV is defined as GTV plus a safety margin [GTV plus 5 mm safety margin for MRI-guidance; GTV plus 3 mm safety margin for CT-guidance (16)], taking adjacent organs at risk (OAR) into careful consideration. Dose coverage to D100 (i.e. minimum dose enclosing the CTV completely) was calculated automatically and controlled and adapted manually slice by slice. A reference dose of 12-20 Gy was intended to achieve complete ablation of the PTV depending on the histological type of the primary tumor: 12 Gy for GIST, 15 Gy for RCC, 20 Gy for PAC, ASCC, ESCC and GAC. All irradiations were performed as single fraction irradiation using an iridium-192 source. Empiric dose constraints were taken into account as follows: maximum dose of 5 Gy for 1/3 of the liver parenchyma (V5Gy), ≤14 Gy for the small bowel and stomach and ≤18 Gy for the large bowel, respectively, and ≤ 20 Gy for the central bile duct structures (8, 17-19). The reference dose was adjusted correspondingly. There was no limitation regarding higher doses inside the tumor volume. Furthermore, needle track ablation was performed to avert seeding. After irradiation was completed, catheters were removed and puncture tracts were sealed using gelfoam or fibrin tissue glue. Figure 1 depicts an example of the interventional technique and irradiation planning as well as the follow up.
Follow-up. Every 3 months after iBT, clinical, laboratory and imaging follow-up was performed. Imaging included a Gd-EOB-DTPA-enhanced MRI of the liver. A contrast-enhanced whole-body CT was performed in case of contraindications to MRI or at least every 6 months to examine systemic progress. All imaging datasets were reviewed for local, locoregional and systemic recurrences as well as for procedure-related complications. To analyze LTC/CLR, RECIST criteria (RECIST version1.1.) were employed.
Statistical analysis. Data were analyzed using SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY, USA: IBM Corp). LTC/CLR of each tumor was calculated by the Kaplan-Meier estimation. Furthermore, statistical analysis included the Mann-Whitney U-test and the Wilcoxon signed-rank test to compare the two subgroups with limited <4 cm and large ≥4 cm targets. In data interpretation, p≤0.05 was determined as statistically significant. Measures for safety underwent descriptive statistics: acute or late adverse events were defined according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03).
Results
A total of 194 liver metastases with a median diameter of 1.8 cm (range=0.4-13.9 cm; Q1=1.3, Q3=3.4) were treated. In subgroup A, 153 lesions with a diameter <4 cm (mean: 1.8 cm, median: 1.6 cm, range=0.4-3.8 cm) and in subgroup B, 41 lesions with a diameter ≥4 cm (mean: 6.6 cm, median: 6 cm, range=4.0-13.9 cm) were treated. A median minimal enclosing tumor dose (D100) of 17.1 Gy was applied (range=5.0-29.1 Gy) for all CTVs, whereas a median of 17.5 Gy and 16.0 Gy was achieved for group A and B, respectively. However, reference dose was 12-20 Gy depending on the histological type of the primary tumor. CT guidance was used for 73 interventions (median lesion size: 2.7 cm; range=0.6-13.9 cm), MRI for 42 (median lesion size: 1.3 cm; range=0.4-5.7 cm), respectively. Out of 115 interventions, we report 5 severe adverse events classified as grade 3 (4.3%): hematoma followed by an infectious process involving the liver successfully treated with the placement of a transcutaneous drainage and IV antibiotic intervention (n=4), and hepatic hemorrhage successfully treated with angiographic embolization (n=1). Four events occurred in subgroup A and 1 event in B. Median hospital stay of patients was 4 days (range=3-12 days). Patients with a small postinterventional hematoma (not requiring transfusion, radiologic or operative intervention) were monitored for 6-12 days, all followed with abdominal ultrasound.
Exemplary treatment planning and follow-up after high-dose-rate interstitial brachytherapy (iBT) of liver metastases in a 68-years old patient diagnosed with gastric adenocarcinoma. Pre-interventional imaging (A-C) showing a metastasis with a diameter larger than 4 cm in the left lobe (segment IVa and IVb) prior to treatment with iBT (white arrow). A second clinical target volume (CTV) with a diameter smaller than 4 cm is indicated with a black arrow in the right lobe (B). Axial (A) and coronal (B) contrast-enhanced computed tomographic (CT) scans. Axial (C) magnetic resonance imaging (MRI): Gd-EOB-DTPA enhanced T1-weighted image. Peri-interventional acquired contrast-enhanced CT-scans (D-F) with clinical target volume (CTV), catheters and isodose lines. Follow-up imaging (G-I) showing effective local tumor control of the CTV in the left lobe 9 months after iBT (white arrow). The partly depicted CTV in the right lobe was treated identically and also shows reduction of the tumor volume (black arrow). Axial (G) and coronal (H) contrast-enhanced CT slice. Axial (I) MRI: Gd-EOB-DTPA enhanced T1-weighted image.
The median follow-up time after iBT was 6.2 months (range=2.2-92.9 months; Q1=3.3, Q3=18.7). We report an LTC rate of 90.2%, in other words 175 out of the 194 treated target lesions were ablated completely. However, 19 treated target lesions showed local recurrence (A: n=16, B: n=3) within the timespan of 2.4-37.7 months after iBT (median: 6.1 months, mean: 11.8 months), corresponding to a CLR of 9.8%. CLR rates at 12, 18, 24 and 48 months were 6.7%,7.2%, 8.2%, and 9.8% respectively. Subgroup analysis revealed no significant difference in local recurrence between group A and B (A:10.5%, B:7.3%, p=0.339; Figure 2). The recurrent lesions were covered with a median D100 of 17.5 Gy (range=11.5-29.1 Gy). Cumulative progression-free survival and cumulative overall survival ranged from 1.0-46.8 months and 3.1-89.7 months with a median of 4.5 months and 15.7 months, respectively.
Local tumor control after high-dose-rate interstitial brachytherapy according to target size – subgroup analysis. Solid line: target lesion <4 cm, dashed line: target lesion ≥4 cm, +: censored cases.
Discussion
RLCC make up approximately under half of all newly diagnosed malignancies. Despite the overall magnitude, adequately powered clinical trials are lacking in particular for advanced/metastasized disease. Subsequently, in this setting, only few evidence-based results are transferred into new standards and methods for clinical practical guidelines. This may be one of several reasons why the 5-year relative survival is inferior for rare cancers (47%) compared to common cancers (65%) (2).
However, various retrospective studies or uncontrolled case series demonstrated prolonged survival for patients with limited metastatic volume/OMD after an aggressive multidisciplinary treatment including resection or percutaneous RFA of liver metastases, for instance in oligometastatic ASCC or GAC (20-22). Precise clinical definition of OMD varies among publications. In general, OMD is defined as distant metastases limited in number (typically ≤5) and location (typically ≤3, predominantly visceral and pulmonal metastases), but most importantly accessible for regional treatment, aiming for a complete resection/ablation with clear resection/ablation margins (23-25). In this setting, long-term survival or even potential cure can be achieved after surgery as shown in numerous retrospective studies or case series for patients with common or frequent cancers, such as colorectal (6, 26).
For patients with RLCC and OMD, guideline recommendations are limited. For instance, the ESMO guideline for ASCC states: ‘small volume or isolated metastatic disease should be further discussed by an appropriate multidisciplinary team, in case there are surgical or chemoradiation options’, and also for patients with gastric cancer, local treatment of metastases is considered ‘experimental’ (27, 28). However, the ongoing AIO-FLOT5 could elucidate the benefit of local treatment of OMD on survival and the clinical outcome of patients with oligometastatic gastric or gastroesophageal junction cancer by evaluating the effects of perioperative chemotherapy in combination with curative gastrectomy/esophagectomy and resection of metastatic lesions or local ablations procedures (29). The results of this prospective, multicenter, randomized, investigator-initiated phase III trial are eagerly awaited and expected to set new standards of therapies for advanced-stage patients with GAC.
In contrast, according to numerous retro- and prospective trials, clinical outcome for CRC patients has improved over the last 25 years. In fact, for stage IVa-c the 5-year survival rate increased significantly from 4% to 12% with reported 5-year survival rates of 25-40% for patients with OMD (30). Apart from various chemotherapeutic regimens, this fact is also based on the established recommendation to use not only systemic therapy, but also local treatment for patients with OMD (11). The best local treatment for the individual patient is selected from a toolbox of procedures, containing surgical resection and ablative treatments, i.e. local treatments with thermal devices (e.g. RFA) and non-thermal devices (e.g. iBT, SBRT) as well as locoregional treatments with embolic devices (e.g. radioembolisation) and local chemotherapy (31). In particular, local ablative treatments are intended for unresectable liver metastases or lesions at unfavorable/uncommon sites in OMD patients with CRC. In this setting, iBT of the liver has been shown to provide favorable LTC rates of up to 88% after 12 months at a low major complication rate of below 5% (14, 19).
This goes in line with our findings of a complication rate of 4.3% (all recorded events classify as grade 3 severe adverse events) and no mortality. According to the literature, operative mortality for complete hepatic metastasectomy is reported to be up to 5% (6).
Moreover, even though the median follow-up period in our study was rather short (median 6.2 months; range=2.2-92.9 months) we demonstrated a similar LTC rate of 90.2%, corresponding to a CLR of 9.8%. This finding goes in line with reported LTC rates of 89%-95% after iBT of primary and secondary liver malignancies (32-34), indicating that recurrence after iBT of the liver does not predominantly depend on the primary tumor entity. In fact, current literature implies that the risk of recurrence does rather correlate with increasing tumor size and applied dose (14, 35). More precisely: Collettini et al. analyzed 179 CRC liver metastases treated with a mean D100 of 19.1 Gy (range=15-20 Gy) and found LTC rates of 94% and 86.8% after 12 and 24 months for lesions with a diameter of < 4 cm, whereas 65.8% and 58.5% was reported for lesions ≥4 cm, respectively. Similarly, recurrences were shown to occur more likely after iBT of primary and secondary malignancies of the lung, if lesions were ≥4 cm compared to <4 cm, with LTC rates after 12 and 24 months of 37% and 32% compared to 85% and 74%, respectively (15).
However, we report contradictory results, since we did not find statistically significant different LTC rates for lesions large (≥4 cm) or limited in size (<4 cm). We hypothesize: the key to these divergent findings is full coverage of the CTV that is more challenging to achieve outright for larger compared to smaller lesions. Moreover, comparable to surgery also for local treatment, the margin status is vitally important and related to LTC and prognosis after treatment (36, 37). Hence, some possible but remediable pitfalls need to be discussed.
First of all, delineation of large GTVs on the planning CT scan is a challenging task since tumor margins are oftentimes irregular and ill-defined and the extent and heterogenous shape of parenchymal tumor invasion is difficult to assess. Furthermore, density distribution within the lesion may be homogeneous or heterogeneous and the difference in contrast between metastases and the surrounding normal liver parenchyma may be limited due to e.g. chemotherapy-induced fatty infiltration of the liver. This leads to an impaired visual discrimination and reduced accuracy in delineation of hepatic metastases on planning CT scans. More information can and must be obtained by a detailed and careful comparison of the target lesion on the basis of corresponding anatomical landmarks on both the pre-interventional MRI and the planning CT images prior to contouring the GTV.
Secondly, in large tumors, doses are frequently reduced in order to protect the remaining healthy liver tissue and adjacent OARs, resulting in a potential poorer coverage of the entire tumor mass. This also explains, why a more extensive radiation of a large CTV is not reasonable. One approach could be distancing the CTV from adjacent OARs by interventionally applied balloon catheters in order to extend the distance in-between to simultaneously allow a higher D100 and protect OARs (38).
Thirdly, in patients with CRC, radiologically invisible micrometastases are found frequently in close proximity to the target lesion. For instance, Nanko et al. observed a mean distance of 7.5 mm (longest distance 38.2 mm) between target margin and micrometastasis. Although the size of the target seemed not to correlate with the presence of micrometastases, the likelihood of more frequent and distant micrometastases emerges as the GTV becomes larger (39). However, little is known about micrometastases around liver metastases of RLCC. Therefore, as a precaution, treatment planning must not only consider the GTV but also the potential extent of subclinical disease around it that is not visible on the CT scans, meaning that adding a safety margin to the GTV is crucial. For instance, Seidensticker et al. suggested that for CRC liver metastases a threshold dose of 15.4 Gy should be delivered at a distance of 21 mm to the GTV in order to avert local recurrences after iBT (37). However, the optimal balance between extending the safety margin and adjusting the appropriate dose to avoid recurrences on one hand and prevent extensive radiation of healthy liver tissue on the other hand has not been found, yet.
Thus, in the view of the above, the likelihood of better coverage of smaller lesions seems obvious, as also indicated by Jonczyk et al.: after iBT of 142 cholangiocarcinomas the authors found an inferior LTC for tumors with a diameter of ≥4 cm compared to <4 cm, however, the subgroup analysis showed no significant difference in LTC, if the target lesion -regardless of size-received full coverage with therapeutic doses (40).
The main limitation of our study is its retrospective study design. Additionally, given the low incidence of each primary tumor entity, we analyzed a heterogenous patient cohort, also with respect to disease stage and previous treatments. Therefore, no substantial evidence is provided regarding oncological outcome. Prospective and preferable randomized trials are needed to evaluate the effect of local treatment on survival in OMD and to potentially set new standards for therapy recommendations. Furthermore, the follow-up is rather short with a median of 6.2 months, however, the cohort consists of 6 different tumor entities with varying survival rates, for instance median survival for advanced pancreatic adenocarcinoma is reported to be 2.8-6.7 months compared to up to 89 months for GIST patients with hepatic metastases (41, 42). This goes in line with the wide range of our follow-up: 2.2-92.9 months.
However, given the paucity of adequately powered trials for advanced/metastatic RLCC, our data demonstrate that iBT is feasible and can be safely and effectively used in the local control of liver metastases of RLCC. Therefore, the method features an additional valuable tool in the management of patients with RLCC and OMD.
In conclusion, our results confirm that iBT is a feasible, safe, and particular effective treatment of oligometastatic liver metastases with a diameter <4 cm and ≥4 cm in patients with RLCC.
Footnotes
Authors' Contributions
C.M. collection of patient data; analysis of the data; interpretation of the results; wrote the manuscript with input from all authors. J.O. collection of patient data; analysis of the data; design of the figures.
R.D. conceived the original idea; interpretation of the results. P.H. planned irradiation; revised the manuscript critically for important intellectual content. T.B. revised the manuscript critically for important intellectual content. A.S. analysis of the data. R.S. collection of patient data; interpretation of the results. M.S. planned and conducted the interventional procedure; interpretation of the results.
J.R. conceived the original idea; planned and conducted the interventional procedure; interpretation of the results. M.Po. planned and conducted the interventional procedure; design and implementation of the study. M.Pe. conceived the original idea; planned and conducted the interventional procedure; design and implementation of the study; supervised the project.
Conflicts of Interest
The Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Received June 22, 2020.
- Revision received July 8, 2020.
- Accepted July 9, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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