Abstract
Objectives This study evaluated the objective response to and toxicity of trans-arterial chemo-embolisation (TACE) followed by radiotherapy and hyperthermia (CERT) in hepatocellular carcinoma patients with portal vein tumour thrombosis. Methods The study design was a single-centre prospective phase II trial. Patients were first treated with TACE, with the first hyperthermia session 1 week later. Respiration-gated radiotherapy (RT) was delivered in 10 fractions of 3–5 Gy after another week. Six sessions of hyperthermia were delivered twice a week according to an energy escalation protocol. Response evaluation was planned at 1 month after RT completion using the modified Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Interim analysis was conducted on patients enrolled from October 2013 to November 2014. During this period, 46 patients (90.2%) who received at least one hyperthermia session were eligible and enrolled. Median follow-up was 6.7 months (range 2.0–15.0 months). Complete response was observed in 10 (21.7%) patients and partial response in 27 (47.8%). Most toxicities were grade I or II. One death was related to severe pneumonia of unknown cause in the left lung and one patient could not complete planned treatment because of continuous elevation of bilirubin after TACE. Late, asymptomatic gastroduodenal toxicities were noticed in 13 (28.3%) patients. Conclusion Preliminary evaluation of CERT showed a promising response rate with acceptable toxicities.
Introduction
Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide and is especially common in Asia [Citation1,Citation2]. Curative modalities such as surgical resection, liver transplantation, and radiofrequency ablation have favourable overall survival rates [Citation3]. More than 70% of HCC patients, however, are diagnosed with inoperable status [Citation4] and about half have portal vein tumour thrombosis (PVTT), the worst prognostic factor for HCC [Citation5].
Radiotherapy (RT) is one of the most verified therapeutic modalities in oncology, with several studies reporting acceptable survival results and a favourable response rate for HCC [Citation6–10]. Among HCC patients with PVTT, responders to RT have more than 20 months of median overall survival [Citation11,Citation12]. Response rates for RT alone are 30–50%, depending on tumour extent, and 50–60% after combined trans-arterial chemo-embolisation (TACE) and RT [Citation13]. Nevertheless, complete response (CR) rates are disappointing.
Hyperthermia is a well-known RT adjunctive, especially for breast and rectal cancer and pelvic tumours such as cervical [Citation14]. Theoretically, hyperthermia improves tumour-cell killing by radiation by affecting synthetic phase, hypoxic status and acidic conditions; these factors are generally accepted as contributing to radioresistant status [Citation15]. Randomised controlled trials show that hyperthermia has a radiosensitising effect [Citation14]. However, combination therapy of hyperthermia and RT is not often given to HCC patients because of the concern about the complications without the prospective evaluation of the efficacy and safety of this therapy.
We designed a phase II trial to evaluate the effectiveness and safety of TACE followed by RT and hyperthermia (CERT) in patients with HCC and PVTT. This study assessed the early outcomes of response rate and toxicities of this multimodal treatment.
Patients and methods
Study design
HCC patients with PVTT were screened to determine eligibility for combined RT and hyperthermia treatment on the day of TACE. Informed consent was obtained.
The super-selective TACE protocol at our institution has been described previously [Citation9]. Pre-RT physical and laboratory examinations were performed on days 5–9 after TACE. Examinations were repeated 1 week later if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels were elevated three-fold or more above normal, or the Child-Pugh score was elevated two or more after TACE. Patients who showed consistently poor clinical examinations were excluded.
The Samsung Medical Centre Institutional Review Board approved this study before research initiation. This trial was registered at clinicaltrials.gov (NCT02290977).
Patients
Eligible patients had HCC diagnosed according to the guidelines of the American Association for the Study of Liver Diseases [Citation16] and PVTT confirmed by a characteristic enhancement pattern on computed tomography (CT) or magnetic resonance imaging (MRI). Other inclusion criteria were unsuitability for curative modalities such as resection or radiofrequency ablation, Eastern Cooperative Oncology Group performance status of 0 to 2, Child-Pugh class A or B within 1 week of treatment start, age 20 years or older, more than 700 mL normal liver volume excluding tumour volume, and adequate organ function measured as absolute neutrophil count >1500 cells/mm3, platelet >50 000 cells/mm3, haemoglobin >8 g/dL, total bilirubin <2 mg/dL, prothrombin time/international normalised ratio <1.7, albumin ≥2.8 g/dL, AST/ALT < six times the upper-normal limit, serum creatinine <1.5 mg/dL and glomerular filtration rate >50 mL/min.
Exclusion criteria were complete obstruction of the main portal vein because of tumour thrombus, other malignancy history within 24 months before treatment, previous history of RT to upper abdomen, less than 12 weeks of expected survival, unstable cardiac or pulmonary disease, or untreated gastroduodenal ulcer or severe gastric varices on screening esophagogastroduodenoscopy (EGD). The study schema is in Supplementary Figure 1.
Radiotherapy
For patients with pre-RT clinical examinations that showed RT was suitable, RT simulation was performed on the same day. Before simulation CT scanning, patients were trained for about 1 h in regular breathing to enhance the therapeutic ratio by making respiration reproducible and predictable. Patients wore video goggles and received audio coaching programmed for the patient’s specific, regular, consistent respiration with feedback from a period of normal respiration. Patient-customised audiovisual guidance was used for simulations and at each treatment session.
The four-dimensional CT simulation process at our institution has been reported previously [Citation9]. Respiration-gated planning for MRI was performed after CT simulation. CT/MRI acquisition and fusion protocols have been described previously [Citation17]. Based on fusion images, target areas were contoured on the end-expiratory (50%) phase of CT images and all RT planning was conducted on these images. Three-dimensional conformal planning used 4 or 5 coplanar or non-coplanar beams of 6 or 10 MV photon beams. Intensity-modulated RT was not used.
Daily radiation fraction sizes were determined from 3.5 to 5.0 Gy in 0.5 Gy intervals according to the percentage of the normal liver volume irradiated at more than 50% of the prescribed dose [Citation9]. A schema of our protocol for fraction size determination is in Supplementary Figure 2. If the stomach and duodenum were exposed to full irradiation doses, daily dose was reduced to 3.0 Gy to avoid gastroduodenal toxicity. The number of fractions was fixed at 10 in all cases.
Irradiation started in the second or third week (± 7 days) after TACE. All patients were treated using a Novalis Tx (Varian Medical System, Palo Alto, CA, USA) machine with daily image guidance using two orthogonal kV images and/or cone beam CT before each treatment session. To verify target positions, patient localisation was evaluated by comparing the position of the fiducial (usually a compact lipiodolised lesion) and/or liver dome on gated fluoroscopy images acquired at 50% phase with digitally reconstructed radiographic images from CT images in the same phase. If fiducial or liver dome positions shifted more than the critical margin of 5 mm, the patient was repositioned and the fiducial position was verified again. If shifts greater than 5 mm were detected again, the isocentre was replaced using an automatic adjustment function.
Hyperthermia
Hyperthermia was administered using a 13.56-MHz capacitive coupling Celsius TCS electro-hyperthermia electromagnetic device (Celsius42+, Cologne, Germany). Hyperthermia was administered biweekly from 1 week after TACE and immediately after irradiation during RT. Hyperthermia sessions were separated by more than 48 h. Six 60-min hyperthermia sessions were administered with an energy escalation protocol from 40 to 200 W. The RT isocentre was used as the centre for hyperthermia. Patient vital signs were checked before and after hyperthermia, and continuous skin temperature was monitored using three glass fibre-optic sensors (Celsius TempSens, Celsius42+).
Response and toxicity evaluation and follow-up
Planned assessments were at least once a week during hyperthermia with or without RT and after treatment completion at 1 and 3 months. Subsequent assessments were every 3 months for the first 24 months and every 6 months afterwards, up to 5 years or until death. To maximise local control, additional TACE was recommended at 1 month for all patients except patients who achieved CR. Triphasic liver CT or MRI and blood work were performed at each follow-up visit and EGD was assessed at 3 months after treatment. Overall and in-field responses were assessed using CT or MRI scans at 1 and 3 months after treatment completion using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [Citation18]. PVTT response was measured using the revised RECIST [Citation19]. Toxicity was evaluated using the US National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 [Citation20].
Statistics
The primary end point was overall objective response rate (ORR), calculated as combined number of patients with CR, partial response (PR), and toxicity from combination CERT. A sample of 87 patients was required to obtain 75% overall ORR by CERT compared with 60% from historical data of TACE followed by RT, with 10% dropout, 95% confidence and 80% power. Secondary end points were local progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS). Survival duration was assessed from date of TACE treatment to date of event monitored or last follow-up.
Probable prognostic factors of overall ORR were evaluated using a chi-square test or Fisher’s exact test, and multivariate analysis was performed by logistic regression model using variables with p values less than 0.1 on univariate analysis. Sequential changes in laboratory and clinical findings were assessed using repeated measures ANOVA. LPFS, PFS and OS were estimated with the Kaplan–Meier method. All calculations were performed using SPSS 22.0 software for Windows (IBM, Armonk, NY, USA) and p < 0.05 was considered statistically significant.
Results
Patients and treatment
Between October 2013 and December 2014, 51 of 56 patients satisfying eligibility criteria were consented and enrolled (). Five patients were excluded for refusal of further treatment (n = 1), RT at another institution without hyperthermia (n = 1), or ineligible status after TACE (n = 3).
Figure 1. CONSORT diagram. RT, radiotherapy; TACE, trans-arterial chemo-embolisation; FU, follow-up.
RT and hyperthermia were started in 46 patients, with 33 receiving all planned treatment. Baseline patient demographics and clinical characteristics are in . The median patient age was 54 years (range 35 to 79) with 38 (82.6%) men. Five patients (10.9%) had Child–Pugh class B, and 12 (26.1%) showed main PVTT. CERT as primary treatment was given to 28 (61.7%) patients.
Table 1. Baseline characteristics of 46 enrolled patients.
Among enrolled patients, 43 received TACE followed by RT at 2-week intervals (±3 days), and three received RT at 19–21 days after TACE. Fraction sizes were 3.0 Gy in 18 patients (39.1%), 3.5 Gy in 17 (37.0%), 4.0 Gy in seven (15.2%) and 4.5 Gy in three (6.5%). The remaining patient received 2.5 Gy with 10 fractions because more than 70% of the normal liver was exposed to half the prescribed dose. Treatment was stopped for one patient after the fifth fraction of 3.5 Gy because of continued total blilirubin elevation (1.4 mg/dL at TACE and 4.6 mg/dL at simulation). The other 45 patients completed planned RT.
Hyperthermia was delivered in at least one session in 46 patients, with 13 who did not complete planned hyperthermia mainly because of pain, a heating sensation, or tightness of the hyperthermia apparatus at the region of application. One patient who did not complete planned RT received a single hyperthermia session.
Treatment response
The response rate after CERT is shown in . Except for two patients who were not followed, response to treatment at 1 month was 10 with CR (21.7%) and 22 with PR(47.8%). At 3 months, except for four patients who were not followed, 13 showed CR (28.3%) and 10 showed PR (21.7%). Therefore, the overall ORR was 69.6% at 1 month and 50.0% at 3 months. At 1 month, in-field CR was 23.9% and PVTT CR was 34.0%; at 3 months, in-field CR was 30.4% and PVTT CR was 43.5%.
Table 2. Objective response according to mRECIST after CERT at 1 and 3 months.
Prognostic factors of treatment response
In chi-square and Fisher’s exact tests, factors that significantly correlated with 1 month overall ORR were Child–Pugh class (p = 0.02) and involvement of main PVTT (p = 0.04). Alpha-fetoprotein (AFP) reduction after CERT showed a tendency to correlate with differences in ORR (p = 0.09). In multivariate analysis with Child–Pugh class, main PVTT, and AFP reduction, Child–Pugh class (p = 0.02, odds ratio (OR) 0.05, 95% confidence interval (CI) 0.004–0.61) and involvement of main PVTT (p = 0.03, OR 0.38, CI 0.16–0.89) were significant factors for 1-month overall ORR. Probable prognostic factors related to ORR are shown in Supplementary Table 1.
Toxicity
Toxicities evaluated during and after treatment showed no grade III or higher toxicities during RT and hyperthermia except for one patient with progressive elevation of total bilirubin who stopped receiving RT after five fractions (). Pain from hyperthermia developed in 37 patients (80.4%), and 13 refused further sessions of hyperthermia after 1–5 sessions.
Table 3. Toxicity profile during or after CERT.
Of 44 patients with follow-up, grade III neutropenia developed in two (4.5%), nausea in one, vomiting in one, diarrhoea in one, and abdominal pain in two (4.5%) at 3 months after treatment. One death related to severe pneumonia of unknown cause in the left lung, which was not exposed to the irradiation field, was observed about 1 month after CERT.
EGD findings before and after RT
EGD findings before and after RT are shown in Supplementary Figure 3. Abnormal EGD findings were recounted in all patients. EGD before RT detected gastroduodenal erosion or erosive gastritis in 16 patients (34.8%), chronic atrophic gastritis or chronic superficial gastritis in 38 (82.6%), portal hypertensive gastritis in 15 (32.6%), oesophageal varix and/or gastric varix in 26 (56.5%), and gastric and/or duodenal ulcer in two (4.3%). Follow-up EGD at 1–3 months after RT showed radiation-induced gastroduodenal ulcers in seven patients (15.6%), gastroduodenitis in two (4.4%), and erosion in four (8.9%) with one patient lost to follow-up. No symptomatic gastroduodenal toxicities were noted.
Changes in laboratory and clinical findings
Changes in laboratory and clinical findings were assessed within 1 week before TACE, 1 week after TACE, and 1 month after RT and hyperthermia. Changes in model for end-stage liver disease (MELD) score, AFP levels and Child–Pugh scores for different time periods are shown in .
Figure 2. Changes in laboratory and clinical findings before and after CERT. MELD scores (A) and Child-Pugh scores (B) were restored without significant differences in contrast to AFP (C) even more decreased at 1-month follow-up after completion of treatments.
MELD scores (p = 0.002) and Child–Pugh scores (p = 0.01) were significantly different before and after TACE; however, the scores showed no significant differences at the 1-month follow-up after treatment completion (p = 0.54 for MELD and p = 0.66 for Child-Pugh). In contrast, AFP decreased from baseline at 1 week after TACE and dropped further at 1-month follow-up after treatment completion (p = 0.04 between baseline and after TACE, p = 0.01 after TACE to 1-month follow-up after treatment completion).
Patterns of failure and additional treatments
Median follow-up for all patients was 6.7 months (range 2.0 to 15.0). At the time of analysis, local progression had developed in seven patients (15.2%), intrahepatic progression in 23 (50.0%) and extrahepatic progression in 19 (41.3%). Intrahepatic and extrahepatic progressions appeared simultaneously or sequentially in 13 (28.3%) patients.
Among 36 patients (78.3%) who received additional treatments after CERT, 34 (73.9%) received TACE, with 11 receiving TACE without evidence of local or intrahepatic progression at 1 month after CERT. Sorafenib was used in nine patients (19.6%) and palliative RT in six (13.0%), including three re-irradiations for local progression in the liver.
Survival outcomes
During follow-up, five deaths were confirmed. At 1 year, LPFS was 75.1%, PFS 29.8%, and OS was 78.9%. Survival curves of these clinical outcomes are shown in .
Figure 3. Kaplan–Meier survival curves of all enrolled patients. Local progression-free survival (LPFS) was 75.1%, progression-free survival (PFS) was 29.8% and overall survival (OS) was 78.9% at 1 year.
Discussion
This interim analysis of a prospective phase II trial was to evaluate the effect and toxicity of CERT. The results so far show safety and feasibility in HCC patients with PVTT. The ORR of treatment was better than previously published data and complications related to treatment were also favourable [Citation10,Citation11,Citation21].
Application of RT for HCC is rapidly increasing with deeper understanding about HCC and the radiobiology of the normal liver and other organs [Citation22,Citation23]. More elaborate RT techniques such as image-guided RT and stereotactic body RT (SBRT) have brought attention to HCC. The use of RT for HCC is increasing, and positive results are reported for HCC patients with PVTT [Citation7,Citation11,Citation12]. RT can be performed safely in the presence of PVTT and might provide a second chance to apply different local therapeutic modalities including towards curative treatment [Citation24].
Our group reported the clinical outcomes of RT for patients with HCC with PVTT [Citation12]. More than 50% showed an objective response at 1 month after RT with a median OS of 22.0 months. In a report about TACE followed by RT for locally advanced HCC in which 95% of patients had vessel invasion, ORR at 1 month after treatment was 51.0%, with 60% of patients living longer than 3 years [Citation9]. This result was confirmed in another large retrospective subjective study of 412 HCC patients with PVTT with about 40% PVTT response and a median OS of 19.4 months in responders [Citation11].
RT for HCC has increased with the adaptation of the SBRT technique. A large prospective phase I/II trial using SBRT for 102 patients with locally advanced HCC demonstrated favourable local control rate of 87% at 1 year, with a median 17 months OS [Citation25]. Grade III or higher toxicities were 30%, comparable to our study.
The dose–response relationship of HCC is well recognised in several studies [Citation21,Citation26]. RT dose, however, is limited because of baseline liver function, liver cirrhosis, tumour extent, and location. Concern about radiation-induced bowel toxicity is another obstacle to delivering sufficient doses [Citation27,Citation28]. Therefore, efficient RT adjuncts are needed for patients who have large tumours or tumours close to the bowel.
TACE or hepatic arterial infusion chemotherapy (HAIC) can be used with RT as a selective radiation sensitiser. Our group reported outcomes for scheduled interval TACE followed by RT for patients with locally advanced HCC uncontrollable by RT alone. We observed an ORR of 51% with 17 months median OS. A prospective study using HAIC and RT followed by consolidative 5-fluorouracil with cisplatin HAIC for patients with HCC with PVTT reported a 45% objective response with 24% actuarial 3-year OS [Citation7].
In many fields of oncology, hyperthermia is the one of the oldest therapeutic modalities with the potential to be an adjunct to RT [Citation14]. Hyperthermia is well known for direct cell-killing effects at temperatures above 41–42 °C. Thermal ablative treatment is a main local therapeutic modality for liver malignancies, especially HCC [Citation29–31]. Hyperthermia has higher efficacy against tumours with hypoxic status, low pH, low blood flow, or in cells in mitosis S phase, which are known to be relatively radioresistant. Hyperthermia can also enhance re-oxygenation of hypoxic tumours by increasing blood flow. Supporting these theoretical principles, synergistic interactions between RT and hyperthermia have been validated in preclinical studies [Citation15].
To enhance responses without increasing toxicities in patients with HCC with PVTT, we conducted this study on CERT. Although biologically equivalent doses (39.0 to 65.3 Gy10) were not relatively high, ORR was comparable or higher than in previous studies [Citation10,Citation11,Citation21]. In addition, the 1-year local control rate was 75%. Considering the primary tumour size (median 7.4 cm) and AFP level (median 272.9 ng/mL), response and local control with CERT were promising. Grade III or higher toxicities, including to the liver and gastroduodenum, were not frequently associated with treatment, and these toxicities were comparable with toxicities after TACE followed by RT without hyperthermia in previously reported studies [Citation9,Citation10]. Though the RT dose prescribed in this study was not high according to quantitative analysis of normal tissue effects in the clinic (QUANTEC) [Citation32], confirming the safety of CERT was informative because liver function and gastroduodenal integrity are commonly limited in HCC patients with cirrhosis.
Although the sample size and follow-up period were not sufficient to conclusively demonstrate efficiency, CERT might be an alternative treatment for sustained local control in patients with HCC with PVTT. Pain during hyperthermia, however, was an obstacle to completing treatment, as were intrahepatic and extrahepatic recurrences.
A major limitation of our study was that we did not assess actual temperature or specific absorption rate of tumours and normal organs [Citation33,Citation34] because of concerns about complications such as tumour or variceal bleeding or infections. This limitation made interpreting the efficacy of the hyperthermia combination difficult, though controversy remains about whether actual tumour temperature measurements in hyperthermia are useful. Although temperature was not determined in this study, elevation of temperature has been confirmed by energy escalation in a pig model [Citation35]. In addition, we used a somewhat higher fraction size than conventional RT. The combined effect of conventional-dose RT and hyperthermia might be beneficial. However, the effect of hyperthermia according to fraction size should be studied further in patients with HCC [Citation36].
Conclusion
We evaluated the efficacy and safety of CERT for patients with HCC with PVTT. In this interim analysis of a prospective phase II trial, CERT had a relatively higher response rate with sustained local control and without significant risk of grade III or higher toxicities. Pain during hyperthermia and outfield intrahepatic and/or extrahepatic progression still occurred. Though the results of this interim analysis evaluating hyperthermia combined with RT were promising, further enrolment and follow-up are planned and we expect that additional data will give more valuable information. A randomized comparison study of standard treatment versus CERT is needed because this trial is a single-arm study.
Disclosure statement
This research was supported by a Samsung Medical Centre grant (GF01130081). The hyperthermia system was rented from Celsius 42+ GmbH for prospective clinical studies using hyperthermia in combination with radiotherapy for primary and metastatic liver tumours. Grants for the clinical studies were provided by BiomediSyn Inc. The authors alone are responsible for the content and writing of the paper.
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