We reviewed the records of 23 consecutive patients with inoperable oral squamous cell carcinoma (15 who underwent superselective IA chemoradiotherapy [iaCRT] using cisplatin and 8 who underwent systemic chemoradiotherapy [CRT]) at the Tokyo Dental College of Ichikawa General Hospital between November 2011 and November 2019. The requirement for informed patient consent was waived due to the study’s retrospective design. This study was approved by the institutional review board of Tokyo Dental College of Ichikawa General Hospital (Approval No. I16-07).
Patients with T3–4 N0–3 M0–1 oral cancer judged inoperable by dentists at the oral cancer center were included in the current study. The patients’ ages ranged from 51 to 91 years. Bone marrow function of the patients was maintained (leukocyte count ≥ 3000/mm3, platelet count ≥ 1,000,000/mm3). Patients had no severe dysfunction of the liver, lungs, or heart, and none had previously received radiotherapy in the head and neck region. They also had no active double cancer at the start of treatment. CRT was selected for the patients who could not stay in bed for several hours during the iaCRT (e.g., due to dementia), who hoped CRT and who had severe neck arteriosclerosis detected by computed tomography (CT). The treatment efficacy was evaluated using the RECIST v1.1 criteria.
The primary site and cervical lymph nodes were assessed by contrast-enhanced CT and contrast-enhanced magnetic resonance imaging (MRI) prior to treatment. All patients were staged according to the 2017 UICC staging system. Four-dimensional CT angiography (4D-CTA) of the carotid artery was performed to detect the morphology and volume of the tumor, and to predict the feeding arteries before treatment. We used a CT machine Aquillion ONE (Canon Medical Systems, Otawara, Japan). Imaging was initiated 2 s after injection of contrast medium and images were taken 18 times every 2 s from 5 s later of injection. We then analyzed the vessel with SYNAPSE VINCENT (FUJIFILM, Tokyo, Japan).
Intra-arterial chemotherapy (iaCRT)
On the day before the first treatment, a peripherally inserted central catheter (PICC) was introduced through the basilic vein into the superior vena cava with US guidance.
Two radiologists with 12 and 6 years’ experience in interventional radiology performed the superselective intra-arterial infusion via a catheter inserted into a branch of the external carotid artery, such as the facial artery or the maxillary artery. IA catheterizations were performed primarily through the right radial artery using a 4 Fr Simmons catheter (Gadelius Medical Co., Tokyo, Japan). If there was difficulty inserting the Simmons catheter into the cervical artery, IA catheterizations were accomplished through the femoral artery using a 4 Fr JB2 catheter (Gadelius Medical Co., Tokyo, Japan). First, cervical carotid angiography was performed to assess the vascular anatomy and any potential pathology. Then, with coaxial technique, a 2.8 Fr microcatheter (Carry HF; UTM Co., LTD, Aichi, Japan) was inserted into the external carotid artery to detect the tumor and vascular anatomy. A 1.5 Fr microcatheter (Carry Leon; UTM Co., LTD, Aichi, Japan) was then inserted into an external carotid artery branch through a 2.8 Fr microcatheter, and digital subtraction angiography (DSA) and cone beam CT during arteriography were performed to locate the feeders of the tumor. We used an AXIOM ARTIS DFA (Siemens AG, Medical Solutions, Forchheim, Germany) until June 2018 and used a Philips Azurion 7 B2015 (Philips Healthcare, Best, The Netherlands) for the remainder of the study period.
Moreover, to minimize damage to normal tissue and to enhance the effect of high-dose cisplatin infusion into the tumor feeders, blood flow in the external carotid artery branches was altered using transcatheter arterial coil embolization. When DSA of the external carotid artery branches detected the tumor feeders and the blood vessels unrelated to the tumor, we embolized the blood vessels unrelated to the tumor with coils.
Cisplatin at 100 mg/m2 and 20 mL of 7% sodium bicarbonate were infused into each feeder at 0.1 to 0.4 mL/second, depending on the thickness of the blood vessel (infusion was faster in thicker blood vessels). The percentage of the dose of cisplatin depended on the state of the DSA and cone beam CT during arteriography. Simultaneously with the IA infusion of cisplatin, sodium thiosulfate (20 g/m2) was administered at 90 to 360 mL/second via the PICC, depending on the cisplatin infusion speed, to neutralize the cisplatin. This protocol was performed weekly for 6 or 7 weeks.
Systemic chemotherapy (CRT)
The chemotherapy regimens for six patients were intravenous cisplatin 100 mg/m2 given in three cycles on days 1, 22, and 43. Two patients were given 400 mg/m2 in the first treatment and 250 mg/m2 in remaining count of cetuximab given total eight cycles weekly for 8 weeks due to decreased renal dysfunction and old age.
External beam radiotherapy (RT) was started on Day 1. Three-dimensional conformal radiotherapy was performed with photon beam energy of 6 or 10 MV and 2 Gy/fraction/day. We defined the gross tumor volume (GTV) by CT and MRI. GTV included the volume of the primary tumor and lymph node metastases. Furthermore, the primary clinical target volume (CTV) was defined as the GTV plus a margin of 5–10 mm to cover the possible area of invasion. The nodal CTV was defined as the GTV plus a margin of 5 mm to cover the possible area of invasion. The planning target volume (PTV) for the CTV was defined as the CTV plus a margin of 5 mm to cover the possible area of set-up variations and internal organ motion. The planned total doses to the primary tumor and the metastatic lymph nodes were both 60–70 Gy/30–35 fractions. We used an ONCOR Impression PLUS (Siemens AG, Medical Solutions, Forchheim, Germany) as the RT machine and a XIO (Elekta Instruments AB, Stockholm, Sweden) as the RT planning system.
Follow-up after the treatment
All patients were evaluated by contrast-enhanced CT at 1–2-month intervals for 1 year after completion of treatment, then at 3–4-month intervals after 2 years following completion of treatment. If they were suspected to have local recurrence, they were evaluated by contrast-enhanced MRI.
Acute adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.0 until 4 weeks after the last chemoradiotherapy or until the patient’s death.
To analyze local control (LC), regional control (RC), locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) rates, survival curves were drawn using the Kaplan–Meier method. OS was calculated from the first day of chemoradiotherapy to the last follow-up or death. DFS was calculated from the first day of chemoradiotherapy until the date of local failure, metastasis to neck lymph nodes, or distant metastasis. LRC was calculated from the first day of chemoradiotherapy to the date of local failure or new- or regrowth of lymph node metastases. RC was calculated from the first day of chemoradiotherapy to the date of new- or regrowth of metastases to neck lymph nodes. LC was calculated from the first day of chemoradiotherapy to the date of local failure. The LC, RC, LRC, DFS, and OS rates were compared with the log-rank test according to the chemoradiotherapy (intra-arterial cisplatin chemoradiotherapy vs. systemic chemoradiotherapy). To evaluate differences in patient characteristics and the response to chemotherapy, Fisher’s exact test was used. p values (p) < 0.05 were considered to be statistically significant. All statistical analyses were performed using EZR .