Abstract
Purpose
Proton beam therapy (PBT), compared with conventional radiotherapy, can deliver high-dose radiation to a tumor, while minimizing doses delivered to surrounding normal tissues. The better dose distribution of PBT may contribute to the improvement in local control rate and reduction in late adverse events. We evaluated therapeutic results and toxicities of PBT combined with selective intra-arterial infusion chemotherapy (PBT-IACT) in patients with stage III–IVB squamous cell carcinoma of the tongue.
Materials and methods
After 2 systemic chemotherapy courses and whole-neck irradiation (36 Gy in 20 fractions), we administered concurrent chemoradiotherapy comprising PBT for the primary tumor [28.6–33 Gy(RBE) in 13–15 fractions] and for the metastatic neck lymph node [33–39.6 Gy(RBE) in 15–18 fractions] with weekly retrograde intra-arterial chemotherapy by continuous infusion of cisplatin with sodium thiosulfate.
Results
Between February 2009 and September 2012, 33 patients were enrolled. The median follow-up duration was 43 months. The 3-year overall survival, progression-free survival, local control rate, and regional control rate for the neck were 87.0, 74.1, 86.6, and 83.9 %, respectively. Major acute toxicities >grade 3 included mucositis in 26 cases (79 %), neutropenia in 17 cases (51 %), and dermatitis in 11 cases (33 %). Late grade 2 osteoradionecrosis was observed in 1 case (3 %).
Conclusions
PBT-IACT for stage III–IVB tongue cancer has an acceptable toxicity profile and showed good treatment results. This protocol should be considered as a treatment option for locally advanced tongue cancer.
Keywords: Tongue cancer, Proton beam therapy, Intra-arterial infusion chemotherapy, Radiotherapy, Chemoradiotherapy, Cisplatin
Introduction
Tongue cancer accounts for about 1 % of all malignant neoplasms and mainly develops in individuals in their 60 s. Recently, the incidence has increased in young people worldwide (Shiboski et al. 2005). In early-stage tongue cancer, brachytherapy achieves a high control rate and retains good function (Shibuya et al. 1993). Because it is difficult to control locally advanced tongue cancer by radiotherapy alone, surgical resection is typically performed. However, surgery markedly reduces patients’ quality of life by affecting social interactions.
Therefore, an effective nonsurgical procedure has been sought. A new method of intra-arterial infusion chemotherapy via the superficial temporal artery (STA) with concurrent radiotherapy has been developed (Fuwa et al. 2008; Mitsudo et al. 2014). Although results of this treatment were not inferior to those of surgery, severe late adverse events were noted, such as lower jaw bone necrosis (Kielbassa et al. 2006).
Proton beams are characterized by their unique Bragg peak (rapid falloff at the distal end) and sharp lateral penumbra and can be used to deliver high-dose radiation to a tumor, while minimizing doses delivered to surrounding normal tissues (Fokas et al. 2009). Better PBT dose distribution may improve the local control rate and reduce adverse events.
In this study, we performed PBT combined with continuous weekly retrograde intra-arterial infusion chemotherapy (IACT), via STA, and evaluated therapeutic effects and toxicities for patients with locally advanced tongue cancer.
Materials and methods
The following patient eligibility criteria were used: (1) previously untreated, (2) pathological confirmation of squamous cell carcinoma (SCC) of the tongue, (3) stage III–IVB (according to the TNM Classification of Malignant Tumors, 2009); patients who need subtotal resection or more extended surgery, (4) Eastern Cooperative Oncology Group performance status of 0–2, (5) age 18–70 years, (6) bone marrow function was maintained (leukocyte count, >3000/mm2; platelet count, >100,000/mm2; hemoglobin, >9 g/dL), and (7) no history of radiotherapy and/or surgery for the head and neck region.
Disease evaluation included a physical examination, chest radiography, computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoroglucose positron emission tomography-computed tomography (FDG-PET/CT). A maximal lymph node diameter of ≥10 mm along the shortest axis on CT or MRI was defined as a positive lymph node. In addition, a positive FDG finding was diagnosed as positive nodal disease.
This study was approved by the ethics committee of our hospital. All patients were required to provide written informed consent before registration.
Treatment procedure
The treatment protocol is shown in Fig. 1. Patients received alternating chemoradiotherapy comprising an initial chemotherapy course followed by conventional wide-field X-ray therapy (XRT) that included the prophylactic cervical lymph node area. Following XRT, patients received a second chemotherapy course. Subsequently, catheterization was performed via STA. Concurrent chemoradiotherapy, comprising daily PBT and weekly retrograde IACT (PBT-IACT) with continuous cisplatin (CDDP) and sodium thiosulfate (STS) infusion, was then administered.
Fig. 1.
Treatment schedule is shown. First, patients received alternating chemoradiotherapy comprising 2 courses of chemotherapy and conventional X-ray therapy that included the prophylactic cervical lymph node area. Subsequently, a catheterization via STA was performed. Then, concurrent chemoradiotherapy, comprising daily proton beam therapy and weekly retrograde intra-arterial infusion chemotherapy with continuous infusion of cisplatin and sodium thiosulfate were administered
Radiotherapy
Radiotherapy was performed 5 times a week. A 6-MV photon beam generated by a linear accelerator, which was delivered through bilateral opposing portals at a dose of 36 Gy in 20 fractions, was used to cover the initial XRT field between the primary lesion and level I–III lymph node region with 1-cm safety margin. In the case with cervical node metastasis over N2 or the lower cervical region, level IVa, Va, Vb lymph node region and supraclavicular fossa (level Vc) were included in the radiation fields (Grégoire et al. 2014). For the latter half of radiotherapy, PBT was performed, which irradiated a concentrated dose on the focused position (Fig. 2). The proton beam dose is reported in Gy(RBE), defined as the physical dose multiplied by a relative biological effectiveness (RBE) value of 1.1. The total PBT dose was 28.6–39.6 Gy(RBE) in 13–18 fractions, delivered by irradiating 2.2 Gy(RBE) per fraction of 150 or 210 MeV proton beams. Irradiation of the primary lesion and metastatic lymph nodes was performed using the dual-portal broad-beam method with multi-leaf collimators. The patient was positioned and immobilized with oral spacer and thermoplastic head mask shell to ensure high repositioning accuracy of the target. The spacer is used to fix the tongue and to avoid extra irradiation to the jawbone. A three-dimensional treatment planning system (Xio-M; CMS Japan, Tokyo, Japan) was used for PBT planning. Gross target volume (GTV), including the primary tumor and regional lymph node metastases, was determined by palpation, MRI, CT, and PET-CT. The clinical target volume (CTV) was defined as GTV with a 3- to 5-mm margin in all directions avoiding the mandibular bone. The CTV was expanded by 3 mm in all directions to create the planning target volume (PTV) to compensate for setup uncertainty and internal margin. Because of the presence of a penumbra and the radiation range, the beam-specific margin must take into account the proximal margin, distal margin, lateral margin, and smearing margin as the margin for bolus (Torres et al. 2009). Doses were calculated using the pencil beam algorithm. The beam line avoided the spinal cord and brain stem. The dose constraints were that the total mandible bone receiving >20 Gy (V20) should be <35 % (ideally, <20 %).
Fig. 2.
Dose distribution of proton beam therapy for the tongue, using a spacer to reduce the dose to the mandible
Chemotherapy
Chemotherapy comprised continuous intravenous 5-fluorouracil (5-FU) administration at a dose of 700 mg/m2 per 24 h on days 1–5, followed by nedaplatin (NDP) at a dose of 110 mg/m2 per 5 h on day 6. When white blood cell (WBC) counts were <1000/mm2 or platelet counts were <25,000/mm2 after chemotherapy, doses of 5-FU and NDP were reduced by 25 % at the next administration. When the serum creatinine levels exceeded 1.5 mg/dL, the dose of the next NDP administration alone was decreased by 25 %. In addition, the next chemotherapy was skipped for patients with WBC counts <3000/mm2 or platelet counts <75,000/mm2 and serum creatinine ≥1.5 mg/dL at the scheduled chemotherapy date.
Intra-arterial infusion chemotherapy
As previously reported (Tohnai et al. 1998; Fuwa et al. 2000), the anterior ear on the affected side was incised under local anesthesia to expose STA. Under fluoroscopy, a thin catheter was selectively inserted into the lingual artery (LA) (Fig. 3a). When the lesion involved the contralateral side, another catheter was inserted into the contralateral side for bilateral arterial injection. When the tumor involved the oral floor and lower gum, the catheter tip was located slightly central to LA in the external carotid artery (ECA) to deliver the drug into the facial artery. We confirmed the arterial injection extent by dyeing as part of a pigment injection test and using digital subtraction angiography. Furthermore, MRI in which the low-dose contrast medium was slowly infused via a catheter was used to determine whether the anticancer drugs delivered via arterial infusion permeated the entire tumor (Fig. 3b) (Nakamura et al. 2011).
Fig. 3.
Flow check methods using digital subtraction angiography (a) and enhanced magnetic resonance imaging (b) to ensure areas of arterial infusion
The CDDP dose was established at 20 mg/m2 when the catheter was inserted into the LA and at 30 mg/m2 when the catheter was inserted into the ECA (Fuwa et al. 2000). When inserting catheters into arteries bilaterally, we set the total infused CDDP dose up to 40 mg/m2 per week (Robbins et al. 1994, 2000). During the arterial CDDP injection over 5 h once a week, STS (a CDDP-neutralizing agent) was intravenously administered at 8 g/m2 to achieve neutralization over 7 h. The arterial injection chemotherapy was repeated 4–6 times.
Patient assessments
According to the Response Evaluation Criteria in Solid Tumors guidelines (RECIST guideline, version 1.1), the antitumor effects were evaluated on the basis of results of physical examination and MRI performed 4 weeks after treatment completion. Follow-up MRI or FDG-PET/CT and a physical examination were performed at 2- to 4-month intervals for the first 2 years after the end of treatment and at 4- to 6-month intervals thereafter.
The primary study endpoint was the overall survival (OS), calculated as the time from the start of protocol treatment to the date of the death from any cause. Progression-free survival (PFS) was calculated as the time from the start of treatment to the first confirmed date of a locoregional progression or recurrence, a first distant metastasis, or the death from any cause. Recurrence was defined as any regrowth of primary tumor or irradiated metastatic cervical lymph nodes. Duration of local control (LC) and regional control (RC) were calculated as the time from the start of the treatment to the first confirmed dates of local and regional failures, respectively. The OS, PFS, LC, or RC for subjects who were alive or lost to follow-up at the time of last contact on or before data cutoff was censored at the date of the last contact alive. The treatment effects were assessed according to the WHO response criteria. Complete response (CR) was defined as disappearance of all known disease, and partial response (PR) was defined as a 50 % decrease after 4 weeks.
Acute and late toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
Statistical analysis
Assuming 4-year accrual time, 3-year follow-up time, expected and threshold 3-year OS rates of 80 and 60 %, respectively, and dropout rate of about 10 %, the required sample size was at least 30 patients. The threshold 3-year OS rate was based on the result of the previous study (Fuwa et al. 2008).
Continuous and categorical variables are presented as medians with ranges and as frequencies with percentages, respectively. The Kaplan–Meier method was used to estimate OS, PFS, LC, and RC curves. In univariate analysis, the log-rank test was used to explore potential factors associated with OS, PFS, LC, and RC. In multivariate analysis, the factors with P < 0.05 in the log-rank analysis were included in the Cox regression with Firth’s penalized likelihood, which can provide a solution to the phenomenon of monotone likelihood that causes parameter estimates of a Cox regression model to diverge, with infinite standard errors. The results are summarized as hazard ratios, 95 % confidence intervals and P values on the basis of the Cox regression with or without Firth’s penalized likelihood, as appropriate. All P values were two-sided; P < 0.05 was considered to indicate statistical significance. Statistical analyses were performed using R (version 3.1.1) with package coxphf for Cox regression with Firth’s penalized likelihood.
Results
Between January 2009 and September 2012, 33 patients with locally advanced tongue cancer were enrolled in this study. The median follow-up duration was 43 months (range 7–68 months).
Patients’ characteristics are shown in Table 1. One patient had advanced inoperable disease and the others needed subtotal resection or more extended surgery. Patients were considered to have completed the course of treatment if they were administered 2 courses of chemotherapy, 4 courses of intra-arterial chemotherapy, and at least 80 % of planned radiological doses. As a result, a total of 24 patients (72.7 %) completed the course of treatment. Twenty-six patients (78.8 %) were able to complete the 2 courses of chemotherapy. The remaining 7 patients (21.2 %) received only 1 course of systemic chemotherapy for the following reasons: rapid tumor growth in 3 (urgent arterial injection was needed), nausea in 1, excessive hiccups in 1, bone marrow toxicity in 1, and interruption for evacuation by earthquake in 1. Two patients (6.1 %) were not able to complete 4 courses of IACT, because of sepsis caused by infection via catheters, and all patients completed the radiation therapy. The median number of IACT was 6 (range 3–8) times, and the median dose of CDDP was 290 (range 90–640) mg. The total radiation doses ranged from 55.8 to 73.0 (median 69.0, mean 66.7) Gy for the primary tumor and from 64.6 to 84 (median 69.0, mean 70.9) Gy in the metastatic cervical lymph nodes.
Table 1.
Patient characteristics
| Characteristics | n or median | (% or range) |
|---|---|---|
| No. of patients | 33 | (100) |
| Age (years) | 53 | (25–69) |
| Sex | ||
| Male | 22 | (67) |
| Female | 11 | (33) |
| ECOG a performance status | ||
| 0 | 0 | (0) |
| 1 | 24 | (73) |
| 2 | 9 | (27) |
| T classification | ||
| T2 | 6 | (18) |
| T3 | 10 | (30) |
| T4a | 17 | (52) |
| N classification | ||
| N0 | 5 | (15) |
| N1 | 12 | (36) |
| N2b | 6 | (18) |
| N2c | 9 | (27) |
| N3 | 1 | (3) |
| Stage | ||
| III | 8 | (24) |
| IV A | 24 | (73) |
| IV B | 1 | (3) |
| Reasons for not performing surgery | ||
| Refusal | 32 | (97) |
| Inoperable advanced | 1 | (3) |
aEastern Cooperative Oncology Group (TNM classification from UICC 2009)
In the affected side, a catheter was selectively inserted into the LA in 23 of 33 patients and was then changed to the ECA in 17 of 23 patients during the treatment. In the remaining 10 patients, a catheter was inserted into the ECA consistently to cover range of existing tumor. In 17 of 33 patients, 2 catheters were inserted bilaterally. A catheter was selectively inserted into the LA in 14 of 17 patients and was then changed to the ECA in 5 of 14 patients in the contralateral side.
Toxicity
Toxicities are shown in Table 2. The major acute adverse events of >grade 3 were as follows: mucositis in 26 (79 %) patients, neutropenia in 17 (51 %), and dermatitis in 11 (33 %). Neutropenic sepsis involving catheter-related infection occurred in 6 patients (18 %). To maintain weight, 9 patients required gastric tube, 5 patients used nasal tube, and 3 patients needed intravenous hyperalimentation. Renal failure was not observed. No patients died of treatment toxicity. The late adverse events evaluated 24 months after treatment were as follows: >grade 2 dental caries in 14 (46 %), >grade 2 dysgeusia in 5 (17 %), grade 1–2 of xerostomia persisted in 18 patients (59 %), and osteonecrosis in 1 (3 %). Dysarthria and dysphagia were not observed.
Table 2.
Adverse events (NCI-CTCAE v.4.0)
| Toxicity | Grade [n (%)] | |||
|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |
| Early (n = 33) | ||||
| Mucositis | 0 | 7 (21) | 26 (79) | 0 |
| Dermatitis | 0 | 22 (67) | 11 (33) | 0 |
| Neutropenia | 1 (3) | 12 (36) | 16 (48) | 1 (3) |
| Anemia | 12 (36) | 13 (39) | 0 | 0 |
| Thrombocytopenia | 5 (15) | 3 (9) | 0 | 0 |
| Nausea | 15 (45) | 10 (30) | 6 (18) | – |
| Dry mouth | 12 (36) | 18 (54) | 3 (9) | – |
| Weight loss | 21 (64) | 10 (30) | 2 (6) | – |
| Hiccups | 4 (12) | 4 (12) | 1 (3) | 0 |
| Hepatobiliary disorders | 1 (3) | 0 | 0 | 0 |
| Fever | 3 (9) | 4 (12) | 0 | 0 |
| Depression | 1 (3) | 2 (6) | 0 | 0 |
| Catheter-related infection | – | 0 | 4 (12) | – |
| Edema (face, neck) | 24 (73) | 0 | 0 | |
| Late (n = 30) (2 years after treatment) | ||||
| Osteonecrosis of jaw | 0 | 1 (3) | 0 | 0 |
| Dysgeusia | 11 (37) | 5 (17) | – | – |
| Xerostomia | 17 (57) | 1 (3) | 0 | – |
| Dental caries | 0 | 10 (33) | 4 (13) | – |
National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0
Response and survival
A CR was achieved in 28 patients (84.8 %) and a PR in 5 (15.2 %). During observation periods, relapse occurred in 8 patients at the following sites: only the primary site in 2; only the cervical lymph node in 3; the primary site and cervical lymph node in 1; the primary site and distant metastasis in 1; and the cervical lymph node and distant metastasis in 1. The median period to recurrence was 6 (range 5–31) months. In these 8 patients, 2 died from locoregional failure 7 and 11 months after the start of treatment. One died of distant metastases 8 months after the start of treatment. The remaining 5 patients underwent salvage surgery. Control was achieved in 3 of these patients; the other 2 patients survived but continued to harbor tumors. Another patient died of leukemia without evidence of disease 34 months after the treatment. Consequently, in the initial treatment, the primary lesions were controlled in 29 of 33 cases. Neck dissection could be avoided in 23 of 28 cases with cervical lymph node metastasis. Distant metastasis was observed in 2 of 33 patients.
Three-year OS, PFS, LC, and RC rates were 87.0 % (95 % CI 75.7–99.9 %), 74.1 % (95 % CI 60.0–91.6 %), 86.6 % (95 % CI 75.0–100 %), and 83.9 % (95 % CI 71.7–98.0 %), respectively (Fig. 4).
Fig. 4.
a Overall survival, b progression-free survival, c local control, and d regional control estimated using the Kaplan–Meier method
Factors associated with survival and locoregional recurrence (Tables 3, 4)
Table 3.
Univariate analysis for baseline characteristics and treatment factors
| Factor | Level | No. | Overall survival | Progression-free survival | Local control | Regional control of neck | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HRa | 95 % CIb | P value | HR | 95 % CI | P value | HR | 95 % CI | P value | HR | 95 % CI | P value | |||
| Age | <53 | 15 | 1 | 0.416 | 1 | 0.568 | 1 | 0.869 | 1 | 0.202 | ||||
| ≥53 | 18 | 2.480 | (0.258, 23.852) | 1.524 | (0.364, 6.387) | 0.848 | (0.119, 6.021) | 3.788 | (0.423, 33.948) | |||||
| Sex | Male | 22 | 1 | 0.746 | 1 | 0.623 | 1 | 0.730 | 1 | 0.515 | ||||
| Female | 11 | 0.689 | (0.072, 6.629) | 0.671 | (0.135, 3.325) | 0.679 | (0.070, 6.526) | 0.488 | (0.054, 4.369) | |||||
| EOCG-PSc | ≦1 | 24 | 1 | 0.962 | 1 | 0.103 | 1 | 0.208 | 1 | 0.004* | ||||
| 2 | 9 | 0.947 | (0.098, 9.104) | 2.981 | (0.743, 11.950) | 0.285† | (0.002, 2.670)† | 12.296 | (1.372, 110.198) | |||||
| T classification | 2 or 3 | 16 | 1 | 0.048* | 1 | 0.025* | 1 | 0.043* | 1 | 0.177 | ||||
| 4a | 17 | 8.832† | (0.942, 1170.638)† | 7.636 | (0.938, 62.177) | 9.113† | (0.972, 1208.026)† | 4.004 | (0.447, 35.865) | |||||
| N classification | ≤1 | 17 | 1 | 0.933 | 1 | 0.896 | 1 | 0.355 | 1 | 0.140 | ||||
| >2 | 16 | 1.088 | (0.153, 7.725) | 1.097 | (0.274, 4.393) | 0.356 | (0.037, 3.437) | 4.521 | (0.505, 40.472) | |||||
| Stage | III | 8 | 1 | 0.245 | 1 | 0.084 | 1 | 0.235 | 1 | 0.184 | ||||
| IVA–IVB | 25 | 3.047† | (0.325, 0403.808)† | 6.170† | (0.768, 798.247)† | 3.124† | (0.333, 414.256)† | 3.828† | (0.434, 502.762)† | |||||
| Treatment period | <84 | 18 | 1 | 0.232 | 1 | 0.238 | 1 | 0.188 | 1 | 0.453 | ||||
| ≥84 | 15 | 3.634 | (0.378, 34.949) | 2.329 | (0.555, 9.768) | 4.108 | (0.426, 39.601) | 1.98 | (0.330, 11.895) | |||||
| Irradiation period | <63 | 19 | 1 | 0.817 | 1 | 0.252 | 1 | 0.219 | 1 | 0.392 | ||||
| ≥63 | 14 | 1.260 | (0.176, 9.023) | 2.268 | (0.539, 9.524) | 3.741 | (0.387, 36.178) | 2.14 | (0.357, 12.817) | |||||
| Catheterization | Ipsilateral | 16 | 1 | 0.285 | 1 | 0.019* | 1 | 0.276 | 1 | 0.020* | ||||
| Bilateral | 17 | 3.218 | (0.334, 31.040) | 8.274 | (1.007, 67.954) | 3.276 | (0.336, 31.926) | 11.878† | (1.343, 1560.619)† | |||||
| Selected artery | LA | 6 | 1 | 0.954 | 1 | 0.159 | 1 | 0.170 | 1 | 0.319 | ||||
| LA-ECA | 18 | 0.770 | (0.069, 8.529) | 0.888† | (0.226, 4.853)† | 0.338† | (0.052, 2.193)† | 1.000† | (0.185, 9.985)† | |||||
| ECA | 9 | 0.655 | (0.041, 10.466) | 0.114† | (0.001,1.403)† | 0.122† | (0.001, 1.503)† | 0.192† | (0.001, 3.619)† | |||||
| Total dose of CDDPd | <PAe | 14 | 1 | 0.085 | 1 | 0.286 | 1 | 0.079 | 1 | 0.862 | ||||
| ≥PA | 19 | 6.711† | (0.715, 889.729)† | 2.373 | (0.476, 11.808) | 6.857† | (0.732, 908.802)† | 1.184 | (0.197, 7.118) | |||||
| Catheter infection | No | 29 | 1 | 0.415 | 1 | 0.165 | 1 | 0.011* | 1 | 0.490 | ||||
| Yes | 4 | 2.488 | (0.258, 24.000) | 3.042 | (0.611, 15.145) | 8.506 | (1.195, 60.560) | 2.176 | (0.241,19.649) | |||||
| Number of chemotherapies | 1 | 7 | 1 | 0.719 | 1 | 0.185 | 1 | 0.793 | 1 | 0.222 | ||||
| 2 | 26 | 0.661 | (0.068, 6.410) | 0.391 | (0.093, 1.642) | 0.748 | (0.077, 7.257) | 0.342 | (0.057,2.050) | |||||
* P < 0.05
† The hazard ratio, 95 % confidence interval, and P value were estimated using Cox regression with Firth’s penalized likelihood
aHazard ratio; b 95 % confidence interval; c Eastern Cooperative Oncology Group performance status; d CDDP, cisplatin; e planned amounts
Table 4.
Multivariate analysis for baseline characteristics and treatment factors
| Factor | Level | No. | Progression-free survival | Local control | Regional control of neck | |||
|---|---|---|---|---|---|---|---|---|
| Adjusted HRa (95 % CIb) | Adjusted P value | Adjusted HR (95 % CI) | Adjusted P value | Adjusted HR (95 % CI) | Adjusted P value | |||
| ECOG-PSc | ≤1 | 24 | – | – | – | – | 1 | 0.069† |
| 2 | 9 | – | – | 4.883† (0.886, 50.977)† | ||||
| T classification | 2 or 3 | 16 | 1 | 0.273 | 1 | 0.096† | – | – |
| 4a | 17 | 3.646 (0.361, 36.82) | 7.321† (0.744, 980.123)† | – | ||||
| Intra-arterial infusion | Ipsilateral | 16 | 1 | 0.221 | – | – | 1 | 0.129† |
| Bilateral | 17 | 4.254 (0.418, 43.28) | – | 6.685† (0.636, 917.141)† | ||||
| Catheter infection | No | 29 | – | – | 1 | 0.061† | – | – |
| Yes | 4 | – | 6.030† (0.914, 39.897)† | – | ||||
* P < 0.05
† The hazard ratio, 95 % confidence interval, and P value were estimated using Cox regression with Firth’s penalized likelihood
aHazard Ratio; b 95 % confidence interval; c Eastern Cooperative Oncology Group performance status
In the univariate analysis, T classification had a significant impact on OS, PFS, and LC. Ipsilateral or bilateral catheterization had a significant impact on PFS and RC. Infection via catheter had a significant impact on LC. PS had a significant impact on neck control.
In the multivariate analysis, there were no significant factors associated with survival and locoregional recurrence.
Discussion
Currently, there are 2 procedures for performing arterial infusion therapy for head and neck cancer: one in which a catheter is inserted into the target artery through STA, as presented in this study, and one in which a catheter is inserted into the target artery through the femoral artery using Seldinger’s procedure (Nakamura et al. 2011). The latter procedure is simpler than the former and facilitates the administration of anticancer agents into several arteries; however, it is inappropriate for drug administration over a long duration; the incidence of catheter operation-related cranial nerve disorders ranges from 2 to 4 % (Robbins et al. 1994). Conversely, few patients experienced cranial nerve disorders after treatment using the former procedure, and it can be used to provide daily chemotherapy and drug administration over a long duration.
In cases of surgery for patients with advanced tongue cancer, the 5-year overall survival rate ranges from 39 to 61 % in stage III patients and from approximately 27 to 38 % in stage IV patients with tongue cancer (Gorsky et al. 2004; Sessions et al. 2002; Fan et al. 2007). Plural studies have reported treatment results of IACT via STA for locally advanced tongue cancer (Fuwa et al. 2008; Mitsudo et al. 2014). Fuwa et al. (2008) reported that in 88 cases of stage III and IV tongue cancer, the 3-year OS was 57 % (III, 67 %; IV, 43 %). Mitsudo et al. (2014) reported that the 5-year OS was 71.3 % (III, 83.1 %; IV, 64.5 %) for 112 cases of oral cancer. In our study, 3-year OS, PFS, and LC rates were 87.0, 74.1, and 86.6 %, respectively. Considering that 17 in 33 cases involved T4 lesions, therapeutic effects were better than that of historical controls.
PBT has Bragg peak properties and can deliver a high radiation dose to the tumor while largely sparing normal tissue. Excellent treatment results have been reported for head and neck cancer (Holliday and Frank 2014). However, there have been few studies on oral cavity cancer. In our study, XRT was initially used for extended field irradiation. This method was adopted because advanced SCC of the tongue has high potential for widespread lymph node metastasis (Gomez et al. 2011). Therefore, it is necessary to irradiate a wider field of the neck. Because it is difficult to cover a wider field by PBT in our facility, we used XRT for the extended field.
A major prognostic factor of tongue cancer is cervical lymph node metastasis (Shibuya et al. 1993). Twenty-eight of 33 cases (85 %) were diagnosed with cervical lymph node metastasis before treatment in this study. Because of the relatively low radiation sensitivity of oral cancer (Inokuchi et al. 2011), neck dissection is the standard treatment. In combination therapy comprising chemotherapy, whole-neck irradiation, and high-dose irradiation via PBT boost, the 3-year local control rate in the regional lymph node metastases was 83.9 %. This result supports the effectiveness of PBT for cervical lymph node metastases. In this study, involving stage III–IVB tongue cancer, distant metastasis was observed in only 2 of 33 patients (6 %). Considering that 11 % of distant metastases were observed in patients receiving intra-arterial injection without systemic chemotherapy for locally advanced oral cavity cancer (Mitsudo et al. 2014), 2 courses of systemic chemotherapy seemed to contribute to the control of micro-distant metastasis. Primary recurrence occurred in GTV irradiated by the proton beam in 4 patients. We retrospectively confirmed that the extent of arterial injection did not cover the tumor in 3 of 4 cases using the MRI flow check method (Fuwa et al. 2000). Furthermore, the usability of IACT was reconfirmed.
The incidence of osteoradionecrosis (ORN) after conventional radiotherapy and intensity-modulated radiation therapy (IMRT) ranges from 2 to 16 % (Kielbassa et al. 2006; Sessions et al. 2002; Gomez et al. 2011; Schuurhuis et al. 2011). In this study, ORN as a late adverse event was observed in only 1 patient. Dose reduction to the mandible using PBT might contribute to prevent ORN. Grades 1–2 of xerostomia developed in 18 patients (60 %), and late grades 2–3 dental caries were observed in 14 patients (46.7 %). Although we used conventional XRT in this study, the use of IMRT instead would probably reduce salivary gland disorders and multiple caries caused by dry mouth.
In this study, a broad-beam method was used to deliver the PBT. The method was difficult to apply in cases with a complicated field. In the future, primary lesions and metastatic cervical lymph nodes, including the prophylactic neck lymph node area, will be able to be irradiated using intensity-modulated proton therapy by a spot scanning system.
Conclusions
This is the first prospective study to demonstrate the effectiveness and toxicities of PBT-IACT via STA with systemic chemotherapy for locally advanced tongue cancer. Survival rates were higher than, or at least similar to, those of surgery. PBT-IACT for stage III–IVB tongue cancer has an acceptable toxicity profile and showed good treatment results. This protocol could be considered as a treatment option for locally advanced tongue cancer.
Compliance with ethical statements
Conflict of interest
We declare that we have no conflict of interest.
Research involving human participants and/or animals
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
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