Preoperative intra-arterial chemotherapy with docetaxel, cisplatin, and peplomycin combined with intravenous chemotherapy using 5-fluorouracil for oral squamous cell carcinoma

H. Hasegawa, T. Kaneko, C. Kanno, M. Endo, M. Yamazaki, T. Kitabatake, T. Monma, E. Takeishi, E. Sato, M. Kano: Preoperative intra-arterial chemotherapy with docetaxel, cisplatin, and peplomycin combined with intravenous chemotherapy using 5-fluorouracil for oral squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2020 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.


The objectivesof this studyweretoevaluatesurvival in 141 patients with stage II–IV oral squamous cell carcinoma (OSCC) treated with preoperative intra-arterial chemotherapy with docetaxel, cisplatin, and peplomycin combined with intravenous chemotherapy using 5-fluorouracil (IADCPIVF) via the superficial temporal artery, and to clarify the prognostic factors. The study population included 59 patients with stage II OSCC, 34 with stage III, and 48 with stage IV. After IADCPIVF, 139 patients underwent surgery; minimally invasive surgeries (MIS) including excisional biopsy were performed on 96 patients with a remarkably good response to IADCPIVF. The primary tumour response rate was 99.3% (complete response rate 56.7%, good partial response rate 17.0%, fair partial response rate 25.5%). Additionally, there were no serious adverse events associated with IADCPIVF. The 5-year overall survival rate was 74.6% (stage II 83.6%, stage III 72.7%, stage IV 64.8%). In the multivariate analysis of survival, T classification and clinical tumour response were significant prognostic factors. Eight (8.3%) of the patients who received MIS had primary recurrence and six were salvaged. In conclusion, IADCPIVF is safe and efficacious for treating OSCC, and MIS could reduce the extent of primary tumour resection in the case of a remarkably good response.

Key words: oral cancer; intra-arterial che- motherapy; docetaxel; cisplatin; peplomycin; 5-fluorouracil.


Intra-arterial chemotherapy for head and neck cancer treatment with radiation and intra-arterial cisplatin (RADPLAT) was first reported by Robbins et al. in 19961. This is a combination of radiation therapy and concurrent intra-arterial chemothera- py using the Seldinger technique to ad- minister high-dose cisplatin (CDDP) via the femoral artery. Since then, favourable treatment outcomes have been demonstrated1–4. However, while this treatment method has an excellent anti- tumour effect, there have been reports of serious complications, such as cerebrovas- cular accidents and cranial nerve disor- ders. Its application is primarily limited to patients with locally advanced cancers, and elderly patients as well as those in generally poor physical health are excluded1–4.
An approach in which a retrograde cath- eter is placed in the superficial temporal artery (STA) was first reported in 19595. Additionally, there have been recent reports of superselective placement of the catheter directly into the target artery via the STA, which have shown excellent treatment outcomes6,7. A long-term in- dwelling catheter enables the administra- tion of a single or multiple anticancer agents continuously or frequently, which is an advantage not found when using the Seldinger technique via the femoral artery. Furthermore, there is a lower risk of cere- brovascular accident, allowing the retro- grade catheter approach to be applied in elderly patients.
The following treatment strategy in- volving intra-arterial chemotherapy using the retrograde catheter approach was designed to establish a highly safe and effective treatment for oral cancer. (1) The treatment regimen included multiple anticancer drugs that are commonly used for the treatment of head and neck cancers. Docetaxel (DOC), CDDP, and peplomy- cin (PEP) were administered continuously via the artery, and 5-fluorouracil (5-FU) was administered systemically at low doses over long periods of time. The use- fulness of this intra-arterial chemotherapy, which is henceforth referred to as IADC- PIVF (intra-arterial chemotherapy with DOC, CDDP, and PEP combined with intravenous chemotherapy using 5-FU), was shown in a pilot study in 20068. (2) Since then, IADCPIVF has been per- formed mainly as preoperative chemother- apy to treat not only locally advanced oral squamous cell carcinoma (OSCC), but also stage II lesions, because of the low incidence of serious complications associ- ated with this therapy. For cases in which IADCPIVF was remarkably effective, an excisional biopsy or intraoral resection of the primary lesion was then performed, without pull-through resection or recon- structive surgery whenever possible, espe- cially in elderly patients9,10.
In this study, the therapeutic results of 141 patients with OSCC were analysed retrospectively to investigate the prognos- tic factors and to evaluate the safety and efficacy of IADCPIVF as preoperative chemotherapy.

Materials and methods


This study was a retrospective analysis of 141 untreated patients with OSCC who underwent IADCPIVF as preoperative chemotherapy between March 2003 and March 2015. Eligible patients had stage T2–T4, N0–N3, and M0 lesions. T2 lesions were included if they were larger than 3 cm. The patients had no severe disorders of the vital organs such as bone marrow, liver, or kidney. Patients with a performance status of 4 (Eastern Cooper- ative Oncology Group, ECOG) were ex- cluded.
IADCPIVF and the study design were approved by the Ethics Committee of Fukushima Medical University, School of Medicine (number 2481), and this two-institution study was performed using the same protocol at Fukushima Medical University Hospital and Ohara General Hospital. Written informed consent was obtained from the patients.

Method for catheter placement

Branches of the external carotid artery were examined preoperatively using three-dimensional computed tomography angiography (3D-CTA). As described in the previous report by the present inves- tigators’ group, an intra-arterial catheter (Anthron P-U catheter, tapering type, dis- tal portion 2.7 Fr; Toray Medical Co., Ltd, Tokyo, Japan) was inserted and placed selectively under local anaesthesia via the STA or occipital artery8–12. During catheter placement in the external carotid artery, the tip of the catheter was placed beneath the bifurcation so that the majori- ty of the contrast agent could flow into the target artery, and the oral cancer and the surrounding mucosa could be macroscop- ically stained with disodium indigotin-dis- ulfonate (Indigo Carmine; Daiichi Sankyo Co., Ltd, Tokyo, Japan). During the super- selective placement, the tip of the catheter was placed directly into the target artery, which enabled all agents to flow into it6,7.

Treatment schedule

In the previous pilot study8, the recom- mended respective total doses of DOC, CDDP, and PEP were 40 mg, 40 mg, and 10 mg/body for patients who had catheter placement in the external carotid artery, and 30 mg, 30 mg, and 10 mg/body for those who had superselective catheter placement. The total dose of 5-FU admin- istered intravenously was 2500 mg/body for both catheter placements. The above total doses of each anticancer drug were administered according to two different time schemes, as described below.
The following 10-day regimen was used for patients who underwent IADCPIVF between 2003 and 2011 (Fig. 1A): via the artery, 15 or 20 mg DOC was admin- istered continuously from day 1 to day 5, and 10 mg PEP was administered contin- uously from day 6 to day 10. In addition, 15 or 20 mg DOC was administered for 3 hours via the artery on day 3, and 15 or 20 mg CDDP on days 4 and 5. Also, 250 mg/ day of 5-FU was administered intrave- nously continuously from day 1 to day 10. In 2012, the treatment period was short- ened to 5 days with no changes in the total dose, in order to lessen the patient’s burden, DOC (30 or 40 mg) was administered con- tinuously from day 1 to day 3, and PEP (10 mg) from day 3 to day 5. In addition, CDDP (15 or 20 mg) was administered on days 2 and 3, and 5-FU (500 mg per day) was given intravenously continuously from day 1 to day 5 (Fig. 1B). A second course of treatment was administered 4 weeks after the first course when necessary.

Radiation therapy

As concurrent radiation therapy, a dose of 30–40 Gray (Gy) was administered early after the introduction of IADCPIVF, even in T2 cases. However, due to the possibility of severe mucositis or bleeding during sur- gery, theapplication of concurrent radiation therapy was limited to cases in which sur- gery was not possible or rejected, and to T3 and T4 cases inwhich invasioninto the bone or muscular layer was prominent.


The response evaluation criteria given in the guidelines for solid tumours of the European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, and National Cancer Institute of Canada were used to determine the treatment effects13. The largest diameter of the tumour was mea- sured before and after IADCPIVF to de- termine the response to treatment. The tumour response was classified as ‘complete response’ (CR), which was complete tumour regression; ‘good partial response’ (gPR), which was a residual tumour of <10 mm; ‘fair partial response’ (fPR), which was a 30% reduction and a residual tumour of 10 mm; or ‘stable disease’ (SD), which was a <30% reduc- tion or <20% increase in the tumour. Surgical procedure Before IADCPIVF, marker points were placed approximately 5 mm from the indurated tumour border (Fig. 2A, B). Re- section of the primary lesion was performed depending on the effect of IADCPIVF, using the following methods, as reported previously10: (1) if the effect was CR, an excisional biopsy was per- formed. The excision margin was inside the marker points and included the muscle layer (Fig. 2C, D). (2) If the effect was gPR, the excision margin was directly on the marker points. For gingival carcinoma, the excision margin was the same as above, and a partial maxillectomy or mar- ginal mandibulectomy was performed. These two methods were considered to be minimally invasive surgeries (MIS). In fPR and SD patients, the resection was performed >5 mm away from the marker points. In all cases, with the exception of gingival carcinoma, the pres- ence or absence of cancer in the muscle layer and mucous membrane margin was confirmed by intraoperative histopatho- logical examination and, if positive, addi- tional resection was performed.

Statistical analysis

The Kaplan–Meier method was used to calculate overall survival (OS) starting from the day the cancer was treated until the patient’s death (due to any cause), and the log-rank test was used to compare survival rates between different patients.

4 Hasegawa et al.

Fig. 2. An actual case of minimally invasive surgery. (A) Macroscopic finding before IADCPIVF. The tumour size was 30 25 15 mm. Marker points were placed approximately 5 mm from the indurated tumour border. (B) Contrast-enhanced magnetic resonance imaging of the tumour in image A; the tumour infiltrates into the muscle layer near the midline. (C) Intraoperative macroscopic findings. A complete response was achieved after IADCPIVF. Thus, an excisional biopsy was performed; the excision margin was inside the marker points and included the muscle layer. (D) Macroscopic findings at 5 years postoperative. There was no dysfunction of swallowing or articulation.
The Cox regression model was used to perform a multivariate analysis of factors affecting OS, including age, cancer site, T classification, N classification, stage, con- current radiation, catheter placement, che- motherapy regimen, clinical tumour response, and MIS. Differences were con- sidered significant when the P-value was <0.05. Results Patient characteristics This study enrolled 141 patients: 85 male and 56 female, with an age range of 27–93 years (median 70 years). Twenty-seven patients were aged 80 years. The sites of oral cancer are shown in Table 1. By T and N classification (Union for Interna- tional Cancer Control (UICC) 2005), 76 patients were diagnosed with T2 disease, 31 with T3, 28 with T4a, and six with T4b; 91 patients were diagnosed with N0 dis- ease and 50 with N1–N3 disease. By stage classification, 59 patients (42%) were di- agnosed with stage II, 34 (24%) with stage III, 41 (29%) with stage IVA, and seven (5%) with stage IVB disease. The observation periods for these patients ranged between 2 and 165 months, with a median of 62 months. One patient who was followed-up for 2 months died of a disease other than OSCC. Four patients were followed-up for less than 24 months: two were unable to visit the hospital because of another medical condition and the other two were trans- ferred to another hospital after more than 12 months of follow-up. Treatment delivery A retrograde intra-arterial catheter was placed in the target position via the STA or occipital artery in all 141 patients. Bilateral IADCPIVF was performed on 17 patients. One course of IADCPIVF was performed in 83 patients and two or more courses in 58 patients. The 10-day regimen was performed for 111 patients and the 5-day regimen for 30 patients. Concurrent radiation therapy was per- formed in 39 (27.7%) of the 141 patients, including seven patients with T2 (9.2%), 12 with T3 (38.7%), 14 with T4a (50%), and six with T4b (100%) disease. After IADCPIVF, 139 patients under- went surgery. Overall, 96 (69.1%) patients underwent MIS, 18 (12.9%) underwent reconstructive surgery, and 25 (18.0%) underwent surgery other than MIS or re- constructive surgery. Two patients refused to undergo surgery. The T classifications of patients who underwent MIS showed that 61 (80.3%) cases were T2, 22 (71.0%) were T3, 10 (35.7%) were T4a, and three (50.0%) were T4b. The T classifications of patients who underwent reconstructive surgery showed that four (5.3%) were T2, one (3.2%) was T3, 12 (42.9%) were T4a, and one (16.7%) was T4b. Among 50 patients with cervical lymph node metastasis, 41 underwent neck dis- section. Twenty-eight of these patients had pathologically positive nodes, while the others had negative nodes. The lesions in seven cases were evaluated as CR after IADCPIVF; therefore, they were only un- der observation. The remaining two patients refused to undergo surgery. Efficacy Treatment efficacy was evaluated for all 141 patients. The primary tumour re- sponse rate was 99.3%; the CR rate was 56.7%, gPR rate was 17.0%, fPR rate was 25.5%, and SD rate was 0.7%. Pathologi- cal CR was found in 64 (46.0%) of the 139 patients (Table 2). The 5-year OS rate was 83.6% in the patients with stage II cancer, 72.7% in those with stage III, 64.8% in those with stage IV, and 74.6% for all stages (Fig. 3A). The cancersite, the 5-year OSratewas 73.4% for the tongue, 55.9% for the floor of the mouth, 75.8% for the lips/buccal mucosa, 82.4% for the maxillary gingiva, and 79.3% for the mandibular gingiva (Fig. 3C). When classi- fied according to treatment efficacy, the 5- year OS rate was 82.5% for CR patients, 82.1% for gPR, and 54.0% for fPR. The rate was significantly higher in the CR and gPR patients than in the fPR patients (P = 0.003 and P = 0.033, respectively) (Fig. 3D). Fur- thermore, according to the surgical method, the 5-year OS rate of the MIS group (80.4%) was significantly higher than that of the non- MIS group (58.9%, P = 0.02) (Fig. 3E). In the multivariate analysis, only the T classification and clinical tumour response were found to have a significant impact on OS; the other factors were not significant (Table 3). Cancer recurrence was found in 49 (34.8%) of the 141 patients. Twenty (14.2%) patients developed arecurrence aris- ing from the primary cancer, 24 (17.0%) developed a recurrence arising from the neck (including secondary cervical lymph node metastasis), and five (3.5%) had distant me- tastasis. Nine of the 20 patients with primary recurrence and 11 ofthe 24 patients with neck recurrence were salvaged (Table 2). Further- more, among the 96 patients who underwent MIS, eight (8.3%) had primary recurrence, six of whom were salvaged. Toxicity There were no adverse events of grade 4 or higher, and no cerebrovascular accidents was no spontaneous bleeding reported. The loss of appetite in 14 (9.9%) patients was mostly due to pain caused by muco- sitis, and most required analgesics. Other events of grade 3 occurred at a low fre- quency. The frequencies of grade 1 and 2 ad- verse events were not low; however, these also improved without an increase in se- verity. In addition, no long-term or late complications including bone marrow, kidney, or pulmonary disorders were found in the patients with long-term ob- servation. Discussion The objective of multi-drug intra-arterial chemotherapy is to effectively administer multiple anticancer drugs in small doses to avoid systemic adverse reactions. This regimen uses synergistic effects from the combination of anticancer drugs to achieve a high anti-tumoural effect. In terms of the synergistic effects of the drugs, CDDP and 5-FU chemotherapy (CF) and DOC, CDDP, and 5-FU chemo- therapy (DCF) have significantly higher synergistic effects and are the standard treatments for advanced head and neck cancer15–17. CDDP and PEP chemothera- py (CP) and CDDP, 5-FU, and PEP che- motherapy (CFP) have also been used to treat head and neck cancer and can have high synergistic effects18. It has been dem- onstrated that an initial administration of CDDP, followed by PEP, offers a strong G2-M phase cytotoxic effect19. IADC- PIVF uses the DCF and CFP treatments and combines them while changing their administration routes and the total dose of each drug, which is less than half of the total dose in these intravenous administra- tion regimens15–18. Currently, intra-arterial chemotherapy is widely used in combination with radical radiation treatment, in which the total radiation dosage is more than 60 Gy, sim- ilar to that in RADPLAT. In intra-arterial chemoradiotherapy by retrograde catheter approach, Fuwa et al.6 reported 5-year OS rates of 62.9% for stage III OSCC and 45.3% for stage IV OSCC, using the con- tinuous infusion of low-dose carboplatin or CDDP. Mitsudo et al.7 also reported a high 5-year OS rate of 71.3% for the treatment of stage III and IV OSCC using low-dose DOC and CDDP. Thus, the ef- fectiveness of intra-arterial chemora- diotherapy by retrograde catheter approach has been demonstrated, because a technique to place a catheter into the target artery directly has been established, making it possible to efficiently provide a continuous administration of anticancer drugs. In contrast, according to the National Comprehensive Cancer Network guide- lines20, the standard treatment for resect- able oral cancer is to perform radical resection and postoperative chemora- diotherapy on high-risk patients. The reported 5-year OS rates according to the cancer stage of patients who have undergone this standard treatment are 61–77% for stage III and 47–60% for stage IV disease21–25. Regarding surgical treat- ment, most patients with stages T3 and T4 disease require reconstructive surgery af- ter radical resection, because of the pres- ence of large tissue defects26. However, there are restrictions when applying recon- structive surgery in the elderly or in patients with generally poor physical described above, because the efficacy of IADCPIVF alone was favourable. Preoperative or induction chemothera- py is performed to preserve organ func- tion and improve survival. In a randomized controlled trial of CF and a randomized phase III study of DCF for resectable OSCC, CR rates were 33% for T2–T4 and 8.1% for T1–T4, respective- ly27,28. Although both studies failed to show an improvement in survival, their results demonstrated that clinical and pathological responses were significant prognostic factors, suggesting that down-staging of the tumour by therapy led to less demolitive surgery. Kirita et al.29 also suggested that MIS could be performed in patients who achieve a good response to preoperative intra-arte- rial chemoradiotherapy (40 Gy) using CDDP or carboplatin in combination with PEP or 5-FU. In the current study, multivariate anal- ysis showed that CR and gPR were good prognostic factors; the CR rate was 56.7%, which is much higher than those reported for CF and DCF therapy. Furthermore, MIS was performed on patients with CR and gPR to IADCPIVF. As a result, the recurrence rate at the primary site was 8.3%, suggesting that radical resection was possible even with MIS, and function- al loss could be minimized. In contrast, only 12.9% of all patients and 21.5% of patients with stage T3–T4 disease under- went reconstructive surgery, suggesting the possibility that reconstructive surgery could be avoided depending on the effect of IADCPIVF. Regarding adverse events, in reports on RADPLAT used for the treatment of head and neck cancer, cerebrovascular acci- dents occurred in 3.3–8.2% of all patients and death during treatment occurred in 2.8–3.8%2,3,30. Similarly, serious adverse reactions occur frequently when high-dose CDDP is used in combination with defini- tive radiation therapy. In IADCPIVF, no cerebrovascular acci- dents occurred using the retrograde cathe- ter approach, indicating a lower risk of such accidents. The general adverse reac- tions were low in intensity. This might be attributed to the small total dose of each health, and the postoperative functional decline is concerning even when the free flap reconstruction is performed success- fully. The results of IADCPIVF and surgical treatment in the current study showed that the 5-year OS rate was 72.7% for patients with stage III cancer and 64.8% for patients with stage IV. These results are not inferior to those of intra-arterial che- moradiotherapy and standard surgical and postoperative radiation treatment. IADC- PIVF was used as the preoperative treat- ment; therefore total radiation dosages of 30 to 40 Gy were administered. While the CR rate is expected to improve in combi- nation with radiation therapy, the occur- rence of severe stomatitis might increase. Therefore, the application of IADCPIVF with radiation therapy was limited, as drug in the IADCPIVF regimen. There- fore, the treatment was successfully com- pleted in elderly patients aged 80 years. Local adverse reactions included intensive mucositis at the treatment site; however, no cases showed signs of increased sever- ity, such as spontaneous bleeding, al- though an analgesic was mostly required. Furthermore, taste disorder or xerostomia did not occur, and quality of life was thus maintained, especially in the group treated without radiation. There are some possible limitations in the present two-institution study. First, short-term follow-up might have affected the treatment outcome. Second, because this was a retrospective study, controlled studies are needed as a matter of course to verify the competitive advantage of IADCPIVF compared with other thera- pies, including RADPLAT. In conclusion, the present study demon- strated that IADCPIVF is safe and effica- cious for the treatment of OSCC. When employed as a preoperative treatment, MIS could possibly reduce the extent of primary tumor resection with remarkably good response, and reconstructive surgery could be avoided depending on the effec- tiveness of the treatment, leading to less demolitive surgery. 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