Japanese Journal of Clinical Oncology Advance Access originally published online on October 23, 2006
Japanese Journal of Clinical Oncology 2006 36(12):822-826; doi:10.1093/jjco/hyl111
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© 2006 Foundation for Promotion of Cancer Research
A Novel Approach to Advanced Carcinoma of the Tongue: Cases Successfully Treated with Combination of Superselective Intra-Arterial Chemotherapy and External/High-Dose-Rate Interstitial Radiotherapy
1 Laboratory of Radiation Therapy, Department of Health Science, School of Medicine
2 Department of Otolaryngology, Head and Neck Surgery, School of Medicine
3 Department of Radiology, School of Medicine
4 Department of Radiology, School of Dentistry, Hokkaido University, Sapporo, Japan
For reprints and all correspondence: Takeshi Nishioka, Laboratory of Radiation Therapy, Department of Health Science, School of Medicine, Hokkaido University, N12 W5, Kita-ku, Sapporo, Japan. 060-0812. E-mail: trout{at}radi.med.hokudai.ac.jp
Received May 20, 2006; accepted August 5, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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OBJECTIVE: This study sought to evaluate the efficacy and safety of a novel treatment regimen, intra-arterial cisplatin infusion plus external/high-dose-rate radiotherapy.
METHODS: Superselective intra-arterial infusion of cisplatin (100–120 mg) was performed concomitantly with external radiotherapy in four patients with locally advanced carcinoma of the tongue. A high-dose-rate brachytherapy boost was performed after combination therapy in all patients. Brachytherapy was performed after external radiotherapy, and the treatment schedule was twice daily, with a fraction of 600 cGy up to a total of 30–48 Gy.
RESULTS: All patients completed the therapy as scheduled. There were no vascular or neurological complications. Grade III acute radiation mucositis developed in all patients but this did not necessitate a treatment break. With a mean follow-up period of 35 months, loco-regional control was obtained for all patients.
CONCLUSIONS: The combination of weekly administration of intra-arterial cisplatin plus external/high-dose-rate radiotherapy seems effective for advanced carcinoma of the tongue.
Key Words: intra-arterial chemotherapy • high-dose-rate brachytherapy • carcinoma of the tongue
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Carcinoma of the tongue can be treated with partial resection or brachytherapy if the tumor is small (1). For advanced disease, extended surgery is generally considered the only curative treatment. However, even experienced surgeons find it difficult to achieve satisfactory overall survival for such cases (2). Loco-regional recurrence is highly distressing, and distant metastasis is not uncommon.
Interstitial brachytherapy (low-dose-rate) is an alternative for such advanced diseases, but even in experienced brachytherapy centers local control of advanced disease is unsatisfactory; up to 30–50% of patients experience local recurrence (3,4). High-dose-rate brachytherapy (HDR) has recently become available and good results have been reported for early stage disease (5,6), but achieving a high local control rate for advanced disease is still difficult (7). To our knowledge, the highest local control rate with HDR is 71% for T3 cases (at 3 years, n=14), reported by the Osaka University group (8); with a 3-year overall survival rate of 57%, three out of the 14 patients (21%) in their study developed soft-tissue necrosis. The typical dose fractionation regimen used was external radiotherapy of 36 Gy in 18 fractions followed by an interstitial boost of 48 Gy in eight fractions (twice daily). The total BED (biologically effective dose: nxdx(1+d/(
/ß)); d, dose per fraction; n, total fractions) of their regimen was around 264 Gy2 assuming /ß of 2 for late-responding tissue. Considering the high BED, the necrosis rate is understandable but still acceptable given the high rate of local control.
In order to achieve high local control with a lesser degree of toxicity, we started to treat advanced cases with a combination of intra-arterial chemotherapy (weekly administration of 100 mg/m2 cisplatin) concurrent with external radiotherapy and a subsequent HDR boost. Total BED was kept below 260 Gy2 in the hope of lowering toxicity. Despite the inclusion of T4 cases, good treatment results were obtained.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Four patients with newly diagnosed stage III–IV (UICC 2002) tongue cancer were treated under our new protocol. The inclusion criteria were large T3 or T4 patients without distant metastasis who refused radical surgery. Patients with tumor extension into the lower gum were excluded. Patient characteristics are summarized in Table 1. Written informed consent was obtained from all patients. The treatment schedule varied to some extent, taking patient condition into consideration; however, the underlying principle was the same (Fig. 1 and Table 1).
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Intra-Arterial (IA) Chemotherapy
Cisplatin (100–120 mg/m2) was infused through a microcatheter placed angiographically to selectively encompass only the dominant blood supply of the targeted tumor (Fig. 2b). In patients with suspicious nodes greater than 2 cm, some of the drug (approximately 20–30 mg) was delivered directly to the region. Cisplatin was injected as rapidly as possible until it refluxed slightly into the more proximal vessels during peak systole. Simultaneously with the cisplatin, sodium thiosulfate (20–24 g) was given intravenously. All arterial catheterizations were accomplished transcutaneously through the femoral artery, and the catheters were removed immediately after infusion. Hydration was started 4 h before IA chemotherapy and a total of approximately 8 l of lactated Ringer's solution was given over a period of 24 h to reduce renal toxicity. A 5HT3-receptor antagonist was given to all patients before arterial infusion to minimize nausea and vomiting.
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External Radiotherapy (ERT)
Patients received a total of 30–50 Gy in 15–20 fractions. Two Gy was given five times a week. The primary and bilateral level I–II nodal areas were irradiated using parallel opposed fields, and bilateral level III–V areas using an anterior–posterior field. All patients were treated with a 6 MV linear accelerator machine.
High-Dose-Rate Interstitial Brachytherapy (HDR)
The general outline of HDR was determined on the basis of weekly examinations during ERT. The median period between the completion of ERT and HDR was 11 days (range, 10–16 days). Patients were given a tracheostomy followed by insertion of catheters designated for HDR. All procedures were carried out under general anesthesia. The catheters were placed with a metal guidance needle which was inserted from the submandibular area into the dorsal part of the tongue (Fig. 2c,d). The needles were carefully arranged to cover the palpable tumor. MR images were also used for estimation of tumor volume and shape. The needles were then replaced with nylon HDR applicators. Figure 3 shows the dose distribution of a patient with T4a cancer (case 1). The dose (600 cGy/fraction) was prescribed at the surface of the tumor in all cases. HDR was carried out twice a day using a micro-Selectron HDR (Nucletron-Oldelft, The Netherlands). For each HDR treatment session, a spacer was placed between the lateral border of the tongue and the lower gum to reduce the dose to the mandible. At least 6 h separated daily treatment sessions.
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Management of Clinically Suspicious Nodal Disease
Neck dissection was performed for patients with persistent nodal disease after radiation mucositis had subsided.
Assessment of Tumor Response and Adverse Side Effects
Tumor response was evaluated both at the time of HDR catheter insertion, to evaluate the effect of IA chemotherapy plus ERT, and 2 months after the completion of HDR. A complete response was defined as the disappearance of tumors for more than 4 weeks, and a partial response as 50% or greater decrease in tumor size. Adverse side effects were assessed according to the Common Toxicity Criteria version 2.0.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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A summary of the results is shown in Table 1. All patients completed therapy as scheduled. There were no vascular injuries associated with the angiography and cisplatin injections. Grade III radiation mucositis developed in all patients, but oral intake was initiated after a median of 25 days (range: 15–38 days) after the completion of HDR. In case 2, a small ulcer developed in the floor of the mouth 3 months after the completion of HDR, but this did not prevent her from oral intake. The other patients have not demonstrated any signs of mandible or soft tissue necrosis during the follow-up period. As for haematologic side effects, Grade III leukopenia developed in two cases and Grade II in another two. Nausea and vomiting were tolerable for most of the patients with Grade I in only one patient.
At the time of HDR catheter insertion, a partial response was obtained for the primary tumor in all patients. At 2 months after the completion of HDR, all patients achieved a complete response for the primary tumor. As for nodal diseases, cases 1 and 2 underwent neck dissection and viable tumor cells were observed in the clinically suspected nodes. During the mean follow-up period of 35 months, one patient died of distant metastasis and the rest are disease-free at present. Loco-regional control was obtained for all patients. A patient with T4aN2b (case 1) has survived 5.8 years after treatment without any sign of disease or complications. Although atrophy is observed in the HDR-treated tissue (Fig. 2e), the mobility of her tongue is only slightly impaired and the patient has no complaints.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Advanced cancers often have multiple nodal metastases (1,9,10) and the loco-regional recurrence rate is high (1). Metastasis can develop in the retropharyngeal nodes, a condition which causes a great deal of suffering (11). Nevertheless there have been few options other than surgical resection.
However, this situation may be changing. Intra-arterial (IA) chemotherapy, which was originally introduced by Robbins et al., has proven effective for advanced head and neck cancers. In their report, a high loco-regional control rate (66% at 1 year and 57% at 2 years) and a high overall survival rate (72% at 1 year and 63% at 2 years) were achieved for T4 head and neck cancers (12). Half (52%) of their patients suffered from oropharyngeal carcinoma, which might have been related to their good results. In our facility, IA chemotherapy combined with radiotherapy is becoming a standard treatment for patients with T4 head and neck cancers who are medically inoperable or refuse surgery. This treatment policy is based on our experience of favorable results for T3–4 patients (nasal or paranasal sinuses were the most common primary sites) (13).
The issue here is whether we should simply apply IA chemotherapy for advanced carcinoma of the tongue. Such studies are still limited in number (14,15), but favorable preliminary results have been reported. Hirai et al. treated 22 stage III–IV patients with oral cavity cancer (tongue, n=12) with 2–3 weekly IA administrations of cisplatin (30–40 mg/m2), followed by surgery or external radiotherapy. They reported an estimated overall survival of 91% for patients who underwent surgery, with a median follow-up period of 20 months (14). Robbins et al. treated 25 oral cancer patients (T3, n=20; T2, n=5; tongue primary, n=20) with 4 weekly IA infusions of cisplatin (150 mg/m2) concurrent with external radiotherapy followed by surgery. With a median follow-up period of 56 months, the local control rate for those patients was 74% (15). Furutani et al. used carboplatin (median dose, 460 mg) for continuous IA infusion in 39 advanced tongue cancer patients (stage II, n=10; III, n=15; IV, n=5; and recurrent cases, n=9). The chemotherapy was used concomitantly with external radiotherapy (ERT), and 21 of those patients were treated with low-dose-rate brachytherapy after ERT. A 3-year progression-free survival of 53.2% was obtained for those patients (16).
Similar to Furutani's approach, our goal was not only local control but organ preservation. Cosmetic changes of the face and the neck that would be expected in extended surgery are of great concern for young female patients, and was one of the main reasons why cases 1, 2, and 3 rejected surgery. Considering the risk of late radiation effects, particularly soft tissue/mandible necrosis, we carefully chose the irradiation dose (BED) (Table 1). These BEDs are lower than those used by the Osaka group, which may be why we had a relatively low complication rate despite weekly IA chemotherapy. Most importantly, all cases of T4 disease were controlled by our regimen, highlighting the effectiveness of combination therapy.
As to the rationale for using IA chemotherapy for carcinoma of the tongue, there are several points. First, tumors are usually supplied by single large artery, making it easy for interventional radiologists to insert a microcatheter and inject a large dose of cisplatin. Second, because of the relatively large diameter of the artery, injury caused by catheter tip movement during angiography is rare. Third, by incorporating IA chemotherapy into a radiation regimen, the external and brachytherapy doses can be reduced, therefore reducing mandibular complication. Recently, several groups reported that IA chemotherapy plus ERT was effective even for metastatic lymphnodes (17,18).
In conclusion, ERT with weekly IA cisplatin infusions, followed by HDR brachytherapy boost resulted in good loco-regional control in three out of four patients with advanced carcinoma of the tongue. Further study with more patients will be needed to fully evaluate this new type of regimen, particularly regarding long-term efficacy and toxicity.
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Acknowledgments |
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This study was supported by a Grant-in-Aid for Scientific Research (B18390325), which was provided by the Ministry of Education, Science and Culture of Japan.
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References |
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