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Continuous selective intraarterial chemotherapy in combination with irradiation for locally advanced cancer of the tongue and tongue base
Oral Oncology 38 (2002) 145–152 www.elsevier.com/locate/oraloncology
Continuous selective intraarterial chemotherapy in combination with irradiation for locally advanced cancer of the tongue and tongue base K. Furutani a,b,*, N. Fuwa a, T. Kodaira a, A. Matsumoto a, M. Kamata a, H. Tachibana a, H. Sakahara b a Department of Radiation Oncology, Aichi Cancer Center Hospital, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Department of Radiology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, Shizuoka 431-3192, Japan
b
Received 17 January 2001; accepted 5 March 2001
Abstract We retrospectively evaluated the results of the concurrent combination therapy of selective continuous intraarterial chemotherapy and radiotherapy in 39 patients with locally advanced cancer of the tongue and tongue base between September 1992 and January 2000. Thirty patients were fresh cases (stage II, 10 patients; stage III, 15; stage IV, five) and nine were recurrent cases. The primary lesion was present in the mobile tongue in 33 patients and the tongue base in six. External irradiation (median dose, 48.6 Gy) was performed in all patients, and interstitial brachytherapy using an Au grain or Cs needle (median dose, 50 Gy) in 21. In intraarterial chemotherapy, a catheter was selectively inserted into the lingual artery via the superficial temporal artery, and carboplatin (CBDCA) was continuously infused (median dose, 460 mg/m2) concurrently with radiotherapy. In 13 patients with cervical lymph node metastasis, two courses of systemic chemotherapy with 5-FU (700 mg/m25 days) and cisplatin (40–50 mg/m22 days) or its analog was also performed. In 37 (94.9%) of the 39 patients in whom this combination therapy was completed, the response rate was 94.6%. The 3-year local control rate, progression-free survival rate, and overall survival rate by Kaplan–Meier’s method were 79.2, 53.2, and 58.9%, respectively. This combination therapy was effective for locally advanced cancer of the tongue and tongue base without causing severe adverse side effects, and a local control rate comparable to that by surgery can be expected. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Head and neck neoplasms; Tongue neoplasms; Tongue; Infusion; Intraarterial; Intraarterial injection; Carboplatin; Radiotherapy
1. Introduction During the past 20-year period, the treatment for locally advanced cancer of the tongue and tongue base has shown marked changes, such as advances in reconstructive surgery. However, the treatment results have only slightly improved. The standard treatment for locally advanced cancer of the tongue and tongue base is surgery, which is frequently extensive. Surgery has the greatest potential for cure. Therefore, many patients undergo extensive surgery, but they should compromise on postoperative marked dysfunction and a decrease in the quality of life. * Corresponding author. Tel.: +81-52-762-6111; fax: +81-52-7528390. E-mail address: [email protected] (K. Furutani).
Radiotherapy has long been used in this field, but the results of radiotherapy performed alone for locally advanced cancer have been poor. Therefore, radiotherapy is usually performed for a palliative intent or in combination with surgery. Another therapeutic option is intraarterial chemotherapy. This method has marked transient local effects, but its therapeutic power is inadequate in terms of control of advanced cancer. Each of the two therapeutic modalities has inadequate effects when performed alone. However, treatment results can be improved by the effective combination of the two methods that allow preservation of the organ. To obtain maximum effects of each method, we took the following measures. (1) It is not the conventional non-selective intraarterial infusion, but the selective infusion that is performed, by inserting a catheter to the lingual artery. (2) The catheter
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is inserted for a long period for continuous drug infusion. (3) Radiotherapy is performed concurrently with intraarterial chemotherapy. We consider that this combination of intraarterial chemotherapy and radiotherapy has potential for improving treatment results with preservation of the organ. At our hospital, the combination of selective continuous intraarterial chemotherapy and radiotherapy has been performed since August 1992 for preservation of the organ and improvement of treatment results in patients with locally advanced head and neck cancers who cannot undergo surgery for certain reasons. Between August 1992 and May 1997, phases I and II studies [1] on the combination of radiotherapy and selective continuous intraarterial chemotherapy with CBDCA was performed. As a result, the local control rate for cancer of the tongue and tongue base was significantly better than that for cancer in other head and neck cancers. This suggested that cancer of the tongue and tongue base among cancers in the head and neck region is an especially good indication for this combination therapy. In this study, patients with cancer of the tongue and tongue base were extracted from about 130 patients with advanced cancer in the head and neck cancers who underwent this combination therapy between September 1992 and January 2000, and its effects and results were evaluated.
2. Patients and methods 2.1. Patients characteristics The subjects were 39 patients with locally advanced cancer of the tongue and tongue base who underwent the combination of radiotherapy and continuous selective intraarterial chemotherapy at the department of radiation oncology, Aichi Cancer Center Hospital between September 1992 and January 2000 (Table 1). The primary lesion was located in the tongue in 33 patients and the tongue base in six. There were 30 males and nine females aged 36–86 years (median, 68 years). Thirty patients were fresh cases, and nine were recurrent cases (five patients with recurrence after surgery and four with recurrence after radiotherapy). Staging was performed according to the TNM Classification of the UICC, 5th edition [2]. Of the 30 patients with fresh cancer, 20 showed stage III–IV, and eight showed N(+). Of the nine patients with recurrent cancer, six showed rT3 or more. For staging, visual examination, palpation, CT, and MRI were performed, and pharyngeal fiberscopy was also performed in patients with cancer of the tongue base. Distant metastasis was evaluated by chest radiograph, abdominal CT, and bone scintigraphy. Surgery was not performed because of patient refusal in 17 patients, advanced age in 10
patients, and advanced cancer for which surgery was considered to be impossible by surgeons in six, poor general condition in four, and coexistent of another cancer in two. 2.2. Patients selection criteria Patients fulfilling all the following criteria were entered into this study: (1) primary lesion 5 large T2 (large T2: lesions with a diameter of 3 cm or more and a thickness of 15 mm or more); (2) cervical lymph node metastasis 4 N2; (3) absence of distant metastasis; (4) definite histopathological diagnosis of squamous cell carcinoma made by biopsy; (5) performance status (PS) of 0–3 according to the Eastern Cooperative Oncology Group criteria (ECOG criteria) [3]; and (6) acquisition of written informed consent for this treatment. 2.3. Treatment methods 2.3.1. Intraarterial chemotherapy Catheterization was performed by the method of Shimizu et al. [4] Under local anesthesia, preauricular region on the affected side was incised, and the superficial Table 1 Patient characteristics
n
Age (years) Median Range
68 36–86
Performance status (ECOG) 1 2 3 Gender Male Female Primary site Tongue Tongue base Fresh case Stage II T2N0:10 III T2N1:3 T3N0:9 T3N1:3 IV T3N2:4 T4N1:1 Recurrent case rT2N0:3 rT3N0:3 rT4N0:1 rT4N2:2
21 16 2
30 9 33 6 30
10 15
5
9
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temporal artery was exposed. Under fluoroscopic guidance, a hook shaped catheter (Medikit Corp., Tokyo, Japan; Fig. 1) was selectively inserted into the lingual artery using a Radifocus guidewire with a diameter of 0.014 inches (Terumo Corp., Tokyo, Japan). In the patients treated before 1998, the hook shaped catheter was indwelled, and continuous intraarterial chemotherapy was performed. However, catheter dislocation was often observed during continuous intraarterial chemotherapy. Therefore, in recent years, we have replaced the hook type catheter by a straight catheter with a 15-cm tapered tip (Fig. 1; ANTHRON P-U: Toray Industries, Inc., Japan) by the guidewire exchange method, inserting the straight type deep into the lingual artery (Fig. 2). In nine patients with a tumor extending beyond the mid-line, catheters were inserted into the bilateral lingual arteries. After guiding the catheter tip into an appropriate position, the catheter was fixed in the skin at three sites around the ear by ligation with nylon thread.
Fig. 1. The three catheters from the left are hook shaped nylon catheters (length, 50-cm; external diameter, 4 Fr) for selective catheterization into the lingual artery. To prevent arterial intimal injury, a soft tip (length, 3-cm) is applied to the catheter tip. There are three curve types of the catheter tip. The straight type catheter on the right side (length, 50-cm; external diameter of the shaft, 5 Fr) has a gradually tapered tip (15 cm) and can be deeply inserted into the lingual artery. This catheter is made of polyurethane, and its surface is coated with heparin resin to prevent thrombosis.
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CBDCA alone was used in intraarterial chemotherapy in all patients excluding one. The daily dose of CBDCA was 15–20 mg/body, and the recommended total dose was 460 mg/m2, which was determined in our phase 1 study [1], in patients treated during the early period. After 1995, since patients with poor renal function and poor PS were also included into the subjects, the total administration dose was determined using the target area under the free carboplatin plasma concentration versus time curve (AUC) according to Calvert’s formula [5]. The total administration dose was AUC 8 in patients who did not undergo systemic chemotherapy and AUC 6 in those who also underwent systemic chemotherapy. The total CBDCA dose per body surface area that was actually administered was 360–780 mg/m2 (median, 460 mg/m2). In only one patient with chronic renal failure on hemodialysis, was the CBDCA dose reduced to 125 mg/m2, to reduce the risk of aggravation of the side effects of CBDCA, and tetrahydropyranyladriamycin (33 mg/m2; THP: MEIJI SEIKA KAISHA, Ltd., Japan) as an analog of adriamycin was used in combination with CBDCA. The drugs were infused using an electrical portable pump (CADD-PCA, Deltec Smiths Industries, USA). Intraarterial chemotherapy was initiated within 1 week after the initiation of radiotherapy, and continuous infusion was performed during the radiotherapy period (including brachytherapy period; Fig. 3).
Fig. 2. Flow check DSA. A flow check DSA in a 80-year-old male with cancer of the tongue base (T3N0M0) in whom a straight tapered catheter was inserted into the left lingual artery. No branches except for a lingual artery were visualized, confirming distribution of the drug only into the lingual artery.
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2.3.2. Radiation therapy External irradiation using 6 MV linear X-rays was performed five times a week at 1.8 Gy per fraction. Parallel opposed lateral fields technique was used until a dose of 36–40 Gy. Thereafter, the irradiation field was reduced, and oblique two opposite ports or the conformation method was used. The total dose on the primary lesion was 27–74 Gy (median, 48.6 Gy). This marked variation in the total dose was because the total dose was determined after determining whether brachytherapy was possible and whether radiotherapy was performed in previous treatment in each patient. In the patients with cervical lymph node metastasis, 6 MV X-rays were used alone or in combination with electron beams with various energies to perform irradiation at a total dose of 64–74 Gy (median, 70 Gy). In the 21 patients in whom brachytherapy was possible, external irradiation was performed at a local dose of about 40–50 Gy, followed by interstitial irradiation using an Au grain (14 patients) or a Cs needle (six) or their combination (one) at a dose of 30–60 Gy (median, 50 Gy). 2.3.3. Systemic chemotherapy In the 13 patients with cervical lymph node metastasis, systemic chemotherapy was also performed; 5-FU and cisplatin (CDDP) were used in seven patients and 5FU and nedaplatin (SHIONOGI & Co., Ltd, Osaka, Japan) [6] as a CDDP analog, in the other six. Continuous intravenous infusion of 5-FU was performed at 700 mg/m2/day from day 1 to 5 (total dose, 3500 mg/ m2), and continuous drip infusion of CDDP at 40–50 mg/m2/day from day 6 to 7 (total dose, 80–100 mg/m2). Nedaplatin was intravenously drip infused over 6 h at 120–140 mg/m2 on day 6.
As shown in Fig. 3, alternating chemoradiotherapy in which anticancer chemotherapy was alternated with radiotherapy was performed first. Intraarterial chemotherapy was initiated after discontinuation of the second systemic chemotherapy and performed concurrently with radiotherapy. In the patients treated including systemic chemotherapy, the total CBDCA dose was AUC six. 2.3.4. Assessment 2.3.4.1. Catheterization technique and treatment completion rate. The technical catheterization success rate, catheter dislocation rate from the lingual artery, intraarterial chemotherapy completion rate, and the presence or absence of catheter-related complications were evaluated. Completion of intraarterial chemotherapy was defined as administration of 80% or more of the planned drug dose. 2.3.5. Adverse side effects Adverse side effects were assessed according to the standard World Health Organization (WHO) criteria [7]. The two patients in whom intraarterial chemotherapy could not be completed were excluded. The evaluation parameters were peripheral blood cell count, liver function, renal function, oral mucositis, and nausea/vomiting. Blood biochemical examination was performed once weekly, and peripheral blood counts were measured two–three times weekly. Complications due to the indwelling catheter were also evaluated. 2.3.6. Assessment of treatment results Treatment results were evaluated 1 month after discontinuation of treatment. The two patients in whom treatment was not completed were excluded from the
Fig. 3. Two protocols of the combination therapy of continuous arterial infusion chemotherapy and radiotherapy. (a) No systemic chemotherapy group: intraarterial chemotherapy is performed concurrently with radiotherapy. (b) Systemic chemotherapy group: intraarterial chemotherapy starts after the second systemic chemotherapy. Ext.RT, external radiotherapy; Brachy, interstitial brachytherapy; CT, systemic chemotherapy.
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assessment of treatment results. Visual examination, palpation, CT, and MRI were performed, and the effects were recorded according to the WHO response criteria [7]. A complete response (CR) was defined as the absence of tumor for 4 consecutive weeks or more, and a partial response (PR) as a reduction in a cross-section of the tumor to 50% or less. No change (NC) was defined as a tumor cross-section reduction rate of less than 50% or an increase in the tumor diameter. As statistical analysis, the local control rate, progression-free survival rate, overall survival rate were analyzed by Kaplan–Meier’s method [8]. In each analysis, calculation was made from the initiation day of treatment. In the calculation of the local control rate, cases without local recurrence were regarded as censored cases. In the calculation of both the progression-free survival rate and overall survival rate, all deaths were regarded as deaths irrespective of the causes of death. Statistical differences were analyzed by the log rank test [9].
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25%). All dislocated catheters were reinserted as soon as its discovery, and selective intraarterial chemotherapy was resumed in all cases. Intraarterial chemotherapy was completed in 37 of the 39 patients (completion rate, 94.9%). In the other two patients, intraarterial chemotherapy was discontinued due to patient’s refusal and aggravation of the general condition caused by progression of metastatic neck disease, respectively. 3.2. Adverse effects 3.2.1. Catheter-related complications Concerning catheter-related troubles, incomplete obstruction of the lingual artery was observed in two patients (5.1%), and its cause was thrombosis due to catheterization. In both patients, infusion of urokinase resulted in recanalization, and subsequent intraarterial chemotherapy could be completed without problems. No major complications such as neurological complications and massive bleeding developed in any patient.
3. Results 3.1. Catheter performance and treatment completion rate In nine of the 39 patients showing tumor invasion beyond the mid-line, catheters were bilaterally inserted. Thus, selective catheterization into the lingual artery was performed a total of 48 times in 39 patients, and catheterization could be successfully performed only by one operation in all cases. The placement period of the 48 catheters was 18–96 days (median, 37 days), during which 12 catheters were dislocated from the lingual artery (dislocation rate,
3.2.2. Infused drug-related adverse effects Adverse effects related to intraarterial chemotherapy were evaluated in the 24 patients who completed intraarterial chemotherapy and did not undergo systemic chemotherapy. As Grade 3 or more adverse effects, leukopenia was observed in three patients (12.5%) thrombocytopenia in two (8.3%), and oral mucositis in one (4.2%). The patient who developed oral mucositis had undergone intraarterial chemotherapy with CBDCA combined with THP. In the patients treated with CBDCA alone, no Grade 3 or more mucositis was observed. The other parameters such as
Fig. 4. Local control rate (3 years) by Kaplan–Meier’s method. Fresh cases, 87.8%; all cases, 79.2%; recurrent cases, 50%.
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Fig. 5. Progression free survival (3 years) by Kaplan–Meier’s method.
the amount of hemoglobin or results of renal and liver function tests showed Grade 2 or less.
(Figs. 5 and 6), showing no significant difference between the patients with fresh and recurrence.
3.3. Treatment results 4. Discussion The follow up after treatment was performed until death or recurrence was confirmed in all patients. The observation period was 9–94.9 months (median, 26.5 months). Treatment effects were assessed 1 month after discontinuation of treatment in the 37 patients who completed intraarterial chemotherapy. CR was observed in 31 patients (83.8%), PR in four (10.8%), and NC in two (5.4%); the response rate (CR+PR) was 94.6%. In November 2000, local control was maintained in 30 patients (three patients had died of another disease). Local recurrence was observed in seven patients, of whom three underwent salvage operation. In two of the three patients, local control was achieved, but the other had recurrence after salvage operation and died of progression of the primary lesion. Two patients with local recurrence underwent no additional treatment and died of progression of the primary lesion. One patient with local recurrence underwent palliative radiotherapy, and the other with local recurrence was treated by radiotherapy and systemic chemotherapy, but both patients died of disease progression. Fig. 4 shows the 3-year local control rate calculated by Kaplan–Meier’s method. The local control rate was 79.2% in all patients, 87.8% in patients with fresh cancer, and 50.0% in those with recurrent cancer, showing a significant difference between fresh and recurrent groups (P=0.007). Late lymph node recurrence was observed in eight patients and distant metastasis in five. The 3-year progression-free survival rate and the 3-year overall survival rate were 53.2 and 58.9%, respectively
The history of intraarterial chemotherapy for head and neck cancers is relatively long. Klopp et al. [10] was the first to report fractional intraarterial infusion of nitrogen mustard in 1950. After that, Sullivan et al. [11] reported continuous intraarterial infusion of methotrexate in 1959. Subsequently, various improvements have been made, and marked local effects of intraarterial chemotherapy mainly as adjunctive therapy for advanced and recurrent cancer have been reported [12–16]. Intraarterial chemotherapy is theoretically advantageous in a high drug concentration in the lesion and reduced systemic toxicity of drugs compared with systemic chemotherapy. There have also been profound basic studies on the pharmacokinetics in intraarterial chemotherapy [17]. However, this method has not yet been widely accepted. This is because of a rather complicated procedure, catheter-related complications, and limitations in its usefulness since non-selective infusion via the external carotid artery was performed in conventional intraarterial chemotherapy. In the 1990s, since selective catheterization into the target artery became possible, attention began being paid again to intraarterial chemotherapy for locally advanced head and neck cancers. There are two methods of selective intraarterial chemotherapy. One is one shot intraarterial infusion by the conventional angiographic procedure, and the other is continuous intraarterial chemotherapy via the superficial temporal artery. One shot intraarterial chemotherapy has actively been
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Fig. 6. Overall survival (3 years) by Kaplan–Meier’s method.
studied by Robbins et al. Recently, they obtained good results by their new method in which weekly high dose CDDP infusion (150mg/m24 times/4 weeks) in combination with intravenous sodium thiosulfate (CDDP neutralizer) infusion [18–22]. On the other hand, intraarterial chemotherapy via the superficial temporal artery also used in this study was developed by Shimizu et al. [4]. By this method, continuous administration is possible, and the synergistic effects of its concurrent combination with radiotherapy can be expected. In addition, due to a low daily dose, this method can be also used in aged patients or patients with a poor PS. However, since the infusion time is long, the catheter is sometimes dislocated from the target artery. In this study, catheter dislocation was observed in 25%. At present, to reduce the incidence of catheter dislocation, we insert a tapered tip catheter into a more distal portion of the lingual artery as described above; though only nine patients in this study were treated using this catheter, and only one showed catheter dislocation. With this new technique, the catheter dislocation problem may be considerably overcome. In this study, the response rate was satisfactory (94.6%). Most previous studies on selective intraarterial chemotherapy for head and neck cancers have shown response rates of about 90% [4, 20–24]. Our results were comparable with or better than these reports. Fein et al. [25] reported a local control rate of 45% for T3 and 0% for T4 even after a short follow-up period (2 years) in patients treated by radiotherapy alone. On the other hand, higher local control rate can be expected by surgery (with or without postoperative radiotherapy) than by radiotherapy alone. Although the operation results have large difference by institutions,
Fein et al. [25] reported 2-year local control rates by surgery of about 82 and 67% for T3 and T4, respectively. Yuen et al. [26] reported 5-year local control rates of 74 and 54% for T3 and T4, respectively. Though our results can not directly been compared with these results, the local control rate was 79.2% in all patients, and 81.5% for T3 in this study. Our subjects included those with recurrent cancer, nevertheless, our results were comparable with surgical results. Though the number of patients is still low, and the observation period is short, this combination therapy is attractive in patients who cannot be surgically treated for certain reason in terms of not only local control but also the quality of life. CBDCA was used in intraarterial chemotherapy because this drug induces only negligible mucositis and infrequently causes renal impairment. When intraarterial chemotherapy is combined with radiotherapy, radiotherapy-induced mucositis is unavoidable, and CBDCA that does not aggravate mucositis is advantageous. Patients undergoing intraarterial chemotherapy often have renal impairment, but the dose of CBDCA can be determined by Calvert’s formula even in the presence of renal impairment. The degree of the blood toxicity of CBDCA was also feasible. However, in this study, the progression-free survival rate and overall survival rate were not satisfactory. Late neck recurrence or distant recurrence were observed about 30%. For further improvement in long-term prognosis, certain measures for these problems are necessary. Therefore, since 1997, we have been carrying out phase I, II studies on the combination of systemic chemotherapy with 5-FU and nedaplatin, intraarterial chemotherapy with CBDCA, and radiotherapy. The
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interim treatment results are good, and the outcome of the combination therapy can be expected. [14] [15]
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Continuous selective intraarterial chemotherapy in combination with irradiation for locally advanced cancer of the tongue and tongue base K. Furutani a,b,*, N. Fuwa a, T. Kodaira a, A. Matsumoto a, M. Kamata a, H. Tachibana a, H. Sakahara b a Department of Radiation Oncology, Aichi Cancer Center Hospital, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Department of Radiology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, Shizuoka 431-3192, Japan
b
Received 17 January 2001; accepted 5 March 2001
Abstract We retrospectively evaluated the results of the concurrent combination therapy of selective continuous intraarterial chemotherapy and radiotherapy in 39 patients with locally advanced cancer of the tongue and tongue base between September 1992 and January 2000. Thirty patients were fresh cases (stage II, 10 patients; stage III, 15; stage IV, five) and nine were recurrent cases. The primary lesion was present in the mobile tongue in 33 patients and the tongue base in six. External irradiation (median dose, 48.6 Gy) was performed in all patients, and interstitial brachytherapy using an Au grain or Cs needle (median dose, 50 Gy) in 21. In intraarterial chemotherapy, a catheter was selectively inserted into the lingual artery via the superficial temporal artery, and carboplatin (CBDCA) was continuously infused (median dose, 460 mg/m2) concurrently with radiotherapy. In 13 patients with cervical lymph node metastasis, two courses of systemic chemotherapy with 5-FU (700 mg/m25 days) and cisplatin (40–50 mg/m22 days) or its analog was also performed. In 37 (94.9%) of the 39 patients in whom this combination therapy was completed, the response rate was 94.6%. The 3-year local control rate, progression-free survival rate, and overall survival rate by Kaplan–Meier’s method were 79.2, 53.2, and 58.9%, respectively. This combination therapy was effective for locally advanced cancer of the tongue and tongue base without causing severe adverse side effects, and a local control rate comparable to that by surgery can be expected. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Head and neck neoplasms; Tongue neoplasms; Tongue; Infusion; Intraarterial; Intraarterial injection; Carboplatin; Radiotherapy
1. Introduction During the past 20-year period, the treatment for locally advanced cancer of the tongue and tongue base has shown marked changes, such as advances in reconstructive surgery. However, the treatment results have only slightly improved. The standard treatment for locally advanced cancer of the tongue and tongue base is surgery, which is frequently extensive. Surgery has the greatest potential for cure. Therefore, many patients undergo extensive surgery, but they should compromise on postoperative marked dysfunction and a decrease in the quality of life. * Corresponding author. Tel.: +81-52-762-6111; fax: +81-52-7528390. E-mail address: [email protected] (K. Furutani).
Radiotherapy has long been used in this field, but the results of radiotherapy performed alone for locally advanced cancer have been poor. Therefore, radiotherapy is usually performed for a palliative intent or in combination with surgery. Another therapeutic option is intraarterial chemotherapy. This method has marked transient local effects, but its therapeutic power is inadequate in terms of control of advanced cancer. Each of the two therapeutic modalities has inadequate effects when performed alone. However, treatment results can be improved by the effective combination of the two methods that allow preservation of the organ. To obtain maximum effects of each method, we took the following measures. (1) It is not the conventional non-selective intraarterial infusion, but the selective infusion that is performed, by inserting a catheter to the lingual artery. (2) The catheter
1368-8375/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(01)00035-5
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is inserted for a long period for continuous drug infusion. (3) Radiotherapy is performed concurrently with intraarterial chemotherapy. We consider that this combination of intraarterial chemotherapy and radiotherapy has potential for improving treatment results with preservation of the organ. At our hospital, the combination of selective continuous intraarterial chemotherapy and radiotherapy has been performed since August 1992 for preservation of the organ and improvement of treatment results in patients with locally advanced head and neck cancers who cannot undergo surgery for certain reasons. Between August 1992 and May 1997, phases I and II studies [1] on the combination of radiotherapy and selective continuous intraarterial chemotherapy with CBDCA was performed. As a result, the local control rate for cancer of the tongue and tongue base was significantly better than that for cancer in other head and neck cancers. This suggested that cancer of the tongue and tongue base among cancers in the head and neck region is an especially good indication for this combination therapy. In this study, patients with cancer of the tongue and tongue base were extracted from about 130 patients with advanced cancer in the head and neck cancers who underwent this combination therapy between September 1992 and January 2000, and its effects and results were evaluated.
2. Patients and methods 2.1. Patients characteristics The subjects were 39 patients with locally advanced cancer of the tongue and tongue base who underwent the combination of radiotherapy and continuous selective intraarterial chemotherapy at the department of radiation oncology, Aichi Cancer Center Hospital between September 1992 and January 2000 (Table 1). The primary lesion was located in the tongue in 33 patients and the tongue base in six. There were 30 males and nine females aged 36–86 years (median, 68 years). Thirty patients were fresh cases, and nine were recurrent cases (five patients with recurrence after surgery and four with recurrence after radiotherapy). Staging was performed according to the TNM Classification of the UICC, 5th edition [2]. Of the 30 patients with fresh cancer, 20 showed stage III–IV, and eight showed N(+). Of the nine patients with recurrent cancer, six showed rT3 or more. For staging, visual examination, palpation, CT, and MRI were performed, and pharyngeal fiberscopy was also performed in patients with cancer of the tongue base. Distant metastasis was evaluated by chest radiograph, abdominal CT, and bone scintigraphy. Surgery was not performed because of patient refusal in 17 patients, advanced age in 10
patients, and advanced cancer for which surgery was considered to be impossible by surgeons in six, poor general condition in four, and coexistent of another cancer in two. 2.2. Patients selection criteria Patients fulfilling all the following criteria were entered into this study: (1) primary lesion 5 large T2 (large T2: lesions with a diameter of 3 cm or more and a thickness of 15 mm or more); (2) cervical lymph node metastasis 4 N2; (3) absence of distant metastasis; (4) definite histopathological diagnosis of squamous cell carcinoma made by biopsy; (5) performance status (PS) of 0–3 according to the Eastern Cooperative Oncology Group criteria (ECOG criteria) [3]; and (6) acquisition of written informed consent for this treatment. 2.3. Treatment methods 2.3.1. Intraarterial chemotherapy Catheterization was performed by the method of Shimizu et al. [4] Under local anesthesia, preauricular region on the affected side was incised, and the superficial Table 1 Patient characteristics
n
Age (years) Median Range
68 36–86
Performance status (ECOG) 1 2 3 Gender Male Female Primary site Tongue Tongue base Fresh case Stage II T2N0:10 III T2N1:3 T3N0:9 T3N1:3 IV T3N2:4 T4N1:1 Recurrent case rT2N0:3 rT3N0:3 rT4N0:1 rT4N2:2
21 16 2
30 9 33 6 30
10 15
5
9
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temporal artery was exposed. Under fluoroscopic guidance, a hook shaped catheter (Medikit Corp., Tokyo, Japan; Fig. 1) was selectively inserted into the lingual artery using a Radifocus guidewire with a diameter of 0.014 inches (Terumo Corp., Tokyo, Japan). In the patients treated before 1998, the hook shaped catheter was indwelled, and continuous intraarterial chemotherapy was performed. However, catheter dislocation was often observed during continuous intraarterial chemotherapy. Therefore, in recent years, we have replaced the hook type catheter by a straight catheter with a 15-cm tapered tip (Fig. 1; ANTHRON P-U: Toray Industries, Inc., Japan) by the guidewire exchange method, inserting the straight type deep into the lingual artery (Fig. 2). In nine patients with a tumor extending beyond the mid-line, catheters were inserted into the bilateral lingual arteries. After guiding the catheter tip into an appropriate position, the catheter was fixed in the skin at three sites around the ear by ligation with nylon thread.
Fig. 1. The three catheters from the left are hook shaped nylon catheters (length, 50-cm; external diameter, 4 Fr) for selective catheterization into the lingual artery. To prevent arterial intimal injury, a soft tip (length, 3-cm) is applied to the catheter tip. There are three curve types of the catheter tip. The straight type catheter on the right side (length, 50-cm; external diameter of the shaft, 5 Fr) has a gradually tapered tip (15 cm) and can be deeply inserted into the lingual artery. This catheter is made of polyurethane, and its surface is coated with heparin resin to prevent thrombosis.
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CBDCA alone was used in intraarterial chemotherapy in all patients excluding one. The daily dose of CBDCA was 15–20 mg/body, and the recommended total dose was 460 mg/m2, which was determined in our phase 1 study [1], in patients treated during the early period. After 1995, since patients with poor renal function and poor PS were also included into the subjects, the total administration dose was determined using the target area under the free carboplatin plasma concentration versus time curve (AUC) according to Calvert’s formula [5]. The total administration dose was AUC 8 in patients who did not undergo systemic chemotherapy and AUC 6 in those who also underwent systemic chemotherapy. The total CBDCA dose per body surface area that was actually administered was 360–780 mg/m2 (median, 460 mg/m2). In only one patient with chronic renal failure on hemodialysis, was the CBDCA dose reduced to 125 mg/m2, to reduce the risk of aggravation of the side effects of CBDCA, and tetrahydropyranyladriamycin (33 mg/m2; THP: MEIJI SEIKA KAISHA, Ltd., Japan) as an analog of adriamycin was used in combination with CBDCA. The drugs were infused using an electrical portable pump (CADD-PCA, Deltec Smiths Industries, USA). Intraarterial chemotherapy was initiated within 1 week after the initiation of radiotherapy, and continuous infusion was performed during the radiotherapy period (including brachytherapy period; Fig. 3).
Fig. 2. Flow check DSA. A flow check DSA in a 80-year-old male with cancer of the tongue base (T3N0M0) in whom a straight tapered catheter was inserted into the left lingual artery. No branches except for a lingual artery were visualized, confirming distribution of the drug only into the lingual artery.
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2.3.2. Radiation therapy External irradiation using 6 MV linear X-rays was performed five times a week at 1.8 Gy per fraction. Parallel opposed lateral fields technique was used until a dose of 36–40 Gy. Thereafter, the irradiation field was reduced, and oblique two opposite ports or the conformation method was used. The total dose on the primary lesion was 27–74 Gy (median, 48.6 Gy). This marked variation in the total dose was because the total dose was determined after determining whether brachytherapy was possible and whether radiotherapy was performed in previous treatment in each patient. In the patients with cervical lymph node metastasis, 6 MV X-rays were used alone or in combination with electron beams with various energies to perform irradiation at a total dose of 64–74 Gy (median, 70 Gy). In the 21 patients in whom brachytherapy was possible, external irradiation was performed at a local dose of about 40–50 Gy, followed by interstitial irradiation using an Au grain (14 patients) or a Cs needle (six) or their combination (one) at a dose of 30–60 Gy (median, 50 Gy). 2.3.3. Systemic chemotherapy In the 13 patients with cervical lymph node metastasis, systemic chemotherapy was also performed; 5-FU and cisplatin (CDDP) were used in seven patients and 5FU and nedaplatin (SHIONOGI & Co., Ltd, Osaka, Japan) [6] as a CDDP analog, in the other six. Continuous intravenous infusion of 5-FU was performed at 700 mg/m2/day from day 1 to 5 (total dose, 3500 mg/ m2), and continuous drip infusion of CDDP at 40–50 mg/m2/day from day 6 to 7 (total dose, 80–100 mg/m2). Nedaplatin was intravenously drip infused over 6 h at 120–140 mg/m2 on day 6.
As shown in Fig. 3, alternating chemoradiotherapy in which anticancer chemotherapy was alternated with radiotherapy was performed first. Intraarterial chemotherapy was initiated after discontinuation of the second systemic chemotherapy and performed concurrently with radiotherapy. In the patients treated including systemic chemotherapy, the total CBDCA dose was AUC six. 2.3.4. Assessment 2.3.4.1. Catheterization technique and treatment completion rate. The technical catheterization success rate, catheter dislocation rate from the lingual artery, intraarterial chemotherapy completion rate, and the presence or absence of catheter-related complications were evaluated. Completion of intraarterial chemotherapy was defined as administration of 80% or more of the planned drug dose. 2.3.5. Adverse side effects Adverse side effects were assessed according to the standard World Health Organization (WHO) criteria [7]. The two patients in whom intraarterial chemotherapy could not be completed were excluded. The evaluation parameters were peripheral blood cell count, liver function, renal function, oral mucositis, and nausea/vomiting. Blood biochemical examination was performed once weekly, and peripheral blood counts were measured two–three times weekly. Complications due to the indwelling catheter were also evaluated. 2.3.6. Assessment of treatment results Treatment results were evaluated 1 month after discontinuation of treatment. The two patients in whom treatment was not completed were excluded from the
Fig. 3. Two protocols of the combination therapy of continuous arterial infusion chemotherapy and radiotherapy. (a) No systemic chemotherapy group: intraarterial chemotherapy is performed concurrently with radiotherapy. (b) Systemic chemotherapy group: intraarterial chemotherapy starts after the second systemic chemotherapy. Ext.RT, external radiotherapy; Brachy, interstitial brachytherapy; CT, systemic chemotherapy.
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assessment of treatment results. Visual examination, palpation, CT, and MRI were performed, and the effects were recorded according to the WHO response criteria [7]. A complete response (CR) was defined as the absence of tumor for 4 consecutive weeks or more, and a partial response (PR) as a reduction in a cross-section of the tumor to 50% or less. No change (NC) was defined as a tumor cross-section reduction rate of less than 50% or an increase in the tumor diameter. As statistical analysis, the local control rate, progression-free survival rate, overall survival rate were analyzed by Kaplan–Meier’s method [8]. In each analysis, calculation was made from the initiation day of treatment. In the calculation of the local control rate, cases without local recurrence were regarded as censored cases. In the calculation of both the progression-free survival rate and overall survival rate, all deaths were regarded as deaths irrespective of the causes of death. Statistical differences were analyzed by the log rank test [9].
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25%). All dislocated catheters were reinserted as soon as its discovery, and selective intraarterial chemotherapy was resumed in all cases. Intraarterial chemotherapy was completed in 37 of the 39 patients (completion rate, 94.9%). In the other two patients, intraarterial chemotherapy was discontinued due to patient’s refusal and aggravation of the general condition caused by progression of metastatic neck disease, respectively. 3.2. Adverse effects 3.2.1. Catheter-related complications Concerning catheter-related troubles, incomplete obstruction of the lingual artery was observed in two patients (5.1%), and its cause was thrombosis due to catheterization. In both patients, infusion of urokinase resulted in recanalization, and subsequent intraarterial chemotherapy could be completed without problems. No major complications such as neurological complications and massive bleeding developed in any patient.
3. Results 3.1. Catheter performance and treatment completion rate In nine of the 39 patients showing tumor invasion beyond the mid-line, catheters were bilaterally inserted. Thus, selective catheterization into the lingual artery was performed a total of 48 times in 39 patients, and catheterization could be successfully performed only by one operation in all cases. The placement period of the 48 catheters was 18–96 days (median, 37 days), during which 12 catheters were dislocated from the lingual artery (dislocation rate,
3.2.2. Infused drug-related adverse effects Adverse effects related to intraarterial chemotherapy were evaluated in the 24 patients who completed intraarterial chemotherapy and did not undergo systemic chemotherapy. As Grade 3 or more adverse effects, leukopenia was observed in three patients (12.5%) thrombocytopenia in two (8.3%), and oral mucositis in one (4.2%). The patient who developed oral mucositis had undergone intraarterial chemotherapy with CBDCA combined with THP. In the patients treated with CBDCA alone, no Grade 3 or more mucositis was observed. The other parameters such as
Fig. 4. Local control rate (3 years) by Kaplan–Meier’s method. Fresh cases, 87.8%; all cases, 79.2%; recurrent cases, 50%.
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Fig. 5. Progression free survival (3 years) by Kaplan–Meier’s method.
the amount of hemoglobin or results of renal and liver function tests showed Grade 2 or less.
(Figs. 5 and 6), showing no significant difference between the patients with fresh and recurrence.
3.3. Treatment results 4. Discussion The follow up after treatment was performed until death or recurrence was confirmed in all patients. The observation period was 9–94.9 months (median, 26.5 months). Treatment effects were assessed 1 month after discontinuation of treatment in the 37 patients who completed intraarterial chemotherapy. CR was observed in 31 patients (83.8%), PR in four (10.8%), and NC in two (5.4%); the response rate (CR+PR) was 94.6%. In November 2000, local control was maintained in 30 patients (three patients had died of another disease). Local recurrence was observed in seven patients, of whom three underwent salvage operation. In two of the three patients, local control was achieved, but the other had recurrence after salvage operation and died of progression of the primary lesion. Two patients with local recurrence underwent no additional treatment and died of progression of the primary lesion. One patient with local recurrence underwent palliative radiotherapy, and the other with local recurrence was treated by radiotherapy and systemic chemotherapy, but both patients died of disease progression. Fig. 4 shows the 3-year local control rate calculated by Kaplan–Meier’s method. The local control rate was 79.2% in all patients, 87.8% in patients with fresh cancer, and 50.0% in those with recurrent cancer, showing a significant difference between fresh and recurrent groups (P=0.007). Late lymph node recurrence was observed in eight patients and distant metastasis in five. The 3-year progression-free survival rate and the 3-year overall survival rate were 53.2 and 58.9%, respectively
The history of intraarterial chemotherapy for head and neck cancers is relatively long. Klopp et al. [10] was the first to report fractional intraarterial infusion of nitrogen mustard in 1950. After that, Sullivan et al. [11] reported continuous intraarterial infusion of methotrexate in 1959. Subsequently, various improvements have been made, and marked local effects of intraarterial chemotherapy mainly as adjunctive therapy for advanced and recurrent cancer have been reported [12–16]. Intraarterial chemotherapy is theoretically advantageous in a high drug concentration in the lesion and reduced systemic toxicity of drugs compared with systemic chemotherapy. There have also been profound basic studies on the pharmacokinetics in intraarterial chemotherapy [17]. However, this method has not yet been widely accepted. This is because of a rather complicated procedure, catheter-related complications, and limitations in its usefulness since non-selective infusion via the external carotid artery was performed in conventional intraarterial chemotherapy. In the 1990s, since selective catheterization into the target artery became possible, attention began being paid again to intraarterial chemotherapy for locally advanced head and neck cancers. There are two methods of selective intraarterial chemotherapy. One is one shot intraarterial infusion by the conventional angiographic procedure, and the other is continuous intraarterial chemotherapy via the superficial temporal artery. One shot intraarterial chemotherapy has actively been
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Fig. 6. Overall survival (3 years) by Kaplan–Meier’s method.
studied by Robbins et al. Recently, they obtained good results by their new method in which weekly high dose CDDP infusion (150mg/m24 times/4 weeks) in combination with intravenous sodium thiosulfate (CDDP neutralizer) infusion [18–22]. On the other hand, intraarterial chemotherapy via the superficial temporal artery also used in this study was developed by Shimizu et al. [4]. By this method, continuous administration is possible, and the synergistic effects of its concurrent combination with radiotherapy can be expected. In addition, due to a low daily dose, this method can be also used in aged patients or patients with a poor PS. However, since the infusion time is long, the catheter is sometimes dislocated from the target artery. In this study, catheter dislocation was observed in 25%. At present, to reduce the incidence of catheter dislocation, we insert a tapered tip catheter into a more distal portion of the lingual artery as described above; though only nine patients in this study were treated using this catheter, and only one showed catheter dislocation. With this new technique, the catheter dislocation problem may be considerably overcome. In this study, the response rate was satisfactory (94.6%). Most previous studies on selective intraarterial chemotherapy for head and neck cancers have shown response rates of about 90% [4, 20–24]. Our results were comparable with or better than these reports. Fein et al. [25] reported a local control rate of 45% for T3 and 0% for T4 even after a short follow-up period (2 years) in patients treated by radiotherapy alone. On the other hand, higher local control rate can be expected by surgery (with or without postoperative radiotherapy) than by radiotherapy alone. Although the operation results have large difference by institutions,
Fein et al. [25] reported 2-year local control rates by surgery of about 82 and 67% for T3 and T4, respectively. Yuen et al. [26] reported 5-year local control rates of 74 and 54% for T3 and T4, respectively. Though our results can not directly been compared with these results, the local control rate was 79.2% in all patients, and 81.5% for T3 in this study. Our subjects included those with recurrent cancer, nevertheless, our results were comparable with surgical results. Though the number of patients is still low, and the observation period is short, this combination therapy is attractive in patients who cannot be surgically treated for certain reason in terms of not only local control but also the quality of life. CBDCA was used in intraarterial chemotherapy because this drug induces only negligible mucositis and infrequently causes renal impairment. When intraarterial chemotherapy is combined with radiotherapy, radiotherapy-induced mucositis is unavoidable, and CBDCA that does not aggravate mucositis is advantageous. Patients undergoing intraarterial chemotherapy often have renal impairment, but the dose of CBDCA can be determined by Calvert’s formula even in the presence of renal impairment. The degree of the blood toxicity of CBDCA was also feasible. However, in this study, the progression-free survival rate and overall survival rate were not satisfactory. Late neck recurrence or distant recurrence were observed about 30%. For further improvement in long-term prognosis, certain measures for these problems are necessary. Therefore, since 1997, we have been carrying out phase I, II studies on the combination of systemic chemotherapy with 5-FU and nedaplatin, intraarterial chemotherapy with CBDCA, and radiotherapy. The
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interim treatment results are good, and the outcome of the combination therapy can be expected. [14] [15]
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