- Email: [email protected]
Combination Therapy of Superselective Intra-arterial Nedaplatin Infusion and Radiation Therapy for Oral Cancer
Goto Asian J Oral Maxillofac Surg Yamashita, 2004;16:97-102. CLINICAL OBSERVATIONS
Combination Therapy of Superselective Intra-arterial Nedaplatin Infusion and Radiation Therapy for Oral Cancer Yoshio Yamashita, Masaaki Goto Department of Oral and Maxillofacial Surgery, Saga Medical School, Saga, Japan
Abstract Objective: Nedaplatin, which is a cisplatin-derivative, has been reported to be an effective anti-tumour agent for head and neck cancer. The purpose of this study was to address the feasibility of a combination of radiotherapy with superselective intra-arterial therapy using nedaplatin in patients with oral cancer. Patients and Methods: Fourteen patients with oral cancer were treated with chemotherapy by superselective intra-arterial infusion of nedaplatin (90 to 100 mg/m2) combined with concurrent radiation therapy (30 Gy). After evaluation, patients underwent surgery as a therapeutic procedure (resection of the primary tumour and/or the neck). Results: Complete and partial response rates were achieved by 8 patients (57.2%) and 6 patients (42.8%), respectively. Histological effects classified according to Oboshi-Shimosato’s criteria were grade IV in 5 patients, grade IIb in 5, grade IIa in 3, and grade I in 1. Grade IV mucositis was observed in 3 patients (21.4%). All patients were free from renal dysfunction, which is one of the adverse effects of cisplatin. After a median follow-up of 24 months, the locoreginal control rate was 100%. Conclusion: The results indicate that a combination therapy of superselective intra-arterial nedaplatin infusion and radiation therapy can be delivered safely with good efficacy for locoregional management of oral cancer. Key words: Chemotherapy, Infusion, Oral cancer, Radiotherapy
Introduction At present, cisplatin (CDDP) is the chemotherapy of choice for head and neck cancer.1,2 However, CDDP has severe side effects such as nephrotoxicity, which necessitates preventive hydration of patients to prevent renal failure. When platinum compounds are used in cancer therapy in general, one important problem is the renal toxicity. Nedaplatin (cis-diammineglycolate platinum, CDGP), a second-generation platinum complex developed in Japan, is designed to reduce this adverse effect of CDDP.3,4 In a preclinical study, the renal toxicity of CDGP was clearly milder than that of CDDP.5-9 Indeed, patients receiving CDGP do not need complex management of body Correspondence: Yoshio Yamashita, Department of Oral and Maxillofacial Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan. Tel: (81 952) 34 2397; Fax: (81 952) 34 2044; E-mail: [email protected]
Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
fluids compared with that required for patients receiving CDDP. Moreover, CDGP has been shown to have an anti-tumour effect comparable to or greater than that of CDDP in experimental tumours in mice, and human head and neck cancer xenograft in nude mice.6 Since CDGP is a CDDP analogue, CDGP might work well with powerful anti-tumour drugs for oral cancer. On the other hand, the anti-tumour efficacy is closely related to the drug concentration in the tumour.10 To improve the anti-tumour effect, the authors used intra-arterial CDGP. Intra-arterial chemotherapy is an attractive method to achieve a high drug concentration in the tumour.11-13 This clinical study was performed using a catheter inserted into the femoral artery by the Seldinger method, with radiotherapy. Radiochemotherapy has been used to 97
Nedaplatin Infusion and Radiation Therapy for Oral Cancer
achieve synergistic tumour response and to improve prognosis. In fact, combination regimens using concurrent radiotherapy with CDDP have been reported with encouraging results.13-15 We have used CDGP in radiochemotherapy of cancers of the oral region to determine whether CDGP can be substituted for CDDP. In this study, we evaluated the efficacy and side effects of this CDGP regimen.
Patients and Methods
to the Seldinger method.16-18 The femoral artery was exposed by a skin incision in the inguinocrural region. The catheter was manipulated under fluoroscopic guidance until it reached the target artery. CDGP was administered over 30 minutes using an infusion pump. Granisetron 3 mg was given as antiemetic treatment twice a day starting immediately after administration of the CDGP by the Seldinger method. All patients were hydrated intravenously at 1000 ml/day for 1 day.
Fourteen patients with malignant tumours in the oral region who were referred to the Saga Medical School in Japan were treated between 1999 and 2002. Routine computed tomography (CT) and magnetic resonance imaging (MRI) of the head and neck, general scintigraphy, chest X-ray, and laboratory studies were performed. The eligibility criteria for receiving the combined radiochemotherapy were performance status of 1 or less according to the World Health Organization (WHO) scale, adequate renal function, and adequate bone marrow function. The extent of disease was determined according to the tumour-node-metastasis (TNM) system.
The primary lesions and cervical lymph nodes were assessed by visual examination, palpation, MRI, and contrast CT scan. Tumour response was classified as complete response (CR), partial response (PR), or no change (NC). Tumour response was determined by histopathological examination of the resected tumour. Histological change was judged by OboshiShimosato’s criteria.19 Acute toxic reactions were graded according to the WHO scale. The assessment items included changes in peripheral blood cell parameters, renal function, changes in oral mucosa, nausea, vomiting, and hearing loss.
Treatment consisted of a regimen of simultaneous chemotherapy and radiotherapy (Figure 1). Radiotherapy was administered at 3.0 Gy/day, 5 days/week to a total dose of 30.0 Gy. After treatment of 9.0 Gy, chemotherapy by superselective intra-arterial infusion of CDGP (90 to 100 mg/m2) was given according
Surgery was performed approximately 20 days after treatment. Surgical resection of the primary tumour was designed to encompass residual disease and biopsies of selected sites to ensure a clear margin. Radical neck dissection was performed when patients had lymph nodes involved at presentation. Different reconstruction techniques of pectoralis or free flaps were used.
Radiation 3.0 Gy/day
Results
Operation Time
Superselective intra-arterial infusion Nedaplatin 90-100 mg/m2
Figure 1. Treatment schema.
98
Patients’ characteristics are listed in Table 1. Among the 9 men and 5 women (mean age, 64.2 years), no patient had a malignant tumour in another site. The sites of primary disease were as follows: tongue (6/14), gingiva (6/14), and floor of the mouth (2/14). Histological analysis showed squamous cell carcinoma (well and moderately differentiated type). Table 1 illustrates the tumour and lymph node status distribution as follows: T2, T3, T4/N0, N1. Disease stage ranged from II to IV. Table 2 shows acute toxicity by grade severity. Major reactions included bone marrow suppression, nausea and vomiting, and mucositis. Most toxicity was relatively mild for all patients. The only severe (grade IV) Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
Yamashita, Goto Patient number
Age (years)
Sex
Site
Histology
TNM
Response
Outcome
Follow-up (months)
1
66
Male
Tongue
Well
T3N0M0
CR
NED
41
2
64
Female
Lower gingiva
Moderate
T4N1M0
PR
NED
40
3
73
Male
Tongue
Well
T2N0M0
CR
NED
29
4
74
Male
Upper gingiva
Well
T4N0M0
PR
NED
29
5
68
Male
Oral floor
Well
T2N1M0
CR
Deceased
28
6
68
Female
Tongue
Well
T3N0M0
PR
Deceased
25
7
66
Male
Upper gingiva
Well
T4N0M0
PR
NED
22
8
75
Male
Tongue
Moderate
T3N1M0
CR
NED
22
9
53
Female
Tongue
Well
T2N1M0
CR
NED
21
10
70
Female
Upper gingiva
Well
T4N0M0
PR
NED
18
11
62
Male
Lower gingiva
Well
T2N1M0
CR
NED
18
12
51
Male
Tongue
Well
T2N1M0
CR
NED
16
13
60
Female
Upper gingiva
Moderate
T4N1M0
PR
Deceased
13
14
49
Male
Oral floor
Well
T2N1M0
CR
NED
12
Abbreviations: TNM = tumour-node-metastasis; CR = complete response; PR = partial response; NED = no evidence of disease.
Table 1. Disease status and outcomes. Toxicity grade (number of patients)
Complete response
Partial response
Oboshi-Shimosato’s criteria
0
1
2
3
4
Haemoglobin
6
1
7
0
0
T2
6
Leukocytes
2
1
11
0
0
T3
2
Platelets
9
3
2
0
0
T4
Creatinine
11
3
0
0
0
II
1
Nausea/vomiting
5
7
2
0
0
III
7
Mucositis
0
2
9
0
3
IV
Hearing loss
12
1
1
0
0
Table 3. Clinical and pathological response of the primary site.
Table 2. Acute toxicity.
non-haematological toxicity was mucositis (3 patients; 21.4%). The other adverse side effects were all grade 0 to 2. Thrombocytopenia and leukopenia occurred during the second week and resolved by the third week after chemotherapy. Nausea and vomiting occurred for 9 patients (64.3%): 7 (50.0%) had grade 1 and 2 (14.3%) had grade 2. These side effects generally developed 2 or 3 days after CDGP administration and most patients recovered within 5 days. Renal function was impaired only in 3 patients with an elevation of serum creatinine (grade I), which returned to normal within 1 week. No late toxicity has been observed. The clinical response to this regimen is summarised in Table 1. The total response rate was 100%, with CR in 8 patients (57.2%) and PR in 6 patients Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
1
IV
IIb
4
2
1
1
1
2
2
3
1
2
2
5
IIa
I
1
1 1 5
4
1
(42.8%). Histological effect of grade IV, according to the criteria described by Oboshi-Shimosato,19 was noticed in 36% of the patients. Table 3 illustrates the comparison of the tumour progression and pathological response. As of December 2003, no local recurrence was detected over a period of 12 to 41 months (median, 24 months). The 3 patients with neck lymph node metastases were treated with neck dissection (patients 7, 8, and 13).
Discussion The oral and maxillofacial area is involved in some basic functions such as mastication, deglutition, phonation, and respiration. The face plays a key role not only in these functions but also in the self-image of the individual. Surgical treatment of oral cancer usually incurs severe functional loss. With preoperative chemoradiotherapy regimens, the volume of tissue resected can be reduced, thereby improving 99
Nedaplatin Infusion and Radiation Therapy for Oral Cancer
post-surgical function. Simultaneous chemoradiotherapy improves locoreginal tumour control. The clinical purpose of this treatment was to increase locoreginal control, improve survival rates, and allow organ preservation. CDGP, a new platinum complex developed in Japan, is designed to further improve the anti-tumour effect, and to reduce the adverse effects of CDDP, such as renal toxicity.3,4 The anti-tumour effect of CDGP has been shown to be comparable to or greater than that of CDDP in in vivo and in vitro studies.6 Its effectiveness has been recognised in the management of lung cancer,20 oesophageal cancer,21 testicular cancer,3 gynaecological cancer,22 and head and neck cancer.23 CDGP could potentially replace CDDP for the treatment of oral cancer.24 In the current clinical study, patients were treated with a systemic combination chemotherapy by superselective intra-arterial infusion of nedaplatin and radiation therapy, followed by surgical resection. This regimen was effective for the treatment of patients with squamous cell carcinoma of the oral region without severe side effects. After a median followup of 24 months, the locoreginal control rate was 100%. The overall response rate in the primary sites was 100% with 57.2% CR and 42.8% PR rates. Histologically, improvement of at least grade IIa, as described by Oboshi-Shimosato’s criteria,19 was observed in 93% of the primary tumours. The number of patients treated with this regimen was small, and no statistically significant conclusions can be drawn. However, the response rate obtained in this study was satisfactory compared with that of previous reports describing CDDP and 5-fluorouracil (5-FU) chemotherapy.25,26 The CR rates for T2, T3, and T4 disease were 100%, 33%, and 0%, respectively. The CR rates for stages II, III, and IV disease were 100%, 87.5%, and 0%, respectively (Table 3). A similar pattern was obtained for pathological response. These results show that both the clinical and pathological response decreased with tumour progression.27 Additional courses could be more effective against advanced cancer. Currently, another regimen is under way in which chemotherapy with 5-FU 500 mg/m2/day on days 1 to 5 and CDGP 100 mg/m2 100
on day 6 combined with radiation therapy is being evaluated for locally advanced head and neck cancer. Side effects of this regimen were at relatively low grades. Severe renal toxicity, which is one of the adverse effects of CDDP, was not observed in the patients treated with CDGP. In the current clinical study, the main concern was acute damage to the healthy mucosa (21.4%). The toxicity was significant but tolerable with adequate support. This treatment, which is safe and produces a good anti-tumour effect, is a suitable regimen for elderly patients. Anti-tumour efficacy is closely related to the drug concentration in the tumour.10 However, administration of a sufficient dose of anti-tumour agent by the intravenous route is usually difficult for elderly patients. Intra-arterial chemotherapy is an attractive method to achieve a high drug concentration in the tumour. Conventional intra-arterial injection involves introducing a catheter into the superficial temporal artery. However, it is technically difficult and catheter insertion may not be successful due to the artery position. Moreover, the catheter may be dislodged from the targeted artery. In this study, we inserted a catheter into the femoral artery under fluoroscopic monitoring according to the Seldinger method. This approach is relatively easy and enables selective catheter insertion into a target artery. However, continuous drug administration is impossible and catheterisation sometimes causes serious problems such as damage to cranial nerves, in particular.16-18,28 Future goals should be to reduce toxicity by the inclusion of new chemotherapy agents while maintaining the pathologic CR rate. We cannot statistically evaluate the efficacy of our regimen because of the limited number of patients. However, considering the low incidence of adverse effects and high anti-tumour effect of the CDGP and radiation combination, CDGP could potentially replace CDDP for the treatment of certain types of oral cancer. The results indicate that combination chemotherapy by superselective intra-arterial infusion of nedaplatin and radiation therapy is effective for the treatment of patients with squamous cell carcinoma of the oral region. Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
Yamashita, Goto
Acknowledgement The authors thank Dr Michael S Shimizu of the division of Oral & Maxillofacial Surgery at the University Campus (Canada) for critical review of this manuscript.
References 1. Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L. A phase randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257-263. 2. Kish JA, Ensley JF, Jacobs JR, Bins P, Al-Sarraf M. Evaluation of high-dose cisplatin and 5-FU infusion as initial therapy in advanced head and neck cancer. Am J Clin Oncol 1988;11:552-557. 3. Akaza H, Togashi M, Nishio Y, Miki T, Kotake T, Matumura Y, Yoshida O, Aso Y. Phase II study of cis-diammine(glycolato)platinum, 254-S, in patients with advanced germ-cell testicular cancer, prostatic cancer, and transitional-cell carcinoma of the urinary tract. Cancer Chemother Pharmacol 1992;31:187-192. 4. Fuwa N, Kodaira T, Kamata M, Matsumoto A, Furutani K, Tachibana H, Ito Y. Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and nedaplatin (NDP). Am J Clin Oncol 2002;25:565-569. 5. Totani T, Aono K, Komura M, et al. Synthesis of (glycolato-O,O’)diammineplatinum (II) and its related complexes. Chem Lett 1986;3:429-432. 6. Shiratori O, Kanai H, Uchida N, Takeda Y, Totani T, Sato K. Antitumor activity of 254-S, a platinum complex, in rodents. In: Ishigami J, editor. Recent advances in chemotherapy, anticancer section. Tokyo: University of Tokyo Press; 1985:635-636. 7. Suzumura Y, Kato T, Ueda R, Ota K. Effect of treatment schedule on antitumor activity of glycolato-O,O’diammineplatinum (II), a new platinum derivative: comparison with cisdiamminedichloroplatinum (II). Anticancer Res 1989;9:1083-1088. 8. Koenuma M, Kasai H, Uchida N, Wada T, Hattori M, Oguma T, Totani T, Inaba M. Pharmacokinetic correlation between experimental and clinical effects on human non-small cell lung cancers of Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
cis-diammineglycolatoplatinum (254-S) and cisdiamminedichloroplatinum. Anticancer Res 1995;15:417-422. 9. Kameyama Y, Okazaki N, Nakagawa M, Koshida H, Nakamura M, Gemba M. Nephrotoxicity of a new platinum compound, 254-S, evaluated with rat kidney cortical slices. Toxicol Lett 1990;52: 15-24. 10. Frei E III, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980;69: 585-594. 11. Fuwa N, Ito Y, Matsumoto A, Kamata M, Kodaira T, Furutani K, Sasaoka M, Kimura Y, Morita K. A combination therapy of continuous superselective intraarterial carboplatin infusion and radiation therapy for locally advanced head and neck carcinoma. Cancer 2000;89:2099-2105. 12. Newman LA, Robbins T, Logemann JA, Rademaker AW, Lazarus CL, Hamner A, Tusant S, Huang CF. Swallowing and speech ability after treatment for head and neck cancer with targeted intraarterial versus intravenous chemoradiation. Head Neck 2002;24:68-77. 13. Nibu K, Sugasawa M, Asai, M, Ichimura K, Mochiki M, Terahara A, Kawahara N, Asato H. Results of multimodality therapy for squamous cell carcinoma of maxillary sinus. Cancer 2002; 94:1476-1482. 14. Giralt JL, Gonzalez J, Campo JM, Maldonado J, Sanz X, Pamias J, Eraso A, Bescos S, Raspall G. Preoperative induction chemotherapy followed by concurrent chemoradiotherapy in advanced carcinoma of the oral cavity and oropharynx. Cancer 2000;89:939-945. 15. Doweck I, Robbins T, Vieira F. Analysis of risk factors predictive of distant failure after targeted chemoradiation for advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 2001; 127:1315-1318. 16. Kerber CW, Wong WH, Howell SB, Hanchett K, Robbins KT. An organ-preserving selective arterial chemotherapy strategy for head and neck cancer. Am J Neuroradiol 1998;19:935-941. 17. Robbins KT, Kumar P, Regine WF, Wong FS, Weir AB 3rd, Flick P, Kun LE, Palmer R, Murry T, Fontanesi J, Ferguson R, Thomas R, Hartsell W, Paig CU, Salazar G, Norfleet L, Hanchett CB, Harrington V, Niell HB. Efficacy of targeted 101
Nedaplatin Infusion and Radiation Therapy for Oral Cancer
supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Phys 1997;38:263-271. 18. Robbins KT, Wong FS, Kumar P, Hartsell WF, Vieira F, Mullins B, Niell HB. Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 1999;125:670-675. 19. Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinoma. Jpn J Clin Oncol 1971; 1:19-35. 20. Fukuda M, Shinkai T, Eguchi K, Sasaki Y, Tamura T, Ohe Y, Kojima A, Oshita F, Hara K, Saijo N. Phase II study of (glycolato-O,O’) diammineplatinum (II), a novel platinum complex, in the treatment of non-small-cell lung cancer. Cancer Chemother Pharmacol 1990;26:393-396. 21. Yamanaka H, Motohiro T, Michiura T, Asai A, Mori T, Hioki K. Nedaplatin and 5-FU combined with radiation in the treatment for esophageal cancer. Jpn J Cancer Thorac Cardiovasc Surg 1998;46:943-948. 22. Kato T, Noda K, Hirabayashi K, Nishimura H. Phase II study of cisdiammine(glycolato)platinum [254-S], a new platinum complex, for gynecological malignancy. In: Proceedings of the 16th International Congress on Chemother, Anti-cancer Section.
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1989;823:1-2. 23. InuyamaY, Miyake H, Horiuchi M, HayasakaK, Komiyama S, Ohta K. An early phase II clinical study of cis-diammine glycolatoplatinum, 254S, for head and neck cancers. Jpn J Cancer Chemother 1992;19:863-869. 24. Ita M, Okafuji M, Fukuda K, Mitsuoka K, Hanakita T, Hayatsu Y. Concurrent chemoradiotherapy with new platinum compound nedaplatin in oral cancer. Oral Oncology 2003;39:144-149. 25. Taylor SG 4th, Murthy AK, Vannetzel JM, Colin P, Dray M, Caldarelli DD, Shott S, Vokes E, Showel JL, Hutchinson JC. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 1994;12:385-395. 26. Forastiere AA. Overview of platinum chemotherapy in head and neck cancer. Semin Oncol 1994;21:20-27. 27. Doweck I, Denys D, Robbins T. Tumor volume predicts outcome for advanced head and neck cancer treated with targeted chemoradiotherapy. Laryngoscope 2002;112:1742-1749. 28. Maser D, Rasse M, Schopper C, Lagogiannis G, Frass M, Ewers R, Kaye AD, Hofbauer R. A scanning electron microscopic study on thrombogenicity of intraarterial catheters for chemotherapeutic treatment in head and neck cancer. Head Neck 2002;24:566-574.
Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
Combination Therapy of Superselective Intra-arterial Nedaplatin Infusion and Radiation Therapy for Oral Cancer Yoshio Yamashita, Masaaki Goto Department of Oral and Maxillofacial Surgery, Saga Medical School, Saga, Japan
Abstract Objective: Nedaplatin, which is a cisplatin-derivative, has been reported to be an effective anti-tumour agent for head and neck cancer. The purpose of this study was to address the feasibility of a combination of radiotherapy with superselective intra-arterial therapy using nedaplatin in patients with oral cancer. Patients and Methods: Fourteen patients with oral cancer were treated with chemotherapy by superselective intra-arterial infusion of nedaplatin (90 to 100 mg/m2) combined with concurrent radiation therapy (30 Gy). After evaluation, patients underwent surgery as a therapeutic procedure (resection of the primary tumour and/or the neck). Results: Complete and partial response rates were achieved by 8 patients (57.2%) and 6 patients (42.8%), respectively. Histological effects classified according to Oboshi-Shimosato’s criteria were grade IV in 5 patients, grade IIb in 5, grade IIa in 3, and grade I in 1. Grade IV mucositis was observed in 3 patients (21.4%). All patients were free from renal dysfunction, which is one of the adverse effects of cisplatin. After a median follow-up of 24 months, the locoreginal control rate was 100%. Conclusion: The results indicate that a combination therapy of superselective intra-arterial nedaplatin infusion and radiation therapy can be delivered safely with good efficacy for locoregional management of oral cancer. Key words: Chemotherapy, Infusion, Oral cancer, Radiotherapy
Introduction At present, cisplatin (CDDP) is the chemotherapy of choice for head and neck cancer.1,2 However, CDDP has severe side effects such as nephrotoxicity, which necessitates preventive hydration of patients to prevent renal failure. When platinum compounds are used in cancer therapy in general, one important problem is the renal toxicity. Nedaplatin (cis-diammineglycolate platinum, CDGP), a second-generation platinum complex developed in Japan, is designed to reduce this adverse effect of CDDP.3,4 In a preclinical study, the renal toxicity of CDGP was clearly milder than that of CDDP.5-9 Indeed, patients receiving CDGP do not need complex management of body Correspondence: Yoshio Yamashita, Department of Oral and Maxillofacial Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan. Tel: (81 952) 34 2397; Fax: (81 952) 34 2044; E-mail: [email protected]
Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
fluids compared with that required for patients receiving CDDP. Moreover, CDGP has been shown to have an anti-tumour effect comparable to or greater than that of CDDP in experimental tumours in mice, and human head and neck cancer xenograft in nude mice.6 Since CDGP is a CDDP analogue, CDGP might work well with powerful anti-tumour drugs for oral cancer. On the other hand, the anti-tumour efficacy is closely related to the drug concentration in the tumour.10 To improve the anti-tumour effect, the authors used intra-arterial CDGP. Intra-arterial chemotherapy is an attractive method to achieve a high drug concentration in the tumour.11-13 This clinical study was performed using a catheter inserted into the femoral artery by the Seldinger method, with radiotherapy. Radiochemotherapy has been used to 97
Nedaplatin Infusion and Radiation Therapy for Oral Cancer
achieve synergistic tumour response and to improve prognosis. In fact, combination regimens using concurrent radiotherapy with CDDP have been reported with encouraging results.13-15 We have used CDGP in radiochemotherapy of cancers of the oral region to determine whether CDGP can be substituted for CDDP. In this study, we evaluated the efficacy and side effects of this CDGP regimen.
Patients and Methods
to the Seldinger method.16-18 The femoral artery was exposed by a skin incision in the inguinocrural region. The catheter was manipulated under fluoroscopic guidance until it reached the target artery. CDGP was administered over 30 minutes using an infusion pump. Granisetron 3 mg was given as antiemetic treatment twice a day starting immediately after administration of the CDGP by the Seldinger method. All patients were hydrated intravenously at 1000 ml/day for 1 day.
Fourteen patients with malignant tumours in the oral region who were referred to the Saga Medical School in Japan were treated between 1999 and 2002. Routine computed tomography (CT) and magnetic resonance imaging (MRI) of the head and neck, general scintigraphy, chest X-ray, and laboratory studies were performed. The eligibility criteria for receiving the combined radiochemotherapy were performance status of 1 or less according to the World Health Organization (WHO) scale, adequate renal function, and adequate bone marrow function. The extent of disease was determined according to the tumour-node-metastasis (TNM) system.
The primary lesions and cervical lymph nodes were assessed by visual examination, palpation, MRI, and contrast CT scan. Tumour response was classified as complete response (CR), partial response (PR), or no change (NC). Tumour response was determined by histopathological examination of the resected tumour. Histological change was judged by OboshiShimosato’s criteria.19 Acute toxic reactions were graded according to the WHO scale. The assessment items included changes in peripheral blood cell parameters, renal function, changes in oral mucosa, nausea, vomiting, and hearing loss.
Treatment consisted of a regimen of simultaneous chemotherapy and radiotherapy (Figure 1). Radiotherapy was administered at 3.0 Gy/day, 5 days/week to a total dose of 30.0 Gy. After treatment of 9.0 Gy, chemotherapy by superselective intra-arterial infusion of CDGP (90 to 100 mg/m2) was given according
Surgery was performed approximately 20 days after treatment. Surgical resection of the primary tumour was designed to encompass residual disease and biopsies of selected sites to ensure a clear margin. Radical neck dissection was performed when patients had lymph nodes involved at presentation. Different reconstruction techniques of pectoralis or free flaps were used.
Radiation 3.0 Gy/day
Results
Operation Time
Superselective intra-arterial infusion Nedaplatin 90-100 mg/m2
Figure 1. Treatment schema.
98
Patients’ characteristics are listed in Table 1. Among the 9 men and 5 women (mean age, 64.2 years), no patient had a malignant tumour in another site. The sites of primary disease were as follows: tongue (6/14), gingiva (6/14), and floor of the mouth (2/14). Histological analysis showed squamous cell carcinoma (well and moderately differentiated type). Table 1 illustrates the tumour and lymph node status distribution as follows: T2, T3, T4/N0, N1. Disease stage ranged from II to IV. Table 2 shows acute toxicity by grade severity. Major reactions included bone marrow suppression, nausea and vomiting, and mucositis. Most toxicity was relatively mild for all patients. The only severe (grade IV) Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
Yamashita, Goto Patient number
Age (years)
Sex
Site
Histology
TNM
Response
Outcome
Follow-up (months)
1
66
Male
Tongue
Well
T3N0M0
CR
NED
41
2
64
Female
Lower gingiva
Moderate
T4N1M0
PR
NED
40
3
73
Male
Tongue
Well
T2N0M0
CR
NED
29
4
74
Male
Upper gingiva
Well
T4N0M0
PR
NED
29
5
68
Male
Oral floor
Well
T2N1M0
CR
Deceased
28
6
68
Female
Tongue
Well
T3N0M0
PR
Deceased
25
7
66
Male
Upper gingiva
Well
T4N0M0
PR
NED
22
8
75
Male
Tongue
Moderate
T3N1M0
CR
NED
22
9
53
Female
Tongue
Well
T2N1M0
CR
NED
21
10
70
Female
Upper gingiva
Well
T4N0M0
PR
NED
18
11
62
Male
Lower gingiva
Well
T2N1M0
CR
NED
18
12
51
Male
Tongue
Well
T2N1M0
CR
NED
16
13
60
Female
Upper gingiva
Moderate
T4N1M0
PR
Deceased
13
14
49
Male
Oral floor
Well
T2N1M0
CR
NED
12
Abbreviations: TNM = tumour-node-metastasis; CR = complete response; PR = partial response; NED = no evidence of disease.
Table 1. Disease status and outcomes. Toxicity grade (number of patients)
Complete response
Partial response
Oboshi-Shimosato’s criteria
0
1
2
3
4
Haemoglobin
6
1
7
0
0
T2
6
Leukocytes
2
1
11
0
0
T3
2
Platelets
9
3
2
0
0
T4
Creatinine
11
3
0
0
0
II
1
Nausea/vomiting
5
7
2
0
0
III
7
Mucositis
0
2
9
0
3
IV
Hearing loss
12
1
1
0
0
Table 3. Clinical and pathological response of the primary site.
Table 2. Acute toxicity.
non-haematological toxicity was mucositis (3 patients; 21.4%). The other adverse side effects were all grade 0 to 2. Thrombocytopenia and leukopenia occurred during the second week and resolved by the third week after chemotherapy. Nausea and vomiting occurred for 9 patients (64.3%): 7 (50.0%) had grade 1 and 2 (14.3%) had grade 2. These side effects generally developed 2 or 3 days after CDGP administration and most patients recovered within 5 days. Renal function was impaired only in 3 patients with an elevation of serum creatinine (grade I), which returned to normal within 1 week. No late toxicity has been observed. The clinical response to this regimen is summarised in Table 1. The total response rate was 100%, with CR in 8 patients (57.2%) and PR in 6 patients Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
1
IV
IIb
4
2
1
1
1
2
2
3
1
2
2
5
IIa
I
1
1 1 5
4
1
(42.8%). Histological effect of grade IV, according to the criteria described by Oboshi-Shimosato,19 was noticed in 36% of the patients. Table 3 illustrates the comparison of the tumour progression and pathological response. As of December 2003, no local recurrence was detected over a period of 12 to 41 months (median, 24 months). The 3 patients with neck lymph node metastases were treated with neck dissection (patients 7, 8, and 13).
Discussion The oral and maxillofacial area is involved in some basic functions such as mastication, deglutition, phonation, and respiration. The face plays a key role not only in these functions but also in the self-image of the individual. Surgical treatment of oral cancer usually incurs severe functional loss. With preoperative chemoradiotherapy regimens, the volume of tissue resected can be reduced, thereby improving 99
Nedaplatin Infusion and Radiation Therapy for Oral Cancer
post-surgical function. Simultaneous chemoradiotherapy improves locoreginal tumour control. The clinical purpose of this treatment was to increase locoreginal control, improve survival rates, and allow organ preservation. CDGP, a new platinum complex developed in Japan, is designed to further improve the anti-tumour effect, and to reduce the adverse effects of CDDP, such as renal toxicity.3,4 The anti-tumour effect of CDGP has been shown to be comparable to or greater than that of CDDP in in vivo and in vitro studies.6 Its effectiveness has been recognised in the management of lung cancer,20 oesophageal cancer,21 testicular cancer,3 gynaecological cancer,22 and head and neck cancer.23 CDGP could potentially replace CDDP for the treatment of oral cancer.24 In the current clinical study, patients were treated with a systemic combination chemotherapy by superselective intra-arterial infusion of nedaplatin and radiation therapy, followed by surgical resection. This regimen was effective for the treatment of patients with squamous cell carcinoma of the oral region without severe side effects. After a median followup of 24 months, the locoreginal control rate was 100%. The overall response rate in the primary sites was 100% with 57.2% CR and 42.8% PR rates. Histologically, improvement of at least grade IIa, as described by Oboshi-Shimosato’s criteria,19 was observed in 93% of the primary tumours. The number of patients treated with this regimen was small, and no statistically significant conclusions can be drawn. However, the response rate obtained in this study was satisfactory compared with that of previous reports describing CDDP and 5-fluorouracil (5-FU) chemotherapy.25,26 The CR rates for T2, T3, and T4 disease were 100%, 33%, and 0%, respectively. The CR rates for stages II, III, and IV disease were 100%, 87.5%, and 0%, respectively (Table 3). A similar pattern was obtained for pathological response. These results show that both the clinical and pathological response decreased with tumour progression.27 Additional courses could be more effective against advanced cancer. Currently, another regimen is under way in which chemotherapy with 5-FU 500 mg/m2/day on days 1 to 5 and CDGP 100 mg/m2 100
on day 6 combined with radiation therapy is being evaluated for locally advanced head and neck cancer. Side effects of this regimen were at relatively low grades. Severe renal toxicity, which is one of the adverse effects of CDDP, was not observed in the patients treated with CDGP. In the current clinical study, the main concern was acute damage to the healthy mucosa (21.4%). The toxicity was significant but tolerable with adequate support. This treatment, which is safe and produces a good anti-tumour effect, is a suitable regimen for elderly patients. Anti-tumour efficacy is closely related to the drug concentration in the tumour.10 However, administration of a sufficient dose of anti-tumour agent by the intravenous route is usually difficult for elderly patients. Intra-arterial chemotherapy is an attractive method to achieve a high drug concentration in the tumour. Conventional intra-arterial injection involves introducing a catheter into the superficial temporal artery. However, it is technically difficult and catheter insertion may not be successful due to the artery position. Moreover, the catheter may be dislodged from the targeted artery. In this study, we inserted a catheter into the femoral artery under fluoroscopic monitoring according to the Seldinger method. This approach is relatively easy and enables selective catheter insertion into a target artery. However, continuous drug administration is impossible and catheterisation sometimes causes serious problems such as damage to cranial nerves, in particular.16-18,28 Future goals should be to reduce toxicity by the inclusion of new chemotherapy agents while maintaining the pathologic CR rate. We cannot statistically evaluate the efficacy of our regimen because of the limited number of patients. However, considering the low incidence of adverse effects and high anti-tumour effect of the CDGP and radiation combination, CDGP could potentially replace CDDP for the treatment of certain types of oral cancer. The results indicate that combination chemotherapy by superselective intra-arterial infusion of nedaplatin and radiation therapy is effective for the treatment of patients with squamous cell carcinoma of the oral region. Asian J Oral Maxillofac Surg Vol 16, No 2, 2004
Yamashita, Goto
Acknowledgement The authors thank Dr Michael S Shimizu of the division of Oral & Maxillofacial Surgery at the University Campus (Canada) for critical review of this manuscript.
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