Clinical Study Received: September 5, 2013 Accepted after revision: November 20, 2013 Published online: January 28, 2014
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
Phase I Study of Nedaplatin Prior to S-1 in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Dai Sato a Yasunao Kogashiwa a Kiyoaki Tsukahara b Koichi Yamauchi a Naoyuki Kohno a
a
Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, and b Department of Otolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
Key Words Outpatient cancer therapy · Induction chemotherapy · Head and neck cancer · Squamous cell carcinoma
thrombocytopenia. The response rate (RR) was 57.1%. Conclusions: The recommended dose of NDP for a phase II study was determined to be 100 mg/m2. We concluded that our regimen was well tolerated and that the RR was acceptable. © 2014 S. Karger AG, Basel
Abstract Background: We previously reported on the regimen of S-1 plus nedaplatin (NDP), with S-1 was administered orally for 14 days and NDP intravenously on day 8. The maximum tolerated dose (MTD) of NDP was determined to be 90 mg/m2. The main toxicities were neutropenia and thrombocytopenia. This result was tolerated, but we believe there is a more effective and tolerable regimen. Thus, we investigated the S-1 regimen administered orally for 14 days, and NDP intravenously on day 1 in patients with locally advanced head and neck squamous cell carcinoma. Patients and Methods: Oral administration of S-1 (days 1–14) and intravenous NDP (day 1) were tested for patients with advance head and neck cancer in a phase I setting. The dose of S-1 was fixed and the dose of NDP was escalated from 70 mg/m2, with an increase of 10 mg/m2 per step, to find the MTD. Results: A total of 15 patients were registered. The MTD of NDP was determined to be 100 mg/m2. The main toxicities were neutropenia and
© 2014 S. Karger AG, Basel 0009–3157/14/0594–0314$39.50/0 E-Mail [email protected] www.karger.com/che
Introduction
Head and neck squamous cell carcinoma (HNSCC) ranks sixth among the most common cancers, accounting for approximately 5% of all cases of cancer [1]. The disease is potentially curable at an early stage, but 40–50% of patients present with locally advanced disease [2]. Induction chemotherapy is used in clinical practice and is thought to be beneficial for reducing the rate of distant metastases and increasing organ preservation and survival rates [3, 4]. 5-Fluorouracil (5-FU) and cisplatin (CDDP) chemotherapy (PF) is commonly used [5–7], but this treatment usually needs hospitalization because of the continuous infusion of these agents and need for adequate support for gastrointestinal and renal toxicity. Furthermore, the combination chemotherapy regimens Naoyuki Kohno, MD, PhD Department of Otolaryngology, Head and Neck Surgery Kyorin University School of Medicine 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan) E-Mail sukohno @ ks.kyorin-u.ac.jp
comprising 5-FU, CDDP and docetaxel (TPF) improved the rate of progression and overall survival; however, the regimen has been shown to cause severe myelotoxicity [8, 9]. Thus, we wished to develop an outpatient regimen for advanced/recurrent head and neck cancer patients that could be administered safely on an outpatient basis and that would have an antitumor activity equivalent to that of PF. For this purpose, we selected a combination of S-1 plus nedaplatin (NDP). S-1 is an oral anticancer. To improve compliance with treatment and reduce toxicity, oral chemotherapeutic agents have been rigorously tested in Japan. S-1 (Taiho Pahrmaceutical Co. Ltd., Tokyo, Japan) is an oral anticancer agent (tegafur, gimeracil and oteracil potassium at a molar ratio 1:0.4:1) based on the biochemical modulation of 5-FU [10]. S-1 is thought to be potentially more active than 5-FU, and several clinical reports have suggested encouraging clinical results in chemotherapy for gastric [11–13], colorectal [14], biliary tract [15], nonsmall cell lung cancer [16] and HNSCC [17, 18]. NDP is a platinum complex also developed in Japan, and believed to be an active agent for HNSCC [19]. This agent is thought to have an equivalent treatment effect, but with less renal and gastrointestinal toxicity compared with CDDP, and so more convenient administration could be achieved even on an outpatient basis. NDP was also reported to be efficacious and feasible combined with the pre-administration of 5-FU [20, 21]. We expected the synergistic effects of NDP prior to S-1 induction chemotherapy in patients with locally advanced HNSCC because there is a theory that asserts that prior administration of CDDP allows it to act as a biochemical modulator of 5-FU, increasing the antitumor effect. The purpose of this study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of combined S-1 plus NDP for the treatment of advanced HNSCC.
massive fixed soft tissue disease, and gross extension along the pharyngeal wall. The other eligibility criteria were as follows: a patient age of 20–75 years; an Eastern Cooperative Oncology Group performance status of 0 or 1; a life expectancy of at least 3 months; the ability to receive oral treatment, and adequate organ functions, including a leukocyte count of 4,000–12,000/mm3, a platelet count of 100,000/mm3, a hemoglobin level of 9.0 g/dl, serum transaminase (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase levels within twice the upper limit of normal, a serum bilirubin level of 1.5 mg/dl, a serum creatinine level within the upper limit of normal and an estimated creatinine clearance according to the method of Cockcroft-Gault of 80 ml/min. The ethics committee of our hospital approved the study and written informed consent was obtained from each of the patients. Treatment and Dose Escalation Schedule S-1 was given orally twice daily (after breakfast and after dinner) at a fixed dose based on the patient’s body surface area (BSA) as follows: BSA 21 days.
Patients and Methods Patients Patients eligible for this study were required to have histologically proven HNSCC (other than thyroid cancer) and measurable or evaluable lesions. Patients were required to have unresectable lesions with no previous history of treatment for head and neck cancer or recurrent cancer for which only radiotherapy had been administered; prior radiotherapy was permitted if the treatment had been completed at least 4 weeks before patient selection. However, a history of prior chemotherapy was not permitted. The criteria for unresectability were as follows: >180° encasement of the carotid artery; fixation to the prevertebral fascia;
Evaluation of Tumor Response Although this was a phase I study, we evaluated the response to the treatment as a reference for a future phase II study. The response to treatment was assessed based on the sum of the lesion diameters as measured directly with calipers or radiological images according to RECIST (Response Evaluation Criteria in Solid Tumors) using various imaging examinations performed within 2 weeks after administration of NDP in the first course. A complete response was defined as the disappearance of all target lesions for at least 4 weeks. A partial response was defined as a decrease in the sum of the diameters of the target lesions of at least 30%, taking the baseline sum of the diameters as a reference, for at least 4 weeks.
Phase I Study of NDP Prior to S-1 in Head and Neck Cancer
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
315
Table 1. Patient characteristics
Level
Case
Age, years
Sex
Cancer site
TNM stage
BSA, m2
TS-1, mg/day
1 (70 mg/m2)
1-1 1-2 1-3 1-4 1-5 1-6
64 67 67 63 63 63
M M M M M F
Hypopharynx Hypopharynx Hypopharynx Oropharynx Oropharynx Mouth floor
T4aN2b T4bN2c T4aN2c T4aN0 T4aN2c T4aN3
1.61 1.42 1.84 1.44 1.39 1.60
120 100 120 100 100 120
2 (80 mg/m2)
2-1 2-2 2-3
50 46 50
M M M
Larynx Tongue Tongue
T3N0 T4aN2b T3N2b
1.61 1.83 1.73
120 120 120
3 (90 mg/m2)
3-1 3-2 3-3
57 68 62
M M M
Larynx Larynx Larynx
T4bN0 T4aN2b T3N0
1.57 1.72 1.82
120 120 120
4 (100 mg/m2)
4-1 4-2 4-3
58 49 56
M M F
Hypopharynx Oropharynx Hypopharynx
T2N3 T3N2b T2N2c
1.80 1.82 1.54
120 120 120
Progressive disease was defined as an increase in the sum of the diameters of the target lesions of at least 20%, taking the smallest sum as a reference, or the appearance of any new lesions. Stable disease was defined as neither sufficient shrinkage to qualify for partial response, nor a sufficient increase to qualify for progressive disease, taking the smallest sum of the diameters as the reference. The response rate (RR) was regarded as the combined complete response and partial response.
Results
Patient Characteristics A total of 15 patients (13 men and 2 women) with a median age of 58.9 years (range 46–68) were enrolled in this study between June 2008 and March 2010. Table 1 shows the patient characteristics and the treatment schedule. All patients had no history of any previous treatment for head and neck cancer. Determination of the MTD and RD Table 2 shows the toxicities observed at each dose level. At dose level 1 (NDP 70 mg/m2), 1 of the first 3 patients experienced DLT (grade 4 neutropenia, grade 4 anemia, grade 4 thrombocytopenia, grade 3 serum creatinine increase); therefore, an additional 3 patients were started at the same dose. Since only 1 of the 6 patients at this dose level experienced DLT, we proceeded to the next dose level. At dose level 2 (NDP 80 mg/m2), none of the patients experienced DLT; therefore, we advanced to 316
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
dose level 3. At dose level 3 (NDP 90 mg/m2), none of the patients experienced DLT; therefore, we advanced to dose level 4. At dose level 4 (NDP 100 mg/m2), none of the patients experienced DLT. Based on these findings, dose level 4 (NDP 100 mg/m2) will be used as the RD for a phase II study. Response 1 of the 15 patients showed a complete response, and 7, 3 and 3 of the 14 patients showed partial response, no change and progressive disease, respectively. Case 1-1, who had a recurrent lesion and had received pre-radiation therapy, showed progressive disease. The RR of the patients to the treatment regimen examined in this study was 57.1%. The results are shown in table 3.
Discussion
Platinum-based chemotherapy is widely used for recurrent/metastatic HNSCC. Although the combination of TPF has become the more effective induction chemotherapy, the combination of PF has commonly been used for locally advanced HNSCC. The RR has been reported to be >70% when the regimen is used as induction chemotherapy [22–24] and about 30% when it is used for recurrent and/or metastatic disease [25, 26]. It was also reported that a function preservation rate of 66% was achieved without a deSato/Kogashiwa/Tsukahara/Yamauchi/ Kohno
Table 2. Incidence of toxicities
Case 1-1 1-2 1-3 1-4 1-5
Hematological toxicity anemia (G1) thrombocytopenia (G1) leukopenia (G3) neutropenia (G4) thrombocytopenia (G3) thrombocytopenia (G1) leukopenia (G1) neutropenia (G1)
1-6
anemia (G2) leukopenia (G1) neutropenia (G1)
2-1
anemia (G1) thrombocytopenia (G1) anemia (G1) anemia (G1)
Table 3. Tumor response
Nonhematological toxicity
Level
arrhythmia (G1)
1 (70 mg/m2) 2 (80 mg/m2) 3 (90 mg/m2) 4 (100 mg/m2)
hyperkalemia (G2) anorexia (G1) hyponatremia (G1) liver (G1)
CR
PR
NC 1 1 1
1
5 2 2 2
PD
CR = Complete response; PR = partial response; NC = no change; PD = progressive disease.
crease in the survival rate [27]. Recently, two phase III trials [8, 9] studied induction chemotherapy with TPF and provided indirect evidence of the efficacy of induction chemotherapy. The addition of docetaxel to CDDP/5-FU in both studies increased the RR as well as overall survival compared with that achieved with PF alone. Nevertheless, these combinations are stressful to patients, and the continuous infusion of 5-FU in these combinations reduces quality of life and usually needs hospitalization for adequate support for gastrointestinal and renal toxicity. As mentioned earlier, the combination of CDDP, and 5-FU is widely used for HNSCC [5–7]. These two drugs are known to be synergistic [28]. The optimal ad-
ministration order for these two drugs has not been established because of two opposing theories. One theory asserts that prior administration of CDDP allows it to act as a biochemical modulator of 5-FU, increasing the antitumor effect, whereas the other theory claims that prior administration of 5-FU allows it to act as a biochemical modulator of CDDP, increasing the antitumor effect. Scanlon et al. [29] found that cytotoxic activity was synergistically enhanced when CDDP was given before 5-FU in 2,780 human ovarian cancer cells; the cytotoxicity was 76% for CDDP followed by 5-FU and 59% for the reverse sequence. They proposed that CDDP pretreatment blocked methionine uptake into tumor cells and increased the synthesis of intercellular methionine, thus enhancing the cytotoxicity of 5-FU [30]. They also confirmed CDDP inhibition of L-methionine incorporation into ascitic Yoshida sarcoma cells and resultant elevated levels of intracellular reduced folate, i.e. CH2FH4 and FH4, in vivo. The uses of CDDP administered intravenously on day 1 were standard in combined CDDP and 5-FU chemotherapy. NDP was used instead of CDDP in this study because of its less toxic nature, convenience for use on an outpatient basis and antitumor effect as would be expected equivalent to other platinum agents. NDP is a platinum complex, and the spectrum of activity of NDP largely overlaps that of CDDP. Furthermore, skipping 5-FU administration was easy when early myelosuppression occurred, but NDP administration was difficult when myelosuppression occurred with only 5-FU administration. Therefore, the use of NDP administered intravenously on day 1 provides greater flexibility in the treatment schedule and provides the clinician with an opportunity to reduce unexpected toxicities. In our previous study [31], S-1 was given orally at a fixed dose for 14 days and NDP was administered intravenously on day 8 of S-1
Phase I Study of NDP Prior to S-1 in Head and Neck Cancer
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
2-2 2-3 3-1 3-2 3-3
4-1 4-2
anemia (G2) anemia (G1) leukopenia (G2) neutropenia (G2) anemia (G1) leukopenia (G1) neutropenia (G1) anemia (G1) neutropenia (G1) thrombocytopenia (G1) anemia (G1) thrombocytopenia (G1)
liver (G1)
liver (G1) liver (G1)
4-3 G = Grade.
317
administration. The MTD of NDP was determined to be 90 mg/m2, the main toxicities were neutropenia and thrombocytopenia and the RR was 57.1%. In the present study, the MTD of NDP was determined to be 100 mg/m2 and the RR was 80%. Furthermore, the toxicities were the same as in the previous study.
In conclusion, we believe that treatment with S-1 plus NDP was well tolerated and feasible on an outpatient basis. The RR of the patients in our study was 80%, which may be acceptable. A phase II study on the use of this regimen for the treatment of advanced/recurrent head and neck cancer is awaited.
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Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
23 Schuller DE, Metch B, Stein DW, Mattox D, McCracken JD: Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group. Laryngoscope 1988;98:1205–1211. 24 Vokes EE, Mick R, Lester EP, Panje WR, Weichselbaum RR: Cisplatin and fluorouracil chemotherapy does not yield long-term benefit in locally advanced head and neck cancer: results from a single institution. J Clin Oncol 1991;9:1376–1384. 25 Clavel M, Vermorken JB, Cognetti F, et al: Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck: a phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994;5:521–526. 26 Gibson MK, Li Y, Murphy B, et al: Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:3562– 3567. 27 Wolf GT, Forastiere A, Ang K, et al: Workshop report: organ preservation strategies in advanced head and neck cancer – current status and future directions. Head Neck 1999;21: 689–693. 28 Schabel FM Jr, Trader MW, Laster WR Jr, Corbett TH, Griswold DP Jr: cis-Dichlorodiammineplatinum(II): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat Rep 1979; 63: 1459–1473. 29 Scanlon KJ, Newman EM, Lu Y, Priest DG: Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 1986; 83: 8923–8925. 30 Shirasaka T, Shimamoto Y, Ohshimo H, Saito H, Fukushima M: Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent tumor models in vivo. Cancer Chemother Pharmacol 1993; 32: 167– 172. 31 Kogashiwa Y, Yamauchi K, Nagafuji H, et al: Phase I study of S-1 plus nedaplatin in patients with advanced/recurrent head and neck cancer. Chemotherapy 2010;56:453–458.
Sato/Kogashiwa/Tsukahara/Yamauchi/ Kohno
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
Phase I Study of Nedaplatin Prior to S-1 in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Dai Sato a Yasunao Kogashiwa a Kiyoaki Tsukahara b Koichi Yamauchi a Naoyuki Kohno a
a
Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, and b Department of Otolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
Key Words Outpatient cancer therapy · Induction chemotherapy · Head and neck cancer · Squamous cell carcinoma
thrombocytopenia. The response rate (RR) was 57.1%. Conclusions: The recommended dose of NDP for a phase II study was determined to be 100 mg/m2. We concluded that our regimen was well tolerated and that the RR was acceptable. © 2014 S. Karger AG, Basel
Abstract Background: We previously reported on the regimen of S-1 plus nedaplatin (NDP), with S-1 was administered orally for 14 days and NDP intravenously on day 8. The maximum tolerated dose (MTD) of NDP was determined to be 90 mg/m2. The main toxicities were neutropenia and thrombocytopenia. This result was tolerated, but we believe there is a more effective and tolerable regimen. Thus, we investigated the S-1 regimen administered orally for 14 days, and NDP intravenously on day 1 in patients with locally advanced head and neck squamous cell carcinoma. Patients and Methods: Oral administration of S-1 (days 1–14) and intravenous NDP (day 1) were tested for patients with advance head and neck cancer in a phase I setting. The dose of S-1 was fixed and the dose of NDP was escalated from 70 mg/m2, with an increase of 10 mg/m2 per step, to find the MTD. Results: A total of 15 patients were registered. The MTD of NDP was determined to be 100 mg/m2. The main toxicities were neutropenia and
© 2014 S. Karger AG, Basel 0009–3157/14/0594–0314$39.50/0 E-Mail [email protected] www.karger.com/che
Introduction
Head and neck squamous cell carcinoma (HNSCC) ranks sixth among the most common cancers, accounting for approximately 5% of all cases of cancer [1]. The disease is potentially curable at an early stage, but 40–50% of patients present with locally advanced disease [2]. Induction chemotherapy is used in clinical practice and is thought to be beneficial for reducing the rate of distant metastases and increasing organ preservation and survival rates [3, 4]. 5-Fluorouracil (5-FU) and cisplatin (CDDP) chemotherapy (PF) is commonly used [5–7], but this treatment usually needs hospitalization because of the continuous infusion of these agents and need for adequate support for gastrointestinal and renal toxicity. Furthermore, the combination chemotherapy regimens Naoyuki Kohno, MD, PhD Department of Otolaryngology, Head and Neck Surgery Kyorin University School of Medicine 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan) E-Mail sukohno @ ks.kyorin-u.ac.jp
comprising 5-FU, CDDP and docetaxel (TPF) improved the rate of progression and overall survival; however, the regimen has been shown to cause severe myelotoxicity [8, 9]. Thus, we wished to develop an outpatient regimen for advanced/recurrent head and neck cancer patients that could be administered safely on an outpatient basis and that would have an antitumor activity equivalent to that of PF. For this purpose, we selected a combination of S-1 plus nedaplatin (NDP). S-1 is an oral anticancer. To improve compliance with treatment and reduce toxicity, oral chemotherapeutic agents have been rigorously tested in Japan. S-1 (Taiho Pahrmaceutical Co. Ltd., Tokyo, Japan) is an oral anticancer agent (tegafur, gimeracil and oteracil potassium at a molar ratio 1:0.4:1) based on the biochemical modulation of 5-FU [10]. S-1 is thought to be potentially more active than 5-FU, and several clinical reports have suggested encouraging clinical results in chemotherapy for gastric [11–13], colorectal [14], biliary tract [15], nonsmall cell lung cancer [16] and HNSCC [17, 18]. NDP is a platinum complex also developed in Japan, and believed to be an active agent for HNSCC [19]. This agent is thought to have an equivalent treatment effect, but with less renal and gastrointestinal toxicity compared with CDDP, and so more convenient administration could be achieved even on an outpatient basis. NDP was also reported to be efficacious and feasible combined with the pre-administration of 5-FU [20, 21]. We expected the synergistic effects of NDP prior to S-1 induction chemotherapy in patients with locally advanced HNSCC because there is a theory that asserts that prior administration of CDDP allows it to act as a biochemical modulator of 5-FU, increasing the antitumor effect. The purpose of this study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of combined S-1 plus NDP for the treatment of advanced HNSCC.
massive fixed soft tissue disease, and gross extension along the pharyngeal wall. The other eligibility criteria were as follows: a patient age of 20–75 years; an Eastern Cooperative Oncology Group performance status of 0 or 1; a life expectancy of at least 3 months; the ability to receive oral treatment, and adequate organ functions, including a leukocyte count of 4,000–12,000/mm3, a platelet count of 100,000/mm3, a hemoglobin level of 9.0 g/dl, serum transaminase (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase levels within twice the upper limit of normal, a serum bilirubin level of 1.5 mg/dl, a serum creatinine level within the upper limit of normal and an estimated creatinine clearance according to the method of Cockcroft-Gault of 80 ml/min. The ethics committee of our hospital approved the study and written informed consent was obtained from each of the patients. Treatment and Dose Escalation Schedule S-1 was given orally twice daily (after breakfast and after dinner) at a fixed dose based on the patient’s body surface area (BSA) as follows: BSA 21 days.
Patients and Methods Patients Patients eligible for this study were required to have histologically proven HNSCC (other than thyroid cancer) and measurable or evaluable lesions. Patients were required to have unresectable lesions with no previous history of treatment for head and neck cancer or recurrent cancer for which only radiotherapy had been administered; prior radiotherapy was permitted if the treatment had been completed at least 4 weeks before patient selection. However, a history of prior chemotherapy was not permitted. The criteria for unresectability were as follows: >180° encasement of the carotid artery; fixation to the prevertebral fascia;
Evaluation of Tumor Response Although this was a phase I study, we evaluated the response to the treatment as a reference for a future phase II study. The response to treatment was assessed based on the sum of the lesion diameters as measured directly with calipers or radiological images according to RECIST (Response Evaluation Criteria in Solid Tumors) using various imaging examinations performed within 2 weeks after administration of NDP in the first course. A complete response was defined as the disappearance of all target lesions for at least 4 weeks. A partial response was defined as a decrease in the sum of the diameters of the target lesions of at least 30%, taking the baseline sum of the diameters as a reference, for at least 4 weeks.
Phase I Study of NDP Prior to S-1 in Head and Neck Cancer
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
315
Table 1. Patient characteristics
Level
Case
Age, years
Sex
Cancer site
TNM stage
BSA, m2
TS-1, mg/day
1 (70 mg/m2)
1-1 1-2 1-3 1-4 1-5 1-6
64 67 67 63 63 63
M M M M M F
Hypopharynx Hypopharynx Hypopharynx Oropharynx Oropharynx Mouth floor
T4aN2b T4bN2c T4aN2c T4aN0 T4aN2c T4aN3
1.61 1.42 1.84 1.44 1.39 1.60
120 100 120 100 100 120
2 (80 mg/m2)
2-1 2-2 2-3
50 46 50
M M M
Larynx Tongue Tongue
T3N0 T4aN2b T3N2b
1.61 1.83 1.73
120 120 120
3 (90 mg/m2)
3-1 3-2 3-3
57 68 62
M M M
Larynx Larynx Larynx
T4bN0 T4aN2b T3N0
1.57 1.72 1.82
120 120 120
4 (100 mg/m2)
4-1 4-2 4-3
58 49 56
M M F
Hypopharynx Oropharynx Hypopharynx
T2N3 T3N2b T2N2c
1.80 1.82 1.54
120 120 120
Progressive disease was defined as an increase in the sum of the diameters of the target lesions of at least 20%, taking the smallest sum as a reference, or the appearance of any new lesions. Stable disease was defined as neither sufficient shrinkage to qualify for partial response, nor a sufficient increase to qualify for progressive disease, taking the smallest sum of the diameters as the reference. The response rate (RR) was regarded as the combined complete response and partial response.
Results
Patient Characteristics A total of 15 patients (13 men and 2 women) with a median age of 58.9 years (range 46–68) were enrolled in this study between June 2008 and March 2010. Table 1 shows the patient characteristics and the treatment schedule. All patients had no history of any previous treatment for head and neck cancer. Determination of the MTD and RD Table 2 shows the toxicities observed at each dose level. At dose level 1 (NDP 70 mg/m2), 1 of the first 3 patients experienced DLT (grade 4 neutropenia, grade 4 anemia, grade 4 thrombocytopenia, grade 3 serum creatinine increase); therefore, an additional 3 patients were started at the same dose. Since only 1 of the 6 patients at this dose level experienced DLT, we proceeded to the next dose level. At dose level 2 (NDP 80 mg/m2), none of the patients experienced DLT; therefore, we advanced to 316
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
dose level 3. At dose level 3 (NDP 90 mg/m2), none of the patients experienced DLT; therefore, we advanced to dose level 4. At dose level 4 (NDP 100 mg/m2), none of the patients experienced DLT. Based on these findings, dose level 4 (NDP 100 mg/m2) will be used as the RD for a phase II study. Response 1 of the 15 patients showed a complete response, and 7, 3 and 3 of the 14 patients showed partial response, no change and progressive disease, respectively. Case 1-1, who had a recurrent lesion and had received pre-radiation therapy, showed progressive disease. The RR of the patients to the treatment regimen examined in this study was 57.1%. The results are shown in table 3.
Discussion
Platinum-based chemotherapy is widely used for recurrent/metastatic HNSCC. Although the combination of TPF has become the more effective induction chemotherapy, the combination of PF has commonly been used for locally advanced HNSCC. The RR has been reported to be >70% when the regimen is used as induction chemotherapy [22–24] and about 30% when it is used for recurrent and/or metastatic disease [25, 26]. It was also reported that a function preservation rate of 66% was achieved without a deSato/Kogashiwa/Tsukahara/Yamauchi/ Kohno
Table 2. Incidence of toxicities
Case 1-1 1-2 1-3 1-4 1-5
Hematological toxicity anemia (G1) thrombocytopenia (G1) leukopenia (G3) neutropenia (G4) thrombocytopenia (G3) thrombocytopenia (G1) leukopenia (G1) neutropenia (G1)
1-6
anemia (G2) leukopenia (G1) neutropenia (G1)
2-1
anemia (G1) thrombocytopenia (G1) anemia (G1) anemia (G1)
Table 3. Tumor response
Nonhematological toxicity
Level
arrhythmia (G1)
1 (70 mg/m2) 2 (80 mg/m2) 3 (90 mg/m2) 4 (100 mg/m2)
hyperkalemia (G2) anorexia (G1) hyponatremia (G1) liver (G1)
CR
PR
NC 1 1 1
1
5 2 2 2
PD
CR = Complete response; PR = partial response; NC = no change; PD = progressive disease.
crease in the survival rate [27]. Recently, two phase III trials [8, 9] studied induction chemotherapy with TPF and provided indirect evidence of the efficacy of induction chemotherapy. The addition of docetaxel to CDDP/5-FU in both studies increased the RR as well as overall survival compared with that achieved with PF alone. Nevertheless, these combinations are stressful to patients, and the continuous infusion of 5-FU in these combinations reduces quality of life and usually needs hospitalization for adequate support for gastrointestinal and renal toxicity. As mentioned earlier, the combination of CDDP, and 5-FU is widely used for HNSCC [5–7]. These two drugs are known to be synergistic [28]. The optimal ad-
ministration order for these two drugs has not been established because of two opposing theories. One theory asserts that prior administration of CDDP allows it to act as a biochemical modulator of 5-FU, increasing the antitumor effect, whereas the other theory claims that prior administration of 5-FU allows it to act as a biochemical modulator of CDDP, increasing the antitumor effect. Scanlon et al. [29] found that cytotoxic activity was synergistically enhanced when CDDP was given before 5-FU in 2,780 human ovarian cancer cells; the cytotoxicity was 76% for CDDP followed by 5-FU and 59% for the reverse sequence. They proposed that CDDP pretreatment blocked methionine uptake into tumor cells and increased the synthesis of intercellular methionine, thus enhancing the cytotoxicity of 5-FU [30]. They also confirmed CDDP inhibition of L-methionine incorporation into ascitic Yoshida sarcoma cells and resultant elevated levels of intracellular reduced folate, i.e. CH2FH4 and FH4, in vivo. The uses of CDDP administered intravenously on day 1 were standard in combined CDDP and 5-FU chemotherapy. NDP was used instead of CDDP in this study because of its less toxic nature, convenience for use on an outpatient basis and antitumor effect as would be expected equivalent to other platinum agents. NDP is a platinum complex, and the spectrum of activity of NDP largely overlaps that of CDDP. Furthermore, skipping 5-FU administration was easy when early myelosuppression occurred, but NDP administration was difficult when myelosuppression occurred with only 5-FU administration. Therefore, the use of NDP administered intravenously on day 1 provides greater flexibility in the treatment schedule and provides the clinician with an opportunity to reduce unexpected toxicities. In our previous study [31], S-1 was given orally at a fixed dose for 14 days and NDP was administered intravenously on day 8 of S-1
Phase I Study of NDP Prior to S-1 in Head and Neck Cancer
Chemotherapy 2013;59:314–318 DOI: 10.1159/000357469
2-2 2-3 3-1 3-2 3-3
4-1 4-2
anemia (G2) anemia (G1) leukopenia (G2) neutropenia (G2) anemia (G1) leukopenia (G1) neutropenia (G1) anemia (G1) neutropenia (G1) thrombocytopenia (G1) anemia (G1) thrombocytopenia (G1)
liver (G1)
liver (G1) liver (G1)
4-3 G = Grade.
317
administration. The MTD of NDP was determined to be 90 mg/m2, the main toxicities were neutropenia and thrombocytopenia and the RR was 57.1%. In the present study, the MTD of NDP was determined to be 100 mg/m2 and the RR was 80%. Furthermore, the toxicities were the same as in the previous study.
In conclusion, we believe that treatment with S-1 plus NDP was well tolerated and feasible on an outpatient basis. The RR of the patients in our study was 80%, which may be acceptable. A phase II study on the use of this regimen for the treatment of advanced/recurrent head and neck cancer is awaited.
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Sato/Kogashiwa/Tsukahara/Yamauchi/ Kohno
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