Japanese Journal of Clinical Oncology Advance Access published online on March 1, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyl138
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© 2007 Foundation for Promotion of Cancer Research
Dose Escalation Study of Nedaplatin with 5-Fluorouracil in Combination with Alternating Radiotherapy in Patients with Head and Neck Cancer
1 Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya
2 Division of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
For reprints and all correspondence: Nobukazu Fuwa, 1-1 Kanokoden, Chikusaku, Nagoya, 464-8681, Japan. E-mail: nfuwa{at}aichi-cc.jp
Received July 19, 2006; accepted October 13, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: This study, with a large number of patients, confirms that after administration of 5-fluorouracil (5FU), a higher dose of nedaplatin (NDP) can be safely administered rather than a single therapy of NDP, as demonstrated in a phase I study.
Methods: The subjects were 52 patients with stage II–IV (M0) head and neck cancer other than nasopharyngeal cancer. Alternating chemoradiotherapy was performed using the following method. Initially, chemotherapy was administered. For chemotherapy, 5FU at 700 mg/m2/24 h was intravenously administered for 5 days (days 1–5), and NDP was administered on day 6. We established three dose groups: level 1, 120 mg/m2; level 2, 140 mg/m2; and level 3, 150 mg/m2 (n = 13 or more per group).
Results: The maximum acceptable dose of NDP (150 mg/m2) was confirmed. The 5-year overall survival rates were 77% (95% CI: 66–90%) in all subjects and 75% (95% CI: 61–92%) in the stage III/IV patients. The 5-year progression-free survival rates were 73% (95% CI: 62–87%) in all subjects and 72% (95% CI: 57–89%) in the stage III/IV patients. Conclusions: After administration of 5FU, a higher dose of NDP can be safely administered. This alternating chemoradiotherapy showed potent antitumor effects. The efficacy of chemotherapy with NDP and 5FU should be compared to that of chemotherapy with CDDP and 5FU.
Key Words: head and neck cancer • alternating chemoradiotherapy • nedaplatin • 5-fluorouracil • radiotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Currently, cisplatin (CDDP) is administered as a key drug for chemotherapy for head and neck cancer (1–3). However, CDDP causes digestive disorders, such as nausea and vomiting, and renal damage, raising a clinically important issue (4–8).
Nedaplatin (NDP) is the second-generation platinum complex that was developed in Japan to relieve the side effects of CDDP, including digestive symptoms and renal toxicity, and to enhance its antitumor effects (9). In clinical practice, NDP does not cause severe digestive symptoms or renal toxicity (10). It has been suggested that NDP is as effective as CDDP or more effective than CDDP in patients with squamous cell carcinomas such as head and neck cancer (11–14), cervical carcinoma (15, 16), and esophageal cancer (17–19). Currently, single therapy with CDDP is rarely administered to treat these carcinomas. To achieve more potent antitumor effects, CDDP is combined with 5-fluorouracil (5FU) (20–23).
Combination therapy with NDP and 5FU may exhibit synergistic effects in vivo (24). In addition, it has been confirmed that NDP therapy after administration of 5FU reduces bone marrow toxicity more than 5FU therapy after administration of NDP, thereby enhancing antitumor effects (25). Our phase I study suggested that NDP therapy after administration of 5FU allows a higher dose of NDP compared to single therapy with NDP (26,27). Therefore, the combination of NDP and 5FU may reduce adverse reactions and enhance antitumor effects more than the standard combination of CDDP and 5FU.
In this clinical study, we performed alternating chemoradiotherapy, in which chemotherapy with NDP and 5FU was combined with radiotherapy, in 52 patients with head and neck cancer, excluding nasopharyngeal cancer, without distant metastasis. We employed this alternating therapy based on good results in patients with nasopharyngeal cancer and a low incidence of mucositis, which is a limitation of concurrent therapy with 5FU and radiation (28,29).
The primary endpoint of this study was to confirm in a large number of patients that, after administration of 5FU, a higher dose of NDP can be safely administered in comparison to single therapy with NDP, as demonstrated in a phase I study. The secondary endpoint of this study was to confirm the efficacy of this therapy by calculating the 5-year overall/progression-free survival rates.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Selection
The subjects met the following criteria: (i) patients with squamous cell carcinoma of the head and neck other than nasopharyngeal cancer; (ii) patients with stage II or higher lesions (without distant metastasis) according to the TNM staging published in 1997 (30); (iii) patients in whom the performance status (PS) was evaluated as 0–2 according to the classification described by the Eastern Cooperative Oncology Group (ECOG); (iv) ages ranged from 15 to 74 years; (v) bone marrow function was maintained (leukocyte count: 3000/mm2 or more, platelet count: 100 000/mm2 or more); (vi) patients without liver, kidney, heart, or lung dysfunction in whom 24-h creatinine clearance was 60 ml/min or more; (vii) patients untreated for this cancer; (viii) patients without active double cancer at the start of treatment who had not undergone radiotherapy in the head and neck region; and (ix) patients from whom written informed consent was obtained.
To determine the extent of tumor infiltration, we employed magnetic resonance imaging (MRI) and pharyngeal fiberscopy in the primary lesion, and computed tomography (CT) or MRI in the cervical lymph nodes. To investigate remote metastasis, we performed chest X-P, hepatic echography or CT, bone scintigraphy and upper digestive tract endoscopy.
For combination therapy with radiation and chemotherapeutic agents, we employed alternating therapy. Patients with nasopharyngeal cancer achieved good results (28,29). Initially, chemotherapy was administered, followed by 4 weeks of radiotherapy (irradiation method A; wide field irradiation) 2 days after chemotherapy, a second course of chemotherapy after 2 days, and a second course of a reduced field radiotherapy (irradiation method B) after 2 days.
This clinical trial was approved by the Ethics Committee of Aichi Cancer Center Hospital.
Radiation Therapy
Radiotherapy was performed five times a week by irradiating 1.8–2 Gy of photon beam in a fraction using a 6 MV linear accelerator. The initial irradiation (irradiation method A) was performed five times a week for 4 weeks at a radiation dose of 1.8 Gy (total dose: 36 Gy). The late irradiation (irradiation method B) was performed five times a week for 3 weeks at a radiation dose of 2 Gy (total dose: 30 Gy) (A+B: 66 Gy).
In irradiation method A, using the bilateral opposing portal irradiation method, 36 Gy in 20 fractions was irradiated between the primary lesion and the middle cervical lymph nodes with a 2-cm safety margin; whereas 36 Gy of photon beam was irradiated between the lower cervical part and the supraclavicular fossa using the anterior single irradiation method. In patients without cervical lymph node metastasis, we did not perform irradiation between the inferior cervical region and the supraclavicular fossa.
In irradiation method B, an area involving the tumor site on the initial consultation and a 1-cm safety margin was established as the planning target volume (PTV). In the primary site, either the conformal radiation method or the bilateral opposing portal irradiation was selected. In the cervical lymph node region, a 1-cm safety margin was established around the site of lymph node metastasis detected on the initial consultation, and anteroposterior opposing portal irradiation of a 6 MV photon beam or electronic beam irradiation was performed. The radiation dose for the spinal cord was established as 40 Gy or less. In patients with tongue cancer in whom low dose rate brachytherapy was possible, brachytherapy was performed instead of irradiation method B.
Chemotherapy
For chemotherapy, 5FU at 700 mg/m2/24 h was intravenously administered for 5 days (days 1–5). NDP was dissolved in 500 ml of physiological saline, and intravenously administered over 6 h on day 6. In our phase I study, the maximum acceptable dose (MAD) of NDP was 150 mg/m2; however, the phase I study investigated a small number of patients and the dose of NDP was established based on the results of one course of chemotherapy (27). Considering that the protocol of this clinical study involves two courses of chemotherapy, we established three dose groups: level 1, 120 mg/m2; level 2, 140 mg/m2; and level 3, 150 mg/m2. At least 13 patients per group were registered based on calculations using the continual reassessment method (31).
On the day of NDP administration, the daily volume of drip infusion was 2000 ml. As anti-emetic agents, the combination of a steroid and ondansetron hydrochloride or granisetron hydrochloride was administered before administration of NDP.
When the serum creatinine level was 1.5 mg/dl or more at the start of the second chemotherapy, chemotherapy was not performed. In patients with a leukocyte count of 3000/mm2 or less, or a platelet count of 100 000/mm2 or less, chemotherapy was postponed, and radiotherapy was performed. When hematological data 2 weeks after radiotherapy did not meet the above criteria, the second chemotherapy was not performed. When the first chemotherapy decreased the leukocyte count to 1000/mm2 or less or the platelet count to 25 000/mm2 or less, the doses of 5FU and NDP in the subsequent chemotherapy were reduced by 25%. In patients with a serum creatinine level exceeding 1.5 mg/dl, the dose of NDP was decreased by 25%.
Patient Assessments
Concerning toxicity, we investigated changes in the leukocyte count, neutrophil count, platelet count, and hemoglobin level, liver function, kidney function, changes in the oral mucosa and vomiting in accordance with the WHO criteria. During treatment, the complete cell count was measured at least twice a week and blood biochemistry was performed once a week. To evaluate the antitumor effects of this therapy, pharyngeal fiberscopy and MRI were performed within 2 months after the end of treatment. The treatment response of the cervical lymph nodes was evaluated based on the MRI or CT findings and the palpation findings in accordance with the WHO criteria (32).
The subjects consulted the outpatient clinic at 4-week intervals for 1 year after the end of treatment, at 8-week intervals in the second and third years of follow-up, and at 3-month intervals after 3 years of follow-up. Follow-up MRI was performed at 4-month intervals for 2 years after the end of treatment and at 6-month intervals thereafter. Chest X-rays were performed at 6-month intervals and liver echography or CT and bone scintigraphy were performed every year until 3 years after the end of treatment.
We calculated the overall survival (OS) rate, progression-free survival (PFS) rate, cause-specific survival rate, local relapse-free survival rate and distant metastasis-free survival rate by the Kaplan–Meier method (33).
Survival was calculated (as of 1 July 2006), using the start of treatment as the starting point. In calculating PFS, the day on which an increase in the tumor size was confirmed, the day on which a new lesion was confirmed and the day of death related to another disease despite tumor control were regarded as events. In calculating OS, deaths related to various causes were regarded as events.
Patients who died of disorders/factors other than cancer were classified as primary disease-related death when the tumor was not controlled at death. Patients, whose death was associated with treatment-related adverse effects that could not be ruled out despite tumor control, were classified as primary disease-related death.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients' Characteristics
Between November 1997 and June 2003, 53 patients were registered. However, we evaluated 52 patients excluding one who desired surgery during treatment (Table 1). The subjects consisted of 41 males and 11 females. Ages ranged from 26 to 74 years, with a median of 58 years. The PS score was evaluated as 0 in 32 patients, 1 in 16 patients and 2 in four patients. Concerning the site, 21 patients had oral cancer, 12 patients had laryngeal cancer, nine patients had oropharyngeal cancer, and eight patients had hypopharyngeal cancer. Primary lesions were unclear in two patients. In all patients, the histopathological type was squamous cell carcinoma. According to the TNM staging published in 1997, the stage was evaluated as II in 19 patients, III in 15 patients, IVA in 16 patients and IVB in two patients. In six patients, surgery was not considered to be possible or appropriate based on the extent of tumor infiltration. The remaining 46 patients refused surgery. In the 52 patients, we investigated the adverse reactions and antitumor effects of this therapy and the survival rate.
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Follow-up studies were sufficiently performed in all the 52 patients as at July 2006. The median follow-up duration for all patients was 67 months (range: 6–105 months).
Treatment Delivery
Radiotherapy was completed in all patients. The total radiation dose ranged from 30.6 Gy to 72 Gy in primary lesions (median: 66 Gy) and from 45 Gy to 76.2 Gy in metastatic cervical lymph node lesions (median: 66 Gy). Brachytherapy was performed in 15 patients with tongue cancer, one patient with oral floor cancer, and one patient with buccal mucosal carcinoma (total: 17 patients). The sources of radiation consisted of Au grain implant in 11 patients, cesium needle implant in five patients and the two implants in one patient. The radiation dose of the brachytherapy ranged from 40 to 60 Gy (median: 50 Gy). The radiotherapy period ranged from 27 to 75 days, with a median of 57 days.
The dose of NDP was established as 120 mg/m2 in 17 patients, 140 mg/m2 in 14 patients and 150 mg/m2 in 21 patients. The number of chemotherapy courses was one in three patients, two in 46 patients, and three in three patients; 94% of the patients underwent two courses or more of chemotherapy. In the three patients, chemotherapy was discontinued after the end of the first course for refusal, susurrus aurium and bone marrow toxicity.
The treatment period involving chemotherapy and radiotherapy ranged from 44 to 87 days, with a median of 66 days.
Toxicity
Toxicity is summarized in Table 2. Grade 3 or higher toxic changes included granulocytopenia in 15 patients, thrombopenia in 15 patients, anemia in seven patients, mucocitis in four patients, vomiting in one patient and liver dysfunction in one patient. Grade 2 nephropathy was observed in three patients. However, in these patients, the abnormal findings returned to the normal values.
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Blood toxicity increased with an increase in the dose of NDP. However, there was no increase in the incidence of nephropathy or vomiting. In the level 3 (150 mg/m2) group (n = 21), grade 4 granulocytopenia was noted in two patients and grade 4 thrombopenia in four patients, confirming that the MAD is 150 mg/m2, as demonstrated in a phase I study (27).
Treatment Results
Complete response (CR) was achieved in 51 patients and partial response (PR) in one patient. In the patient with PR, cervical lymph node dissection was performed after treatment, and there were no residual cancer cells. Relapse was detected in seven patients: primary sites, two patients; cervical lymph node, three patients; primary site and cervical lymph node, one patient; and distant metastasis, one patient. Of the patients with relapse, surgery was performed in three patients, chemoradiation therapy in one patient, and chemotherapy in one patient. Cancer was controlled in only one patient who underwent surgery in the primary lesion (as of September 2005). Ten patients died: seven patients died of primary diseases, one patient died of another disease and two patients died from non-medical events.
Figure 1 shows overall survival curve. The 5-year survival rate for all subjects was 77% (95% confidence interval: 66–90%) and the 5-year survival rate for the stage III/IV patients was 75% (95% CI: 61–92%). Figure 2 shows progression-free survival curve. The 5-year survival rate for all subjects was 73% (95% CI: 62–87%) and the 5-year survival rate for the stage III/IV patients was 72% (95% CI: 57–89%).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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As described above, NDP is a second-generation CDDP derivative that was developed to enhance the antitumor effects of CDDP and relieve renal dysfunction and digestive disorders such as vomiting (9). In clinical practice, the incidences of renal dysfunction and digestive disorders were low (10), and the antitumor effects of NDP differed among the histopathological types; in particular, this agent exhibited potent antitumor effects in patients with squamous cell carcinoma (11–19). In addition, an in vivo study suggested that NDP therapy after administration of 5FU allows a higher dose of NDP compared to 5FU therapy after administration of NDP, enhancing the antitumor effects (24,25).
The maximum tolerable dose (MTD) of NDP alone was 120 mg/m2 (26). In our phase I study, the MTD and MAD were 160 and 150 mg/m2, respectively, when NDP was administered on day 6 after administration of 5FU at 3500 mg/m2/5 days, suggesting that the dose of NDP can be markedly increased (27). In this study involving a large number of patients, similar results were obtained; no patient showed grade 3 or higher renal dysfunction. Grade 3 or higher vomiting was noted in only one patient, confirming a low incidence of renal dysfunction and digestive disorders. Furthermore, the incidence of blood toxicity, especially thrombopenia, increased with an increase in the dose of NDP. However, the incidences of renal dysfunction and digestive symptoms did not increase. In comparison to the adverse effects of CDDP in the literature (4–8), NDP caused more marked blood toxicity, especially thrombopenia, and less frequently caused renal dysfunction and digestive symptoms.
The survival rates of this study were very satisfactory. As noted earlier, the 5-year overall survival rates in the subjects and the stage III/IV patients were 77 and 75%, respectively. The 5-year progression-free survival rates were 73 and 72%, respectively. We must consider that surgery was impossible or inappropriate in only six patients. However, our results markedly exceeded the results of chemoradiation therapy in the literature (34–39), suggesting the efficacy of chemotherapy with 5FU and NDP and the usefulness of alternating chemoradiotherapy.
Currently, the concurrent method in which radiotherapy and chemotherapy are concurrently performed is mainly employed in the treatment of head and neck cancer. Only a few studies have reported on the alternating method. However, its efficacy was confirmed in a randomized controlled study involving patients undergoing radiotherapy alone (39,40) and a large-scale meta-analysis (41). In the concurrent method, treatment-related adverse effects, especially mucositis, may occur, making administration of high-dose CDDP and 5FU difficult; therefore, in most patients, the doses of CDDP and 5FU are decreased (34,35) or single therapy with CDDP is administered (1,37).
Adelstein conducted a comparative study in patients with advanced cancer in which surgery was impossible, excluding nasopharynx and paranasal cancer, and established three groups. One group was treated by radiotherapy alone. Another group was treated by concurrent therapy with high-dose CDDP, which was administered three times every 3 weeks, and radiotherapy. A third group was treated by concurrent therapy with high-dose CDDP/5FU and radiotherapy involving discontinuation for about 3 weeks in the course (1). One of the reasons for the discontinuation period was to reduce mucositis related to concurrent therapy with CDDP/5FU and radiotherapy. The survival rate was highest in the group treated by concurrent therapy with high-dose CDDP, which was administered three times every 3 weeks, and radiotherapy. There was no marked difference in the survival rate between the group treated by radiotherapy alone and the group treated by concurrent therapy with high-dose CDDP/5FU and radiotherapy involving discontinuation for about 3 weeks in the course. This finding does not reflect that the combination of high-dose CDDP and 5FU exhibits less potent antitumor effects than high-dose CDDP, but suggests that 3 weeks of discontinuation in the course of treatment reduces the antitumor effects of this combination.
Alternating therapy facilitates administration of high-dose anticancer agents, since it causes milder mucositis than concurrent therapy. The results of our treatment in which alternating therapy was employed were good and the rate of treatment completion was also sufficiently high (28,29,39,40). When high-dose anticancer agents are required and the irradiation field is extensive, alternating therapy may be very significant. Either concurrent or alternating therapy should be selected in accordance with the adverse effects and purpose of anticancer agents, and the site and size of the irradiation field.
In conclusion, NDP therapy after administration of 5FU allowed a higher dose compared to single therapy with NDP. In addition, the antitumor effects of this therapy were marked and the adverse effects were within the permissible ranges. In a comparative study, combination chemotherapy with NDP and 5FU should be compared with the current standard therapy with CDDP and 5FU for head and neck cancer. Alternating chemoradiotherapy achieves good compliance in administering high-dose chemotherapy and should be compared with the concurrent method, which is currently used as standard therapy for head and neck cancer, in a comparative study.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgment |
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This study was supported by a Grant-in-Aid for Cancer Research (14–12) by the Ministry of Health, Labour and Welfare of Japan.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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