Pubmed Result

1. Gan To Kagaku Ryoho. 2016 Feb;43(2):243-6.
[Maxillary Cancer with Metastasis to the Rouviere Nodes -- Complete Response to

Chemoradiotherapy Using a Selective Intra-Arterial Infusion Technique].
[Article in Japanese]
Yamashiro K(1), Heianna J, Azama K, Iraha Y, Yamashiro T, Kinoshita R, Toita T,

Toyama M, Agena S, Maeda H, Suzuki M, Murayama S.
Author information:
(1)Dept. of Radiology, University of the Ryukyus Hospital.
We report a case of advanced maxillary cancer with multiple lymph node

metastases, including metastasis to the Rouviere nodes, which were successfully
treated with chemoradiotherapy using a selective intra-arterial infusion
technique.A 71-yearold man presented to our hospital with complaints of a
staggering gait and epistaxis.He was diagnosed with maxillary cancer (squamous
cell carcinoma)classified as T4a disease.Because multiple lymph node metastases
were detected, including metastasis to the Rouviere nodes, radical surgical
treatment was considered inadequate.Thus, the patient was treated with concurrent
chemoradiotherapy with selective intra-arterial infusion of nedaplatin and
docetaxel.After chemoradiotherapy, the maxillary cancer and lymph metastasis
nearly resolved and the patient achieved a complete response.No additional
surgery was needed, and the patient was discharged.We suggest that
chemoradiotherapy using a selective intra-arterial infusion technique is a highly
effective treatment option for patients with maxillary cancer and metastasis to
the Rouviere nodes.
PMID: 27067691 [Indexed for MEDLINE]
2. Auris Nasus Larynx. 2015 Oct;42(5):377-81. doi: 10.1016/j.anl.2015.02.005. Epub

2015 Mar 3.
Management for squamous cell carcinoma of the nasal cavity and ethmoid sinus: A
single institution experience.
Homma A(1), Nakamaru Y(2), Sakashita T(2), Onimaru R(3), Terasaka S(4), Tsuchiya
K(3), Yoshida D(3), Yasuda K(3), Hatakeyama H(2), Furusawa J(2), Mizumachi T(2),
Kano S(2), Shirato H(3), Fukuda S(2).
Author information:
(1)Department of Otolaryngology-Head & Neck Surgery, Hokkaido University Graduate
School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Electronic address: ak-homma@med.hokudai.ac.jp.
(2)Department of Otolaryngology-Head & Neck Surgery, Hokkaido University Graduate
School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
(3)Department of Radiology, Hokkaido University Graduate School of Medicine,
Sapporo, Japan.
(4)Department of Neurosurgery, Hokkaido University Graduate School of Medicine,
Sapporo, Japan.
OBJECTIVE: Here we report our experience of patients with squamous cell carcinoma
(SCC) of the nasal cavity and ethmoid sinus (NC&ES) together with an analysis of
treatment outcomes.
METHODS: A retrospective analysis was performed using data from 25 consecutive
patients treated between 2000 and 2012. Four patients were diagnosed with T1, 3
with T2, 4 with T3, 7 with T4a, and 7 with T4b disease. No patient had lymph node
metastasis.
RESULTS: Twelve patients were treated with surgery with/without radiotherapy and
with/without chemotherapy. Of these, 4 underwent endoscopic surgery without an
open approach and 3 required an anterior skull base approach. Thirteen were
treated with radiotherapy; 1 with radiotherapy alone, and 4 and 8 with
intravenous and intra-arterial chemotherapy, respectively. The 5-yr overall
survival for T1-3, T4a, and T4b disease was 53.9%, 71.4%, and 29.0%,
respectively. The 5-yr disease-specific survival for T1-3, T4a, and T4b disease
was 74.1%, 71.4%, and 29.0%, respectively.
CONCLUSION: Our treatment policy for patients with SCC of NC&ES, which basically
follows the NCCN guideline, was considered to be appropriate. However, several
points in terms of surgery and non-surgical approach remain to be solved through
further research.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.anl.2015.02.005
3. J Stroke Cerebrovasc Dis. 2014 Feb;23(2):387-9. doi:

10.1016/j.jstrokecerebrovasdis.2013.01.014. Epub 2013 Feb 17.
5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation

fulfilling criteria for recombinant tissue plasminogen activator therapy.
Kinno R(1), Kii Y(2), Uchiyama M(3), Owan Y(3), Yamazaki T(3), Fukui T(3).
Author information:
(1)Department of Internal Medicine, Showa University Northern Yokohama Hospital,
Kanagawa, Japan. Electronic address: kinno@med.showa-u.ac.jp.
(2)Department of Rehabilitation Medicine, Showa University Northern Yokohama
Hospital, Kanagawa, Japan.
(3)Department of Internal Medicine, Showa University Northern Yokohama Hospital,
Kanagawa, Japan.
A 61-year-old man underwent systemic chemotherapy with intravenous infusion of

nedaplatin and 5-fluorouracil. On the day after the final drug administration, he
suddenly experienced difficulty in speaking followed by left-sided weakness. His
National Institutes of Health Stroke Scale score was 12. A computed tomographic
scan of the brain performed 4 hours after symptom onset revealed no
abnormalities. Because all eligibility criteria were fulfilled, he immediately
underwent intravenous recombinant tissue plasminogen activator therapy. He
recovered from neurologic complications on day 14. An initial magnetic resonance
imaging scan of his brain revealed a hyperintense area in the bilateral white
matter and corpus callosum, and these abnormalities had improved on the follow-up
scan. We diagnosed him with 5-fluorouracil-induced leukoencephalopathy with acute
stroke-like presentation. Our experience suggests that 5-fluorouracil-induced
leukoencephalopathy potentially fulfills all eligibility criteria for recombinant
tissue plasminogen activator therapy.
Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All

rights reserved.
DOI: 10.1016/j.jstrokecerebrovasdis.2013.01.014
4. Oral Oncol. 2010 Dec;46(12):860-3. doi: 10.1016/j.oraloncology.2010.10.001. Epub
2010 Nov 2.
Superselective intra-arterial chemoradiotherapy with docetaxel-nedaplatin for

advanced oral cancer.
Kobayashi W(1), Teh BG, Sakaki H, Sato H, Kimura H, Kakehata S, Nagahata M.
Author information:
(1)Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate
School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan.
wako@cc.hirosaki-u.ac.jp
Cisplatin-based, superselective, intra-arterial chemotherapy concurrent with

radiotherapy (SSIACRT) has gained wide acceptance as a common/curative treatment
for advanced head and neck cancer. We combined nedaplatin (CDGP) with docetaxel
(DOC) as a new combination in SSIACRT for advanced oral squamous cell carcinoma
in 2003. Twenty-two patients with advanced oral cancer were treated by
radiotherapy (66 Gy) concurrent with superselective intra-arterial DOC (40
mg/body) and CDGP (80 mg/m²) infusion between 2003 and 2009. Complete response
was achieved in 18 (81.8%) of the 22 patients. Of the 17 patients with positive
neck disease, 16 (94%) were assessed as disease-free. The 5-year overall survival
rate was 78.5%, and the major adverse effects were leukocytopenia and mucositis.
Five patients (22.7%) developed distant metastases post-treatment. These results
indicate that intra-arterial docetaxel-nedaplatin infusion concurrent with
radiotherapy is efficacious for advanced oral cancer. The side effects are easily
manageable, and the most important outcome of the treatment is the preservation
of patients' quality of life (QOL) and improved prognosis.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.oraloncology.2010.10.001
5. Pharm Res. 2010 Sep;27(9):1893-9. doi: 10.1007/s11095-010-0189-4. Epub 2010 Jun

15.
Pharmacokinetics and toxicodynamics of oxaliplatin in rats: application of a

toxicity factor to explain differences in the nephrotoxicity and myelosuppression
induced by oxaliplatin and the other platinum antitumor derivatives.
Hanada K(1), Suda M, Kanai N, Ogata H.
Author information:
(1)Department of Biopharmaceutics, Meiji Pharmaceutical University, 2-522-1
Noshio, Kiyose, Tokyo 204-8588, Japan. hanada@my-pharm.ac.jp
PURPOSE: We previously reported that the product of the area under the plasma
concentration-time curve (AUC(p)) and a toxicity factor, which in turn was
defined as the product of the apparent ratio of tissue to plasma concentration
(Kp(app)) and the apparent hydrolysis rate constant (k(hydrolysis)), was a
determinant of the different degrees of toxicities induced by platinum drugs,
cisplatin, carboplatin and nedaplatin. We tested this model with oxaliplatin.
METHODS: Oxaliplatin was administered to rats by intravenous bolus or infusion,
and the linearity of pharmacokinetics, total clearance and the Kp(app) at steady
state were determined. k(hydrolysis) was determined in vitro. Nephrotoxicity was
estimated from blood urea nitrogen (BUN) level and myelosuppression from platelet
count.
RESULTS: The platelet count decreased dose-dependently, but BUN did not increase
significantly. The degree of decrease in platelet count caused by oxaliplatin and
the other three platinum drugs was not explained by the differences of AUC(p) and
AUC for the bone marrow but was fitted by a combination of AUC(p) and the
toxicity factor (r = 0.908, P < 0.001).
CONCLUSION: The product of AUC(p) and the toxicity factor is a useful predictor
of the degree of toxicity of oxaliplatin as has been observed with other platinum
drugs.
DOI: 10.1007/s11095-010-0189-4
6. Gan To Kagaku Ryoho. 2009 Apr;36(4):631-5.
[Two cases of recurrent oral cancer responding to radiochemotherapy with

selective intra-arterial infusion of nedaplatin].
Yamashita Y(1), Kuroda Y, Yamamoto T, Goto M.
Author information:
(1)Department of Oral and Maxillofacial Surgery, Saga Medical School.
Nedaplatin, a cisplatin derivative, has been reported to be an effective

anti-tumor agent for head and neck cancer. We experienced two patients with
advanced recurrent oral cancers who received combination therapy of
intra-arterial nedaplatin infusion and radiation therapy, and tumoricidal effects
were obtained in these cases. At the end of 3 courses, a partial response(PR)was
obtained with regression of the tumor in the first case, and FDGPET showed a
complete regression of recurrent tumor for a complete response(CR)in another
case. This combination therapy is quite safe and effective for the treatment of
advanced oral cancers.
7. Gan To Kagaku Ryoho. 2009 Feb;36(2):309-12.
[A case of elderly esophageal adenocarcinoma successfully treated with daily

low-dose nedaplatin (CDGP) and continuous infusion of 5-FU combined with
radiation].
Osawa S(1), Yamada T, Iwaizumi M, Hamaya Y, Takagaki K, Nishino M, Kodaira C,

Muramatsu A, Yoshida K, Sugimoto K, Futami H, Furuta T, Ikuma M.
Author information:
(1)First Dept. of Medicine, Hamamatsu University School of Medicine.
We report an elderly patient with esophageal adenocarcinoma in whom a complete

response (CR) was obtained by chemoradiotherapy using daily low-dose nedaplatin
(CDGP) and continuous infusion of 5-FU. A 86-year-old man who had non-tuberculous
mycobacterial infection was admitted for dysphagia, and diagnosed with Stage II A
(T2N0M0) esophageal adenocarcinoma of the lower esophagus according to the TNM
classification (sixth edition) of the International Union against Cancer (UICC).
Chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5- FU was
performed, and thereafter one cycle of chemotherapy using CDGP and 5-FU was
added. As the side effects of treatment, grade 3 leucopenia was observed while he
was receiving chemoradiotherapy. A year later, he presented with grade 2
pericardial and pleural effusion and recovered with conservative treatment. CR
was obtained and has been continued for two years. Definitive chemoradiotherapy
using daily low-dose CDGP and continuous infusion of 5-FU is an effective choice
for elderly and high-risk patients with esophageal adenocarcinoma.
8. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008 Jun;105(6):714-9. doi:
10.1016/j.tripleo.2007.11.023. Epub 2008 Apr 24.
Treatment results of continuous intra-arterial CBDCA infusion chemotherapy in

combination with radiation therapy for locally advanced tongue cancer.
Fuwa N(1), Kodaira T, Furutani K, Tachibana H, Nakamura T.
Author information:
(1)Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
nfuwa@aichi-cc.jp
OBJECTIVE: The objective of this study was to improve the treatment results for
locally advanced tongue cancer. A combination of radiotherapy with continuous
intra-arterial therapy using CBDCA was used.
STUDY DESIGN: According to TNM staging (1997), 29 patients had stage III lesions
and 11 patients had stage IV (M0) lesions. A catheter was inserted through the
lingual artery in 26 patients, through the external carotid artery in 11
patients, and through the faciolingual trunk in 2 patients. CBDCA was
continuously infused for 4 to 6 weeks. With IA chemotherapy, external irradiation
(median dose: 46.8 Gy) was simultaneously performed, and 1 to 2 courses of
systemic chemotherapy were performed in 19 patients before intra-arterial
chemotherapy.
RESULTS: The 5-year local control rate was 65%. The 5-year OS rate was 39.5%.
There were no clinically significant adverse side effects.
CONCLUSION: Continuous IA CBDCA and concurrent radiation therapy can be delivered
safely with good efficacy for locally advanced carcinoma of the tongue.
DOI: 10.1016/j.tripleo.2007.11.023
9. J Pharm Pharmacol. 2008 Mar;60(3):317-22. doi: 10.1211/jpp.60.3.0006.
Use of a toxicity factor to explain differences in nephrotoxicity and

myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin
and nedaplatin in rats.
Hanada K(1), Asano K, Nishimura T, Chimata T, Matsuo Y, Tsuchiya M, Ogata H.
Author information:
(1)Department of Biopharmaceutics, Meiji Pharmaceutical University, 2-522-1
Noshio, Kiyose, Tokyo 204-8588, Japan. hanada@my-pharm.ac.jp
The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in
their toxicity. The relationships between the pharmacokinetics of these drugs and
developed parameters for predicting their nephrotoxicity and myelosuppression
were investigated. The drugs were administered to male Wistar rats by intravenous
bolus or infusion, and linearity of pharmacokinetics, total clearance and the
apparent ratio of tissue concentrations of unchanged drug to plasma concentration
(Kp app) at steady state were determined. Apparent hydrolysis rates of each drug
were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by
blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to
platinum was estimated as the product of the area under the plasma
concentration-time curve for unchanged drug (AUC p), Kp app and the apparent
hydrolysis rate constant (k hydrolysis), and toxicity factor was defined as the
product of Kp app x k hydrolysis as an intrinsic drug parameter. The relationship
between AUC p x toxicity factor and BUN fitted well to an Emax model. In bone
marrow, this function was also correlated with platelet count. In summary, the
product of AUC p x toxicity factor is a factor determining the pharmacokinetics
of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this
toxicity factor may be a useful parameter for predicting the degree of toxicity
of platinum antitumour compounds.
DOI: 10.1211/jpp.60.3.0006
10. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008 Jun;105(6):783-9. doi:
10.1016/j.tripleo.2007.07.031. Epub 2008 Feb 21.
A new method of selective intra-arterial infusion therapy via the superficial

temporal artery for head and neck cancer.
Fuwa N(1), Kodaira T, Furutani K, Tachibana H, Nakamura T.
Author information:
(1)Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
nfuwa@aichi-cc.jp
OBJECTIVE: We proposed a new selective intra-arterial infusion method via the

superficial temporal artery for preventing dislocation of the catheter.
STUDY DESIGN: This study included 92 patients who were treated by this
combination therapy between May 1999 and December 2004. Primary tumor sites
included the tongue in 73 patients, base of the tongue in 6 patients, floor of
mouth in 4 patients, buccal mucosa in 4 patients, and other sites in 5 patients.
Seventy-three patients had untreated lesions and 19 patients had recurrent
lesions. Under fluoroscopy, a catheter was inserted into the target artery
through the superficial temporal artery using a catheter exchange method.
RESULTS: In 76 (83%) of 92 patients, a catheter was successfully inserted into
the target artery. In 4 patients, the catheter fell out of the selected artery
during treatment.
CONCLUSION: This selective intra-arterial method will be an important modality
for advanced tongue cancer.
DOI: 10.1016/j.tripleo.2007.07.031
11. Gan To Kagaku Ryoho. 2007 Nov;34(11):1777-81.
[Clinical trial of chemotherapy by superselective intra-arterial infusion of

nedaplatin (CDGP) and 5-FU with concurrent radiotherapy for advanced oral
cancer].
Aoki K(1), Tatebayashi S, Imai Y, Yamakawa N, Yagyuu T, Kajihara A, Nakagawa H,

Kirita T.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Nara Medical University.
Nedaplatin (CDGP) is one of the platinum-derivatives to further improve the

anti-tumor effect and to reduce adverse effects of cisplatin, such as renal
toxicity. The present study evaluated the efficacy and adverse events of
chemotherapy by superselective intra-arterial infusion of CDGP and 5-FU combined
with concurrent radiotherapy in patients with advanced squamous cell carcinoma of
the oral cavity. Sixteen patients were treated with CDGP plus 5-FU in combination
with concurrent irradiation of 40.60 Gy. Ten patients were treated as a
preoperative therapy and 6 as a definitive therapy. The overall clinical response
rate was 93.8% and histological effects according to the grading system of
Shimosato et al. were seen in 13/16 (81.2%). Adverse events were observed in all
patients. Mucositis, leucopenia and thrombocytopenia (>Grade 2) were seen in 13
(81.3%), 11 (68.8%) and 8 (50.0%) of 16 patients, respectively. The overall
2-year and 4 months survival rate was 86.2%. One patient have died of disease and
another of other causes. Concurrent chemoradiotherapy using CDGP plus 5-FU was
tolerated with good clinical and histological effects,resulting in good local
control for advanced oral carcinoma.
12. Gan To Kagaku Ryoho. 2007 Aug;34(8):1319-21.
[Squamous cell carcinoma of the bladder treated with a new combined chemotherapy
regimen, intraarterial nedaplatin and pirarubicin plus intravenous methotrexate
and vincristine--second case report in Japan].
Shigehara K(1), Kitagawa Y, Nakashima T, Shimamura M, Katayanagi K, Kurumaya H.
Author information:
(1)Dept. of Urology, Ishikawa Prefectural Central Hospital.
We report our second patient treated successfully with a new combined

chemotherapy regimen of intra-arterial pirarubicin and nedaplatin plus
intravenous methotrexate and vincristine for squamous cell carcinoma (SCC) of the
bladder. A 57-year-old man consulted our hospital in September 2005 for treatment
of bladder tumors diagnosed in another hospital. Magnetic resonance imaging (MRI)
showed an extravesical invasive tumor on the anterior wall of the bladder, and
clinical stage T2bN0M0 was diagnosed. Transurethral cold-cup biopsy was
performed, and pathological examination revealed SCC. After he received two
courses of this new combined intra-arterial chemotherapy regimen using
nedaplatin, tumors were detected in MRI and cystoscopy. We performed partial
cystectomy in January 2006. Postoperative pathological examination revealed no
tumor cells (pathological CR). There were no severe adverse reactions by this
chemotherapy regimen. He has been alive without evidence of disease.
13. Gan To Kagaku Ryoho. 2007 May;34(5):725-8.
[A feasible study of docetaxel/nedaplatin combined chemotherapy for relapsed or

refractory esophageal cancer patients as a 2nd-line chemotherapy].
Matsumoto H(1), Hirai T, Hirabayashi Y, Murakami H, Higashida M, Kawabe Y,

Urakami A, Yamashita K, Tsunoda T.
Author information:
(1)Dept. of Surgery, Division of Gastroenterology, Kawasaki Medical School.
As a 2nd-line treatment for relapsed or refractory esophageal cancer patients

after chemoradiotherapy, we performed a combination chemotherapy of DOC/CDGP for
11 patients. Intravenous drip infusion of DOC 30 mg/m(2)and CDGP 30 mg/m(2)on
days 1, 8 and 15, and 4 weeks treatment was assumed as 1 cycle. We treated 8 of
11 patients with more than 2 cycles, and 4 of 8 patients were treated with
radiation therapy (RT). The effects by RECIST revealed partial response (PR) in 2
patients (50%), stable disease (SD) in 1 patient and progress disease (PD) in 1
patient without RT, and PR in 3 patients and not effective in 1 patient with RT,
respectively. There was no treatment-related death nor adverse event of grade 4.
The Hematological toxicities of leukopenia of grade 3 were observed in 3
patients. Non-hematological toxicites more than grade 3 were not observed. The
combination chemotherapy of DOC/CDGP was concluded to be safe and effective for
relapsed or refractory esophageal cancer patients as a 2nd line treatment.
[Nedaplatin (NDP)-combination therapy (NDP/5-FU,NDP/S-1) for oral cancer].
Maruoka Y(1), Ando T, Ogiuchi Y, Ogiuchi H.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, School of Medicine,Tokyo Women's
Medical University, Japan.
PURPOSE: The present study evaluated the efficacy and safety of

nedaplatin-combination therapy (NDP/5-FU [5-FU arm] or NDP/S-1 [S-1 arm] ) for
the treatment of oral squamous cell carcinoma.
PATIENTS AND METHOD: Previously non-treated oral squamous cell carcinoma patients
were eligible. Patients received 5-FU 600 mg/m(2)iv, as a 24-hour infusion (day 1
to 5) followed by NDP 80 to 100 mg/m(2) iv (day 1), or S-1 60 to 80 mg/m(2)
orally twice a day (day 1 to 14) followed by NDP 80 mg/m(2) iv (day 8) every 28
days for one or two cycles.
RESULTS: In total, 32 patients (18 in the 5-FU arm, 14 in the S-1 arm) were
enrolled. Twenty patients were male and 12 were female. Median age was 57 years
(range 20 years to 87 years). Thirty-one patients had a performance status (PS)
oF 0, and 1 patient had a PS 1. Three patients were stage I, 12 stage III, and 12
were stage IV. The overall response rate was 69% (5-FU arm,72%;S-1 arm,64%). Two
patients achieved a complete response, 20 patients a partial response, and 10
patients had no change. Grade 3 leucopenia, grade 3 and 4 thrombocytopenia and
liver injury occurred in 6% (one in the 5-FU arm, and one in the S-1 arm), 9%
(two in the 5-FU arm, and one in the S-1 arm), and 3% (one in the 5-FU arm),
respectively. No other severe toxicities were observed.
RESULTS: Response rate and toxicities were similar in both arms. However, the
psychosocial stress on patients in the S-1 arm was reduced compared to that in
the 5-FU arm, which required hospitalization for a longer period. The outcome in
the present study needs further investigation.
15. Oral Oncol. 2007 Nov;43(10):1014-20. Epub 2007 Jan 26.
Chemoradiation therapy using radiotherapy, systemic chemotherapy with

5-fluorouracil and nedaplatin, and intra-arterial infusion using carboplatin for
locally advanced head and neck cancer - Phase II study.
Fuwa N(1), Kodaira T, Furutani K, Tachibana H, Nakamura T, Daimon T.
Author information:
(1)Department of Radiation Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden,
Chikusa-ku, Nagoya 464-8681, Japan. nfuwa@aichi-cc.jp
To improve the treatment results for locally advanced head and neck cancer,
chemoradiation therapy by radiotherapy, systemic chemotherapy with 5-fluorouracil
(5FU) and nedaplatin (NDP), and intra-arterial therapy using carboplatin (CBDCA)
was performed. Thirty-two patients were entered into the study between July 1997
and August 2002. According to the TNM staging (1997), 14 patients had stage III
lesions, and 19 patients had stage IV (M0) lesions. Alternating chemoradiotherapy
was performed by the following regimen. Initially, systemic chemotherapy was
administered, followed by 4 weeks of radiotherapy (36Gy/20 fractions; wide field
irradiation) starting 2 days after chemotherapy, a second course of systemic
chemotherapy 2 days after radiotherapy, and a second course of a reduced field
radiotherapy (30Gy/15 fractions) 2 days after chemotherapy. Arterial injection
therapy was administered in the latter half of radiotherapy after the end of the
second course of systemic chemotherapy. For systemic chemotherapy, 5FU at
3500mg/m(2)/120h was intravenously administered for 5 days (Days 1-5), and NDP at
120mg/m(2)/6h was administered on Day 6. An intra-arterial agent using CBDCA was
continuously infused by a portable electrical pump for 4 (to 6) weeks. The total
dose of CBDCA was AUC 6 as established by Calvert's formula. The 5-year local
control rate was 59%. The 5-year overall survival rate was 51%. There were no
clinically significant adverse effects. Chemoradiation therapy by radiotherapy,
systemic chemotherapy, and intra-arterial chemotherapy for locally advanced head
and neck cancer may be useful for improving treatment results.
DOI: 10.1016/j.oraloncology.2006.11.019
16. Int J Clin Oncol. 2006 Aug;11(4):329-31.
Squamous cell carcinoma of the bladder: a patient treated successfully with a new
combined chemotherapy regimen, intraarterial nedaplatin and pirarubicin plus
intravenous methotrexate and vincristine.
Shigehara K(1), Kitagawa Y, Nakashima T, Shimamura M.

Author information:
(1)Department of Urology, Ishikawa Prefectural Central Hospital, 2-1
Kuratsukihigashi, Kanazawa 920-8530, Japan. kshigehara@ipch.jp
We report a case of squamous cell carcinoma (SCC) of the bladder treated

successfully with intraarterial chemotherapy using nedaplatin. A 75-year-old
woman was admitted to our hospital in March 2004 with gross hematuria.
Cystoscopic examination showed tumors on the anterior bladder wall. Computed
tomography (CT) scans and magnetic resonance imaging (MRI) revealed extravesical
invasion of the tumors, and a clinical diagnosis of T3bN0M0 was made.
Transurethral biopsy was performed, and histopathological examination revealed
SCC, grade 2-3, invasive. The patient received a new combined chemotherapy,
intraarterial nedaplatin and pirarubicin plus intravenous methotrexate and
vincristine. After two courses of the chemotherapy, CT scans and MRI demonstrated
no tumor in the bladder. Transurethral bladder-wall biopsy was performed in
November 2004, and histopathological examination of the specimen revealed no
definite tumors. The patient is alive without evidence of disease more than 1
year after the chemotherapy.
DOI: 10.1007/s10147-006-0571-8
17. Cancer Chemother Pharmacol. 2007 Apr;59(5):575-80. Epub 2006 Aug 16.
Pharmacokinetics of low-dose nedaplatin and validation of AUC prediction in

patients with non-small-cell lung carcinoma.
Niioka T(1), Uno T, Yasui-Furukori N, Takahata T, Shimizu M, Sugawara K, Tateishi

T.
Author information:
(1)Department of Pharmacy, Hirosaki University Hospital, Hirosaki 036-8563,
Japan. tniio-hki@umin.ac.jp
PURPOSE: The aim of this study was to determine the pharmacokinetics of low-dose
nedaplatin combined with paclitaxel and radiation therapy in patients having
non-small-cell lung carcinoma and establish the optimal dosage regimen for
low-dose nedaplatin. We also evaluated predictive accuracy of reported formulas
to estimate the area under the plasma concentration-time curve (AUC) of low-dose
nedaplatin.
PATIENTS AND METHODS: A total of 19 patients were administered a constant
intravenous infusion of 20 mg/m(2) body surface area (BSA) nedaplatin for an
hour, and blood samples were collected at 1, 2, 3, 4, 6, 8, and 19 h after the
administration. Plasma concentrations of unbound platinum were measured, and the
actual value of platinum AUC (actual AUC) was calculated based on these data. The
predicted value of platinum AUC (predicted AUC) was determined by three
predictive methods reported in previous studies, consisting of Bayesian method,
limited sampling strategies with plasma concentration at a single time point, and
simple formula method (SFM) without measured plasma concentration. Three error
indices, mean prediction error (ME, measure of bias), mean absolute error (MAE,
measure of accuracy), and root mean squared prediction error (RMSE, measure of
precision), were obtained from the difference between the actual and the
predicted AUC, to compare the accuracy between the three predictive methods.
RESULTS: The AUC showed more than threefold inter-patient variation, and there
was a favorable correlation between nedaplatin clearance and creatinine clearance
(Ccr) (r = 0.832, P < 0.01). In three error indices, MAE and RMSE showed
significant difference between the three AUC predictive methods, and the method
of SFM had the most favorable results, in which %ME, %MAE, and %RMSE were 5.5,
10.7, and 15.4, respectively.
CONCLUSIONS: The dosage regimen of low-dose nedaplatin should be established
based on Ccr rather than on BSA. Since prediction accuracy of SFM, which did not
require measured plasma concentration, was most favorable among the three methods
evaluated in this study, SFM could be the most practical method to predict AUC of
low-dose nedaplatin in a clinical situation judging from its high accuracy in
predicting AUC without measured plasma concentration.
DOI: 10.1007/s00280-006-0298-2
18. Gynecol Oncol. 2006 Sep;102(3):493-9. Epub 2006 Feb 14.
Intraarterial cisplatin/nedaplatin and intravenous 5-fluorouracil with concurrent

radiation therapy for patients with high-risk uterine cervical cancer.
Kawase S(1), Okuda T, Ikeda M, Ishihara S, Itoh Y, Yanagawa S, Ishigaki T.
Author information:
(1)Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya
city, Japan.
OBJECTIVE: The purpose of this study was to determine the effectiveness of the
combination of intraarterial and intravenous concurrent chemoradiation therapy
(CIAIV-CCRT) for the treatment of high-risk uterine cervical cancer.
METHODS: Between January 2000 and November 2004, we reviewed 45 cervical cancer
patients treated by CIAIV-CCRT. The numbers of patients with stage IB2, IIA, IIB,
IIIA, IIIB, and IVA were 3, 6, 14, 1, 17, and 4, respectively. Patients with
stage III and IVA or patients with tumors >3 cm in diameter were enrolled in this
study. Two sessions of CCRT were administered every 3 weeks using a combination
of 70 mg/m2 x h(-1) cisplatin or 50 mg/m2 x h(-1) nedaplatin via the bilateral
uterine artery and 2800 mg/m2 x 96 h(-1) 5-fluorouracil intravenously. Patients
concurrently received external beam radiation therapy and brachytherapy. A
nonrandomized control group of 47 patients who underwent radiation therapy alone
between 1993 and 2000 was used for comparison.
RESULTS: Of the 45 patients, 28 (62%) exhibited complete response and 16 (36%)
exhibited partial response. One IIIB patient (2%) did not show any response. The
5-year overall survival (OAS) rates in the CCRT group and control group were
80.6% and 54.9%, respectively. With regard to late toxicities, no statistically
significant differences were observed between the two groups. In uni- and
multivariate analyses, positive pelvic lymph node showed a statistically
significant influence on the OAS in the CIAIV-CCRT group (P = 0.049).
CONCLUSION: These preliminary results suggest that CIAIV-CCRT can improve the
prognosis of patients with high-risk cervical cancer.
DOI: 10.1016/j.ygyno.2006.01.009
19. Cancer Chemother Pharmacol. 2006 Nov;58(5):570-6. Epub 2006 Feb 4.
A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy

in patients with esophageal cancer.
Sato Y(1), Takayama T, Sagawa T, Okamoto T, Miyanishi K, Sato T, Araki H, Iyama

S, Abe S, Murase K, Takimoto R, Nagakura H, Hareyama M, Kato J, Niitsu Y.
Author information:
(1)Fourth Department of Internal Medicine, Sapporo Medical University, South 1
West 16, Chuo-ku, 060-8543, Sapporo, Japan.
PURPOSE: To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum

(nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in
the treatment of esophageal cancer. The purpose of the phase II trial is to
determine efficacy and further define the side effect profile.
METHODS: Twenty-six patients with clinical stage I to IVA squamous cell carcinoma
of the esophagus were enrolled in a non-surgical treatment comprised of a fixed
dose of fluorouracil (400 mg/m2 administered as continuous intravenous infusion
on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m2 in level
1, 50 mg/m2 in level 2, or 60 mg/m2 in level 3 on days 1 and 8), repeated twice
every 3 weeks with concurrent radiotherapy (60 Gy).
RESULTS: Between July 1998 and February 2004, a total of 26 patients entered this
trial, all of whom were considered evaluable for toxicity assessment. In phase I
of the study, 12 patients were treated in sequential cohorts of three to six
patients per dose level. The maximum tolerated dose was reached at level 3 with
two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended
dosing schedule is level 2. Of the 20 patients treated at the RD level 2,
including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had
grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4
patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4
esophagitis. Other toxicities were relatively mild and usually of grade 2 or
less. Objective responses were noted in the 26 patients (overall response rate,
88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates
were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months.
CONCLUSIONS: The combination of nedaplatin and 5-FU with radiation is a feasible
regimen that shows promising antitumor activity with an acceptable safety profile
in patients with esophageal cancer.
DOI: 10.1007/s00280-006-0193-x
20. J Chemother. 2005 Oct;17(5):550-4.
Phase I trial of nedaplatin and paclitaxel for patients with non-small cell lung
cancer.
Yoshiike F(1), Koizumi T, Kitaguchi Y, Hatayama O, Yasuo M, Sasabayashi M,

Wakamatsu H, Fujimoto K, Kubo K.
Author information:
(1)First Department of Internal Medicine, Shinshu University School of Medicine,
Japan.
A phase I study was conducted to evaluate the maximum tolerated dose and
feasibility of combination with nedaplatin (NDP) and paclitaxel in patients with
non-small cell lung cancer (NSCLC). Fifteen patients under 75 years old, with
unresectable NSCLC who had not previously received chemotherapy or radiotherapy,
with a performance status of 0-1, were enrolled. The dose escalation levels
(NDP/Paclitaxel; mg/m2 day 1) were 80/150 (level 1), 80/180 (level 2), 90/180
(level 3) and repeated every 28 days. All patients receiving level 3 had
dose-limiting toxicity. One patient developed grade 4 neutropenia with infection,
two had incomplete recovery of neutropenia and thrombocytopenia by the 28th day
after the first cycle of chemotherapy. Non-hematologic toxicities, including
nephrotoxicity, nausea/vomiting, alopecia, and hypersensitivity reaction, were
tolerated. Three of the 15 patients achieved partial responses. We concluded that
the recommended dose was paclitaxel 180 and NDP 80 mg/m2 due to the hematologic
toxicity.
DOI: 10.1179/joc.2005.17.5.550
21. Gan To Kagaku Ryoho. 2005 Sep;32(9):1267-71.
[Clinical trial of chemotherapy by superselective intra-arterial infusion of

nedaplatin combined with radiotherapy for advanced oral cancer].
Yamshita Y(1), Shikimori M, Goto M.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Saga Medical School.
Nedaplatin (CDGP) is designed to further improve the anti-tumor effect and to

reduce adverse effects of cisplatin (CDDP), such as renal toxicity. We previously
reported a combination therapy of superselective intraarterial CDGP infusion, and
radiation therapy could be delivered safely with good efficacy for locoregional
management of oral cancer. However, both the clinical and pathological response
decreased with tumor progression. This study was performed to assess the
feasibility of a new chemotherapy regimen by superselective intraarterial
infusion of CDGP in patients with advanced oral carcinomas. This regimen is under
way in which chemotherapy with 5-FU 500 mg/day on days 1 to 5 and superselective
intra-arterial infusion of CDGP on day 6 combined with radiation therapy is being
evaluated for locally advanced oral cancer. Eight patients were treated with this
regimen. After evaluation of the response, patients underwent surgery as a
therapeutic procedure. Both the complete and partial response rates were achieved
in each 3 patients (37.5%), respectively. Histological effects classified
according to Oboshi-Shimosato's criteria were grade IVa in 2 patients, grade III
in 1, grade IIb in 1, grade IIa in 3, and grade I in 1. All patients were free
from renal dysfunction, which is one of the adverse effects of CDDP. Moreover,
most toxicity was relatively mild in all patients.
22. Praxis (Bern 1994). 2005 Feb 9;94(6):187-98.
[Platinum compounds: metabolism, toxicity and supportive strategies].
[Article in German]
Lipp HP(1), Hartmann JT.
Author information:
(1)Universitätsapotheke, Universitätsklinikum der Eberhard-Karls-Universität
Tübingen.
Although the leading platinum compounds, cisplatin, carboplatin, and oxaliplatin,

share some structural similarities, there are marked differences between them in
therapeutic uses, pharmacokinetics, and adverse effects profiles. Compared with
cisplatin, carboplatin has inferior efficacy in germ-cell tumors, head and neck
cancers, and bladder and esophageal carcinomas, whereas the two drugs appear to
have comparable efficacy in ovarian cancer, extensive small-cell lung cancers
(SCLC), and advanced non-small-cell lung cancers (NSCLC). Oxaliplatin belongs to
the group of diaminocyclohexane (DACH) platinum compounds. It is the first
platinum-based drug that has marked efficacy in colorectal cancer when given in
combination with 5-fluorouracil and folinic acid. Nedaplatin has been registered
in Japan, whereas other derivatives, like JM216 (which is the only orally
available platinum derivative), ZD0473, BBR3464, and SPI-77 (a liposomal
formulation of cisplatin), are still under investigation. The adverse effects of
platinum compounds are reviewed together with possible prevention strategies.
DOI: 10.1024/0369-8394.94.6.187
23. Nihon Jibiinkoka Gakkai Kaiho. 2004 Nov;107(11):990-7.
[Pharmacodynamics of tongue tissue and plasma after intraarterial infusion of

cis-diammine glycolato platinum (CDGP)].
Matsui T(1), Kano M.
Author information:
(1)Department of Otolaryngology, Fukushima Medical University School of Medicine,
Fukushima.
We measured total Pt concentration in serum and tongue tissue in CDGP

intraarterial infusion with male rats. Subjects were 40 male rats sorted into
intraarterial infusion (n=20), intravenous infusion (n=20), and CDGP infusion
groups at a dose of 10 mg/kg. Total Pt concentration was measured every 30
minutes for 120 minutes after CDGP infusion was completed. Total Pt concentration
in tongue tissue was measured on the dosage and nondosage side. Total Pt
concentration on the dosage side of tongue tissue of the intraarterial infusion
group was higher than in the intravenous infusion group for 120 minutes. Total Pt
concentration in intraarterial infusion group tongue tissue on the dosage side
was higher than on the nondosage side for 120 minutes. Serum total Pt
concentration, total Pt concentration in nondosage side tongue tissue, AUC of
total Pt in serum, elimination half-life (t1/2) did not show a difference in the
intraarterial or intravenous infusion groups. Total Pt AUC in tongue tissue on
the intraarterial infusion group dosage side was greater than in others. In
intraarterial infusion of CDGP, Pt concentration in tongue tissue is higher than
in intravenous infusion. Serum Pt concentration, did not differ by group. This
study showed that intraarterial infusion of CDGP has the potency to become a
chemotherapy indication the same as intravenous infusion, in addition to the
target organ.
[Clinical study for determination of the dosage formula for intra-arterial

infusion chemotherapy with nedaplatin].
Ohbayashi Y(1), Miyake M, Iwasaki A, Ogawa T, Nagahata S, Toyama Y, Ohkawa M.

Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa
University.
Area under the curve (AUC) is a very important parameter for determination of
optimal dosage of antineoplastic agents in order to avoid side effects and
achieve high effectiveness. Also, even if a certain dosage is administered,
measured AUC is different in each individual. Therefore, it is important to
determine the formula of the dosage of antineoplastic agents. We treated oral
cancer using an intra-arterial infusion chemotherapy with nedaplatin (CDGP).
Eighteen patients were treated with CDGP at the Department of Oral and
Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical University, from
October 1998 to June 2002. The correlation among expected AUC, dosage, CDGP
clearance and 24 hr creatinine clearance in all chemotherapy was monitored and
examined. The obtained formula in the dosage of intra-arterial infusion
chemotherapy with Nedaplatin was as follows. dosage = AUC x (0.027 x CCr + 7.17).
25. Br J Cancer. 2004 Jun 1;90(11):2092-6.
Combination phase I study of nedaplatin and gemcitabine for advanced

non-small-cell lung cancer.
Kurata T(1), Tamura K, Yamamoto N, Nogami T, Satoh T, Kaneda H, Nakagawa K,

Fukuoka M.
Author information:
(1)Department of Medical Oncology, Kinki University School of Medicine, 377-2
Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
To establish the toxicities and maximum tolerated dose (MTD) of nedaplatin with
gemcitabine, and to observe their antitumour activity, we conducted a combination
phase I study in advanced non-small-cell lung cancer (NSCLC). Patients received
nedaplatin (60-100 mg m(-2) given intravenously over 90 min) on day 1, and
gemcitabine (800-1000 mg m(-2) given intravenously over 30 min) on days 1, 8,
every 3 weeks. In total, 20 patients with locally advanced or metastatic NSCLC
who received no prior chemotherapy or one previous chemotherapy regimen were
enrolled. The most frequent toxicities were neutropenia and thrombocytopenia;
nonhaematological toxicities were generally mild. Three out of six patients
experienced dose-limiting toxicities (neutropenia, thrombocytopenia and delayed
anaemia) at dose level 4, 100 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine,
which was regarded as the MTD. There were three partial responses, for an overall
response rate of 16.7%. The median survival time and 1-year survival rate were
9.1 months and 34.1%, respectively. This combination is well tolerated and active
for advanced NSCLC. The recommended dose is 80 mg m(-2) nedaplatin with 1000 mg
m(-2) gemcitabine. This combination chemotherapy warrants a phase II study and
further evaluation in prospective randomised trials with cisplatin- or
carboplatin-based combinations as first-line chemotherapy for advanced NSCLC.
DOI: 10.1038/sj.bjc.6601817
PMCID: PMC2409510
26. Br J Cancer. 2004 Mar 22;90(6):1125-8.

Phase I study of cisplatin analogue nedaplatin (254-S) and paclitaxel in patients
with unresectable squamous cell carcinoma.
Sekine I(1), Nokihara H, Horiike A, Yamamoto N, Kunitoh H, Ohe Y, Tamura T,

Kodama T, Saijo N.
Author information:
(1)Divisions of Internal Medicine and Thoracic Oncology, National Cancer Center
Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. isekine@ncc.go.jp
The recommended phase II dose of paclitaxel 180 mg m(-2) given as a 3-h infusion
followed by nedaplatin 100 mg m(-2) in a 1-h infusion every 3-4 weeks was
determined in 52 chemo-naive patients with unresectable squamous cell carcinoma
(SCC), with a promising response rate for lung SCC of 55%.
DOI: 10.1038/sj.bjc.6601700
PMCID: PMC2409664
27. Gan To Kagaku Ryoho. 2004 Jan;31(1):41-4.
[Clinical study of the area under the blood concentration-time curve of targeting
intra-arterial infusion chemotherapy with nedaplatin for primary oral cancer].
Ohbayashi Y(1), Miyake M, Iwasaki A, Ogawa T, Nagahata S, Toyama Y, Ohkawa M.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical
University.
We treated oral cancer using a targeting intra-arterial infusion chemotherapy

with CDGP (nedaplatin); dosages were determined by the original formula. We
compared the expected AUC (area under the curve) with the actual AUC in primary
oral cancer cases to assess the optimal dosage of CDGP for intra-arterial
chemotherapy and to study relevance of AUC, effectiveness of independent
chemotherapy and side effects. Eleven cases were treated at the Department of
Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical University,
from October 1998 to June 2002. The results are as follows. 1) A correlation was
seen between the AUC and degree of thrombocytopenia. 2) AUC may reveal renal
function, especially for GFR. 3) The response rate of the targeted intra-arterial
infusion chemotherapy with CDGP was remarkably high and serious side effects were
not observed. It appears that the set-up of the optimum dose should be decided
based on the actual AUC. 4) There was about a 4/3 difference between the value of
the expected AUC and the actual AUC. The equation for dosages based on the actual
AUC needs to be studied further.
28. Oncology. 2003;65(2):102-7.
Phase I study of combination chemotherapy using irinotecan hydrochloride and

nedaplatin for advanced or recurrent cervical cancer.
Machida S(1), Ohwada M, Fujiwara H, Konno R, Takano M, Kita T, Kikuchi Y,
Komiyama S, Mikami M, Suzuki M.
Author information:
(1)Department of Obstetrics and Gynecology, Jichi Medical School, Tochigi, Japan.
OBJECTIVE: We performed a phase I clinical study to evaluate combination

chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin
(CPT-11/nedaplatin) for cervical cancer.
METHODS: This study included patients with primary or recurrent cervical cancer.
The regimen for CPT-11/nedaplatin therapy consisted of CPT-11 administered 3
times over 2 weeks (days 1, 8 and 15) and nedaplatin infused intravenously as a
single dose (day 1). This course was repeated at 4-week intervals. The step 1
doses of the two agents were 50 mg/m(2), respectively. Dose escalation was
performed in tandem. Plasma CPT-11, SN-38, total platinum, and filterable
platinum levels were measured.
RESULTS: In step 3 (CPT-11, 60 mg/m(2); nedaplatin, 60 mg/m(2)), dose-limiting
toxicity was observed in 2 of 3 patients. The step 3 doses were regarded as the
maximum tolerated doses. The incidences of grade 3/4 adverse events in the first
courses (n = 12) [and all courses (n = 45)] were: leukopenia 33% (22%),
neutropenia 42% (31%), anemia 17% (20%), nausea 8% (7%), and diarrhea 8% (7%).
Following CPT-11 administration, the mean areas under the curve (AUC; ng.h/ml) of
SN-38 were 0.11 at 50 mg/m(2) and 0.17 at 60 mg/m(2). Following nedaplatin
administration, the mean AUCs (microg x h/ml) of filterable platinum were 6.0 at
50 mg/m(2), and 6.0 at 60 mg/m(2). The response rate was 50% (2 complete
responses and 2 partial responses).
CONCLUSION: The recommended doses of CPT-11 and nedaplatin for a phase II
clinical study were established as 50 and 60 mg/m(2), respectively.
Copyright 2003 S. Karger AG, Basel
DOI: 10.1159/000072333
29. Gan To Kagaku Ryoho. 2003 Mar;30(3):377-82.
[Neoadjuvant intraarterial chemotherapy with nedaplatin, peplomycin and mitomycin

C for advanced cervical cancer].
Umeki H(1), Yamaguchi Y, Tsugata M, Wakana K, Somekawa Y, Shimabukuro K, Ohara M,

Terauchi T, Ichimura M, Otsuka I, Aso T.
Author information:
(1)Dept. of Obstetrics and Gynecology, Toride Kyodo Hospital.
The aim of the present study was to examine the usefulness of neoadjuvant
intraarterial chemotherapy (NAC) using nedaplatin as key drug to improve the
prognosis in case of advanced cervical cancer. Twenty-five cases of advanced
cervical cancer (15 cases of stage II with high risks, 10 of stage III, referred
to as the 254-S group) treated by NAC using nedaplatin, mitomycin C and
peplomycin were compared with 30 cases (22 cases of stage II with high risks, 8
of stage III, referred to as the CDDP group) treated using cisplatin and
mitomycin C which is the conventional regimen, in terms of measurable response,
pathological response, rate of lymph node metastasis, cumulative survival rate,
side effects and relapse style. According to the evaluation by measurable
responses, the response rate was 90% (CR 52%) in the 254-S group and 75% (CR 15%)
in the CDDP group. For pathological response of the specimen, the CR rate was 16%
in the 254-S group and 23% in the CDDP group. The rate of lymph node metastasis
extracted surgically was 33% and 41%, respectively. The cumulative survival rate
in the 254-S group was about 10% better than in the CDDP group, but no
significant difference was found. Leucopenia of both groups was of the same
grade. In the 254-S group, although thrombocytopenia was more critical than in
the CDDP group, there was a slight tendency to kidney toxicity. The locoregional
recurrence rate was 12% in the 254-S group and 30% in the CDDP group. The distant
metastasis rate was 16% and 27%, respectively. Although neoadjuvant intraarterial
chemotherapy using nedaplatin as a key drug was useful to improve the prognosis
of advanced cervical cancer, measures against recurrence outside the pelvis and
individualization of medical treatment were considered to lead to a further
improvement of the prognosis.
30. Nihon Shokakibyo Gakkai Zasshi. 2002 Oct;99(10):1191-6.
[Clinical study of the combination of small amount of nedaplatin (CDGP)/5-FU with

radiation for the treatment of esophageal cancer].
Inaba H(1), Tsuda T, Miyazaki A, Watanabe Y, Nakaya S, Koitabashi Y, Ogihara K,

Hara T, Kato N, Kobayashi Y, Nakagawa T, Kitajima S, Endo T, Iino S, Hoshikawa Y.
Author information:
(1)Division of Gastroenterology and Hepatology, Department of Internal Medicine,
St. Marianna University School of Medicine.
Recently chemoradiotherapy for esophageal cancer has been drawing public

attention to the issue of quality of life maintenance for patients. Although the
standard method of chemoradiotherapy is CDDP/5FU, it has been claimed that CDGP
(a derivative of CDDP) alone is more effective than CDDP for the treatment of
esophageal cancer due to its low nephro- and digestive toxicity. We used a small
amount of CDGP/5-FU in combination with radiation instead of CDDP, for the
treatment of esophageal cancer and performed clinical examination of patients.
The partial response rate was 80% and the complete response rate was 50%. Major
side-effects were leukopenia, neutropenia, thrombocytopenia and anemia. Further
study of dosage and schedule is necessary, however, CDGP/5-FU combined with
radiation therapy could be used as choices of chemoradiotherapy for esophageal
cancer in the future.
31. Gan To Kagaku Ryoho. 2002 Jun;29(6):905-9.
[Chemotherapy by superselective intraarterial infusion of nedaplatin combined

with radiotherapy for oral cancer].
Yamashita Y(1), Goto M, Katsuki T.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Saga Medical School.
Nedaplatin (CDGP), which is a CDDP derivative, has been reported to be an

effective anticancer agent for head and neck cancer. This study was performed to
assess the feasibility of chemotherapy by superselective intraarterial infusion
of nedaplatin (CDGP) in patients with oral cancers. Ten patients were treated
with chemotherapy by superselective intraarterial infusion of CDGP combined with
radiotherapy. The complete and partial response rates were 7/10 (70%) and 3/10
(30%), respectively. Nine patients showed grade 1-2 hematological toxicity
including leukocytopenia and anemia. Thrombocytopenia of grade 4 was seen in only
one patient. However, all the patients were free from renal dysfunction. From
these results, it is suggested that this combination therapy might be quite
effective and safe. Further study will be needed to determine its efficacy
against oral cancer.
32. Int J Clin Pharmacol Res. 2001;21(3-4):105-10.
Intravenous nedaplatin and intraarterial cisplatin with transcatheter arterial

embolization for patients with locally advanced uterine cervical cancer.
Adachi S(1), Ogasawara T, Tsubamoto H, Oku H, Hori Y, Tsuji Y, Takemura T, Koyama

K.
Author information:
(1)Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.
adachi@hyo-med.ac.jp
Nedaplatin is a platinum analog that has less renal toxicity and higher efficacy
for uterine cervical cancer than cisplatin. Intraarterial cisplatin has been
shown to be more effective than intravenous cisplatin in the treatment of
cervical cancer. To improve the prognosis of cervical cancer, we studied
combination chemotherapy of intravenous nedaplatin and intraarticular cisplatin
with transcatheter arterial embolization (TAE). The criteria for selecting
patients for this study were as follows: age 16-75 years, stage Ib2-IV according
to the classification of the International Federation of Gynecology and
Obstetrics (FIGO), performance status between 0 and 2, a creatinine clearance of
>40 ml/min, adequate bone marrow and adequate renal and hepatic function.
Thirty-two patients, aged 29-72 years (median: 55) were treated. FIGO stage was
Ib2 in seven patients, IIa in seven patients, IIb in four, IIIa in one, IIIb in
seven and IVa in six. Twenty-four patients had squamous cell carcinoma, three had
adenocarcinoma and five had adenosquamous carcinoma. Written informed consent was
obtained from all patients. Nedaplatin (30-70 mg/m2) was administered
intravenously on day 1 and cisplatin (70 mg/m2) was administered intraarticularly
via both uterine arteries on day 3 using the Seldinger method. TAE was then
performed. This course of treatment was repeated every 3 weeks for 2-3 cycles.
Response to the therapy was defined by magnetic resonance imaging. Partial
response was found in 59% patients (19/32) and complete response in 34% (11/32),
with an overall response rate of 94% (30/32). Myelosuppression was manageable. No
grade 2 neurotoxicity was observed. The median follow-up was 32 months (6-53
months), with 84% of patients showing an overall survival of 1 year and 77%
showing an overall survival of 2 years. These results show that this combination
chemotherapy effected a high response rate. However, its influence on long-term
survival remains to be determined.
33. Nihon Igaku Hoshasen Gakkai Zasshi. 2002 Feb;62(2):65-72.
[Current and future state of chemoradiotherapy for head and neck cancer].
Fuwa N(1).
Author information:
(1)Department of Radiation Oncology, Aichi Cancer Center Hospital.
Radiation therapy was the conventional treatment for locally advanced,

nonresectable head and neck cancer. However, therapeutic results were poor with
this treatment modality, and chemoradiotherapy has been used in an effort to
improve therapeutic results. Improved local-regional control and disease-free or
overall survival have been shown in several randomized trials using a concurrent
or alternative approach. Induction chemotherapy (neoadjuvant chemotherapy),
however, has not been shown to improve local-regional control or survival.
Induction chemotherapy followed by definitive radiotherapy may be useful in the
selection of patients who are likely to benefit from non-surgical organ
preservation treatment schemes. Further clinical trials are needed to clarify the
most suitable combination of chemotherapy and radiation. Intraarterial
chemotherapy combined with radiation therapy for head and neck cancer has been
attempted for many years. However, the indications, clinical significance, and
selection of suitable anti-cancer drugs remain unclarified. The modern
superselective intraarterial approach should be re-evaluated. Many head and neck
cancers have been found to overexpress the receptor to epidermal growth factor
(EGFR). Antibodies such as IMC-C225 that specifically target EGF receptors with
radiotherapy and/or chemotherapy may prove to be valuable contributors to the
treatment of advanced head and neck cancer.
34. Gan To Kagaku Ryoho. 2001 Jul;28(7):979-86.
[Concurrent chemoradiation therapy with nedaplatin for high-risk cervical

cancer--clinical investigation of adverse events].
Kamiura S(1), Kobayashi K, Ohira H, Seino H, Hashimoto N, Sawai K, Samejima Y,

Saji F.
Author information:
(1)Dept. of Gynecology, Osaka Medical Center for Cancer and Cardiovascular
Diseases.
A clinical investigation of adverse events was conducted to confirm the safety of

concurrent chemotherapy using nedaplatin (cisplatin derivative) and radiotherapy
in the high-risk carcinoma of the uterine cervix. Seven patients who were treated
with radical radiotherapy and 5 patients who were treated with adjunctive
radiotherapy after radical hysterectomy and pelvic lymphadenectomy were eligible
for the study. Nedaplatin was given intravenously at 70 mg/m2 on day 1 and day
29, and a total of 24 courses of nedaplatin administration were observed. None of
the planned radiotherapy was postponed or discontinued due to side effects. Major
adverse effects observed were gastrointestinal effects such as anorexia (66.7%),
nausea and vomiting (33.3%) and diarrhea (66.7%). Grade 3 (in the 2nd course) and
Grade 4 (in the 1st course) diarrhea was observed in one patient, which was
easily relieved by antidiarrheal. Hematologic side effects were also major,
including leukopenia (62.5%), neutropenia (75.0%), anemia (75.0%), and
thrombocytopenia (33.3%). Hematologic effects were generally moderate; no Grade 4
(severe) effects were observed. Although these hematologic effects were lasting
longer compared with radiation therapy alone, there were no significant
differences in the seriousness of these side effects. Concurrent chemoradiation
therapy with nedaplatin 70 mg/m2 every 4 weeks was safe and adverse effects were
self-limited or resolved with medical management. Dose escalation in the phase
III clinical study may be considered.
[Targetting intra-arterial infusion chemotherapy with nedaplatin for oral

cancer].
Iwasaki A(1), Toyama Y, Saitou H, Ohkubo N, Imagawa N, Ogawa T, Ohbayashi Y,

Tanizaki A, Miyake M, Nagahata S, Hino I, Ohkawa M.
Author information:
(1)Dept. of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical
University.
36. Cancer. 2001 Jan 1;91(1):74-9.
Phase I/II study of intravenous nedaplatin and intraarterial cisplatin with

transcatheter arterial embolization for patients with locally advanced uterine
cervical carcinoma.
Adachi S(1), Ogasawara T, Wakimoto E, Tsuji Y, Takemura T, Koyama K, Takayasu Y,

Inoue J, Nakao N.
Author information:
(1)Department of Obstetrics and Gynecology, Hyogo College of Medicine,
Nishinomiya City, Hyogo, Japan. adachi@hyo-med.ac.jp
BACKGROUND: Nedaplatin, a platinum analog with less renal toxicity and similar
efficacy for cervical carcinoma, recently has been shown to have a synergistic
effect on cervical carcinoma lines in combination with cisplatin. To determine
the clinical efficacy of this combination in patients with cervical carcinoma,
the authors conducted a Phase I/II study of intravenous nedaplatin and
intraarterial cisplatin combined with transcatheter arterial embolization (TAE).
METHODS: Eligibility criteria were as follows: cervical carcinoma (Stages IB2-IV;
International Federation of Gynecology and Obstetrics), 16-70 years of age,
performance status between 0 and 2, and adequate bone marrow, renal, and hepatic
function. Nedaplatin (40-70 mg/m2) was administered intravenously on Day 1
followed by intraarterial administration of cisplatin (70 mg/m2) on Day 3 via
both uterine arteries by using the Seldinger method. This then was followed by
TAE. This course of treatment was repeated every 3 weeks for 3 cycles.
RESULTS: Patient data were as follows: age 37-68 (median, 55 years) and Stages
IB2:4, IIA:3, IIB:2, IIIA:1, IIIB:3, IVA:2 carcinoma. The response to therapy was
defined by magnetic resonance imaging as follows: partial response in 60% (9 of
15) of patients, complete response in 40% (6 of 15) of patients, and an overall
response rate of 100% (95% confidence interval, 78-100%). Myelosuppression was
manageable. Grade 3/4 renal toxicity was observed in 2 patients who received 70
mg/m2 of nedaplatin. Thirteen patients received radical hysterectomy, 1 patient
received lymph node sampling, and 11 patients received adjuvant radiotherapy or
chemotherapy.
CONCLUSIONS: The maximum tolerable dose was 70 mg/m2 nedaplatin, and the
dose-limiting toxicity was renal toxicity. The recommended dose was 60 mg/m2
nedaplatin intravenously followed by 70 mg/m2 cisplatin intraarterially.
Intravenous nedaplatin followed by intraarterial cisplatin with TAE appears to be
very effective for locally advanced cervical carcinoma.
Copyright 2001 American Cancer Society.
37. Nihon Kokyuki Gakkai Zasshi. 2000 Feb;38(2):122-5.
[Thymic carcinoma successfully treated by a combination of intra-arterial

infusion chemotherapy and surgery].
Kitami A(1), Suzuki T, Kamio Y, Suzuki S, Hori G, Ueshima Y, Suzuki H.
Author information:
(1)Department of Thoracic and Cardiovascular Surgery, Showa University Fujigaoka
Hospital, Yokohama, Japan.
A 47-year-old man with thymic carcinoma that had invaded the inner pericardium
and adhered to the superior vena cava and right atrium at first operation was
treated with intra-arterial infusion chemotherapy (nedaplatin and adriamycin)
through the internal thoracic artery. After 2 courses of modified ADOC therapy
(nedaplatin, adriamycin, vincristine, and cyclophosphamide), chest computed
tomographic (CT) scans revealed a 47% reduction in tumor size. No adverse effects
due to the anticancer drugs were observed. Resection of the tumor included part
of the upper lobe of the right lung and pericardium. Examination of resected
tumor tissue specimens revealed viable cancer cells and extensive fibrosis. The
diagnosis was thymic anaplastic carcinoma. We concluded that intra-arterial
selective infusion chemotherapy utilizing an ADOC regimen can be of value as a
treatment for thymic carcinoma.
38. Gan To Kagaku Ryoho. 1999 Dec;26(14):2209-15.
[Phase I study of a combination chemotherapy of nedaplatin and cisplatin].
Nishida M(1), Satoh Y, Nishide K, Tsunoda H, Kubo T.
Author information:
(1)Dept. of Obstetrics and Gynecology, Institute of Clinical Medicine, University
of Tsukuba.
A new platinum complex, nedaplatin, has been reported to be effective for both
ovarian and cervical cancers. We designated a phase I dose-escalation study of a
combination chemotherapy of nedaplatin and cisplatin to investigate the
dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Six patients,
including two with advanced cervical cancer, three with ovarian clear cell
adenocarcinoma and one with endometrial clear cell adenocarcinoma, were enrolled
in this study. The doses of the two agents were escalated alternatively, i.e., a
tandem method, from 40 to 80 mg/m2 by 20 mg/m2. Nedaplatin and cisplatin were
administrated by intravenous drip infusion and repeated after an interval of at
least 4 weeks, as a rule. The major toxicity observed was hematotoxicity. One of
the 6 patients dropped out of this study because of severe hematotoxicity after
80 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin were administered. With a dose
of 80 mg/m2 nedaplatin and 80 mg/m2 cisplatin, severe neutropenia was found in
all 6 patients, and thrombocytopenia and anemia were found in 1 patient,
respectively. A slight hearing loss was detected by audiometry in 5 patients, but
no one was inconvenienced in daily life. Mild nausea and vomiting were also
observed in all 6 patients. In conclusion, the DLT of this combination therapy
was hematotoxicity and the MTD was 80 mg/m2 for nedaplatin and 60 mg/m2 for
cisplatin, respectively. Thus, 60 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin
may be recommended for combined administration.
39. Jpn J Clin Oncol. 1999 Jun;29(6):299-302.
A dose-finding study of nedaplatin and cyclophosphamide for patients with

gynecological malignancies.
Ito K(1), Adachi S, Itani Y, Koyama M, Hori K, Chin R, Shintani M, Beppu K, Kawai
S, Saito K.
Author information:
(1)Department of Obstetrics and Gynecology, Hyogo Prefectural Nishinomiya
Hospital, Japan.
BACKGROUND: Nedaplatin is a new analogue of cisplatin with similar efficacy but

less renal toxicity. We investigated the appropriate dose of nedaplatin in
combination with cyclophosphamide for patients with gynecological malignancies.
METHODS: Nine patients (five with ovarian cancer and four with uterine cervical
cancer) were studied. Three patients received 60 mg/m2 of nedaplatin combined
with 500 mg/m2 of cyclophosphamide every 4 weeks. Another three patients were
each administered 80 or 100 mg/m2 of nedaplatin with the same dose of
cyclophosphamide. A total of 27 courses was given.
RESULTS: No patient needed dose reduction due to myelosuppression and no severe
adverse events were observed.
CONCLUSIONS: Treatment with 100 mg/m2 of nedaplatin and 500 mg/m2 of
cyclophosphamide is feasible for patients with gynecological malignancies.
However, phase II studies are needed to clarify the efficacy of this combination
chemotherapy.
40. Jpn J Clin Oncol. 1999 Feb;29(2):106-8.
A case of advanced esophageal cancer showing a long-term complete response with

chemotherapy with nedaplatin alone.
Satoh T(1), Tsushima K, Saitoh S, Hizawa Y, Tamura Y, Fukuda S, Yamada Y, Tohno

H, Takasugi T, Sakata Y, Munakata A.
Author information:
(1)First Department of Internal Medicine, Hirosaki University School of Medicine,
Aomori, Japan. tsatoh-hki@umin.u-tokyo.ac.jp
We describe a case of advanced esophageal cancer treated successfully by

chemotherapy with nedaplatin alone. A 60-year-old male with type 2 advanced
esophageal cancer, which was located in the upper part of the esophagus and had
invaded adjacent organs, was treated with nedaplatin 150 mg/body (100 mg/m2)
given intravenously every 4 weeks from January 6, 1991. He achieved a partial
response (PR) and was discharged in March 1991. Subsequently, he received
nedaplatin 75 mg/body in an out-patient setting almost every month until August
1992. Toxicities were tolerable and included mild thrombocytopenia and
nausea/vomiting. From serial evaluation in October 1993, the esophageal tumor was
not observed. After 7 years since initial chemotherapy was administered, he still
survives without the disease.
[Pharmacokinetic comparison between cisplatin and nedaplatin in hepatic arterial

chemotherapy using complete hepatic venous isolation and charcoal hemoperfusion].
Muramatsu S(1), Ku Y, Kuroda Y.
Author information:
(1)First Dept. of Surgery, Kobe University School of Medicine.
We undertook a pharmacokinetic comparison between cisplatin and nedaplatin in

hepatic arterial chemotherapy using complete hepatic venous isolation and
charcoal hemoperfusion (HVI.CHP). Dogs received a 20-min hepatic arterial
infusion of either 4 mg/kg cisplatin (Group I, n = 5) or 4 mg/kg nedaplatin
(Group II, n = 5) under HVI.CHP. The CHP filter adsorption ratios did not differ
significantly between the two groups. Drug clearance fractions by HVI.CHP in
group II (free pt 45.9%, total pt 55.1%) were significantly higher than those in
group I (free pt 23.4%, total pt 27.5%) (p < 0.05). In contrast, hepatic
extraction ratios in group I tended to be higher than those in group II. These
results indicated that extrahepatic distribution of cisplatin became lower than
that of nedaplatin, when given via the hepatic artery, and that the
pharmacokinetic advantage of HVI.CHP would be greater when a drug like nedaplatin
with a relatively low hepatic extraction ratio is used. Thus, we concluded that
nedaplatin is a more suitable drug than cisplatin.
42. Jpn J Clin Oncol. 1997 Dec;27(6):442-4.
Combination chemotherapy using intravenous nedaplatin (254-S) and intraarterial

cisplatin (CDDP) with transcatheter arterial embolization (TAE) for a patient
with uterine cervical cancer: a case report.
Adachi S(1), Yamasaki N, Ogasawara T, Takayasu Y, Takemura T, Koyama K.
Author information:
(1)Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.
A 45-year-old Japanese woman with a bulky (75 x 40 mm) stage 2a uterine cervical
cancer was treated with 87 mg (50 mg/m2) of nedaplatin (254-S) intravenously and
120 mg (70 mg/m2) of cisplatin (CDDP) intraarterially with transcatheter arterial
embolization (TAE). She received three courses of this combination chemotherapy
and showed a complete response, as confirmed by magnetic resonance imaging. A
radical hysterectomy was performed and the pathological findings revealed the
absence of carcinoma cells. This type of combination chemotherapy seems to be
effective for the treatment of locally advanced uterine cervical cancer.
43. Obstet Gynecol. 1995 Aug;86(2):265-8.
Platinum concentrations in uterus and serum after internal iliac arterial

infusion of platinum compounds in rabbits.
Kigawa J(1), Minagawa Y, Itamochi H, Kanamori Y, Ishihara H, Terakawa N.
Author information:
(1)Department of Obstetrics and Gynecology, Tottori University School of
Medicine, Yonago, Japan.
OBJECTIVE: To compare three platinum compounds, and study the pharmacokinetics of

these compounds after systemic and intra-arterial infusion.
METHODS: Adult female rabbits received infusions of 1.7 mg/kg cisplatin, 10 mg/kg
carboplatin, or 6 mg/kg cisdiammine(glycolato)platinum (254-S) via the internal
iliac artery or jugular vein. The doses were equitoxic. Platinum tissue
concentration in uterus and platinum serum levels were measured after internal
iliac arterial or intravenous (i.v.) infusion with these platinum compounds.
RESULTS: Platinum uterine concentration after intra-arterial infusion was
significantly higher than that after i.v. infusion for each drug (P < .05). The
ratios of platinum uterine concentration after intra-arterial infusion to those
after i.v. infusion were 2.24 for cisplatin, 1.83 for carboplatin, and 1.67 for
254-S measured 20 minutes after drug administration. The area under the curve of
filtrated platinum (micrograms/mL.hours) was significantly lower for cisplatin
compared with carboplatin and 254-S in both infusion methods (1.5 for cisplatin,
32.1 for carboplatin, and 16.0 for 254-S after i.v. administration, and 0.8,
30.9, and 15.2 after intra-arterial administration, respectively).
CONCLUSION: Cisplatin produced the highest ratio of uterine to serum
concentration of platinum after intra-arterial infusion.
44. Anticancer Res. 1994 May-Jun;14(3B):1383-7.
Pharmacokinetics of platinum in cancer patients following intravenous infusion of

cis-diammine(glycolato)platinum, 254-S.
Ota K(1), Oguma T, Shimamura K.
Author information:
(1)Aichi Cancer Center, Nagoya, Japan.
The pharmacokinetics of platinum in cancer patients were examined following an

intravenous infusion of cis-diammine(glycolato) platinum, 254-S. The plasma
concentrations of total platinum, which decreased biexponentially after the
infusion, were proportional to the dose over the range of 10 to 120 mg/m2,
suggesting linearity of the pharmacokinetics. The plasma concentrations of
ultrafilterable platinum were similar to those of total platinum and there was
little difference in the pharmacokinetic parameters between total platinum and
ultrafilterable platinum. These findings show that almost all of the platinum
derivative is unbound, which is thought to be the active form, in plasma after
administration of 254-S. Platinum was eliminated from blood faster when given as
254-S rather than as cisplatin because of the low protein binding. The urinary
recovery within 24 hours was about half of the dose, suggesting that platinum
given as 254-S was distributed to various tissues and organs in an active form.
45. Cancer. 1993 May 1;71(9):2769-75.
Combination chemotherapy with 254-S, ifosfamide, and peplomycin for advanced or

recurrent cervical cancer.
Hirabayashi K(1), Okada E.
Author information:
(1)Department of Obstetrics and Gynecology, Fukuyama National Hospital, Japan.
BACKGROUND: Based on the fact that combination chemotherapy with cisplatin,

ifosfamide, and bleomycin generated a 69% response rate in patients with
recurrent cervical cancer; that 254-S (a cisplatin analogue) monotherapy
generated a 46.3% response rate for cervical cancer, which was higher than those
generated by cisplatin and carboplatin in historic comparison; and that
peplomycin is a bleomycin analogue with improved pulmonary toxic effects, a
combination regimen with 254-S, ifosfamide, and peplomycin was evaluated in an
animal experiment and a clinical study in patients with advanced or recurrent
cervical cancer with an expectation that the regimen might show a higher efficacy
than 254-S monotherapy and the combination regimen including cisplatin.
METHODS: In the clinical testing, 254-S was administered intravenously (IV) at
80-100 mg/m2, ifosfamide was administered IV at 1500 mg/patient for 5 days, and
peplomycin was administered intramuscularly at 5 mg/patient for 6 days. This
treatment was repeated every 4 weeks.
RESULTS: As a result, this regimen showed additive or synergistic antitumor
effects in mice receiving B16 melanoma transplants. In the clinical study, 83.8%
and 60.9% response rates were obtained in 37 previously untreated patients with
Stage III or IV cervical cancer and 23 with recurrent cervical cancer,
respectively. The dose-limiting factor was bone marrow toxic effects, which were
tolerable. The other toxic effects were mild, and there were no deaths.
CONCLUSIONS: From these results, this combination regimen was thought worthy of
evaluation in a Phase III comparative study in patients with advanced or
recurrent cervical cancer.
[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for

advanced breast cancer].
Koyama H(1), Ogawa M, Kuraishi Y, Tominaga K, Yoshida M, Taguchi T.
Author information:
(1)Department of Surgery, Center for Adult Diseases, Osaka, Japan.
A phase II clinical study of 254-S, a new anticancer platinum complex for

advanced breast cancer, was conducted by the 254-S Breast Cancer Study Group
consisting of 6 institutions nation-wide. Considering the results of the phase I
clinical study, 254-S was administered at 100 mg/m2 by intravenous drip infusion
and this administration was repeated at least 2 times at 4-week intervals. Of 19
patients registered, 16 were evaluable for tumor response (complete cases).
Partial response (PR) was obtained in 2 patients, for a 12.5% response rate.
Major toxic effects observed were hematotoxicity thrombocytopenia and leukopenia,
and gastrointestinal toxicity (nausea and vomiting, and anorexia), though there
was no case in which the treatment with 254-S had to be discontinued due to the
toxic effect.

cervical cancer of the uterus].
Noda K(1), Ikeda M, Yakushiji M, Nishimura H, Terashima Y, Sasaki H, Hata T,

Kuramoto H, Tanaka K, Takahashi T, et al.
Author information:
(1)Dept. of Obstetrics and Gynecology, Kinki University School of Medicine.
A phase II clinical study of 254-S, a new anticancer platinum complex, for

cervical cancer was conducted by the 254-S Cervical Cancer Study Group consisting
of 10 institutions. 254-S was administered at 80 mg/m2 by intravenous drip
infusion and this administration was repeated at least 2 times at 4-week
intervals, in principle. Forty of 45 patients registered, were eligible and 38
were evaluable for tumor response (complete cases). Complete response (CR) and
partial response (PR) were obtained in 4 (10.5%) and 9 patients (23.7%),
respectively, for a 34.2% response rate. Against squamous cell carcinoma, a 38.2%
response rate (4 CR and 9 PR in 34 patients) was obtained. The response rate
obtained in patients with no prior chemotherapy was 40.0% (2 CR and 8 PR in 25
patients), while that in patients with prior chemotherapy was 23.1% (2 CR and 1
PR in 13 patients). Major toxic effects observed were hematotoxicity, including
thrombocytopenia (35.1%), leukopenia (73.0%), anemia (75.7%), gastrointestinal
toxicity such as nausea and vomiting (83.8%) and anorexia (83.8%). Nephrotoxicity
observed was in the form of an elevation of serum creatinine with an incidence of
2.7% and a decrease in creatinine clearance with an incidence of 21.7%. In
comparison with the results obtained in the phase II clinical study for
gynecological cancers in which 254-S was administered at 100 mg/m2, the response
rate obtained in this study was slightly lower but thrombocytopenia and
leukopenia observed were less frequent and milder. Based on these results, it was
concluded that 254-S is a very useful anticancer agent for the treatment of
cervical cancer.
[A late phase II clinical study of cis-diammine glycolato platinum, 254-S, for

head and neck cancers].
Inuyama Y(1), Miyake H, Horiuchi M, Hayasaki K, Komiyama S, Ota K.
Author information:
(1)Dept. of Otolaryngology, School of Medicine, Keio University.
A late phase II clinical study of 254-S, a new anticancer platinum complex, for
head and neck cancer was conducted by the 254-S Head and Neck Cancer Study Group
consisting of 31 institutions. As in the early phase II study for head and neck
cancers, 254-S was administered at 100 mg/m2 by 60 min intravenous drip infusion,
repeated at least twice at 4-week intervals. Of 80 cases registered, 66 were
regarded as complete cases evaluable for tumor response. Complete response (CR)
was observed in 7 patients (10.6%), partial response (PR) in 22 (33.3%), no
change (NC) in 24 and progressive disease (PD) in 13, for a 43.9% response rate.
Two CR and 11 PR (37.1% response rate) were obtained in 35 patients with prior
chemotherapy, including 2 CR and 7 PR (33.3% response rate) in 27 patients
previously treated with cisplatin. Of 70 patients evaluable for toxicity, side
effects were observed in 60 patients (85.7%). Major toxic effects were
hematotoxicity, including leukopenia (62.9%), thrombocytopenia (40.0%) and anemia
(45.7%), gastrointestinal toxicity, including nausea and vomiting (64.3%), and
anorexia (47.1%); grade 3 or 4 thrombocytopenia was found in 20.0% of the
patients, and this toxicity was regarded as the dose limiting factor.
Nephrotoxicity observed was mild and infrequent. Based on these results, it was
concluded that 254-S is a very useful anticancer agent for the treatment of head
and neck cancer.
[An early phase II clinical study of cis-diammine glycolato platinum, 254-S, for
head and neck cancers].
Inuyama Y(1), Miyake H, Horiuchi M, Hayasaki K, Komiyama S, Ota K.
Author information:
(1)Dept. of Otolaryngology, School of Medicine, Keio University.
An early phase II clinical study of 254-S, a new anticancer platinum complex, for
head and neck cancer was conducted by the 254-S Head and Neck Cancer Study Group
consisting of 10 institutions. Based on the results obtained in the phase I
study, 254-S was administered at 100 mg/m2 by 60 min intravenous drip infusion
after being dissolved in 300 ml of 5% xylitol. In principle, the 254-S
administration was repeated at least 2 times at 4 week intervals. Hydration was
performed, if needed. All 24 cases registered were regarded as complete cases
evaluable for tumor response. Complete response (CR) was observed in 4 patients
(16.7%), partial response (PR) in 5 (20.8%), no change (NC) in 11 and progressive
disease (PD) in 4, for a 37.5% response rate. Three CR and 3 PR (40.0%) were
obtained in 15 patients with prior chemotherapy, including 1 CR and 2 PR (33.3%)
in 9 patients previously treated with cisplatin. Side effects were observed in 19
patients (79.2%). Major toxic effects were hematotoxicity, including
thrombocytopenia (58.3%), leukopenia (58.3%) and anemia (33.3%), and
gastrointestinal toxicity, including nausea and vomiting (45.8%) and anorexia
(37.5%). Abnormal parameter changes on renal function were found in 2 patients
(8.3%). Based on these results, it was concluded that 254-S is potentially a
useful anticancer agent for the treatment of head and neck cancer, and should be
further investigated in a late phase II clinical study.
[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum

(II)].
Ota K(1), Wakui A, Majima H, Niitani H, Inuyama Y, Ogawa M, Ariyoshi Y, Yoshida

O, Taguchi T, Kimura I, et al.
Author information:
(1)Dept. of Internal Medicine, Aichi Cancer Center, Japan.
A new platinum complex 254-S had a superior preclinical therapeutic indices

compared to cisplatin, showing decreased renal and gastrointestinal toxicities.
Phase I clinical study with a single dose schedule was conducted to investigate
the safety, toxicity, pharmacokinetics and possible efficacy against various
advanced cancers by a cooperative study of 10 institutions. The drug was
administered by i.v. infusion for 60 min dissolved in 250 ml of 5% xylitol
solution, without the use of hydration and antiemetics. At least 3 patients at
each dose level of 10, 20, 40, 80, 100 and 120 mg/m2 were tested and 28 patients
were entered into this study. Myelosuppression, especially thrombocytopenia,
appeared strongly at dose level of 80 mg/m2 and dose limiting thrombocytopenia
was found in 2 of 5 patients. Leukocytopenia was also dose-related but moderate.
Platelet and WBC nadirs occurred around 3 weeks after administration with
recovery in about one week. Although slight elevation of BUN and creatinine were
temporarily observed in a few cases, no significant renal toxicity was observed.
Anorexia, nausea and vomiting were observed in the majority of patients, but
milder than cisplatin. In conclusion, 254-S has demonstrated reduced
non-hematologic toxicities as compared to cisplatin. This drug appears to be well
tolerated and 120 mg/m2 was maximum tolerated dose. The recommended dose for
phase II studies was thought to be 100 mg/m2 by i.v. infusion every 4 weeks.
[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for primary

lung cancer].
Furuse K(1), Fukuoka M, Kurita Y, Ariyoshi Y, Niitani H, Yoneda S, Fujii M,

Hasegawa K, Nishiwaki Y, Tamura M, et al.
Author information:
(1)Dept. of Internal Medicine, National Kinki Central Hospital for Chest
Diseases.
A phase II clinical study of 254-S, a new anticancer platinum complex, for

primary lung cancer was conducted by the 254-S Lung Cancer Study Group consisting
of 15 institutions nation-wide. Considering the results of the phase I clinical
study, 254-S was administered at 100 mg/m2 by intravenous drip infusion and this
administration was repeated at least 2 times at 4-week intervals. Of 75 patients
registered, 61 patients consisting of 22 with small cell lung cancer (SCLC) and
39 with non-small cell lung cancer (NSCLC) were evaluable for complete tumor
response. Partial response (PR) was obtained in 17 patients, for a 27.9% response
rate. The response rate for SCLC was 40.9% (9 PR in 22 patients) and that for
NSCLC was 20.5% (8 PR in 39 patients). In SCLC patients with no prior
chemotherapy, a 50.0% (5 PR in 10 patients) response rate was obtained. In those
with prior chemotherapy, the response rate was 33.3% (4 PR in 12 patients). In
NSCLC patients with no prior chemotherapy, a 22.6% (7 PR in 31 patients) response
rate was obtained. In hose with prior chemotherapy, the response rate was 12.5%
(1 PR in 8 patients). Major toxic effects observed were hematotoxicity such as
thrombocytopenia and leukopenia, and gastrointestinal toxicity such as nausea,
vomiting and anorexia. Nephrotoxicity observed was mild and infrequent in spite
of the low-volume hydration performed. Based on these results, it was concluded
that 254-S is a useful anticancer agent for the treatment of primary lung cancer.
52. Gan To Kagaku Ryoho. 1992 Apr;19(4):483-8.

gastrointestinal cancers. 254-S Gastrointestinal Cancer Study Group].
Taguchi T(1), Wakui A, Nabeya K, Kurihara M, Isono K, Kakegawa T, Ota K.
Author information:
(1)Dept. of Surgery, Osaka University, Suita, Japan.
A phase II clinical study of 254-S, a new anticancer platinum complex for
gastrointestinal cancers, was conducted by the 254-S Gastrointestinal Cancer
Study Group consisting of 16 institutions. 254-S was administered at 100 mg/m2 by
intravenous drip infusion. This administration was repeated at 4-week intervals.
The cases in which 254-S could be administered at least two times were regarded
as complete cases evaluable for tumor response; of 75 cases registered, 53 were
complete cases (29 cases with esophageal cancer, 12 with stomach cancer and 12
with colon cancer). As a result, 15 partial responses (PR) were obtained in the
29 patients with esophageal cancer and 1 PR from the 12 patients with stomach
cancer, for a 51.7% and 8.3% response rate, respectively. 5 PR (55.6%) were
obtained in 9 esophageal cancer patients with prior chemotherapy, including 2 PR
in 4 patients previously treated with cisplatin. Major toxic effects observed
were hematotoxicity including thrombocytopenia (59.0%), leukopenia (68.9%) and
anemia (57.4%) and gastrointestinal toxicity such as nausea and vomiting (63.9%)
and anorexia (41.0%); since grade 3 or 4 thrombocytopenia was observed with an
incidence of 27.9%, careful monitoring seems to be required during the treatment
with this product. Abnormal parameter changes on renal function included
elevations of BUN (18.0%) and serum creatinine (9.8%). Based on these results, it
was concluded that 254-S is a useful anticancer agent for the treatment of
esophageal cancer.
53. Cancer Res. 1991 Mar 1;51(5):1472-7.
Phase I study and pharmacological analysis of cis-diammine(glycolato)platinum

(254-S; NSC 375101D) administered by 5-day continuous intravenous infusion.
Sasaki Y(1), Amano T, Morita M, Shinkai T, Eguchi K, Tamura T, Ohe Y, Kojima A,

Saijo N.
Author information:
(1)Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
A phase I study of cis-diammine(glycolato)platinum (254-S; NSC 375101D) was

conducted in 15 patients with refractory or relapsing malignancy by 5-day
continuous i.v. infusion. Three to 5 patients per dose were given 50, 75, 87.5,
or 100 mg/m2/120 h (10-20 mg/m2 daily for 5 days). Toxicity evaluation and
pharmacokinetic analysis were performed in 15 and 14 patients, respectively.
Thrombocytopenia and neutropenia were the dose-limiting toxicities at the maximum
tolerated dose of 87.5 mg/m2/120 h (17.5 mg/m2/day); however, nonhematological
toxicities including renal toxicity, nausea and vomiting, and peripheral
neuropathy were mild and well tolerated. The nadir of platelets and neutrophils
was observed 4 and 5 weeks, respectively, after the initiation of drug infusion.
Plasma and urine samples were obtained during and after infusion for
quantification by atomic absorption spectrophotometry of total and free platinum
levels derived from 254-S. The maximum level of total platinum was obtained after
120 h of infusion, whereas the steady state concentration of free platinum in the
patients given 75 mg/m2 or more was over 0.1 microgram/ml. Free platinum levels
declined monophasically, with half-lives of 0.65-2.56 h/100 mg/m2 dose. The mean
area under the concentration versus time curve (AUC) in the patients treated with
75 mg/m2 was 1069 micrograms/ml, which was similar to that obtained in the
patients receiving 100 mg/m2 of 254-S by i.v. drip infusion over 30 min. There
was a direct correlation between the dose administered and the AUC of platinum (R
= 0.757, P = 0.002) or the steady state plasma concentration of free platinum (R
= 0.763, P = 0.002). The percentage of platinum excreted in urine 144 h after the
initiation of infusion ranged from 73.1 to 100% for each dose level. No
significant relationship was established between creatinine clearance in patients
before treatment and the AUC or steady state concentration of free platinum. The
plasma platinum AUC showed a linear correlation with the percentage of change in
leukocytes [formula: see text] (R = 0.736, P = 0.003). In conclusion, the
recommended phase II dose for a continuous infusion of 254-S is 75.5 mg/m2/120 h
every 6 hours.
54. Gan To Kagaku Ryoho. 1990 Nov;17(11):2221-7.
[Pharmacokinetics of cis-diammine (glycolato) platinum (254-S), a new platinum

antitumor agent, following an intravenous and intraperitoneal infusion bioactive
platinum concentration profile].
Hirabayashi K(1), Okada E, Oguma T, Shimamura K.
Author information:
(1)Fukuyama National Hospital, Hiroshima.
The pharmacokinetics of cis-diammine (glycolato) platinum (254-S) was

investigated in cancer patients following intravenous and intraperitoneal
infusion. The serum concentrations of total and unbound 254-S were determined by
bioassay and chemical assay as platinum. Platinum detected by bioassay was
thought to be active and unchanged 254-S. Almost all of platinum in plasma were
found to be active and unbound to protein because of no differences in the
concentrations determined by bioassay and chemical assay and in plasma and plasma
filtrate. In abdominal ascites, platinum concentrations determined by bioassay
corresponded with those determined by chemical assay, suggesting that 254-S was
stable in abdominal ascites. The Cmax and AUC of active 254-S in plasma
determined by bioassay following an intraperitoneal infusion were about 60% and
60-80% of those following an intravenous infusion, respectively. These results
showed that 254-S was well absorbed into systemic circulation from abdominal
ascites as an active form. It is concluded that antitumor effect may be obtained
following an intraperitoneal infusion of 254-S as well as for the reduction of
abdominal ascites.

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