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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2–3 CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2–3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0–1.0) and 0.3 (0–1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0–2.1) and 0.5 (0–3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2–3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients. (Cancer Sci 2011; 102: 162–165)

Cisplatin, despite its severe toxicity, has been used in cancer chemotherapy for more than 30 years because of its significant therapeutic efficacy.(1) Although carboplatin, an analog of cisplatin with a milder toxicity profile, was also introduced for clinical use, randomized trials and meta-analyses showed that cisplatin-based chemotherapy was slightly superior to carboplatin-based chemotherapy in terms of the response rate and survival, at least in certain subgroups, without any significant increase in the incidence of severe toxicities among patients with germ cell tumor,(2) head and neck cancer,(3) and non-small-cell lung cancer.(4) In addition, cisplatin was shown to have a significant role in the treatment of bladder cancer, cervical cancer, esophageal cancer, ovarian cancer and small cell lung cancer, although carboplatin is being used increasingly in the treatment of some of these cancers as an alternative chemotherapeutic agent.(5) Thus, cisplatin still plays a pivotal role in the systemic treatment of a variety of solid tumors.

Renal toxicity is a major dose-limiting factor of cisplatin in most drug administration schedules.(6) Although the exact mechanism is unclear, the greatest concentration of platinum and widespread necrosis are reportedly observed in the proximal tubules of the kidney. This tubular impairment leads to a secondary reduction of renal blood flow and the glomerular filtration rate, potentiating the primary tubular damage. This vicious cycle causes delayed deterioration of renal function, as an increase in the serum creatinine (CRN) level typically appears 6–7 days after cisplatin administration in humans.(6) The standard prophylaxis for cisplatin nephrotoxicity is infusion of 1–4 L of normal saline on the day of cisplatin administration.(6) Although this vigorous hydration diminishes life-threatening renal toxicity, 7–40% of patients still develop a mild to moderate increase of serum CRN levels, which influences the subsequent cisplatin therapy.(7,8)

Generic substitutes serve as lower-cost alternatives to the more costly brand-name drugs for patients.(9) If it can be shown that a generic formulation is “essentially similar” in qualitative and quantitative composition to an innovator preparation, then the formulation can be marketed as “generic” without the need for expensive regulatory clinical trials. However, whether generic cisplatin formulations are truly therapeutically identical and interchangeable with innovator formulation of the drug has not yet been investigated. The objective of this study was to compare the severity of renal toxicity between an innovator cisplatin formulation and a generic substitute.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

Patient selection.  Patients were retrospectively selected for this study according to the following criteria: (i) a histological or cytological diagnosis of thoracic malignancy; (ii) no prior chemotherapy, except for a combination of uracil and ftorafur (UFT) as adjuvant chemotherapy after surgery; (iii) chemotherapy with a regimen that included 80 mg/m2 of cisplatin; and (iv) receiving treatment as an inpatient at the National Cancer Center Hospital between November 2000 and March 2009. In this period, the innovator cisplatin formulation was administered between November 2000 and May 2004, and CISPLATIN for I.V. infusion (MARUKO), a generic cisplatin formulation, was administered thereafter. Patients with abnormal elevation of serum CRN before the start of chemotherapy were excluded from the current study.

Cisplatin administration.  Cisplatin was administered at a dose of 80 mg/m2 by intravenous infusion over 60–120 min on day 1 in combination with other chemotherapeutic agents, 40 g of mannitol and 3000 mL of hydration. On days 2–5, 2000 mL of intravenous infusion fluids were administered over 8 h. Antiemetic prophylaxis consisted of a 5HT3-antagonist and 16 mg of dexamethasone on day 1, followed by 8 mg of dexamethasone on days 2 and 3, 4 mg on day 4 and 2 mg on day 5. These treatments were repeated every 3–4 weeks. This sequence of administration was consistently maintained during the study period.

Data collection and statistical analyses.  The patients’ baseline characteristics, including age, sex and performance status (PS), pretreatment CRN level (CRNpre), chemotherapy regimen received, number of chemotherapy cycles administered and the maximum CRN level (CRNmax) during the first cycle and all cycles of chemotherapy were retrospectively obtained from medical charts. The patients’ list was encoded and anonymized. The median CRNmax, median increase in the serum CRN levels (difference between CRNpre and CRNmax), and the Common Toxicity Criteria–Adverse Event (CTC-AE ver. 3.0) grades of the CRNmax were compared between patients treated with the innovator cisplatin formulation (group 1) and those treated with the generic formulation (group 2); these evaluations were performed for the entire study population, as well as separately for the female and male patients, because the normal range of the serum CRN level differs between the sexes. Mann–Whitney tests were used to evaluate continuous variables, and Chi-squared tests for categorical variables. The Dr SPSS II 11.0 for Windows software (SPSS Japan Inc., Tokyo, Japan) was used for the statistical analyses.

This study was approved by the president of the National Cancer Center Hospital, Tokyo, Japan. The institutional review board and ethical review committee decided to exempt this study from the usual review process because of its retrospective nature.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

Of the 639 patients assessed for eligibility in this study, 627 patients met the inclusion criteria; 12 patients were excluded because of abnormal CRNpre levels. An additional 10 patients were excluded because they were treated with the innovator cisplatin formulation in the first cycle of chemotherapy, but with the generic formulation in subsequent cycles. Thus, a total of 617 patients were included as the subjects of this study. Of these, 296 patients were treated with the innovator cisplatin formulation (group 1) and 321 were treated with the generic formulation (group 2) (Fig. 1). The median age of the patients was 60 years in both groups, and female patients accounted for 24% of all patients (Table 1). There were no meaningful differences in the PS, CRNpre levels, height, weight or number of chemotherapy cycles between the groups.

image

Figure 1.  Flow of patients. In the present study there was a total of 296 patients treated with an innovator cisplatin formulation (group 1) and 321 patients treated with a generic cisplatin formulation (group 2). CRNpre, pretreatment serum creatinine level.

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Table 1.   Patient characteristics
CharacteristicsGroup 1† (n = 296)Group 2‡ (n = 321)P-value
N (%)N (%)
  1. †Patients treated with innovator formulation. ‡Patients treated with generic formulation. CRNpre, pretreatment serum creatinine level.

Sex
  Females72 (24)77 (24)0.93
  Males224 (76)244 (76)
Age (years)
  Median (range)59.5 (18–77)60.0 (18–75)0.85
Height (cm)
  Median (range)164 (146–181)165 (143–189)0.03
Weight (kg)
  Median (range)60.6 (35.3–102)60.3 (33.9–106)0.76
PS
  0–1294 (99)317 (99)0.69
  2–32 (1)4 (1)
CRNpre
  Median (range)0.7 (0.3–1.1)0.7 (0.3–1.1)0.17
No. cycles
  1–2121 (41)123 (38)0.56
  3–5175 (59)198 (62)
  Median (range)3 (1–5)3 (1–4)

The median (range) CRNmax levels during the first cycle of chemotherapy were 0.7 (0.5–1.8) mg/dL and 0.7 (0.5–1.6) mg/dL in the female patients of group 1 and group 2, respectively (P = 0.25), while they were 1.0 (0.5–4.5) mg/dL and 1.1 (0.6–4.2) mg/dL, respectively, in the male patients of group 1 and group 2, respectively (P = 0.016). These differences were even more pronounced when the CRNmax levels during all cycles of chemotherapy were evaluated. The median (range) CRNmax level in the female patients did not differ between groups 1 and 2 (0.8 [0.5–1.8] mg/dL vs 0.9 [0.6–2.5] mg/dL, P = 0.22), whereas that in the male patients was higher in group 2 than in group 1 (1.1 [0.5–4.5] mg/dL vs 1.3 [0.7–4.2] mg/dL, P < 0.001).

The increases in the serum CRN levels (differences between the CRNmax and CRNpre levels) during the first cycle of chemotherapy are summarized in Table 2. The median increase of the serum CRN levels did not differ between the female patients of groups 1 and 2, while it was higher in the male patients of group 2 than in those of group 1. However, the percentage of patients with a significant increase of serum CRN levels (0.7 mg/dL or higher) did not differ between groups 1 and 2 in the entire subject population, in the female patients alone, or in the male patients alone. The clinical significance of the increase in serum CRN levels was assessed using the CTC-AE grade of serum CRN. The CRN CTC-AE grades during the first cycle of chemotherapy did not differ between groups 1 and 2 in the entire subject population, in the females alone, or in the males alone (Table 2).

Table 2.   Increase in serum creatinine levels and toxicity grades during the first cycle of chemotherapy
 Group 1† (n = 296)Group 2‡ (n = 321)P-value
N (%)N (%)
  1. †Patients treated with innovator formulation. ‡Patients treated with generic formulation. CTC-AE, Common Toxicity Criteria–Adverse Event ver. 3.0.

Increase in serum creatinine levels (mg/dL)
Total
  0–0.3242 (81.8)238 (74.1)0.070
  0.4–0.635 (11.8)51 (15.9)
  ≥0.719 (6.4)32 (10.0)
  Median (range)0.2 (0–1.0)0.2 (0–1.2)0.054
Female
  0–0.364 (88.9)66 (85.7)0.76
  0.4–0.65 (6.9)8 (10.4)
  ≥0.73 (4.2)3 (3.9)
  Median (range)0.2 (0–1.0)0.2 (0–1.2)0.90
Male
  0–0.3178 (79.5)172 (70.5)0.070
  0.4–0.630 (13.4)43 (17.6)
  ≥0.716 (7.1)29 (11.9)
  Median (range)0.2 (0–2.1)0.2 (0–3.6)0.027
CTC-AE grade
Total
  0211 (71.3)208 (64.8)0.20
  169 (23.3)87 (27.1)
  2–316 (5.4)26 (8.1)
Female
  043 (59.3)40 (51.9)0.60
  123 (31.9)28 (36.4)
  2–36 (8.3)9 (11.7)
Male
  0168 (75.0)168 (68.9)0.29
  146 (20.5)59 (24.2)
  2–310 (4.5)17 (7.0)

There was a definite increase in the serum CRN levels during all cycles of chemotherapy (Table 3). The median increase in the serum CRN levels did not differ between the female patients of groups 1 and 2, while it was higher in the male patients of group 2 than in those of group 1. The percentage of patients with an increase in CRN levels of ≥0.7 mg/dL did not differ between the female patients of groups 1 and 2, but was higher in the male patients of group 2 than in those of group 1 (33.2%vs 17.9%, P < 0.001). The percentage of patients with grade 2–3 CRN CTC-AE in the male patients was 20.9% in group 2 and 9.4% in group 1 (P < 0.001), although no significant difference was noted between the female patients of groups 1 and 2 (Table 3).

Table 3.   Increase in serum creatinine levels and toxicity grades during all cycles of chemotherapy
 Group 1† (n = 296)Group 2‡ (n = 321)P-value
N (%)N (%)
  1. †Patients treated with innovator formulation. ‡Patients treated with generic formulation. CTC-AE, Common Toxicity Criteria–Adverse Event ver. 3.0.

Increase in serum creatinine levels (mg/dL)
Total
  0–0.3177 (59.8)146 (45.5)<0.001
  0.4–0.671 (24.0)85 (26.5)
  ≥0.748 (16.2)90 (28.0)
  Median (range)0.3 (0–2.1)0.4 (0–3.6)<0.001
Female
  0–0.349 (68.1)52 (67.5)0.99
  0.4–0.615 (20.8)16 (20.8)
  ≥0.78 (11.1)9 (11.7)
  Median (range)0.2 (0–1.0)0.3 (0–1.8)0.68
Male
  0–0.3128 (57.1)94 (38.5)<0.001
  0.4–0.656 (25.0)69 (28.3)
  ≥0.740 (17.9)81 (33.2)
  Median (range)0.3 (0–2.1)0.5 (0–3.6)<0.001
CTC-AE grade
Total
  0160 (54.1)122 (38.0)<0.001
  1102 (34.5)129 (40.2)
  2–334 (11.5)70 (21.8)
Female
  030 (41.7)24 (31.2)0.44
  129 (40.3)34 (44.2)
  2–313 (18.1)19 (24.7)
Male
  0130 (58.0)98 (40.2)<0.001
  173 (32.6)95 (38.9)
  2–321 (9.4)51 (20.9)

Since we unexpectedly found a distinct trend of increase in the CRN levels in the female and male patients, we studied the gender difference (Table 4). The increase in CRN levels was higher in the male than female patients, while the CRN CTC-AE grades were more severe in the female than male patients.

Table 4.   Gender differences in the increase of serum creatinine levels and toxicity grades during the first and all cycles of chemotherapy
 Females (n = 149)Males (n = 468)P-value
N (%)N (%)
  1. CTC-AE, Common Toxicity Criteria–Adverse Event ver. 3.0.

During the first cycle of chemotherapy
An increase in CRN (mg/dL)
  0–0.3130 (87.2)350 (74.8)0.006
  0.4–0.613 (8.7)73 (15.6)
  ≥0.76 (4.0)45 (9.6)
  Median (range)0.20 (0–1.2)0.20 (0–3.6)<0.001
CTC-AE grade
  083 (55.7)336 (71.8)0.001
  151 (34.2)105 (22.4)
  2–315 (10.1)27 (5.8)
During all cycles of chemotherapy
An increase in CRN (mg/dL)
  0–0.3101 (67.8)222 (47.4)0.001
  0.4–0.631 (20.8)125 (26.7)
  ≥0.717 (11.4)121 (25.9)
  Median (range)0.20 (0–1.8)0.40 (0–3.6)<0.001
CTC-AE grade
  054 (36.2)228 (48.7)0.023
  163 (42.3)168 (35.9)
  2–332 (21.5)72 (15.4)

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

This study showed that the renal toxicity was slightly more severe in the patients who were treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among male patients. This result was not attributable to biased prognostic factors for cisplatin-induced renal toxicity, including age, PS, dose of cisplatin or the number of chemotherapy cycles pointed out previously,(7,8) because these variables were distributed equally between patients who were treated with the generic and innovator cisplatin formulations. Higher CTC-AE grades as well as increased serum CRN levels during chemotherapy were observed in patients treated with the generic cisplatin formulation, and therefore this renal toxicity can be as severe as it influences subsequent therapies of the patients.

The generic drug is exactly the same as the innovator drug in its basic composition and property, including cisplatin content, solvent and pH and osmotic pressure of the solution, but the additives to stabilize the solution may not be identical. Thus, this small difference is considered to result in the increased renal toxicity of the generic drug. Unlike the basic composition and property of drugs, the influence of additives can not be easily examined. It is much simpler to use the same additives in the manufacturing process of generic drugs.

We never expected that the association between increased renal toxicity and administration of the generic cisplatin formulation would be more evident in male patients, and this result prompted us to compare the renal toxicity between the sexes. A rise in the serum CRN levels during chemotherapy was more frequent in male patients, while the CTC-AE grades were more severe in the female than male patients. This is probably because men generally have a larger and more muscular physique that leads to higher CRN production and a higher upper limit of the normal range of the serum CRN level in men than in women. In previous studies, a rise in serum CRN during cisplatin-containing chemotherapy was found to be slightly more frequent in female patients, but the difference was only mild and of no clinical significance. Thus, there seems to be only a small difference, if any, in the responses to nephrotoxic agents between the sexes, and males are unlikely to be more vulnerable to cisplatin. Another possible explanation for the current results might be the relatively low volume of hydration in male patients, because the infusion volume administered was the same in male and female patients despite the larger physique of male patients. However, the explanation attributed to this small difference in the infusion volume might not be plausible, because the volume of hydration was not clearly associated with cisplatin-induced renal toxicity in a previous study.(8)

Because this study has suggested that generic cisplatin might be slightly more toxic to the kidneys, some kind of countermeasures are necessary. First, the content of hydration and timing of mannitol administration should be reconsidered to avoid renal toxicity. We had not included magnesium in the hydration fluid, but recent randomized trials showed that addition of magnesium was effective in reducing cisplatin-induced renal toxicity.(10,11) We have administered mannitol after cisplatin infusion, but the National Cancer Center Hospital (NCCH) guideline recommends using mannitol before cisplatin infusion. If these countermeasures fail to reduce renal toxicity, then the use of generic cisplatin would not be recommended.

A major limitation of the present study is that the generic and innovator cisplatin formulations were not allocated in a randomized fashion to the study population, but was determined by the period of the treatment. Although cisplatin administration in our hospital was consistent throughout the study period, there might be unknown factors associated with renal toxicity influenced by the study period.

Generic formulations are approved without clinical trials in Japan, as well as in other countries. This system has worked well to reduce drug costs safely, provided that the drug has a potentially low toxicity profile. However, the results of this study suggest that more attention should be given to the developmental system of generic formulations, especially in relation to anticancer agents, which might have severe and life-threatening toxicities. One possibility is disclosure of the drug manufacturing process so that drug companies can strictly follow the process when they develop a generic formulation of the original drug. Utmost importance should also be given to post-marketing surveys. A survey of at least 1000 treated patients can define the toxicity profile of a new formulation. These revisions of the developmental process might offer safer generic formulations to patients without further increase of the medical costs.

In conclusion, renal toxicity was slightly more severe in patients treated with a generic cisplatin formulation than in those treated with an innovator formulation, especially among male patients. This result suggests that more attention should be given to the developmental system of generic formulations, especially in those drugs that have a narrow therapeutic window, such as anticancer agents.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

The authors thank Mika Nagai for her assistance in the preparation of this manuscript.

Disclosure Statement

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References

The authors indicate no potential conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure Statement
  8. References
  • 1
    Reed E. Cisplatin and its analogues. In: DeVitaV, LawrenceT, RoesnbergS, eds. Cancer: Principles & Practice of Oncology, 8th edn. Philadelphia: Wolters Kluwer Lippincott Williams & Wilkins, 2008; 41926.
  • 2
    Horwich A, Sleijfer DT, Fossa SD et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997; 15: 184452.
  • 3
    De Andres L, Brunet J, Lopez-Pousa A et al. Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J Clin Oncol 1995; 13: 1493500.
  • 4
    Ardizzoni A, Boni L, Tiseo M et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007; 99: 84757.
  • 5
    Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17: 40922.
  • 6
    Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecol Oncol 1993; 50: 14758.
  • 7
    de Jongh FE, van Veen RN, Veltman SJ et al. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003; 88: 1199206.
  • 8
    Stewart DJ, Dulberg CS, Mikhael NZ et al. Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods. Cancer Chemother Pharmacol 1997; 40: 293308.
  • 9
    Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Potential savings from substituting generic drugs for brand-name drugs: medical expenditure panel survey, 1997–2000. Ann Intern Med 2005; 142: 8917.
  • 10
    Willox JC, McAllister EJ, Sangster G et al . Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial. Br J Cancer 1986; 54: 1923.
  • 11
    Bodnar L, Wcislo G, Gasowska-Bodnar A et al . Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study. Eur J Cancer 2008; 44: 260814.