Long-term serum platinum changes and their association with cisplatin-related late effects in testicular cancer survivors

Figures & data

Figure 1. Overview of survivors of testicular cancer included in Survey I (1998–2002), Survey II (2007-2008) and present study.

Table 1. Details on demographics, treatment and platinum levels.

Characteristic	Cases (TCS treated with CBCT) (n = 77)	Controls (surgery only) (n = 17)
(A) Demographics and treatment details
Age [years, median (range)]
At TC diagnosis	29 (15–51)	35 (17–55)
At SI	42 (25–59)	47 (25–64)
At SII	50 (34–67)	57 (34–73)
Follow-up time SI [years, median (range)]	12 (5–19)	12 (5–20)
Follow-up time SII [years, median (range)]	20 (13–27)	21 (13–27)
Histology [n (%)]
Seminoma	13 (17)	1 (6)
Non-seminoma	64 (83)	16 (94)
Initial Royal Marsden Stage [n (%)]
I	10 (13)	17 (100)
IMk + and II	40 (52)
III	3 (4)
IV	24 (31)
Treatment regimens [n (%)]
BEP alone	32 (42)
CVB alone	25 (32)
Both BEP and CVB	3 (4)
Other CBCT combinations^a	17 (22)
Cumulative cisplatin dose [mg, median (range)]^b	800 (178–3095)
CBCT cycles [n (%)]
1–2	4 (5)
3–4	62 (81)
>4	11 (14)
Relapse [n (%)]		1 (6)^c
Cis ≤ 850 mg group (n = 59)	8 (14)
Cis > 850 mg group (n = 18)	3 (17)
Radiotherapy [n (%)]		0 (100)
Cis ≤ 850 mg group (n = 59)	7 (12)
Cis > 850 mg group (n = 18)	1 (6)
RPLND [n (%)]		9 (53)
Cis ≤ 850 mg group (n = 59)	37 (63)
Cis > 850 mg group (n = 18)	17 (94)
(B) Platinum serum levels and change in Pt level (Pt decline) from SI to SII per year
Pt SI [ng/L, median (range)]	75 (26–377)	0 (0–478)
Cis ≤ 850 mg group (n = 59)	64 (26–305)
Cis > 850 mg group (n = 18)	201 (51–377)
Pt SII [ng/L, median (range)]	64 (0–725)	0 (0–91)
Cis ≤ 850 mg group (n = 59)	43 (0–725)
Cis >850 mg group (n = 18)	91 (26–204)
Pt decline [ng/L/year, median (range)]	4.2 (–93.0 to 26.6)	0.0 (–9.1 to 52.2)
Cis ≤ 850 mg group (n = 59)	3.0 (–93.0 to 16.4)
Cis > 850 mg group (n = 18)	7.9 (–0.8 to 26.6)

TCS: testicular cancer survivors; CBCT: cisplatin-based chemotherapy; n: number; TC: testicular cancer; SI: Survey I; SII: Survey II; IMk+: pathological values of the serum markers AFP and/or hCGbeta, without other signs of metastases; BEP: bleomycin, etoposide, cisplatin; CVB: cisplatin, vinblastine, bleomycin; RPLND: retroperitoneal lymph node dissection; cis ≤ 850 mg group: received cumulative <850 mg cisplatin; cis > 850 mg group: received cumulative >850 mg cisplatin; Pt: serum platinum.

^a 72 men received cisplatin as the only platinum-based chemotherapy.

^b 5 men received carboplatin (the dose is calculated to equivalent clinical dose of cisplatin), of these only one man received both carboplatin and cisplatin.

^c Local relapse 7 months after orchiectomy, treated with surgery.

Figure 2. (A) Pt levels at SI and SII for 94 participants, illustrated according to treatment modality and follow-up in years. Pt: platinum; cases: treated with chemotherapy; controls: treated with surgery only. (B) Pt levels at SI (blue dots) and SII (orange dots) for 77 CBCT-treated TCS, arranged according to follow-up time at SI. Pt: serum platinum; SI: survey I (1998–2002); SII: survey II (2007–2008); CBCT: platinum-based chemotherapy; TCS: testicular cancer survivors.

Figure 3. Cumulative risk of second cancer among all 76 men included in the analysis, and time to the second cancer diagnosis among 12 men diagnosed with second cancer after Survey II.

Table 2. Hazard ratios of second cancer diagnosed after survey II.

	Unadjusted	Adjusted*
Predictive variables	HR 95% CI	HR 95% CI
Age at diagnosis	1.05 (0.97–1.13)
Age at SII	1.02 (0.94–1.10)
Cumulative cisplatin dose, per 100 mg**	0.90 (0.74–1.22)
Pt at SI (per 50 ng/L)	1.16 (0.78–1.73)
Pt at SII (per 50 ng/L)	1.22 (1.05–1.42)
Pt decline SI-SII (per 10 ng/L/year)	0.78 (0.62–0.99)	0.67 (0.50–0.90)
Smoking status at SII
Never smoker	1.00 (reference)	1.00 (reference)
Previous smoker	2.77 (0.46–16.7)	3.95 (0.54–29.1)
Current smoker	9.14 (1.88–45.0)	13.9 (2.16–89.3)
Physical activity level at SII
High	1.00 (reference)
Middle	0.60 (0.07–5.06)
Low	1.77 (0.54–5.81)

HR: hazard ratio; 95% CI: 95% confidence interval; Pt: serum platinum; SI: survey I; SII: survey II.

Significant associations are marked as bold.

* Analyses are adjusted for smoking with never smokers as reference.

** Overall 4 men received carboplatin as the only platinum agent, one received both cisplatin and carboplatin. The corresponding cisplatin dose was calculated by dividing the carboplatin dose by four.

Figure 4. Median serum platinum at Survey I (SI) and Survey II (SII) for 77 testicular cancer survivors after chemotherapy, in different groups based on the renal function in either SI or SII and cumulative cisplatin dose.

Table 3. Odds ratios of increased symptoms between SI to SII of paresthesias in hands and feet, Raynaud’s in hands and feet, tinnitus and hearing impairment using ordinal logistic regression models*.

	Model 1	Model 2
Symptom changing between SI and SII	OR 95% CI	OR 95% CI
Change in paresthesias, hands
Pt decline (per 10 ng/L/year)	1.98 (1.09–3.59)	1.70 (1.02–2.85)
Cisplatin dose (per 100 mg)		1.21 (0.97–1.52)
Change in paresthesias, feet
Pt decline (per 10 ng/L/year)	0.72 (0.46–1.13)	0.72 (0.46–1.14)
Cisplatin dose (per 100 mg)		1.00 (0.87–1.14)
Change in Raynaud’s, hands
Pt decline (per 10 ng/L/year)	0.94 (0.68–1.32)	0.93 (0.66–1.31)
Cisplatin dose (per 100 mg)		1.03 (0.90–1.18)
Change in Raynaud’s, feet
Pt decline (per 10 ng/L/year)	1.32 (0.89–1.95)	1.31 (0.88–1.95)
Cisplatin dose (per 100 mg)		1.01 (0.88–1.15)
Change in tinnitus
Pt decline (per 10 ng/L/year)	1.51 (1.01–2.27)	1.48 (1.00–2.21)
Cisplatin dose (per 100 mg)		1.05 (0.91–1.21)
Change in hearing impairment
Pt decline (per 10ng/L/year)	1.22 (0.86–1.73)	1.22 (0.86–1.75)
Cisplatin dose (per 100 mg)		0.99 (0.86–1.13)

SI: survey I; SII: survey II; Pt: platinum; OR: odds ratio; CI: confidence interval.

* Model 1 includes Pt decline and model 2 includes Pt decline and cisplatin dose. All analyses are adjusted for age.

Significant associations are marked as bold.