Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

Figures & data

Figure 1. Flow chart of childhood cancer survivors with hearing impairment at discontinuation of treatment.

Figure 2. Childhood cancer survivors with hearing impairment at discontinuation of treatment (Münster ≥2b). Survivors with hearing impairment that persisted with equal severity (A). Survivors with aggravating hearing impairment over time (B). Survivors with >2 grade loss over time are depicted in red and indicated by an asterisk. Hearing did not recover in any of the survivors.

Table 1. Studies focusing on the course of hearing impairment after discontinuation of platinum treatment.

							Course of ototoxicity
Study (years)	Hearing loss after Rx (n)	Age at diagnosis, years (range)	Diagnosis	Cranial RT	Platinum	TCD platinum, mg/m^2	Permanent	(Partial) recovery	FU time, median years (range)
Al-Khatib (2010) [19]	13/31	0.4–17	Hodgkin's lymphoma, non-Hodgkin's lymphoma, brain tumor, retinoblastoma, osteosarcoma, optic glioma	No	Cisplatin, Carboplatin, Both	CIS only:292 (54–575)//both (CIS): 200 (56–345)//CARBO only: 1811 (261–15550)//both (CARBO): 283 (170–396)	13/13 (100%)	0/13 (0%)	3.4 (1.5–5.6)
Berg (1999) [6]	9/28	0.6–15	Neuroblastoma, osteosarcoma, medulloblastoma, germ cell tumor, CNS tumor, PNET, ependyoma, glioma	No	Cisplatin	480 (105–600)	9/9 (100%)	0/9 (0%)	N/A
Bertolini (2004) [7]	5/74	0–17	Neuroblastoma, osteosarcoma, hepatoblastoma, germ cell tumor	No	Cisplatin, Carboplatin, Both	CIS: 400 (80–800)//CARBO: 1600 (400–8000)	5/5 (100%)	0/5 (0%)	7 (2–14)
Brock (1991) [2]	14/29	2.2 (0.1–13.5)	Neuroblastoma, germ cell tumor, osteosarcoma, hepatoblastoma	No	Cisplatin	540 (400–1860)	14/14 (100%)	0/14 (0%)	4
Einarsson (2011) [8]	3/15	0.4–18	Carcinoma, PNET, osteosarcoma, neuroblastoma, germ cell tumor, hepatoblastoma, Wilms' tumor, germinoma, rhabdomyosarcoma, and glioma	Yes	Cisplatin, Carboplatin, Both	CIS only: 595 (180–820)//both (CIS): 192 (58–730)//CARBO only: 1910 (1000–3016)//both (CARBO): 1030 (410–5200)	1/1 (100%)^*	0/1 (0%)	2.3
Knight (2005) [9]	14/67	0.7–20.4	Germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, PNET, and Wilms’ tumor	Yes	Cisplatin, Carboplatin, Both	CIS: 491//CARBO: 4701	14/14 (100%)	0/14 (0%)	1.7 (0.5–3.6)
Nitz (2013) [20]	55/112	13.6 (IQR 10.3–16.3)	Osteosarcoma, soft tissue sarcoma	Yes	Cisplatin, Carboplatin, Both	CIS only: 360 (IQR 360–480)//both (CIS): 240 (IQR 240–360)//CARBO only: 1500//both (CARBO): 1200 (IQR 600–3000)	51/55 (92.7%)	4/55 (7.3%)^**	N/A
Qaddoumi (2012) [21]	12/60	0.7 (0.1–13.6)	Retinoblastoma	Yes	Carboplatin	3850 (2580–4480)	10/12 (96.7%)	2/12 (16.7%)^**	6.1 (0.3–13.3)
Stohr (2005) [22]	20/42	3.3–38	Osteosarcoma	No	Cisplatin	360 (120–600)	18/20 (80%)	2/20 (10%)	1 year after post-therapeutic audiogram
Current study (2016)	61/168	9.4 (0.1–7.2)	Osteosarcoma, neuroblastoma, germ cell tumors, hepatoblastoma, rhabdomyosarcoma, nephroblastoma, and Hodgkin lymphoma	No	Cisplatin, Carboplatin, Both	CIS only: 480 (180–950)//both (CIS): 400 (182–570)/CARBO only: 3415 (104–9350)//both (CARBO): 1700 (992–6043)	61/61 (100%)	0/61 (0%)	5.5 (1.0–28.8)

CARBO, carboplatin; CIS, cisplatin; FU, follow-up; PNET, primary neuro ectodermal tumor; RT, radiotherapy; Rx, treatment; TCD, total cumulative dose.

^* No follow-up data of 2 cases.

^** Not described whether hearing function improved to normal ranges.

Table 2. Münster and SIOP Boston classification for platinum-induced ototoxicity.

Grade	Münster classification	Audiological assessment according to WHO classification	SIOP Boston classification
0	≤10 dB HL at all frequencies	No considerable damage	≤20 dB HL at all frequencies
1	>10 and ≤20 dB HL at one or more frequencies	Questionable, commencing damage	>20 dB HL >4 kHz
2	>20 dB HL at ≥4 kHz	Moderate damage	>20 dB HL at ≥4 kHz
2a	>20 – ≤40 dB
2b	>40 – ≤60 dB
2c	>60 dB
3	>20 dB HL at < 4 kHz	Impaired compensable with hearing aid	>20 dB HL at ≥2 kHz
3a	>20 – ≤40 dB
3b	>40 – ≤60 dB
3c	>60 dB
4	≥80 dB at < 4 kHz	Loss of function, compensable by cochlear implantation	>40 dB HL at ≥2 kHz

Abbreviations: HL = hearing loss, SIOP = International Society of Pediatric Oncology, WHO = World Health Organization

Table 3. Characteristics of the survivors.

		Hearing impairment n = 61
Age at diagnosis, median years (range)		9.4 (0.1–17.2)
Gender, n (%)
	Male	32 (52.5)
	Female	29 (47.5)
Childhood malignancy, n (%)
	Sarcoma^*	36 (59)
	Brain tumor	2 (3.3)
	Hepatoblastoma	6 (9.8)
	Neuroblastoma	11 (18)
	Nephroblastoma	1 (1.6)
	Germ cell tumor	5 (8.2)
	Hodgkin lymphoma	—
Platinum compound, n (%)
	Cisplatin	46 (75.4)
	Carboplatin	2 (3.3)
	Both	13 (21.3)
Total cumulative dose, mg/m^2 (range)
	Cisplatin only	480 (180-990)
	Carboplatin only^**	1288 and 3230
	Cisplatin both	400 (300-570)
	Carboplatin both^**	1700 (992-3938)

Abbreviations: FU = follow-up, TCD = total cumulative dose

^* Osteosarcoma and rhabdomyosarcoma

^** 2/2 CCS treated with carboplatin only were not treated with autologous stem cell transplantation (ASCT); 8/13 CCS treated with both platinum compounds received high-dose carboplatin (1500–3375 mg/m²) as part of ASCT; 5/13 treated with both platinum compounds were not treated with ASCT (992–3938 mg/m² carboplatin).

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