University of Groningen
Survivorship care after testicular cancer
Boer, Hindrik
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Boer, H. (2019). Survivorship care after testicular cancer: New insights in late effects of treatment and approaches to shared-care follow-up. Rijksuniversiteit Groningen.
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Long-term and late effects of germ-cell
testicular cancer treatment and
implications for follow-up
Chapter 2
2
Hege S. Haugnes1,2, George J. Bosl3, Hink Boer4, Jourik A. Gietema4, Marianne Brydøy5,6,
Jan Oldenburg7, Alv A. Dahl7,8, Roy M. Bremnes1,2, Sophie D. Fosså7,8.
1Department of Oncology, University Hospital of North Norway, Tromsø, Norway 2Institute of Clinical Medicine, University of Tromsø, Norway 3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA 4Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands 5Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway 6Department of Oncology, Haukeland University Hospital, Bergen, Norway 7Division of Cancer Medicine and Radiotherapy, Oslo University Hospital, Norway 8Medical Faculty, University of Oslo, Norway
Abstract
Germ-cell testicular cancer (TC) represents a malignancy with very high cure rates. After the introduction of cisplatin-based chemotherapy in the late 1970s, the 5-year survival rate has increased considerably, and is currently above 95%. Since TC usually is diagnosed before the age of 40, these men can expect to live for another 40-50 years after being successfully treated. This success, however, is hampered by an increased risk of long-term and late effects of treatment. Secondary malignant neoplasms and cardiovascular disease represent the most common potentially life-threatening late effects typically occurring more than 10 years after treatment. Other long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism and psycho-social problems. The incidence and time to onset of these various side-effects vary according to treatment type and intensity. There is still little knowledge about underlying mechanisms and genetic susceptibility of the various adverse effects. Apart from treatment burden, it is not yet possible to identify patients who are at high risk for certain late effects after TC treatment.
In this clinical review, we present the current status regarding different somatic and psychosocial long-term late effects after treatment for TC, based on Medline searches and our own research. Moreover, we postulate recommendations for general medical evaluations that should begin after treatment is completed and continue during follow-up.
Introduction
The treatment of germ-cell (GC) testicular cancer (TC) represents a medical success story with today’s 5-year survival rates exceeding 95%.1 The improved prognosis is primarily due to the
effectiveness of cisplatin-based chemotherapy in the treatment of advanced disease, timing of surgery to remove residual disease, and the establishment of effective salvage regimens.2
TC affects mostly young men at their peak of family life, reproduction, education and career, with a life expectancy of 40-50 years after successful cancer treatment. Consequently, there has been an increased attention towards long-term effects of cancer treatment during the last decade, which has resulted in attempts to decrease treatment-related toxicity while maintaining the high cure rates.3 Despite these attempts, treatment-related toxicity has emerged
as an important issue for this young patient population. But since studies of late effects of cancer treatment are retrospective in nature, it should be pointed out that the current knowledge represents complications of treatment administered several years to decades ago.4
Long-term survivors are defined as individuals who are disease-free 5 years or more after primary treatment.4 Some side-effects of cancer treatment develop during treatment
and may persist during follow-up, e.g. peripheral neuropathy. These side-effects are referred to as long-term effects, while late effects become manifest months to years after completion of treatment.4 Secondary non-GC cancers and cardiovascular disease are examples of late effects.
These represent the most serious and potentially life-threatening effects of cancer treatment. Apart from treatment burden, it is presently not possible to identify patients at high risk for certain somatic long-term and late effects of TC treatment. A recent review paper on TC survivorship has recommended specific future research directions to elucidate the underlying mechanisms of the long-term and late effects.5
Based on Medline searches and our own research, we herein summarize the current knowledge regarding the different somatic and psychosocial long-term and late effects after TC treatment. We postulate recommendations for maintaining health and general medical evaluations that should begin after treatment and continue beyond the 10-year follow-up. Methods
Medline databases were used to identify original articles and reviews on long-term and late effects of TC treatment. The phrases used during the search process included “testicular cancer” or “germ cell cancer” combined with “survivors”, “late effects”, “morbidity”, or “long-term effects” and phrases reflecting the different toxicities (e.g. “myocardial infarction”, “cardiovascular disease”, “hypertension”). Articles published during the past two decades were preferentially included. Only articles published in English until 31st of December 2011 were reviewed. The majority of
included publications were based on participants who were in a durable complete remission, preferably long-term survivors as previously defined. The list of references was reviewed by all authors of this review.
Most studies on late effects of cancer treatment have been retrospective in nature.4 Thus, no
prospective randomized trials on late effects from testicular cancer treatment have been published.
Secondary malignant neoplasms
The development of a non-GC second malignancy represents one of the most severe late effects following treatment for TC. In addition,1-5% of TC survivors (TCSs) develop a contralateral TC6
which probably reflects common etiologic factors. A contralateral TC is not regarded a late effect of treatment and we make no further comment on its origin or management.
In a series of 40,576 TCSs, the overall post-TC observed/expected (O/E) ratio for developing a solid second cancer was 1.55 (95% confidence interval [CI] 1.48-1.62) in 10-year survivors,7 which is in
agreement with other large population-based studies (Table 1).8, 9 The O/E ratio was 2.6 (95% CI
2.1-3.2) for leukemia, mostly acute myeloid leukemias (AML) and lymphoblastic leukemias.(10) Concern has been raised regarding the association between etoposide and AML. However, the absolute risk of etoposide-induced AML after four cycles or less of standard chemotherapy is very low, and was reported to be less than 0.2% in chemotherapy-treated patients.10 The risk
of etoposide-induced AML is probably dose-dependent, and after high-dose etoposide the risk of AML has been ranging from 0.5% to 2.6% in several studies.11-13 Therapy-related leukemia is
usually diagnosed within the first 10 years after treatment for TC.14 Solid second malignancies are
generally diagnosed after a latency of at least 10 years and may be induced by both radiotherapy and chemotherapy (Table 1).7-9
Most radiation-induced malignancies are located within or close to initial abdominal radiation fields (bladder, stomach, pancreas and colon cancer). The statistically increased relative risks for solid cancers after cytotoxic treatment (Table 1) are to a great extent based on “old fashioned” cytotoxic treatment with larger radiotherapy fields and higher radiation and chemotherapy doses than used today.15 The role of modern risk-adapted treatment on the late development of a solid
second cancer is less clear.
The radiation exposure from repeated CT scans during follow-up could theoretically contribute to an increased risk for solid cancers.16, 17 Theoretical estimates of lifetime cancer risk range from
1.9% for an 18-year old to 1.2% for a 40-year old patient during surveillance for stage I TC,16 but
these are estimated phantom data, not patient data, and should be interpreted with caution. These hypotheses, based on extrapolations from Hiroshima and other data, are not supported at this time by clinical studies that demonstrate that such risk exists. A recent publication by van Walraven et al did not find any association between radiation exposure and risk of second cancers in 2569 men after treatment for low-grade TC, but the follow-up time was only median 11.2 years.18 Hence, given the very low risk, the relative risk/benefit should be considered when
making decisions about the use of CT in patient care. Some guidelines recommend MRI instead of CT during follow-up to reduce the risk of radiation-induced cancer, but there is no definitive study at this time.
Table 1.
Sec
ond c
anc
ers (solid tumors and leuk
emias) in long-t erm t esticular c anc er sur viv ors ( TCSs). eviations: No , n
umbers; gen pop
, gener al population; y , y ears; R T, r adiother ap y; CT , chemother ap y; RR, r elativ
e risk SIR, standar
diz ed incidenc e r atio; EAR, ex cess absolut e risk
bl
es
c
ha
pt
er
2
bl e 1. Se co nd c an ce rs (s ol id tu m or s an d le uk em ia s) in lo ng -te rm te sti cu la r c an ce r s ur vi vo rs (T CS s) . Fi rs t a ut ho r Ye ar o f di ag no si s No . o f p at ie nt s Pa ti en t c ha ra ct er is ti cs Ri sk o f s ec on d ca nc er co m pa re d w it h ge n po p Ma in re su lts Tr av is (2 00 5) (7 ) 1943 -20 01 40 57 6 20 98 4 (1 0-y su rvi vo rs ) Ch em ot he ra py Ra di ot he ra py CT a nd R T Da ta fr om po pu la tio n-ba se d c an ce r r eg is tr ie s. 1. 8 (1 .3 -2. 5) (R R) 2. 0 (1 .9 -2. 2) 2. 9 (1 .9 -4. 2) TC Ss a re a t s ig ni fic ant ly inc re as ed ri sk o f s ol id c anc fo r a t le as t 3 5 ye ar s af te r t re at m en t. The ri sk fo r s ec on d ca nc er d ec re as ed w ith inc re as ag e at te st ic ul ar c an ce r d iag no sis . Ca nc er s of th e lu ng (R R 1. 5) , c ol on (R R 2. 0) , b la dd 2. 7) p an cr ea s (R R 3. 6) a nd s to m ac h (R R 4. 0) a cc ou fo r 6 0% o f t he to ta l e xc es s. Ri ch ia rd i ( 20 06 ) (8 ) 1943 -20 00 29 51 1 Da ta fr om po pu la tio n-ba se d c an ce r r eg is tr ie s. No tr ea tm en t d et ail s w er e in cl ud ed . Ov er al l S IR w as 1 .6 5 ( 1. 57 -1. 73) fo r s ol id tu m or s af me di an 8 .3 y ea rs fo llo w -up . S IR s fo r m os t s ol id c an ra ng ed b et w ee n 1 an d 2, a nd in cre as ed w ith in cre fo llo w -up . Va n den B el t-Du se bo ut (2 00 7) (9 ) 1965 -19 95 2707 (5 -y su rvi vo rs ) Su rg er y on ly Ra di ot he ra py Ch em ot he ra py RT a nd C T 0. 7 (0 .4 -1. 3) (SI R) 1. 7 (1 .5 -2. 0) 1. 4 (0 .9 -2. 1) 3. 0 (2 .0 -4. 4) Ov er al l S IR w as 1 .7 (1 .5 -1. 9) a fte r m ed ia n 17. 6 ye ar fo llo w -up . T he ri sk o f s ec on d ca nc er w as 2 .6 (1 .7 -4. af te r i nf rad iap hr ag m at ic R T an d 2. 1 (1 .4 -3. 1) a fter ch em ot he ra py in co m pa ris on to s ur ge ry o nl y. Ho w ar d (2 00 8) (1 0) 1943 -20 01 42 72 2 (1 -y su rvi vo rs ) Su rg er y on ly Ra di ot he ra py Ch em ot he ra py RT a nd C T Da ta fr om po pu la tio n-ba se d c an ce r r eg is tr ie s. 1. 6 (0 .8 -2. 9) (O /E ) 2. 7 (1 .9 -3. 6) 3. 9 (1 .8 -7. 3) 4. 5 (0 .7 -13. 8) Se co nd ar y le uk em ia d ev el op ed in 89 pa tie nt s, w EAR a t 1 0. 8. p er 10 0. 000 pe rs on ye ar s. St at is tic al ly si gn ifi ca ntl y el eva te d ris ks w er e ob se rve d fo r a cu my el oi d le uk emi a an d ac ut e ly mp ho bl as tic le uk emi Ex ce ss c um ul at iv e le uk em ia ri sk w as 0 .2 3% b y 30 af te r T C di ag no sis . br ev ia tio ns : N o, n um be rs ; g en p op , g en er al p op ul at io n; y , y ea rs ; R T, ra di ot he ra py ; C T, c he m ot he ra py ; R R, re la tive ri sk S IR , s ta nd ar di ze d in ci de nc e ra tio ; E A R, e xc es s ab so kCardiovascular disease and Raynaud’s phenomenon Cardiovascular disease
Case reports on potentially life-threatening cardiovascular disease (CVD) during or shortly after treatment date back to the 1980s.19 The frequency of late cardiac morbidity among TCSs was
reported for the first time in 2000 by Meinardi et al. among 87 patients aged ≤50 years at the time of analysis.20 Subsequent reports on CVD in TCSs estimated the magnitude of the problem. Zagars
et al. reported on cardiac mortality in survivors of testicular seminoma treated with radiotherapy only.21 Of note, the cardiac-specific standardized mortality ratio (SMR) was first after 15 years of
follow-up significantly elevated at 2.02 (99% CI 1.22-3.16).21 A large international study by Fosså et
al. in 38,907 at least one-year TCSs reported a SMR for all circulatory diseases of 1.58 (95% CI 1.25-2.01) in men who received chemotherapy after 1975.22
Table 2 summarizes the prevalence of coronary artery disease (CAD) found in recent studies, subdivided in different treatment groups.20, 23-25 In a large nationwide cohort study
performed by Van den Belt-Dusebout et al,24 non-seminoma survivors younger than 45 years
had a significantly increased standardized incidence ratio for myocardial infarction (MI) at 2.06 (95% CI 1.15-3.41). A substantial part of the analysis was based on patients treated with regimens no longer used, thus supplementary studies are needed to ascertain the burden of the current standard regimens. A recent Norwegian study reported a significantly increased risk of CAD after bleomycin, etoposide and cisplatin (BEP) in comparison to age-matched controls, but this publication did not include mortality.25
Mechanisms behind treatment-induced CVD are not yet accurately elucidated. Both direct vascular damage and indirect effects through gradual development of CVD risk factors26
may contribute to the eventual cardiovascular damage. A significantly higher prevalence of hypertension was found in chemotherapy-treated TCSs, while diabetes was more prevalent after radiotherapy alone or in combination with chemotherapy, as compared with patients treated with other modalities and healthy controls.25, 27 In particular, the clustering of CVD risk factors into
the metabolic syndrome28 might be the mediating link between cytotoxic treatment and CVD.
Patients treated with cisplatin-based chemotherapy more often develop the metabolic syndrome in comparison to controls or other treatment groups.29, 30
Inflammation and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis.31 Microalbuminuria, and circulating levels of von Willebrand factor and
plasminogen activating inhibitor 1 (PAI-1), markers representing endothelial dysfunction, are all significantly more prevalent in chemotherapy-treated TCSs.32 Cisplatin is detectable in serum
several years after administration,33, 34 and it is hypothesized that small amounts of cisplatin may
continuously stimulate the endothelium. However, there are no data to support that hypothesis. C-reactive protein was recently proposed as a potential marker for cardiovascular disease in TCSs,35 suggesting chronic endothelial activation.
Raynaud’s phenomenon
Many patients experience Raynaud’s phenomenon (RP) both during and after treatment.36 This
typical white discoloration of the digits and subsequent pain and redness is prevalent in 15-45% in chemotherapy-treated TCSs several years after treatment.36-39 The phenomenon is thought to
be a consequence of direct vascular damage in the digital arteries,40 but neurologic effects may
also be involved in the abnormal vasoregulation causing vasospasms.41 Bleomycin is considered
Ta bl e 2. R isk o f c or on ar y ar te ry d is ea se (C A D ) i n lo ng -te rm te sti cu la r c an ce r s ur vi vo rs (T CS s) . Ab br ev ia tio ns : N o, n um be rs ; f u, fo llo w -up ; y , y ea rs ; SI R, s ta nd ar di ze d in ci de nc e ra tio ; M I, m yo ca rd ia l i nf ar ct io n; A P, a ng in a pe ct or is ; C T, c he m ot he ra py ; R T, ra di ot he ra py ; R R, re la tiv e ris k; C VB , c is pl at in , v in bl as tin e an d bl eo my ci n; B EP , b le omy ci n, e to po si de a nd c isp la tin ; H R, h az ard ra tio ; n s, no t s ig ni fic an t; CV D , c ar di ov as cu la r d ise as e. *I nc lu si on c rit er io n: a ge ≤ 50 at ti m e of a na ly sis . †T he e nd po in t w as “c ar di ac e ve nt ” d ef in ed a s (1 ) p at ie nt d ie d fro m a M I o r s imi la r c ar di ac re la te d ep iso de ; ( 2) a ng in a or M I re po rt ed o n G P fo rm s; (3 ) c ar di ac a bn or m al ity o n th e as se ss m en t f or m at th e lo ng -te rm fo llo w -up c lin ic v isi t; (4 ) a ng ina o r c he st p ai n re po rt ed o n cl ini c vi si t; (5 ) c ar di ac su rg er y fo r c or ona ry a rt er y di se as e. Fi rs t au th or Ye ar o f di ag no si s No . o f pa tie nt s Me dia n fu (r an ge ), y Tr ea tm en t c ha ra ct er is tic s St at is tic al me th od Ri sk o f C A D (9 5% C I) Co m m en ts Me in ar di (2 00 0) (1 6) 1977 -19 87 87* (1 0-y su rvi vo rs ) 14 (10 -20 ) A ll tr ea te d w ith c isp la tin -co nt ai ni ng th er ap y SI R 7. 1 (1 .9 -18. 3) Tw o TC Ss w ith M I a nd thr ee pa tie nt s w ith A P w ith pr ov en my oc ard ia l i sc he mi a. Hu dd ar t (2 00 3) (1 9) 1982 -19 92 992 10 (0 -20) Su rg er y on ly Ra di ot he ra py C he m ot he ra py CT a nd R T RR 1. 0 (re fe re nc e)† 2. 4 (1 .0 -5. 4) † 2. 6 (1 .2 -5. 8) † 2. 8 (1 .1 -7. 1) † No re st ric tio ns re ga rd in g fo llo w -up du ra tio n. R R adj us te d fo r a ge . “C ar di ac e ve nt ” a s m ea sur ed en dp oi nt , s ee def in iti on b el ow . Va n den Be lt-Du se bo ut (2 00 6) (2 0) 1965 -19 95 2339 (5 -y su rvi vo rs ) 18 (5 -38) Su rg er y on ly RT in fra di ap hr ag m at ic (i nf) RT m ed ia st in um (m ed ) Ch em ot he ra py CT a nd R T in f CT a nd R T m ed SI R Treatm ent gr ou ps 0. 8 (0 .5 -1. 2) 0. 7 (0 .6 -0. 9) 1. 6 (1 .1 -2. 4) 1. 2 (0 .8 -1. 6) 1. 3 (0 .7 -2. 3) 2. 3 (1 .2 -3. 9) MI e ve nt s > 5 ye ar s af te r d ia gn osi s. Ca rd io va sc ul ar d at a w er e ob ta in ed fro m m ed ic al re co rd s an d th ro ug h qu es tio nn air es s en t t o pa tie nt s' ge ne ra l p ra ct iti on er s. Co m pa re d wi th a ge -ma tc he d co nt ro ls . <4 5 ye ar s 45 -54 ye ar s ≥ 54 ye ar s SI R Attain ed ag e 1. 6 (1 .0 -2. 5) 1. 5 (1 .1 -2. 0) 0. 9 (0 .7 -1. 1) Ha ug ne s (2 01 0) (2 1) 1980 -19 94 990 (1 3-y su rvi vo rs ) 19 (13 -28 ) Su rg er y on ly Ra di ot he ra py Ch em ot he ra py (CV B al on e) Ch em ot he ra py (B EP a lo ne ) CT a nd R T HR ns ; no t r ep or te d ns ; no t r ep or te d ns ; no t r ep or te d 3. 1 (1 .2 -7. 7) 4. 8 (1 .6 -13. 9) MI > 2 ye ar s af te r di agn os is . F at al ev en ts ex cl ud ed . A ll sel f-re po rt ed CV D v al id at ed b y us e of m ed ic al re co rd s. Co mp are d w ith a ge -ma tc he d co nt ro ls . Table 2. R isk of c or onar y ar ter y disease ( CAD) in long-t erm t esticular c anc er sur viv ors ( TCSs). Abbr eviations: No , n umbers; fu , follo w -up; y, years; SIR, standar diz ed incidenc e ratio; MI, my oc ar dial inf ar ction; AP , angina pect oris; CT , chemother ap y; RT , r adiother ap y; RR, relativ e risk ; CVB
, cisplatin, vinblastine and bleomy
cin; BEP
, bleomy
cin, et
oposide and cisplatin; HR, haz
ar d r atio; ns , not signi fic ant; C VD , c ar dio vascular disease . *Inclusion crit erion: age ≤ 50 at time of analysis . †T he endpoint w as “c ar diac ev ent ” de fined as (1) patient died from a MI or similar car diac relat ed episode; (2) angina or MI repor ted on GP forms; (3) car diac abnormalit y on the assessment
form at the long-t
erm follo
w
-up clinic visit; (4) angina or chest pain r
epor
ted on clinic visit; (5) c
ar diac sur ger y for c or onar y ar ter y disease .
Pulmonary toxicity
Pulmonary toxicity was identified as the major dose-limiting side-effect of bleomycin treatment already in the 1970s.42, 43 Bleomycin may cause pneumonitis, occasionally progressing to
pulmonary fibrosis during or shortly after administration of bleomycin. As there are no agreed criteria to define bleomycin pulmonary toxicity (BPT), the long-term prevalence of patients with non-fatal BPT varies between 7% and 21%.44-47 Fatal BPT has been reported to occur in 1-3% of
patients treated with bleomycin.44, 48 In a British study where 835 patients were evaluated median
7.4 years following treatment, multivariate analyses showed that decreased renal function (hazard ratio [HR] 3.3), age above 40 years (HR 2.3), initial stage IV disease (HR 2.6) and cumulative bleomycin dose >300 000 IU (300 units) were associated with increased risks of BPT.44 Interestingly,
the bleomycin hydrolase genotype was not found to be associated with the development of BPT or with changes in pulmonary function tests.47
Prior studies evaluating pulmonary function after treatment for TC concluded that possible reductions in the pulmonary function during or shortly after treatment were normalized during follow-up.43, 49-52 In a Norwegian study reporting long-term spirometry data from 1.049
TC survivors after median 11 years follow-up, men treated with large cumulative cisplatin doses and/or pulmonary surgery had significantly decreased spirometry variables compared with men treated with surgery only.53 Only cisplatin dose (p=0.007) and age (p=0.008) were significantly
associated with restrictive lung disease in multivariate analyses that included cumulative bleomycin (maximum: 360 000 IU/360 units), etoposide and vinblastin doses. The reduced pulmonary function was subclinical in the majority of these patients.
Population-based epidemiological studies have shown an association between pulmonary function and all-cause mortality.54, 55 Furthermore, TCSs cured by chemotherapy
after 1975 are at a 2.5-fold increased risk to die of respiratory disease compared with the normal population 22. The lungs are highly vascularized organs, and chemotherapy-induced endothelial
dysfunction is a possible mechanism that is involved in the reduced pulmonary function.56
Nephrotoxicity
Nephrotoxicity is a well-recognized acute and long-term effect of both radio- and chemotherapy for TC.57, 58 Studies in animals and humans have shown that cisplatin damages the proximal and
distal tubular epithelium and collecting ducts, and in the rat it also produces glomerular damage at the highest doses.59, 60 A statistically significant increase in serum creatinine and a decrease
in serum magnesium (Mg) from baseline measurements are often detectable after 4 cycles of standard cisplatin-based therapy.61, 62 Mg loss may lead to hypomagnesemia, hypokalemia,
and hypocalcemia. Less commonly, cisplatin may also induce sodium wasting and proteinuria, particularly after high cumulative cisplatin doses.63-67 Studies also show that neither serum
creatinine nor calculated creatinine clearance based on 24h urine collections is a sensitive measure of renal damage.66, 68, 69 The severity of renal damage during cisplatin treatment can
Pre-existing intrinsic renal disease augments cisplatin nephrotoxicity, as does the co-administration of other nephrotoxic drugs.
The acute nephrotoxic effects of cisplatin may be partly, but not completely, reversible. Long-term studies of renal function show persistent changes from baseline values years after completion of treatment, with little evidence of improvement over time.57, 58, 71, 72 The increased prevalence
of loss of albumin in the urine (microalbuminuria) with increasing follow-up duration may be considered a sign of vascular damage within the kidney.32 The clinical implications of these
changes are unclear, but they may possibly contribute to a reported increase in cardiovascular toxicity, including hypertension and myocardial infarction observed in patients a decade or more after cisplatin-based treatment.23-25 Renal artery stenosis several years after para-aortic irradiation,
resulting in severe hypertension, has been reported in some case reports.73, 74 Thus, men who
develop severe hypertension after abdominal irradiation should be investigated for renal artery stenosis.
In one report, significant increases in serum renin and aldosterone levels were reported in a majority of normotensive patients at a median of 26 months (range 9-54 months) after treatment.71
More recent data have shown a relationship between reduced glomerular filtration rate and the presence of microalbuminuria, with an increased risk of cardiovascular and all-cause mortality in a general population, and support an association between decreased renal function and risk of sudden cardiac death.75-77
Neuro- and ototoxicity Peripheral neuropathy
Cisplatin-induced neuropathy is typically sensory neuropathy of the distal limbs, with paresthesias being the core symptom. Cisplatin causes degeneration of large dorsal root ganglia neurons with loss of myelinated fibres, both distally in the limbs and proximally in the spinal cord, although other mechanisms may be involved as well.78, 79
The reported incidence of persistent peripheral neuropathy varies according to applied treatment and dose as well as method of assessment. A frequency of 20-40% has typically been stated.80 Three large studies with long follow-up have been published during recent years.37-39
In the Norwegian cohort, 28% of TCSs who received ≤4 cycles of cisplatin-based chemotherapy reported paresthesias, as opposed to 46% following ≥5 cycles and 10% after orchiectomy alone.37
Rossen et al reported similar findings (chemotherapy: 31%; surveillance: 9%),38 while peripheral
neuropathy was somewhat less frequent in the study by Glendenning et al. where 1/3 had received carboplatin-based chemotherapy.39 Paresthesias of the lower limbs may also be associated with
abdominal radiation.37 In severe cases, symptomatic treatment might be tried, but an effective
treatment has not been documented.81
Ototoxicity
Cisplatin-induced ototoxicity represents a distinct feature of cisplatin’s side effects and is presumably caused by selective damage to the outer hair cells of the cochlea,82 leading to tinnitus Chapter 2
and hearing impairment, typically affecting the high frequencies. Reported persistent ototoxicity varies widely with method of investigation, and applied treatment. Bokemeyer et al. reported persistent ototoxic symptoms in 5 to 65%, depending on cisplatin dose.83, 84 Ototoxic symptoms
beyond 5 years following cisplatin-based treatment have been reported in 21-24 % of TCSs.37, 38
The five-day BEP regimen seems preferable to the three-day regimen in regard of minimizing ototoxicity, particularly if 4 cycles are administered.37, 85
The considerable inter-individual variations observed may be due to polymorphisms in glutathione S-transferases,86, 87 or other candidate genes associated with cisplatin-induced
neuro-and ototoxicity.88, 89
Cognitive function
Cognitive function in TCSs has been addressed in a few studies 1-11 years following TC treatment.85, 90-93 Although some report cognitive complaints (self-reported) to be rather common irrespective
of cancer treatment or to increase following chemotherapy (≤4 cycles),92, 93 a permanent decline in
neuropsychological performance has not been documented in any study. Cognitive complaints have rather been related to emotional distress and fatigue.
Avascular necrosis
Testicular cancer survivors treated with chemotherapy seem to have an increased risk of developing avascular necrosis (osteonecrosis) compared to patients treated for other solid tumors (REF Shim Drug Safety 2008).94 The exact reason for this vulnerability is not known, but
is probably multifactorial. Most reported cases have also received corticosteroids. The femoral head is most commonly affected, often bilaterally.94, 95 Based on three reports, Winquist et al
estimated an overall crude incidence of 1.5% following chemotherapy for testicular cancer. Cook et al reported an overall prevalence of 3,8% in 103 consecutive patients invited to attend an MRI scan of the hips.96 Avascular necrosis should be suspected in patients presenting with pain in the
inguinal region (or upper thigh/buttocks). A limp and decreased hip motion may also be present. If suspected, an MRI should be performed in case of normal plain x-ray, and the involvement of an orthopedic surgeon in the management of these patients is imperative.94
Hypogonadism
Subnormal testosterone values have been reported in TCSs treated with chemotherapy compared to healthy controls,30 and following more than four chemotherapy cycles,97, 98 or combination of
chemotherapy and RT when compared to men treated with surgery only.99 Subclinical Leydig cell
dysfunction with increased LH has been found in several studies.30, 84, 97, 98, 100-102
In long-term follow-up studies where similar reference levels for testosterone were applied (<10nmol/l or <2.6ng/ml), overall 12%-16% had subnormal testosterone values or used androgen replacement therapy (ART).97-99 Similar estimates were found in the Norwegian cohort,
Figure 1. Fraction of men with “manifest or subclinical” hypogonadism according to
treatment in the Norwegian cohort. Dark blue (lower): Used androgen replacement therapy (ART) at follow-up (manifest hypogonadism); Medium blue (middle): low s-testosterone (<10nmol/l) at follow-up (manifest hypogonadism); Light blue (upper): Elevated s-LH (≥12 IU/l) and normal s-testosterone at follow-up (subclinical hypogonadism). (P= .014 for manifest hypogonadism (ART or low testosterone) versus normal testosterone, P<.001 for any hypogonadism (ART, low testosterone and/or elevated LH) versus no hypogonadism). RT, radiotherapy; ≤850 mg, cumulative cisplatin dose ≤850 mg; >850 mg, cumulative cisplatin dose >850 mg. Surgery RT £ 850 mg > 850 mg Le ve ls of h yp og on ad is m (% ) 0 5 10 15 20 25 30 35
where overall 15%, ranging from 8% to 18% depending on treatment, of men younger than 65 years had hypogonadism by this definition (testosterone <10 nmol/l or used ART) (Fig 1, p=.014) (personal communication, M Brydøy).
Chapter 2
Figure 1. Fraction of men with “manifest or subclinical” hypogonadism according to treatment in the Norwegian cohort. Dark blue (lower): Used androgen replacement therapy (ART) at follow-up (manifest hypogonadism); Medium blue (middle): low s-testosterone (<10nmol/l) at follow-up (manifest hypogonadism); Light blue (upper): Elevated s-LH (≥12 IU/l) and normal s-testosterone at follow-up (subclinical hypogonadism). (P= .014 for manifest hypogonadism (ART or low testosterone) versus normal testosterone, P<.001 for any hypogonadism (ART, low testosterone and/or elevated LH) versus no hypogonadism). RT, radiotherapy; ≤850 mg, cumulative cisplatin dose ≤850 mg; >850 mg, cumulative cisplatin dose >850 mg.
Low testosterone levels are significantly associated with increased prevalence of the metabolic syndrome(103) and an increased risk for CVD mortality as well as respiratory disease mortality in epidemiological studies.104, 105 Subclinical hypogonadism might also enhance the risk of
osteoporosis, although data on this subject are inconclusive.106, 107
The relatively high frequency of Leydig cell dysfunction implies that the hormonal status of TC survivors should be regularly assessed. However, there is currently no evidence supporting testosterone replacement therapy to prevent late effects such as CVD, and treatment decisions should be guided by clinical symptoms.(108)
Fertility and sexuality Fertility
At long-term follow-up of cohorts of TC survivors with known intentions to conceive a child, overall post-treatment conception and paternity rates vary from 49% to 82% (Table 3).99, 109-112
Some investigators report an association between the likelihood of paternity with cumulative chemotherapy dose,110, 113 but preservation of antegrade ejaculation following RPLND is the most
critical factor for conception without use of cryopreserved sperm.110, 111 After primary RPLND,
Beck et al. recently reported that 99% preserved antegrade ejaculation after nerve-sparing surgery,114 higher than 91-93% previously reported.115, 116 After nerve-sparing post-chemotherapy
RPLND, 71-89% retain antegrade ejaculation,116-119 compared to 25% following full bilateral
Table 3. Post tr eatment conc eption and pat ernit y r at es among testicular cnc er (T C) sur viv ors with kno wn int entions to conc eiv e a child follo wing TC tr eatment (donor insemination ex cluded)* *Numbers ar e post-tr eatment when not speci fied as pr e-tr eatment (pr e). Abbr eviations: No , n umbers; fu , follo w -up; y, years; RPLND , r etr operit oneal lymph node dissection; CT , chemother ap y; R T, r adiother ap y; FSH, follicle stim ulating hormone . †Without infer tilit y tr eatment. T he use of cr yopr eser ved semen w as not speci fied . ‡Both chemother ap y gr
oups included patients additionally tr
eat ed with R T or RPLND . § R at es r efer t o 15-y actuarial r at es . Ta bl e 3. Po st tr eat m en t c on ce pt io n an d pat er ni ty rat es am on g te st ic ul ar c anc er (T C) s ur vi vo rs w ith kno w n int ent io ns to c onc ei ve a c hi ld fo llo w ing T C tr ea tm ent (do no r in se m in at io n ex cl ud ed )* . Fi rs t a ut ho r No . o f T C su rv iv or s in cl ud ed Me dia n fu (r an ge ), y Tr ea tm en t c ha ra ct er is tic s Co nc ep tio n/ pa te rn ity ac co rd in g to tr eat m en t Ma in re su lts Sp er m on (20 03) (1 03 ) 88 (12 0 pr e) 7 (2 -19) Su rv ei lla nc e RP LN D RT ≤4 CT c yc le s ≤ 4 CT c yc le s + R PL N D (p rim ar y or s ec on da ry ) No s ig nif ic an t d iff er en ce s be tw ee n t re at m en t g ro ups . 59% (52/ 88 ) f at he re d fo llo w in g TC tr ea tm en t, in cl ud ing cr yo pr es er ve d se m en in 7 . 4 3% (3 8/8 8) co nce iv ed w ith in on e ye ar of a tt em pt s. Pr ior to TC tr ea tm en t, 78 % (9 3/ 12 0) fa th er ed , 6 6% (7 9/ 12 0) c on ce iv ed w ith in o ne y ea r o f atte m pts . Hu yg he (2 00 4) (1 00 ) 16 4 (2 28 pr e) 8 (3 -27) RT 2-4 ch em ot her ap y cy cl es 67% (11 0/ 164) c on ce iv ed fo llo w ing T C tr ea tm ent co m pa re d to 9 1% (2 08 /2 28 ) p rio r t o TC . Cu m ul at iv e co nce pt io n ra te s lo w er fo llo w in g RT th an c he m ot he ra py . (P < 0. 01 ). Hu dd ar t ( 20 05 ) (9 0) 207 A t l ea st 5 y Su rv ei lla nc e Ch em ot he ra py RT Ch em ot he ra py /R T 88% (8 5% †) co nc ei ve d 75% (71% †) c on ce iv ed 85% (82% †) c on ce iv ed 83% (67% †) c on ce iv ed 82% (16 9/ 207) c on ce iv ed fo llo w ing T C tr ea tm ent (in cl ud in g in fe rt ili ty tr ea tm en t i n 10 ). 77 % (1 59 /2 07 ) c on ce ive d w ith ou t i nfe rti lity tr ea tm en t (p = .0 3 fo r c he m ot he ra py v s su rv ei lla nc e) Me n w ith e le va te d FS H le ss lik el y to h av e co nc ei ve d (6 8% ) t ha n m en w ith n or m al F SH le ve ls (9 1% ). (P < .0 01 ) Br yd øy (2 00 5) (1 01 ) 552 11 (4 -21) Su rv ei lla nc e RP LN D RT Cisp la tin ≤ 8 50 m g‡ Ci sp la tin > 85 0 m g‡ 81% fa th er ed (92% 15 -y§ ) 77% fa th er ed (7 8% 1 5-y§ ) 65% fa th er ed (72% 15 -y§ ) 62% fa th er ed (64% 15 -y§ ) 38% fa th er ed (48% 15 -y§ ) 65% (36 1/ 552) h ad fa th er ed b y fo llo w -up (w ith out cr yo pr es er ve d sp er m , b ut in cl ud in g ot he r i nf er til ity tr ea tm en ts in 3 6) 71% o ve ra ll 15 -y ac tu ar ia l p os t-tr ea tm en t pa te rn ity ra te s (p < .0 01 a cc or di ng to tr ea tm en t g ro up ) Dr y ej ac ul at io n w as th e m os t n eg at iv e pr ed ic to r. Me n di ag no se d 19 89 -1994 w er e m or e lik el y to h av e fa th er ed th an m en d ia gn os ed 1 98 0-1988. (P < .001) *N um be rs a re p os t-tr ea tm en t w he n no t s pe ci fie d as pr e-tr ea tm en t ( pr e) . A bb re vi ati on s: N o, n um be rs ; f u, fo llo w -up ; y , y ea rs ; R PL N D , r et ro pe rit on ea l l ym ph n od e di ss ec tio n; CT , ch em ot he ra py ; R T, ra di ot he ra py ; F SH , f ol licl e st im ul at in g ho rm on e. †W ith ou t i nf er til ity tr ea tme nt . T he u se o f c ry op re se rv ed s eme n w as n ot s pe ci fie d. ‡B ot h ch emo th er ap y gr ou ps in cl ud ed p at ie nt s ad di tio na lly tr ea te d w ith R T or R PL N D . § Ra te s re fe r to 1 5-y ac tu ar ia l r at e
Lampe et al. defined prognostic groups for spermatogenic recovery based on repeated sperm analyses pre- and post-chemotherapy in 178 men.121 Overall, 80% recovered
some spermatogenesis by 4 years after chemotherapy, if not azoospermic (<1 mill/ml) prior to treatment.121 Carboplatin-based regimens and ≤4 cycles were positively related to recovery.
Petersen et al. found that 19% were azoospermic 5 years after 4 BEP cycles, and 47% after ≥3cycles of a more dose intensive regimen.122 Gandini et al. reported that 94% and 97% had recovered
some spermatogenesis two years after RT and 2 to 4 cycles of chemotherapy, respectively.123
Information regarding fertility following more recently introduced chemotherapy regimens is sparse.124, 125 Recovery of spermatogenesis following high-dose chemotherapy with
stem cell support has also been reported (5/10 patients).126 TC patients should be informed that
the recovery from chemotherapy-induced azoospermia may take several years. Furthermore, offering cryopreservation is obligatory prior to chemotherapy.
Sexuality
Besides impaired ejaculatory function, groups of TCSs are reported to experience decreased drive and increased erectile dysfunction when compared to controls.99, 127, 128 Some also report
decreased sexual satisfaction.129 Dahl et al found that overall sexual problems were expressed
by 39% of TCSs versus 36% in controls.128 Interestingly, among men aged 20-39 years, sexual
satisfaction was significantly better compared to controls. Tuinman et al. showed that couples established after a TC diagnosis were less sexually satisfied than couples founded pre-diagnosis.129
However, data within this field are conflicting. Psychosocial health
Fatigue
A significantly higher frequency of chronic (> 6 months’ duration) cancer-related fatigue (CRF) was reported among long-term TCSs in Norway compared with the normative male population (17% and 10%, respectively).130 Significantly higher levels of interleukin-1 receptor antagonist and
C-reactive protein were observed in TCSs with CRF compared to TCSs without CRF, indicating an association between fatigue and inflammation.131
Mental health
Compared to samples of men from the general population, significantly increased levels of anxiety among Norwegian TCSs were associated with peripheral neuropathy, fear of recurrence, economic concerns, alcohol abuse, sexual difficulties, younger age, and a history of treatment for mental problems.132 It is not clear whether TCSs experience more depressive disorders than the
general population, since a significantly increased prevalence has been reported in some studies,
Lifestyle
A recent American study confirmed a previous Norwegian finding of high prevalence of current smoking and problem drinking among TCSs. Their intake of fruit and vegetables was low. However, TCSs were more likely to engage in regular exercise that cancer-free controls.134
Employment
In the U.S., levels of unemployment among TCSs are similar to men in the general population.135
Similarly, Norwegian TCSs reported comparable levels of work engagement as age-matched men in the general population.136 Fleer et al. highlighted the importance of employment on
health-related quality of life in TCSs.137 No data are available with regard to work ability 10 or more years
after diagnosis of TC.
Health-related quality of life (HRQoL)
In most studies, overall HRQoL of TCSs, as assessed by validated questionnaires, has been similar to that of normative samples of age-matched men.138, 139 Although findings may accurately reflect
HRQoL status, these results may also be due to either “response shift” 140 or the use of instruments
that are not targeted to the concerns of TCSs. In one investigation, a subgroup of approximately 15% TCSs reported decreased HRQoL.138
Impact of lifestyle factors
Cancer survivors, in general, are high health care utilizers with several distinct health care issues.4, 141, 142 For TCSs, in particular, the young age at diagnosis and high cure rate, lead to
long-term consequences of therapy which have a greater impact on their lives, families, and society at large than the acute complications from the cytotoxic therapies.22, 25, 143, 144
While treatment-associated long-term risks and complications are brought on by cytotoxic treatment, genetic predisposition and/or common lifestyle factors,145-148 lifestyle is the only variable
subjected to change. In line with this, Aziz argue that the follow-up care of cancer patients should provide the opportunity for maintaining health by lifestyle interventions.4
Prevention such as promoting smoking cessation, better nutrition, and promoting a non-sedetary lifestyle may play key roles in reducing the impact of potential adverse effects of previous cancer therapy.149-151 In a large Dutch population of TCSs, the relative risk of CVD attributed to recent
smoking was 2.6, while the corresponding factor for cisplatin-based chemotherapy was 1.9.24 In
a Norwegian population of long-term TCSs, smoking was associated with decreasing pulmonary function as well as increasing neurological side-effects.37, 53 Additionally, smoking increases the
overall risk of a second malignancy.9 Thus, lifestyle interventions may be particularly important for
TCSs due to the long life expectancy and their increased vulnerability. These interventions may start early in the follow-up period. Demark-Wahnefried and coworkers focus on the “teachable moment” which the cancer diagnosis provides and argue that oncology care providers should not only lead their patients away from disease, but also promote lifestyle changes that may improve the length and quality of life of their patients.142 However, of 160 German TC patients who did
smoke at the time of diagnosis, most changed their tobacco habit, but only 29% managed to quit smoking within 10 years post diagnosis.152 In a randomized physical training intervention in Chapter 2
a Norwegian population of long-term TCSs, training had significant effect on cardiorespiratory fitness among the young and middle-aged, but had no favorable effect on patients’ experience of fatigue, mental distress, or health-related quality of life.153 Hence, substantial intervention efforts
may be required for limited effects, but the potential for improved health and reduced morbidity in long-term TCSs is definitely present.
Conclusions and recommendations for follow-up
In this review we have presented the current status regarding different somatic and psychosocial effects after TC treatment. Current knowledge about adverse effects is based on therapy administered years to decades ago. Although cisplatin-based chemotherapy still is the cornerstone in the treatment of TC, we do not have long-term data regarding the consequences from receiving one or two cycles of BEP or carboplatin in the adjuvant setting, or from receiving other chemotherapy agents such as paclitaxel. Thus, there is clearly a need for ongoing research to elucidate long-term and late effects from current treatment strategies and to minimize the long-term morbidity after TC treatment. To achieve this goal, better knowledge about the pathophysiology behind the term complications, defining risk factors for developing long-term morbidity and identification of predictive factors for adverse effects is required.5
During follow-up of TC patients, there is a gradual shift of focus from detection of tumor recurrence to identification of late effects of treatment and promotion of general health in TCSs. We should recommend our patients to maintain a healthy life-style to reduce the risk of serious late effects as second cancers and CVD. Every cancer patient should have an informative end-of-treatment summary at completion of the treatment together with a survivorship care plan. The focus of the survivorship care plan will change with increasing follow-up duration from early detection of a relapse to measures to maintain health. This survivorship care plan includes tools for acquiring and maintaining a healthy life style and a formal regular check on cardiovascular risk factors and gonadal status. A survivorship care plan can be implemented in addition to the routine oncological follow-up or when the routine follow-up with the oncologist is terminated and taken over by another healthcare giver. If so, there has to be a proper transition of further follow-up with a solid and clear survivorship plan (Fig 2). Currently, the distribution of survivorship plans is recommended in Norway, Sweden and the Netherlands. There are so far no data evaluating the use of a survivorship plan.
In conclusion, the treatment success of men with TC is hampered by the emergence of long-term and late effects of treatment. Knowledge about adverse effects is crucial for all physicians involved in treatment and follow-up of TC patients, and attention towards prevention and identification of adverse effects is essential for these young men.
Figure 2. Survivorship care plan to be delivered to the patient at completion of treatment. The plan includes a treatment summary and short information about side-eff ects from testicular cancer treatment, focusing on modifi able cardiovascular risk factors.
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