Late Eff ects Following Lymphoma Treatment

Contents

12.1 Introduction . . . 259

12.2 Second Malignant Neoplasms . . . 260

12.3 Neurocognitive . . . 261

12.4 Cardiovascular . . . 261

12.5 Pulmonary . . . 263

12.6 Bone and Body Composition . . . 264

12.7 Endocrine . . . 264

12.7.1 Thyroid Gland . . . 264

12.8 Reproductive Endocrine . . . 265

12.8.1 Male Gonadal Function . . . 265

12.8.2 Female Gonadal Function . . . 265

12.8.3 Reproduction . . . 266

12.9 Dental . . . 267

12.10 Spleen . . . 267

12.11 Psychosocial . . . 268

12.12 Mortality . . . 268

12.13 Monitoring for Late Eff ects . . . 269

12.14 Research Challenges for Lymphom . . . . 269

Survivors . . . 269

12.15 Future Directions . . . 273

References . . . 274

12. 1 Introduction

Multimodality therapy for childhood lymphomas has resulted in markedly improved survival over the past several decades. For the period 1985–1994, the fi ve- year survival rate for childhood cancer reported by the National Cancer Institutes Surveillance and End Re- sults (SEER) section was 91% for Hodgkin lymphoma (HL) and 72% for non-Hodgkin lymphoma (NHL) (Ries et al. 1999). Th e multimodal therapy, including the multiple chemotherapeutic agents responsible for this improved survival, has been shown to result in ad- verse long-term health-related outcomes. Th ese out- comes may manifest months to years aft er the comple- tion of treatment and are commonly referred to as “late eff ects”. Late eff ects include second malignant neo- plasms, organ dysfunction, and adverse psychosocial sequelae. Treatment-related late eff ects can be due to surgery, radiation therapy, chemotherapy, or their combination. For radiotherapy, total dose and fraction size, organ or tissue volume, and machine energy are the most critical parameters. For chemotherapy, the important factors are agent type, single and cumula- tive dose, and schedule. Host factors such as genetic predisposition, inherent tissue sensitivities, capacity for normal tissue repair, premorbid organ function, and health behaviors may modify treatment-related toxicities, but have not been well studied.

Considerable data regarding the late eff ects of ther- apy have been published by the Childhood Cancer Survivor Study ( CCSS) and will be reported in this re- view. Th e CCSS, a cohort study of 14,054 individuals, was established to address specifi c hypotheses related to long-term health-related outcomes in childhood can cer survivors (Robison et al. 2002). Th e cohort was constructed from rosters of all children treated at each

D.L. Friedman • A.T. Meadows

Late Eff ects Following

Lymphoma Treatment

of the 26 participating institutions in the USA and Canada. Inclusion criteria included: (1) diagnosis of one of the following forms of childhood cancer before 21 years of age: leukemia, HL, NHL, neuroblastoma, soft -tissue sarcoma, bone cancer, malignant central nervous system (CNS) tumor, or kidney tumor; (2) initial treatment at one of the collaborating institutions between January 1, 1970, and December 31, 1986; and (3) survival for at least 5 years following diagnosis.

Participants completed several comprehensive self-re- port questionnaires concerning medical and psycho- social outcomes, and detailed treatment data were collected on all participants from the treating institu- tions.

As therapy for HL and NHL oft en utilize similar classes of chemotherapy agents and both may utilize radiotherapy, we discuss potential late eff ects for both lymphomas combined, by organ system. Where there are signifi cant diff erences for late eff ects by type of lymphoma, this has been noted.

12.2 Second Malignant Neoplasms

Several large studies have examined the incidence and spectrum of second malignant neoplasms ( SMNs) in childhood lymphoma survivors, particularly for HL (Bhatia et al. 2003; Inskip 2001; Metayer et al. 2000;

Neglia et al. 2001; Swerdlow et al. 2000; Wolden et al.

1998). In an analysis of SMN in the CCSS, which ex- cluded patients with retinoblastoma, the SIR for SMN in the cohort was 6.4, with a 20-year incidence of 3.2%

and an absolute excess risk of 1.88 malignancies per 1000 years of patient follow-up. Risk of SMN was ele- vated for all primary childhood cancer diagnoses, with the lowest SIR reported for NHL (3.2) and the highest for HL (9.7). In multivariate analyses, adjusted for ra- diation exposures, SMNs were independently associ- ated with a childhood cancer diagnosis of HL and ex- posure to alkylating agents, among other variables (Neglia et al. 2001). In large cohorts of HL survivors followed over time, the risk of leukemia appears to pla- teau at 10−15 years posttherapy, while the risk of sec- ond solid malignancies, sarcoma, melanoma, lung, thyroid and gastrointestinal, and particularly breast cancer rises with ongoing follow-up, with a lifetime

risk still unknown (Bhatia et al. 2003; Neglia et al.

2001; Wolden et al. 1998). Although data exist that suggest an increased risk in female survivors, even ac- counting for breast cancer, results are not consistent.

While the gender eff ect is not consistent among stud- ies, diagnosis at younger age and therapy for relapsed disease are consistently associated with increased risk (Acharya et al. 2003; Bhatia et al. 2003; Green et al.

2000; Metayer et al. 2000; Neglia et al. 2001; Swerdlow et al. 2000; van Leeuwen et al. 2000b; Wolden et al.

1998).

Patients who have undergone autologous stem cell transplantation for lymphoma have a risk of develop- ing second malignancies. Information regarding risk factors predisposing to secondary carcinogenesis is largely derived from studies of cohorts including ado- lescent and adult patients. Metayer and colleagues conducted a case-control study of 56 patients with sec- ondary MDS/AML and 168 matched controls within a cohort of 2,739 patients receiving autologous trans- plants for HL or NHL. In multivariate analyses, risks of MDS/AML signifi cantly increased with the intensity of pretransplantation chemotherapy and with mech- lorethamine or chlorambucil, compared with cyclo- phosphamide-based therapy. Th e use of TBI at doses of 12 Gy or less did not appear to increase the leukemia risk, but TBI doses of 13.2 Gy or more increased the risk signifi cantly. Th ere is a suggestion that peripheral blood stem cells may increase the risk of MDS/AML compared with bone marrow graft s (Metayer et al.

2003). In a series of 493 patients treated for NHL at Th e University of Texas M.D. Anderson Cancer Cen- ter, 22 patients developed MDS or AML. Multiple lo- gistic regression analyses showed that TBI was inde- pendently associated with an increased risk of developing MDS/AML, and patients receiving TBI in combination with cyclophosphamide and etoposide were more likely to develop MDS/AML than patients who received TBI with cyclophosphamide or thiotepa (Hosing et al. 2002). In a series from the City of Hope National Medical Center, among 612 patients treated for lymphoma, 22 developed MDS or acute leukemia, with an estimated cumulative incidence of 8.6%±2.1%

at 6 years. Multivariate analyses revealed stem cell

priming with etoposide and pretransplant radiothera-

py to be signifi cant risk factors (Krishnan et al. 2000).

Data related to 467 French patients treated with autol- ogous transplantation for HL were matched with 1,179 conventionally treated patients listed in international databases. Th ere were 18 secondary cancers, leading to a 5-year cumulative incidence of 8.9%. Risk factors for second cancer were age 40 years or older, the use of peripheral blood as a source of stem cells, and treat- ment for relapsed disease. Solid tumors were more fre- quent in patients treated with transplantation, al- though the incidence of MDS and AML was similar in the two groups (Andre et al. 1998).

12.3 Neurocognitive

Survivors of NHL may be at risk for neurocognitive late eff ects if they have received CNS-directed thera- pies, such as cranial radiation or intrathecal chemo- therapy. Due in part to the heterogeneity of type of treatment for NHL, this has not been well studied among lymphoma survivors. When neurocognitive toxicity has been addressed in reports of clinical trials for NHL, the occurrence is relatively uncommon (Cai- ro et al. 2002; Sposto et al. 2001). Th is contrasts with acute lymphoblastic leukemia (ALL), where neurocog- nitive late eff ects have been well studied. However, as similar therapies are utilized, specifi cally intravenous or intrathecal methotrexate and cranial radiotherapy, we will briefl y review the toxicities, with much of the data from ALL survivors.

Toxicities include educational defi cits in both global IQ and in attention and nonverbal cognitive skills (Hill et al. 1997; Meadows et al. 1981; Waber et al. 1995;

Williams et al. 1991), related to cranial radiotherapy or intrathecal chemotherapy, and leukencephalopathy re- lated to intravenous and intrathecal methotrexate (Bleyer 1981; Bleyer et al. 1990; Iuvone et al. 2002).

However, the impact on lymphoma survivors does not appear as signifi cant as in ALL survivors, as is demon- strated by data from the Childhood Cancer Survivor Study. Mitby and colleagues demonstrated a small in- creased risk for the need for special education for sur- vivors receiving intrathecal chemotherapy with (OR, 2.6; 95%CI, 2.30−2.95) or without (OR, 1.3; 95%CI, 1.09−1.78) cranial radiotherapy. However, NHL survi- vors were not at increased risk of requiring special ed-

ucation services, whereas survivors of ALL did exhibit an increased risk. Th us, some caution should be taken in extrapolating adverse long-term outcomes from the ALL survivor group. Despite the fact that NHL survi- vors did not have an increased need for special educa- tion, compared with siblings, they did have an in- creased risk of not completing high school (OR = 1.8;

95%CI 1.15−2.78). Interestingly, survivors of HL in this study who received no specifi c CNS-directed ther- apy also required more special education services than their siblings (OR = 4.4; 95%CI 2.64−7.24) (Mitby et al. 2003).

12.4 Cardiovascular

Lymphoma survivors exposed to doxorubicin are at risk for long-term cardiac toxicity. Th e risks to the heart are related to individual and cumulative anthra- cycline dose, the total and fractional irradiation dose, the volume delivered to diff erent depths and specifi c areas of the heart, age at exposure, latency period, and gender, as discussed below.

Th e eff ects of thoracic radiotherapy are diffi cult to separate from those of anthracyclines, since most chil- dren now treated for lymphoma are exposed to anthra- cyclines whether or not they also receive thoracic ra- diotherapy. Th e pathogenesis of injury diff ers, however, with radiation primarily aff ecting the fi ne vasculature of the heart, and anthracyclines directly damaging myocytes (Fajardo et al. 1976). Late eff ects of radiation to the heart include: delayed pericarditis; pancarditis, which includes pericardial and myocardial fi brosis, with or without endocardial fi broelastosis; myopathy;

coronary artery disease ( CAD); functional valve injury

and conduction defects (Adams et al. 2003; Hancock et

al. 1993; King et al. 1996). A recent series from the

Harvard Joint Center for Radiation Th erapy reported

on a cohort of 48 survivors of pediatric and young

adult HD who received a median dose of mediastinal

radiotherapy of 40.0 Gy (27−51.7 Gy), with only four

having also received anthracycline therapy. In 43 for

whom echocardiography results were available, all had

signifi cantly decreased mean left ventricular mass,

end-diastolic dimension and end-diastolic wall thick-

ness, with 17 also exhibiting abnormal end-systolic

wall stress. In addition, 20 had a signifi cant valve de- fect. Autonomic dysfunction was evident in 50% of the patients, and peak oxygen uptake during exercise was decreased in 30% (Adams et al. 2004). However, with current techniques and reduced doses of radiotherapy, these eff ects are unlikely following treatment for child- hood cancer. In a study of 635 patients treated for childhood HL, 12 patients died of cardiac disease, in- cluding seven deaths from acute myocardial infarc- tion, but these deaths occurred in patients treated dur- ing childhood with 42−45 Gy. In the same population of survivors, the actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years (occurring only in children treated with higher radiation doses). Among children treated with 15−26 Gy, none developed radia- tion-associated cardiac problems (Hancock et al.

1993).

Increased risk of doxorubicin-related cardiomyopa- thy is well documented among survivors of HL and NHL, as well as other forms of childhood cancer such as ALL and sarcoma where anthracyclines are utilized.

Anthracycline-related cardiomyopathy is associated with female sex, cumulative doses greater than 200−300 mg/m

, younger age at time of exposure, and increased time from exposure (Kremer and Caron 2004; Kremer et al. 2001; Lipshultz et al. 2000; Nysom et al. 1998b;

Sorensen et al. 2003). Cardiac abnormalities related to doxorubicin exposure may not manifest for many years aft er exposure. Th e Institut Gustave Roussy re- cently evaluated cardiac abnormalities in 229 15+-year survivors of childhood cancer treated with doxorubi- cin at a mean dose of 344 mg/m

(range 40−600 mg/

m

) between 1968 and 1982. Signifi cant cardiac dis- ease with a fractional shortening <25%, ejection frac- tion <50%, end-systolic wall stress >100 g cm

, or clinical heart failure was seen in 89 patients (39%) of whom 65 were asymptomatic. (Pein et al. 2004) Th ere was no threshold for the anthracycline dose in this study, although risk increased with increasing dose.

Neither age at time of treatment nor gender infl uenced the risk. Radiotherapy exposure increased risk 4-fold (95%CI 1.0−17.5), as did longer time since treatment, even aft er 15 years (Pein et al. 2004). Kremer and col- leagues recently systematically reviewed the literature on subclinical cardiotoxicity following treatment with anthracyclines for childhood cancer. A clear dose-re-

sponse was noted with ranges of subclinical cardiotox- icity of 15.5−27.8% and abnormal aft erload of 19−52%, for those who received doses in excess of 300 mg/m

. In those who were treated with cumulative doses be- low this level, the reported range for abnormal left ventricular function was 0−15.2% (Kremer and Caron 2004).

Th ese data support the need for clinical protocols that evaluate lower doses of anthracyclines and employ other methods of cardioproctection when reduction in dose is not possible. In addition, long-term cardiac surveillance for survivors who have been exposed to anthracyclines is clearly indicated. For women, this is of additional importance during pregnancy, when the cardiac volume increases dramatically in the last tri- mester and during labor, and therefore, cardiac work- load increases dramatically. Overt congestive heart failure has been reported, although due to small case series, the magnitude of the risk remains undeter- mined (Hinkle et al. 2004a; Pan and Moore 2002).

Other strategies to decrease the risk of cardiotoxic- ity from anthracyclines have including altering the route of administration. To date, albeit with relatively short follow-ups, there does not appear to be a benefi t compared to what was expected from consecutive di- vided daily doses or continuous infusion, as compared with bolus administration of a single dose (Ewer et al.

1998; Gupta et al. 2003; Levitt et al. 2004; Lipshultz et al. 2002).

Similarly, the use of dexrazoxane (DZR) has been evaluated as a potential cardioprotectant agent. De- spite early adult and pediatric data that this agent de- creased acute toxicity (Anderson 2005; Lipshultz 1996;

Schiavetti et al. 1997; Swain et al. 1997; Venturini et al.

1996; Wexler et al. 1996), the long-tem benefi t is un-

clear. While a deleterious antitumor eff ect of dexra-

zoxane has not yet been reported in pediatric trials, it

has been reported in one adult trial (Swain and Vici

2004), resulting in more restricted recommendations

for its use in adult trials (Schuchter et al. 2002). In ad-

dition, it may contribute to increased acute hemato-

logic and infectious disease toxicity and increased risk

of second cancers (Schwartz et al. 2003). Given the la-

tency time to development of severe cardiac abnor-

malities following doxorubicin exposure, it will be

many years before it is known whether dexrazoxane is

successful in reducing long-term cardiotoxicity in pe- diatric patients.

Another approach in the amelioration of doxorubi- cin-induced left ventricular (LV) dysfunction has been the use of the angiotensin-converting enzyme inhibi- tor enalapril. However, the results are still too prelimi- nary to make any conclusions regarding long-term benefi t. While early improvement in LV function and structure have been reported, longer-term mainte- nance of this eff ect has not been consistent across stud- ies (Lipshultz et al. 2002; Silber et al. 2004).

Rhythm disturbances are also reported following doxorubicin exposure. Schwartz and colleagues stud- ied electrocardiograms in 52 long-term survivors of childhood cancer who had been treated with anthra- cyclines. Prolongation of QTc of >0.43 were noted in six of 22 patients who had received cumulative anthra- cycline doses of >300 mg/m

, compared with 0 of 15 patients who had received lower anthracycline doses.

Th oracic radiotherapy increased the risk in both groups, although the higher anthracycline dose group still demonstrated a greater frequency of prolongation of QTc. Exercise further prolonged the QTc in 6 of 10 patients evaluated (Schwartz et al. 1993).

12.5 Pulmonary

Pulmonary fi brotic disease is seen as a late complica- tion following radiation therapy. In the modern man- agement of pediatric lymphoma, radiotherapy is oft en given in combination with chemotherapy, including agents with independent pulmonary toxicity, such as bleomycin, utilized for the treatment of HL. Acute pneumonitis, manifested by fever, congestion, cough, and dyspnea, can follow radiotherapy alone at doses of

>40 Gy to focal lung volumes, or aft er lower doses when combined with anthracyclines (Mah et al. 1987).

Although it is uncommon with contemporary therapy, asymptomatic reduction in lung function, manifested by a reduction in diff usion capacity or restrictive or obstructive patterns on formal testing, may occur.

Bleomycin-associated pulmonary fi brosis with per- manent restrictive disease is dose-dependent, usually occurring at doses >200−400 U/m

, higher than those currently used in pediatric HL (Bossi et al. 1997; Fryer

et al. 1990; Kreisman and Wolkove 1992). Meff erd and colleagues evaluated lung function in 20 pediatric HL patients treated with MOPP/AVBD and 15−25 Gy mantle radiation and found 55% to have abnormal dif- fusion capacity (Meff erd et al. 1989). Marina and col- leagues evaluated serial pulmonary function in chil- dren treated with COP/ABVD and mantle radiotherapy and found 65−73% to have only mildly decreased or normal diff usion capacity (Marina et al.

1995). Similar abnormalities of pulmonary function were reported by Nysom and colleagues in survivors of childhood ALL, HL, and NHL (Nysom et al. 1998a,c).

Since symptomatic pulmonary disease was rare in all of these studies, it is diffi cult to predict what will be the impact of mild abnormalities of pulmonary function as the survivors age. A prospective study of pulmonary function from Stanford University of 145 teenagers and adults with HL treated from 1980 to 1990 evalu- ated patients prior to treatment, early aft er treatment (<15 months), and more than 36 months aft er therapy (Horning et al. 1994). Some 32% of patients treated with mediastinal radiotherapy alone (median dose 44 Gy), 37% treated with mediastinal radiotherapy (me- dian dose 44 Gy) and bleomycin (median dose 112 U), and 19% treated with bleomycin (median dose 120 U) without mediastinal radiotherapy had a reduction in forced vital capacity (FVC) below 80%; only 7% of the entire study population had a reduction in diff usion capacity below 70%. Mediastinal radiotherapy was the only therapeutic factor that increased the risk. No pa- tients had signifi cant disease to warrant hospitaliza- tion (Horning et al. 1994).

Despite these data, it is diffi cult to estimate the

prevalence of pulmonary dysfunction in childhood

lymphoma survivors. Clinical evaluations coupled

with functional and quality of life assessments are

needed in very long-term survivors in whom treat-

ment for cancer is well known. An analysis of self-re-

ported pulmonary complications of 12,390 survivors

of common childhood malignancies (including HL

and NHL) has been reported by the CCSS. Compared

with a sibling control group, survivors were more like-

ly to have lung fi brosis, recurrent pneumonia, chronic

cough, pleurisy, use of supplemental oxygen therapy,

abnormal chest wall, exercise-induced shortness of

breath, and bronchitis with relative risks ranging from

1.2 to 13.0, highest for lung fi brosis and lowest for bronchitis. Th e 25-year cumulative incidence of lung fi brosis was 5% for those who received chest radio- therapy and <1% for those who received pulmonary toxic chemotherapy. Treatment-related risk factors in- cluded chest radiation for lung fi brosis, supplemental oxygen therapy, recurrent pneumonia, exercise-in- duced shortness of breath, and chronic cough. Cyclo- phosphamide was associated with exercise-induced shortness of breath, supplemental oxygen therapy, chronic cough, bronchitis, and recurrent pneumonia;

bleomycin with need for supplemental oxygen therapy, bronchitis, and chronic cough; and doxorubicin with an increased risk of emphysema, supplemental oxygen therapy, chronic cough, and shortness of breath. One survivor treated for NHL had undergone a lung trans- plant, and three HL survivors developed adenocarci- noma of the lung as a second malignancy. It is expected that second cancers and other clinical manifestations of treatment aff ecting the lungs will continue to in- crease as the survivors age (Mertens et al. 2002).

12.6 Bone and Body Composition

Survivors of pediatric lymphoma may be at an elevated risk for decreased bone mineral density. Risk factors include increased age at time of exposure, estrogen de- fi ciency, female gender, corticosteroid use and type, growth hormone defi ciency, and cranial radiation.

Prevalence, chronicity, and severity are not consistent across studies, and therefore, the risk remains poorly defi ned (Aisenberg et al. 1998; Kim et al. 2004; Nysom et al. 2001; Ratcliff e et al. 1992; van Leeuwen et al.

2000a; Vassilopoulou-Sellin et al. 1999). An increased incidence of fractures and osteonecrosis may also be present in these patients, but as was true for osteopenia and osteoporosis, this has not been systematically studied in large groups of HL survivors (Enrici et al.

1998; Hancock et al. 1978; Hanif et al. 1993; Mould and Adam 1983; Prosnitz et al. 1981, 1982; Th ornton et al. 1997; Tombolini et al. 1992). Bisphosphonates, cal- cium supplements, and hormone replacement therapy, used in the general population with reduced bone mineral density, are potential interventions (Greens- pan et al. 2000; Kim et al. 2004; Sherman 2001). Fur-

ther research into the type and frequency of screening, the population at highest risk, and interventions are clearly indicated for survivors of HL and NHL, where attempts have been made over the past decade to de- crease doses of corticosteroids (HL & NHL), alkylating agents (HL & NHL), methotrexate (NHL), and cranial radiotherapy (NHL). For lymphoma survivors who have undergone HSCT, there is a lack of consensus re- garding the risk and incidence of decreased bone min- eral and the recommendations for intervention (Ebel- ing et al. 1999; Gandhi et al. 2003; Nysom et al. 2000;

Schimmer et al. 2001).

12.7 Endocrine 12.7.1 Thyroid Gland

Th yroid dysfunction, manifested most oft en by pri- mary hypothyroidism but also hyperthyroidism, goi- ter, or nodules, is a common delayed eff ect of radiation therapy fi elds that include the thyroid gland, mantle, and neck, such as HL. In children treated with radia- tion therapy, most who develop hypothyroidism do so within the fi rst 2−5 years following treatment, but new cases can occur later. Th yroid dysfunction varies with the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis (Gleeson et al. 2002). For example, criteria for the di- agnosis of hypothyroidism, the most frequently re- ported abnormality, may include either elevated thy- roid-stimulating hormone (TSH), depressed thyroxine (T4), or both (Hancock et al. 1995; Oberfi eld et al.

1997; Shalet 1996; Sklar 1999).

Th e incidence of hypothyroidism has decreased

with the lower cumulative doses of radiotherapy em-

ployed in the newer protocols. In a study of 1677 chil-

dren and adults with HL who were treated with radia-

tion therapy between 1961 and 1989, the actuarial risk

at 26 years for overt or subclinical hypothyroidism was

47%, with a peak incidence at 2−3 years aft er treat-

ment (Hancock et al. 1991). In a study of HL patients

treated between 1962 and 1979, hypothyroidism oc-

curred in four of 24 patients who received mantle dos-

es of <26 Gy, but in 74 of 95 patients who received >26

Gy. Th e peak incidence occurred at 3−5 years aft er

treatment with a median of 4.6 years (Constine et al.

1984). A cohort of childhood HL survivors treated be- tween 1970 and 1986 were evaluated for thyroid dis- ease by use of a self-report questionnaire in the CCSS (Sklar et al. 2000). Among 1791 survivors, 34% report- ed that they had been diagnosed with at least one thy- roid abnormality. For hypothyroidism, there was a clear dose response with a 20-year risk of 20% for those who had received less than 35 Gy, 30% following 35−44.9 Gy and 50% following >45 Gy to the thyroid gland. Compared to the general age-matched popula- tion, the relative risk for hypothyroidism was 17.1, for hyperthyroidism 8.0, and for thyroid nodules 27.0. Th e time elapsed since the diagnosis was a risk factor for both hypo- and hyperthyroidism, where the risk in- creased in the fi rst 3−5 years aft er the diagnosis. For nodules, the risk increased 10 and more years aft er the diagnosis. Women were at increased risk for hypothy- roidism and thyroid nodules (Sklar et al. 2000).

12.8 Reproductive Endocrine 12.8.1 Male Gonadal Function

Spermatogenesis is highly sensitive to cyclophospha- mide and other alkylating agents, such as procarbazine and nitrogen mustard, drugs commonly used to treat HL (Ben Arush et al. 2000; Gerres et al. 1998; Hill et al.

1995; Kulkarni et al. 1997). Th ere is a dose-response eff ect for oligospermia and azoospermia, so that infer- tility is a common complication of therapy with COPP, MOPP, and other combinations. Only four cycles of COPP can lead to germ cell aplasia in the majority of boys treated with this combination for HL (Hobbie et al. 2005). In a report by Bokemeyer and colleagues, long-term gonadal toxicity was compared between groups of survivors of HL and NHL. Both groups had received comparable median cumulative doses of cy- clophosphamide, but only the patients with HL had received procarbazine. Th e incidence of gonadal toxic- ity among the HL survivors was more than 3-fold greater than in the NHL survivors. In fact, the only men in the NHL group who had elevation of FSH had received far higher doses of cyclophosphamide than the mean (Bokemeyer et al. 1994). Endocrine function

is not aff ected by the doses that destroy germ cells, and boys can progress through puberty and have normal level of testosterone in spite of having received very high doses of alkylating agents (Chapman et al. 1979;

Cicognani et al. 2003; Qureshi et al. 1972).

Prepubertal boys are not spared, although boys who are older at the time of treatment may be more sensi- tive to germ cell ablation (Dhabhar et al. 1993). Reduc- tion in total doses of alkylating agent therapy in mul- tiagent protocols may be expected to result in less male infertility (Hill et al. 1995; Kulkarni et al. 1997; Re- lander et al. 2000; Schellong et al. 1999). Review of the available studies suggests that males who receive less than 4 g/m

of cyclophosphamide, without testicular or cranial radiation or any other alkylating agent, are likely to retain their fertility. Conversely, cumulative doses above 9 g/m

confer a greater risk of infertility.

Th e degree and permanency of radiotherapy-in- duced damage to the male reproductive system are de- pendent upon dose, fi eld, and schedule. Th e germinal epithelium is damaged by much lower doses (<1 Gy) of radiotherapy than are Leydig cells (20–30 Gy) (Th omson et al. 2002). Doses less than 30 Gy are un- likely to aff ect testosterone production, so boys treated with these doses usually progress through puberty normally. Although temporary oligospermia can oc- cur aft er these very low radiation doses, permanent azoospermia results from doses of >3–4 Gy. Th e po- tential for a return of spermatogenesis in the interme- diate dose range of 1−3 Gy is variable (Ash 1980; Lush- baugh and Casarett 1976). Scatter from abdominal radiation with doses >20 Gy for HL can cause transient elevation in follicle-stimulating hormone (FSH) and oligospermia, but no eff ect was seen with lower doses (Kinsella et al. 1982).

12.8.2 Female Gonadal Function

Unlike the situation in males, hormonal function and potential for fertility are synchronous in females. Pre- pubertal females possess their lifetime supply of oo- cytes with no new oogonia formed aft er birth. Risk of menstrual irregularity, ovarian failure, and infertility increase with age at treatment (Bath et al. 2002; Hill et al. 1995; Mayer et al. 1999; Th omson et al. 2002).

Th erefore, amenorrhea and premature ovarian failure

occur more commonly in adult women treated with cyclophosphamide and other alkylating agents than in adolescents, with prepubertal females tolerating cu- mulative doses as high as 25 g/m

(Damewood and Grochow 1986; Kreuser et al. 1992). However, several large studies of survivors treated through the 1980s have shown elevated relative risks for infertility and premature ovarian failure in female survivors of lym- phoma (Byrne et al. 1987; Chiarelli et al. 1999). In a study of childhood cancer survivors treated between 1945 and 1975, the relative fertility of married survi- vors of childhood HL and NHL was 0.77 (95%CI 0.64−0.92) and 0.81 (95%CI 0.56−1.16), respectively, compared with sibling controls. Among female survi- vors of adolescent HL, the relative risk for premature ovarian failure between 21 and 30 years was 3.35 and between 31 and 40 years, 1.27, compared with sibling controls. Relative risk between the ages of 21 and 30 rose to 9.6 for those treated with radiotherapy below the diaphragm and alkylating agents (Byrne 1999). In another study of 719 survivors treated between 1964 and 1988, of whom 29% were lymphoma survivors, overall there was a 15.5% failure to conceive. Increas- ing doses of abdominopelvic radiotherapy and increas- ing doses of alkylating agents resulted in an increase in premature ovarian failure and a fertility defi cit in the entire cohort (Chiarelli et al. 1999).

Risk-adapted protocols for HL with avoidance of long-term toxicities as a primary study goal have been developed in the last decade. Substitution of cyclo- phosphamide for mechlorethamine appears to have signifi cantly reduced the risk of ovarian dysfunction, which is then further lessened by a reduction in total dose of both agents (Hudson 2002; Linch et al. 2000;

Schwartz 2003). Investigators are now collecting data on premature menopause in the group of women treated more recently in order to determine the full impact of these modifi cations in therapy.

12.8.3 Reproduction

With more childhood cancer survivors retaining their fertility, pregnancy outcome data are now becoming available. Th e CCSS cohort reported 1082 pregnancies among HL survivors and 300 among NHL survivors.

Th e relative risks for live births, compared with female

siblings, were 0.79 (95%CI 0.66−0.95) and 0.80 (95%CI 0.59−1.1) between HL and NHL survivors, respective- ly. Th e risk for medical abortion was increased among HL survivors, compared with siblings (RR = 1.46;

95%CI 1.12−1.91). Th e risk for stillbirths or miscar- riage was not signifi cantly elevated for either group.

Chemotherapy did not increase the risk of an adverse outcome (Green et al. 2002). In the same cohort, Green and colleagues also evaluated the pregnancy outcomes of partners of male survivors in this cohort. Compared with partners of male siblings, there was an increased risk for stillbirths among partners of male NHL survi- vors (RR = 4.19; 95%CI 1.13−15.5). Th ere was no dif- ference in live births, still births, or medical abortions among the partners of the male lymphoma survivors and partners of male siblings (Green et al. 2003).

Progress in reproductive endocrinology has result- ed in the availability of several options for preserving or permitting fertility in patients about to receive po- tentially toxic chemotherapy or radiotherapy (Bath et al. 2002; Th omson et al. 2002). For males, cryopreser- vation of spermatozoa before treatment is an eff ective method to circumvent the sterilizing eff ect of therapy.

Although pretreatment semen quality in patients with cancer may be less than that noted in healthy donors, the decline in semen quality and the eff ect of cryodam- age to spermatozoa from patients with cancer are sim- ilar to those of normal donors (Agarwal 2000; Hallak et al. 1998; Khalifa et al. 1992; Muller et al. 2000). For those unable to bank sperm, newer technologies such as testis sperm extraction may be an option, as demon- strated for male survivors of germ cell tumors who had postchemotherapy nonobstructive azoospermia (Da- mani et al. 2002). Further micromanipulative techno- logic advances such as intracytoplasmic sperm injec- tion and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryo- preserved spermatozoa from cancer patients, capable of successful fertilization (Damani et al. 2002; Pfeifer and Coutifaris 1999).

In pre- and postpubertal females, cryopreservation

of ovarian cortical tissue or enzymatically extracted

follicles and in vitro maturation of prenatal follicles are

of potential clinical use. To date, most of this technol-

ogy has been performed in laboratory animals (Baha-

dur and Steele 1996; Donnez et al. 2000; Newton 1998).

Another option available to the postpubertal female is the stimulation of ovaries with exogenous gonadotro- pins and retrieval of mature oocytes for cryopreserva- tion. However, only a few oocytes can be harvested aft er stimulation of the ovaries (Donnez et al. 2000). In vitro fertilization and subsequent embryo cryopreser- vation have also been successful. Ethical issues regard- ing risk and benefi ts, assent and consent, and disposi- tion of gametes are yet to be worked out (Dudzinski 2004). Furthermore, all these approaches harbor the risk that malignant cells will be present in the speci- men and reintroduced in the patient at a later date.

Th ose with hematologic or gonadal tumors would be at greatest risk for this eventuality (Donnez et al. 2000;

Newton 1998).

With increased use of assisted fertility techniques in survivors of childhood cancer, the risk of congenital anomalies will need to be followed closely, due to re- ports of increased anomalies in off spring born by in vitro fertilization or intracytoplasmic sperm injection (Bonduelle et al. 2002; Ericson and Kallen 2001; Han- sen et al. 2002; Serafi ni 2001; Simpson and Lamb 2001).

12.9 Dental

In a study of the eff ects of chemotherapy on oral and dental structures and craniofacial growth in 30 survi- vors of childhood lymphoma, eruption status, root malformations, premature apexifi cation, agenesis, crown anomalies, soft -tissue abnormalities, gingival and periodontal status, enamel defects and discolor- ations, and craniofacial growth status of the subjects were documented and compared with fi ndings in 20 healthy children. Statistically signifi cant diff erences between the study and control groups were found for plaque index, enamel hypoplasia, discolorations, and agenesis (Alpaslan et al. 1999). In another case con- trol study of 36 long-term survivors of NHL treated with multiagent chemotherapy and 36 controls, the survivors had signifi cantly higher plaque index, more enamel discolorations, and root malformations (Oguz et al. 2004).

Salivary gland irradiation incidental to treatment HL causes a qualitative and quantitative change in

salivary fl ow, which can be reversible aft er doses of

<40 Gy, but may be irreversible aft er higher doses, depending on whether sensitizing chemotherapy, such as doxorubicin, is also administered. Dental caries are the most serious consequence. Th e use of topical fl uoride can dramatically reduce the frequen- cy of caries, and saliva substitutes and sialagogues can ameliorate sequelae, such as xerostomia (Makkonen and Nordman 1987; Maxymiw and Wood 1989).

Th ese fi ndings give further impetus to the need for routine dental and dental hygiene evaluations for sur- vivors of childhood lymphoma. However, despite known risk factors, dental practices among survivors are less than recommended for the general population (Yeazel et al. 2004).

12.10 Spleen

Splenectomy increases the risk of life-threatening in- vasive bacterial infection (American Academy of Pedi- atrics 2003). Since it is no longer standard practice to perform a staging laparotomy for pediatric HL, the previously described long-term complications, both related to surgery and altered immune function, should no longer be an issue for most survivors of childhood HL (Jockovich et al. 1994; Kaiser 1981). However, chil- dren may be rendered asplenic by radiation therapy to the spleen in doses of >40 Gy (Coleman et al. 1982;

Weiner et al. 1995). Low-dose involved fi eld radiation (21 Gy) given together with multiagent chemotherapy does not appear to adversely aff ect splenic function (Weiner et al. 1995).

For patients with surgical or functional asplenia,

prophylactic antibiotics, generally penicillin, are rec-

ommended to be taken daily for life. Th ese recommen-

dations are based on general pediatric practice, but the

benefi t of prophylactic antibiotics in asplenic cancer

survivors has not been studied. Older survivors oft en

report discontinuing antibiotics and should therefore

be instructed to take penicillin at the onset of febrile

illness. Medical care should be sought promptly for fe-

vers >38.5ºC. Patients should receive antibiotic pro-

phylaxis for dental work and should be immunized

against meningococcus, hemophilus infl uenzae B, and

Streptococcus pneumoniae (American Academy of Pe- diatrics 2003).

12.11 Psychosocial

Survivors of pediatric lymphoma are at risk for adverse psychologic outcomes. Among 4914 survivors of leu- kemia and lymphoma in the Childhood Cancer Survi- vor Study, 5.4% reported symptoms of depression, with equal reporting across diagnostic groups. In addi- tion, 15% of the 1843 HL survivors and 11.4% of the 902 NHL survivors reported somatic distress. Reports of symptoms of depression or somatic distress were higher among the lymphoma survivors than a cohort of siblings. For survivors of HL, female gender, lower household income, less than a high school education, and lack of current employment increased the risk for depression and somatic distress symptoms, with older age also increasing the risk for somatic distress. Among the NHL survivors, lower educational attainment and lack of current employment increased the risk of both depression and somatic distress, with lower household income also increasing the risk for somatic distress (Zebrack et al. 2002). Results from the Italian Multi- centric Study on Long-Term Survivors of Childhood Cancer support the fi nding of psychological distress.

In this cohort, survivors of leukemia and lymphoma reported that feelings of anxiety, depression, panic at- tacks, and fear of recurrence were increased, with dif- ferences more marked when compared with friends or other relatives of the case compared to siblings (Cutti- ni et al. 2003).

Th ese data underscore the need to address both physical and psychosocial factors that may impact the health status and quality of life in long-term survivors of lymphoma.

12.12 Mortality

Patients who have initially been cured of HL are at in- creased risk of early mortality from disease, treatment, and external causes. In a series from St. Jude Children’s Research Hospital, Hudson and colleagues studied late events in 387 pediatric HL patients treated from 1968

to 1990 treated on four consecutive trials, with a me- dian follow-up of 15.1 years (Hudson et al. 1998). Cu- mulative incidence of 25-year cause-specifi c mortality was 9.8+1.6% for Hodgkin disease, 8.1%+2.6% for sec- ond cancers, 4.0%+1.8% for cardiac disease, 3.9%+1.5%

for infection, and 2.1%+0.8% for accidents. Standard- ized mortality ratios showed excess mortality from cardiac disease (SMR = 22, 95%CI 8−48) and infection (SMR=18, 95%CI 7−38) (Hudson et al. 1998). In a re- cent analysis of 1261 patients treated for HL in the Netherlands between 1965 and 1987, which included 329 patients under the age of 21 years, with a median follow-up of 17.8 years, the relative risk of death from all causes other than HL was 6.8 times that of the gen- eral population. Of note, in patients treated under the age of 21 years, the relative risk of death from solid tumors was 14.8 and from cardiovascular disease, 13.6 (Aleman et al. 2003). In the Childhood Cancer Survi- vor Study, there was an elevated risk of death for initial 5-year survivors of HL and NHL from second malig- nancies (HL: SMR = 24.0, 95%CI 19.2−29.7; NHL:

SMR = 15.6, 95%CI 9.6−23.7), cardiac disease (HL:

SMR = 12.0, 95%CI 6.5−22.4; NHL: SMR = 6.5, 95%CI

2.3−14.0), and pulmonary disease (HL: SMR = 13.8,

95%CI 9.3−19.4; NHL: SMR = 14.7, 95%CI 6.1−35.4)

(Mertens et al. 2001). In a similar study from the Nor-

dic countries using registry data, HL patients experi-

enced the highest proportion of deaths (19.4%) and

were noted to have excess mortality from second ma-

lignancy, pulmonary disease, and disease of the heart

and circulatory system. However, this study also dem-

onstrated the importance of changes in therapy over

time to decrease the risk of late eff ects. In the HL pa-

tients, comparing patients diagnosed from 1960 to

1979 with those diagnosed from 1980 to 1989, the

overall death hazard ratio was decreased (0.34, 95%CI

0.23−0.52) (Moller et al. 2001). Th is is related to a de-

crease in deaths from the primary cancer without an

associated increase in mortality from second cancers

or treatment-related toxicities. Th e former refl ects im-

provements in therapeutic effi cacy, and the latter re-

fl ects changes in therapy made as a consequence of the

study of the causes of late eff ects.

12.13 Monitoring for Late Eff ects

Th e American Society of Pediatric Hematology/On- cology, the International Society of Pediatric Oncolo- gy, and the American Academy of Pediatrics support the need for long-term monitoring of adverse long- term sequelae for all childhood cancer survivors. Th is is especially important for survivors of pediatric lym- phoma. Tables 12.1 and 12.2, adapted from the Chil- dren’s Oncology Group (COG) Long-term Follow-up Guidelines (Landier et al. 2004), summarize the com- mon late eff ects seen in lymphoma survivors and gen- eral guidelines for monitoring studies. Survivors should seek care from professionals with expertise in the recognition and management of late eff ects (Ar- cecci 1996; Harvey et al. 1999; Masera et al. 1997;

Meadows et al. 1998; Sanders et al. 1997). To support this, more information on the late eff ects of childhood cancer is being published in both oncology and gen- eral pediatric, nursing, and family practice journals (Eshelman et al. 2004; Friedman and Meadows 2002;

Oeffi nger 2003; Oeffi nger and Hudson 2004). Th e Children’s Oncology Group and others have published guidelines for survivors and health care providers. Th e COG Long-term Follow-up Guidelines are accompa- nied by detailed health links about exposures, risks for late eff ects, and monitoring, and all are available on a public website (Landier et al. 2004). In the United Kingdom, both the SIGN guidelines and the UKCCSG

“Aft er Cure Booklet” are available on a public website.

Th e “Aft er Cure Booklet” provides patient information including health education and information leafl ets on a range of late sequelae (Blacklay et al. 1998).

It is well acknowledged that survivors need to be educated about their diagnosis, treatments received, need for monitoring, and recommended disease pre- vention practices (Blacklay et al. 1998; Hudson et al.

1999, 2004; Landier et al. 2004; Oeffi nger and Hudson 2004). Health promoting behaviors should be stressed for survivors of childhood lymphoma, and patient in- formation has been shown to enhance attitude to fol- low-up and infl uence adverse life style behaviors (Eiser et al. 2000; Hudson et al. 1999, 2004).

12.14 Research Challenges for Lymphoma Survivors

Although outcomes research in pediatric oncology has been carried on for over 25 years, there continue to be considerable challenges. Many late eff ects have long and variable latency periods, and lifetime risks remain undetermined. Changes in therapeutic approaches, designed in part to decrease late eff ects, combined with improved survivorship mandate the need for on- going studies that focus on health-related outcomes of newer treatment approaches that are not limited to a simple analysis of cure. Monitoring guidelines cur- rently in place are based, in part, on long-term data from survivors treated with therapies that are no lon- ger being used (Landier et al. 2004). Perhaps the great- est challenge is that in order to clearly quantify the magnitude of risk, studies of late eff ects require ascer- tainment of aff ected and unaff ected survivors. Incom- plete follow-up can result in a reduction in study pow- er and selection bias. Patients who participate in long-term follow-up may diff er in systematic and im- portant ways from those who do not participate.

Risk factor analyses require a quantitative rather than qualitative approach in documenting and report- ing late eff ects. However, despite eff orts to the contrary, to date we do not yet have a satisfactory and uniformly accepted manner of quantifying late eff ects, as is evi- denced by the eff orts of the Radiation Th erapy Oncol- ogy Group (RTOG) Late Eff ects Working Group (Ru- bin et al. 1995). As childhood cancer survivors enter adulthood and are followed by a combination of pedi- atric, radiation oncology, and primary care specialists, such scoring systems must be usable by a broad variety of health care professionals.

Outcomes-based research may be diffi cult to carry

out in an acute care clinic model, where acute clinical

needs take precedence. It is challenging to spend the

time required to enroll patients on research protocols,

conduct unbiased research, and balance the needs of

the individual patient with those of the scientifi c com-

munity. In addition, funding boundaries for clinical

and research goals may become blurred, and in an era

of emphasis on cost containment, these must be delin-

eated as clearly as possible. If research is to lead to

changes in the standard of care for patients, it is im-

Table 12.1 General guidelines for radiation late eff ects: assessment and management System Potential eff ects Monitoring guidelines

Central nervous system

Cognitive dysfunc- tion

Leukencephalo- pathy

History (annually):

Assessment of educational and/or vocational progress

Cognitive, motor or sensory defi cits, seizures, and other neurologic symptoms.

Neurocognitive testing baseline, then periodically as clinically indicated for patients with evidence of impaired educational or vocational progress Physical examination (annually):

Neurologic exam

CT or MRI brain plus MR angiography

Dental Salivary gland dysfunction

Regular dental care including fl uoride applications.

Use of sialogues Cardiac Cardiomyopathy

Pericarditis Coronary artery disease Valvular disease

History (annually):

SOB, DOE, orthopnea, chest pain, palpitations. If under 25 years: abdominal symptoms (nausea, vomiting).

Physical exam (annually):

Cardiac exam Diagnostic studies:

EKG for evaluation of QTc interval at entry into long-term follow-up and then as clinically indicated dependent on dose and volume of RT and anthracyclines Additional considerations:

Cardiology consultation in patients with subclinical abnormalities on screening evaluations, left ventricular dysfunction, dysrhythmia, or prolonged QTc interval.

Additional cardiology evaluation in patients who received > 300 mg/m

or < 300 mg/m

plus chest radiation or TBI who are pregnant or planning pregnancy to include an EKG and echocardiogram before and periodically during pregnancy (especially during 3rd trimester) and monitoring during labor and delivery due to risk of cardiac failure.

Pulmo- nary

Pulmonary fi brosis History (annually):

Cough, SOB, DOE, wheezing Physical exam (annually):

Pulmonary exam Diagnostic studies:

Pulmonary function tests (PFTs) (including DLCO and spirometry) and CXR baseline at entry into long-term follow-up and prior to general anesthesia.

Repeat as clinically indicated in patients with abnormal or progressive pulmo- nary dysfunction

Thyroid Overt or compen- sated hypothyroid- ism

Thyroid nodules or cancer

Hyperthyroidism

Physical examination (annually):

Thyroid palpation

Laboratory tests (annually):

Free T4; TSH

portant to assess what types of evaluation will provide the most valuable information for the greatest number of patients in the most cost-eff ective fashion. Survivor- ship research carried out within a long-term follow-up clinic can be either institution-initiated, cooperative group-sponsored, or population-based. Maintaining a current database will facilitate data collection analysis.

In addition, having a means for tracking survivors is vital for collecting long-term data on individuals

whose care has been transferred to a community-based setting. Approaches for integrating research activities into institutional models of survivor care have been described (Hinkle et al. 2004b; Hudson et al. 2004).

Primary reliance on patients can be an eff ective ap- proach to obtaining data, for both retrospective and prospective analyses, as is evidenced by the CCSS (Ro- bison et al. 2002). Independent studies of the effi cien- cy, reliability, validity, and utility of self-reported me- System Potential eff ects Monitoring guidelines

Go- nadal (female)

Delayed/arrested puberty

Early menopause Ovarian failure

History (annually):

Pubertal (onset, tempo), menstrual, pregnancy; sexual function (vaginal dryness, libido), medication use impacting sexual function.

Physical exam (annually):

Height, weight, Tanner stage Laboratory (baseline):

FSH, LH, estradiol at 13 years and as clinically indicated in patients with:

– Delayed puberty, irregular menses or primary or secondary amenorrhea – Clinical signs and symptoms of estrogen defi ciency

Go- nadal (male)

Germ cell failure Infertility/azoosper- mia

Leydig cell dysfunc- tion

Hypogonadism Delayed/arrested puberty

History (annually):

Pubertal (onset, tempo), sexual function (erections, nocturnal emissions, libido), medication use impacting sexual function

Physical exam (annually):

Height, weight, Tanner stage, testicular volume by Prader orchiometry Laboratory (baseline):

FSH, LH, testosterone at age 14 and as clinically indicated in patients with:

– Delayed puberty

– Clinical signs and symptoms of testosterone defi ciency Semen analysis

Bone Osteopenia Bone mineral density > 1 and <

2.5 SD below mean Osteoporosis Bone mineral density > 2.5 SD below mean Osteonecrosis (avascular necrosis – AVN)

Bone density evaluation (DEXA or quantitative CT) baseline at entry into long- term follow-up and then as clinically indicated

History (annually):

Joint pain, swelling, immobility, limited range of motion Physical exam (annually):

Musculoskeletal exam Imaging studies:

MRI as clinically indicated by signs or symptoms suggestive of AVN Second

malig- nancies

Sarcomas CNS tumors Breast cancer Melanoma

Non-melanoma skin cancer

Thyroid cancer Other solid tumors

Complete physical examinations annually

Attention paid to organs in radiation fi eld

Diagnostic imaging as clinically indicated

Mammography to screen for female breast cancer

Table 12.2 General guidelines for chemotherapy late eff ects: assessment and management

System Agents Potential

eff ects

Monitoring guidelines

Dental Chemotherapy Root, enamel and gingival changes

Dental exam and cleaning every six months Regular dental care including fl uoride applications.

Baseline panorex prior to dental procedures to evaluate root development.

Cardiac Anthracyclines Cardiomyo- pathy Arrhythmias

History (annually):

SOB, DOE, orthopnea, chest pain, palpitations. If under 25 years:

abdominal symptoms (nausea, vomiting).

Physical exam (annually):

Cardiac exam Diagnostic studies:

EKG for evaluation of QTc interval at entry into long-term follow- up and then as clinically indicated

Additional considerations:

Cardiology consultation in patients with subclinical abnormali- ties on screening evaluations, left ventricular dysfunction, dysrhythmia, or prolonged QTc interval.

Additional cardiology evaluation in patients who received > 300 mg/m

or < 300 mg/m

plus chest radiation or TBI who are pregnant or planning pregnancy to include an EKG and echocardiogram before and periodically during pregnancy (especially during 3rd trimester) and monitoring during labor and delivery due to risk of cardiac failure.

Pulmo- nary

Bleomycin Restrictive lung

disease

History (annually):

Cough, SOB, DOE, wheezing Physical exam (annually):

Pulmonary exam Diagnostic studies:

PFTs (including DLCO and spirometry) and CXR baseline at entry into long-term follow-up and prior to general anesthesia.

Repeat as clinically indicated in patients with abnormal or progressive pulmonary dysfunction

Go- nadal (fe- male)

Alkylating agents Delayed/

arrested puberty Early meno- pause Ovarian failure

History (annually):

Pubertal (onset, tempo), menstrual, pregnancy; sexual function (vaginal dryness, libido), medication use impacting sexual function.

Physical exam (annually):

Height, weight, Tanner stage Laboratory (baseline):

FSH, LH, estradiol at 13 years and as clinically indicated in patients with:

– Delayed puberty, irregular menses or primary or secondary amenorrhea

– Clinical signs and symptoms of estrogen defi ciency

dical and psychologic complications will be necessary in the assessment of this approach for long-term fol- low-up.

12.15 Future Directions

Although associations between certain therapeutic ex- posures and adverse physiologic outcomes of child- hood lymphoma are well known, the mechanisms un-

derlying many of these outcomes remain largely unknown and are ripe for study. In spite of having re- ceived similar treatment for specifi c forms of lympho- ma, there is considerable variability in the proportion of survivors that develop treatment-related toxicities.

Are these merely stochastic or chance events, or do host-related factors, such inherited diff erences in drug metabolism and activation, radiation sensitivity, and DNA repair have an impact on the risk of long-term toxicity? While morbidity and premature mortality

System Agents Potential

eff ects

Monitoring guidelines

Go- nadal (male)

Alkylating agents Germ cell failure Infertility/

azoospermia Leydig cell dysfunction Hypogonadism Delayed/

arrested puberty

History (annually):

Pubertal (onset, tempo), sexual function (erections, nocturnal emissions, libido), medication use impacting sexual function Physical exam (annually):

Height, weight, Tanner stage, testicular volume by Prader orchiometry.

Laboratory (baseline):

FSH, LH, testosterone at age 14 and as clinically indicated in patients with:

– Delayed puberty

– Clinical signs and symptoms of testosterone defi ciency Semen analysis

Bone Corticosteroids+/–

methotrexate Alkylating agents (due to hypogo- nadism) Corticosteroids

Osteopenia Bone mineral density > 1 and

< 2.5 SD below mean

Osteoporosis Bone mineral density > 2.5 SD below mean Osteonecrosis (avascular necrosis – AVN)

Bone density evaluation (DEXA or quantitative CT) baseline at entry into long-term follow-up and then as clinically indicated

History (annually):

– Joint pain, swelling, immobility, limited range of motion – Physical exam (annually):

– Musculoskeletal exam Imaging studies:

– MRI as clinically indicated by signs or symptoms suggestive of AVN

Second malig- nancies

Alkylating agents:

Topoisomerase II inhibitors

Cyclophospha- mide

Leukemia

Transitional bladder carcinoma

History (annually for 10 years):

Fatigue, bleeding, easy bruising Physical exam (annually for 10 years):

Dermatologic exam (pallor, petechiae, purpura) Laboratory (annually for 10 years):

CBC/diff erential History (annually):

Hematuria, frequency, urgency Laboratory (annually):

Urinalysis

have been examined with respect to treatment expo- sures, their relation to other factors such as environ- mental exposures that are etiologically related to the major problems in an aging population have not been explored. Th ese too require creative research eff orts.

New patterns of late morbidity and mortality may emerge as survivors continue to age, and it is only through continued study that such patterns will be identifi ed, and interventions for treatment and pre- vention designed.

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