VOLUME 24 䡠 NUMBER 10 䡠 APRIL 1 2006

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Risk of Second Malignancy After Non-Hodgkin’s

From the Section of Epidemiology,
Institute of Cancer Research, Sutton,
Surrey; British National Lymphoma
Investigation, Cancer Trials Centre,
London; Department of Haematology,
University College London Medical
School, London; Academic Unit of
Clinical Oncology, Cancer Research
Centre, Weston Park Hospital, Shef-
field; Clinical Oncology, Mount Vernon
Hospital, Northwood, Middlesex,
United Kingdom.
Submitted September 29, 2005;
accepted January 23, 2006.
Supported by The Lymphoma Research
Trust.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to N.Y. Mudie,
MD, PhD, Section of Epidemiology,
Institute of Cancer Research, Sutton,
Surrey SM2 5NG, United Kingdom;
e-mail: nadejda.mudie@icr.ac.uk.
© 2006 by American Society of Clinical
Oncology
Lymphoma: A British Cohort Study
Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins, Paul Smith, Zongkai Qiao, Barry W. Hancock,
Peter J. Hoskin, and David C. Linch
A B S T R A C T
Purpose
To assess long-term site-specific risks of second malignancy following non-Hodgkin’s lymphoma
(NHL) in relation to treatment and demographic factors.
Patients and Methods
A cohort of 2,456 patients with NHL who were first treated from 1973 to 2000 and were younger
than 60 years from centers in the British National Lymphoma Investigation were observed, and
occurrences of second malignancy was compared with expectations based on general population
cancer rates in England and Wales.
Results
In total, 123 second malignancies occurred. Relative risks (RRs) were significantly elevated for all
malignancies combined (RR ⫽ 1.3; 95% CI, 1.1 to 1.6) and for leukemia (RR ⫽ 8.8; 95% CI, 5.1
to 14.1) and lung cancer (RR ⫽ 1.6; 95% CI, 1.1 to 2.3). RRs of malignancy overall diminished
significantly with increasing age at first treatment. Leukemia risk was significantly increased after
chemotherapy (RR ⫽ 10.5; 95% CI, 5.0 to 19.3) and mixed-modality treatment (RR ⫽ 13.0; 95%
CI, 5.2 to 26.7). Relative risks of lung (RR ⫽ 1.9; 95% CI, 1.1 to 3.1) and colorectal (RR ⫽ 2.1; 95%
CI, 1.1 to 3.6) cancers were significantly raised following chemotherapy.
Conclusion
NHL patients are at elevated risk of developing second malignancy, particularly leukemia and lung
cancer. The relative risk is greater with patients who are younger at first treatment. Chemotherapy
predisposes patients toan increased risk of leukemia, and possibly lung and colorectal cancers. The role
of specific drug treatments in the etiology of solid cancers after NHL deserves further investigation.

0732-183X/06/2410-1568/$20.00 J Clin Oncol 24:1568-1574. © 2006 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2005.04.2200

bladder cancer has been linked to cumulative

INTRODUCTION
The incidence of non-Hodgkin’s lymphoma (NHL)
has been increasing for the past 40 years in most
Western countries.1,2 With better treatment, life
expectancy of NHL patients has been improving,3
and hence the risk of iatrogenic malignancy is be-
coming an important concern in long-term survi-
vors. Whereas considerable attention has focused on
late sequelae of Hodgkin’s disease,4 relatively little
information is available about second malignancies
in NHL, as there have been few large studies with
prolonged and complete follow-up.
Several studies,5-9 but not all,10-14 have re-
ported an elevated risk of second malignancy overall
following NHL. Most studies have found increased
risks of leukemia, especially acute nonlymphocytic
leukemia (ANLL),6,9,11,14-17 associated with alkylat-
ing chemotherapy, alone or in combination with
total nodal/body irradiation.18,19 Raised risk of
doses of cyclophosphamide and, to a lesser extent,
to radiotherapy.20,21 There have been sporadic
reports of raised risk of several other solid can-
cers5,6,8,9,13,20,21 and Hodgkin’s disease,9,22 but in-
consistently and without an established relationship
to treatment.
Reports on cancer risks in NHL survivors
beyond 15 years are limited to an international
study conducted by Travis et al7 that demon-
strated a persistent significantly elevated risk of all
malignancies, as well as of cancers of several indi-
vidual sites. With the exception of leukemia, blad-
der, and kidney cancer risks, few studies have
examined the risk of specific second malignancies in
relation to treatment12 and these studies usually only
used data on the initial treatment in their analy-
sis.6,14 The effect of age at first treatment on the risk
of second malignancy has rarely been examined and
has produced conflicting results.7,9,23

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 Second Cancer After Non-Hodgkin’s Lymphoma

To evaluate the risk of second malignancy arising from different

Table 1. Descriptive Characteristics of the Cohort
types of treatment for NHL, we assembled a retrospective cohort of
2,456 United Kingdom patients first treated at ages younger than 60 No. of Person-Years of
Characteristic Patients Follow-Up
years, and observed them for up to 26 years.
Year of first treatment
1973-1979 460 4,727
PATIENTS AND METHODS 1980-1984 504 4,445
1985-1989 705 5,420
1990-1994 566 3,249
The British National Lymphoma Investigation (BNLI) maintains a database
1995-2000 221 589
on the treatment and follow-up of all patients with NHL from clinical trials
Age at first treatment, years
treated in its participating hospitals. From this database, we extracted infor-
⬍ 45 932 7,658
mation on all patients first treated at ages younger 60 years, between June 1,
45-54 937 6,868
1973, and March 31, 2000, except for those who were foreign residents. The
55-59 587 3,904
data on treatments, cancers, deaths, and follow-up to March 31, 2000, were
Follow-up, yearsⴱ
then updated from case notes as necessary. Based on comparison of the BNLI
2 months† to ⬍ 5 2,456 8,728
files with case notes and other sources, we believe that the BNLI data have a
5-9 1,406 5,565
high level of completeness regarding second malignancy.24 Sites of second
10-14 795 2,713
cancer were coded according to the International Classification of Diseases
ⱖ 15 336 1,424
(ICD),25 using the editions that were applicable in England and Wales at the
Stage at diagnosis
time of diagnosis: ICD8 for 1968 through 1978, and ICD9 for 1979 through
I 500 4,992
2000. We bridge-coded the data to ICD9 categories.
II 489 4,007
For each patient in the cohort, person-years at risk of second cancer were
III 499 3,979
calculated by 5-year age group, sex, and calendar year, from 2 months after the
IV 917 5,306
date of first treatment (cancers and person-years in the first 2 months of
Not known 51 146
follow-up were excluded from the analysis to avoid inadvertent inclusion of
Histology
synchronous tumors6) to the date of the end of follow-up, or of second cancer
Follicular 771 7,062
incidence, death, or loss to follow-up, if earlier. Thirty-one patients were
Lymphocytic 168 1,245
excluded from the study because less than 2 months of follow-up was available
Lymphoblastic/Burkitt-type 106 505
for them and a further six patients were excluded due to insufficient treatment
Diffuse large cell‡ 1,163 8,064
data available. For analyses of time since first treatment and type of treatment,
Unclassified or other§ 193 1,389
case subjects were allocated at each point in their follow-up to the analytic cat-
Unknown 55 165
egory applicable at that time. Type of treatment was categorized into chemo-
Sex
therapy, radiotherapy, and mixed-modality treatment. Sub-analyses were also
Male 1,413 10,140
conducted for the two most common chemotherapy regimens: CHOP (cyclo-
Female 1,043 8,290
phosphamide, doxorubicin, vincristine, and prednisolone) and chlorambucil,
Treatment㛳
whether or not the patient had received radiotherapy or any other chemother-
Radiotherapy 328 4,165
apy. It was not practical for us to obtain more detailed therapeutic information
Chemotherapy 1,274 9,392
for the total cohort, and this will be addressed elsewhere by nested case-control
Mixed modalities 854 4,873
studies. Expected numbers of cancers incident in the cohort were calculated for
Total 2,456 18,430
each cancer site by multiplying age-, sex-, and calendar year–specific person-
ⴱ
years at risk in the cohort by the corresponding cancer registration rates in the No. of patients refers to number at the beginning of each follow-up category;
general population of England and Wales. Completeness of cancer registration person-years refer to time accumulated when in these categories (individuals
could contribute to more than one category).
in England and Wales has been assessed to be 90%1; however, cases of non- †Because first 2 months after first treatment was excluded; see Methods.
melanoma skin cancer were excluded from the analysis as their registration is ‡Including diffuse mixed cell lymphoma.
seriously incomplete.1 The ratio of observed to expected numbers of inci- §Other lymphomas include lymphocytic intermediate differentiation and
dent cancers, the standardized incidence ratio (SIR, referred to in the text plasma cell lymphomas.
㛳No. of patients refers to numbers in the treatment categories at the end of
as relative risk [RR]) was calculated with likelihood-based 95% CI from follow-up; person-years refer to time accumulated when in these categories
Poisson models.26 Absolute excess risks of second cancer were calculated (individuals could contribute to more than one category).
by subtracting the expected from the observed number of cases and divid-
ing by the person-years at risk. Cumulative (actuarial) probabilities of
second cancer were calculated by the Kaplan-Meier method.27 Tests for
trend and heterogeneity were calculated as described in Breslow and Day.28
All significance levels cited are two-sided. mon forms of chemotherapy were CHOP, received by 1,219 patients
(mean age, 46 years; 61% male, mainly treated from 1980 to 1994) and
chlorambucil, received by 752 patients (mean age, 48 years; 54% male,
RESULTS
mainly treated from 1973 to 1989).
During follow-up, 123 patients (5.0%) developed a second ma-
The cohort consisted of 2,456 patients (Table 1), 58% (n ⫽ 1,413) of lignancy, 1,230 others died, seven emigrated, 37 patients (1.5%) were
whom were male. The average age at first treatment was 46.5 years lost to follow-up in other ways, and the remaining 1,059 patients
(range, 3 to 59 years), with more than a third of the cohort (n ⫽ 932) survived without second cancer to the end of the study period. No
younger than 45 years. The mean age at first treatment was not signif- patients developed a third primary cancer during the follow-up pe-
icantly different between calendar periods of the study (P ⫽ .20). The riod. Total follow-up was 18,430 person-years, a mean of 7.7 years
majority of patients were treated with chemotherapy, either alone (maximum 26.8 years) per cohort member. The mean length of
(52%) or in combination with radiotherapy (35%). The most com- follow-up was slightly longer for those patients who were younger

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 Mudie et al

when first diagnosed with NHL than those who were older, ranging
from 8.4 years for those younger than 45 years to 6.8 years for those
patients ages 55 to 59 years (data not shown).
The risk of second malignancy overall was significantly increased
(RR ⫽ 1.3; 95% CI, 1.1 to 1.6; P ⬍ .01; Table 2). The risks of lung
cancer (RR ⫽ 1.6; 95% CI, 1.1 to 2.3) and leukemia (RR ⫽ 8.8; 95%
CI, 5.1 to 14.1) were also significantly raised. The risks of several
gastrointestinal and genitourinary cancers, bone and soft tissue can-
cers, and Hodgkin’s disease were also raised, albeit not significantly.
Lung cancer and leukemia were the main contributors to the raised
absolute excess risk. Five of the cases of lung cancer were squamous
cell, three were adenocarcinoma, two were oat/small cell, one was
hurtle cell, one was non–small-cell, four were poorly differentiated
carcinomas, and 12 were of unknown histology.
The raised risk of second cancers overall was confined to men
(RR ⫽ 1.6, 95% CI, 1.3 to 2.0 for men; RR ⫽ 1.0, 95% CI, 0.7 to 1.3 for
women; Pheterogeneity [lt] .05). There were significantly increased risks
in men for leukemia (RR ⫽ 9.7; 95% CI, 5.0 to 16.9) and oropharyn-
geal cancer (RR ⫽ 3.6; 95% CI, 1.2 to 8.3; data not shown). Significant
raised risks of leukemia (RR ⫽ 7.2; 95% CI, 2.3 to 16.8) and soft tissue
cancer (RR ⫽ 10.4; 95% CI, 1.3 to 36.5) occurred in women.
Relative risk of leukemia increased with stage of NHL at
diagnosis (Ptrend ⬍ .05) and was only significant in patients diag-
nosed with stage III disease (RR ⫽ 9.4; 95% CI, 2.6 to 24.1) and
stage IV disease (RR ⫽ 18.7; 95% CI, 9.0 to 34.4; data not shown).
This trend was not apparent for all malignancies overall or for any
individual solid cancer sites.
The relative risk of malignancy overall was raised for each histo-
logic subtype of NHL, although it was significant for only the most
common type, diffuse large cell NHL (RR ⫽ 1.4; 95%CI, 1.0 to 1.8;
data not shown). Similarly, the risk of leukemia was raised for each
histologic subtype, and was raised significantly for follicular NHL
(RR ⫽ 10.4; 95% CI, 4.5 to 20.5), lymphocytic NHL (RR ⫽ 19.5; 95%
CI, 4.0 to 56.9), and diffuse NHL (RR ⫽ 6.2; 95% CI, 2.0 to 14.5).
The relative risk of second cancer overall diminished with in-
creasing age at first treatment (Ptrend ⬍ .05; Table 3), and significant
diminution of relative risk with age was also apparent for cancers of the
mouth and pharynx, stomach (data not shown), and bladder and
urethra. For second cancers overall, absolute excess risk per 10,000
person-years (AER) diminished with age, though the opposite was
true for lung and colorectal cancers and leukemia. Breast cancer risk
was significantly reduced in women first treated at ages 45 to 54 years,
but not for those women who were younger or older than this range.
The risk of second malignancies overall was raised up to 15 years
from diagnosis, but not thereafter, although with wide confidence
intervals (Table 4). The relative risk of leukemia was elevated during

Table 2. Risks of Second Primary Malignancy by Site

Absolute Excess
No. of Risk per 10,000
ICD9 Code Site Cases SIR 95% CI Person-Years
141-149 Mouth and pharynx 5 2.6 0.8 to 6.0 1.7
150 Esophagus 2 0.8 0.1 to 3.0 ⫺0.2
151 Stomach 6 1.5 0.6 to 3.3 1.1
153 Colon 10 1.4 0.7 to 2.6 1.6
154 Rectum 7 1.4 0.6 to 2.9 1.1
157 Pancreas 4 1.6 0.4 to 4.2 0.8
162 Lung 28 1.6ⴱ 1.1 to 2.3 5.8
170 Bone 1 6.8 0.2 to 37.9 0.5
171 Soft tissue 2 4.1 0.5 to 14.7 0.8
172 Melanoma 3 1.4 0.3 to 4.0 0.4
174 Breast (female) 11 0.7 0.3 to 1.2 ⫺5.9
179, 182 Corpus uteri 0 0.0 0.0 to 1.6 ⫺2.9
180 Cervix 2 1.2 0.1 to 4.3 0.4
183 Ovary 1 0.4 0.01 to 2.0 ⫺2.2
185 Prostate 3 0.6 0.1 to 1.6 ⫺2.3
188, 189.3-189.9 Bladder and urethra 8 1.6 0.7 to 3.2 1.7
189.0-189.2 Kidney and ureter 3 1.3 0.3 to 3.8 0.4
191-192, 225.0-225.9, 237.5, 237.6, 237.9, 239.6 Nervous system 3 1.0 0.2 to 3.0 0.3
196-199 Unspecified primary 2 0.4 0.1 to 1.5 ⫺1.5
201 Hodgkin’s disease 2 4.2 0.5 to 15.2 0.8
203 Myeloma 1 0.9 0.0 to 4.8 ⫺0.1
204-208 Leukemia 17 8.8† 5.1 to 14.1 8.2
205 Acute myeloid leukemia‡ 9 13.1† 6.0 to 24.9 4.5
140-172, 174-199 All solid cancers except nmsc§ 103 1.1 0.9 to 1.4 6.5
140-172,174-199, 201, 203-208 All malignancies, except nmsc and NHL§ 123 1.3㛳 1.1 to 1.6 15.4

Abbreviations: SIR, standardized incidence ratio; ICD9, International Classification of Diseases 9th Edition; nmsc, non-melanoma skin cancer; NHL,
non-Hodgkin’s lymphoma.
ⴱ
P ⬍ .05.
†P ⬍ .001.
‡Other leukemias were: four cases acute lymphoid leukemia, one case lymphoblastic leukemia of unspecified chronicity, one case chronic myeloid leukemia,
one case acute leukemia of unspecified type, and one case leukemia not further specified.
§Including, in addition to the cancers detailed above, one cancer of the pleura and one cancer of the testis.
㛳P ⬍ .01.

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 Second Cancer After Non-Hodgkin’s Lymphoma

Table 3. Relative Risks of Second Primary Malignancy of Selected Sites, by Age at First Treatment
Age (years)
⬍ 45 45-54 55-59
No. of No. of No. of
Cancer Site Cases SIR 95% CI AER Cases SIR 95% CI AER Cases SIR 95% CI AER

Mouth and pharynx 4 10.2ⴱ 2.8 to 26.2 4.7 1 1.1 0.03 to 6.2 0.2 0 0.0 0.0 to 5.6† ⫺1.7
Colon and rectum 2 1.4 0.2 to 4.9 0.7 8 1.5 0.7 to 3.0 4.0 7 1.3 0.5 to 2.8 4.6
Lung 1 0.6 0.02 to 3.6 ⫺0.7 13 1.7 0.9 to 3.0 8.1 14 1.7 0.9 to 2.9 14.8
Breast (female) 5 1.1 0.4 to 2.6 0.7 1 0.1‡ 0.004 to 0.8 ⫺8.5 5 1.1 0.3 to 2.5 0.8
Bladder and urethra 2 4.0 0.5 to 14.3 2.0 5 2.3 0.7 to 5.4 4.1 1 0.4 0.01 to 2.4§ ⫺3.3
Leukemia 5 14.4㛳 4.7 to 33.7 6.1 7 8.6㛳 3.4 to 17.6 9.0 5 6.5ⴱ 2.1 to 15.2 10.8
All solid cancers except nmsc 24 1.6‡ 1.0 to 2.4 12.0 45 1.1 0.8 to 1.5 8.2 34 0.9 0.6 to 1.3§ ⫺7.2
All malignancies except nmsc 30 1.9㛳 1.3 to 2.8 18.9 53 1.3 1.0 to 1.7 16.2 40 1.1 0.8 to 1.5§ 7.1
and NHL

Abbreviations: SIR, standardized incidence ratio; AER, Absolute excess risk per 10,000 person-years; nmsc, non-melanoma skin cancer; NHL, non-Hodgkin’s lymphoma.
ⴱ
P ⬍ .01.
†Ptrend ⬍ .01.
‡P ⬍ .05.
§Ptrend ⬍ .05.
㛳P ⬍ .001.

the first 10 years of follow-up, but then diminished, and no cases of
leukemia were diagnosed beyond 15 years. The relative risk of lung
cancer was raised significantly only during the period 5 to 9 years
following first treatment.
Relative risk of second malignancies overall was raised for each
treatment modality (Table 5), but not significantly. Significantly in-
creased risk of leukemia was confined to patients who had received
chemotherapy, with or without radiotherapy. No cases of leukemia
were observed in patients treated with radiotherapy only. The relative
risk of leukemia in the patients who were treated with CHOP was 14.2
(95% CI, 6.8 to 26.2) and in the RR for those treated with chlorambucil
was 19.2 (95% CI, 9.6 to 34.3; data not shown).
The relative risk of mouth and pharynx cancers was significantly
increased in patients treated with mixed modalities and not signifi-
cantly after radiotherapy alone. Risk of colorectal cancer was increased
significantly only in the chemotherapy-treated group (RR ⫽ 2.1; 95%
CI, 1.1 to 3.6), particularly in those patients who were treated with
CHOP (RR ⫽ 2.4; 95% CI, 1.1 to 4.3), but not those treated with
chlorambucil (RR ⫽ 1.4; 95% CI, 0.5 to 3.2).
Risk of female breast cancer was significantly reduced (P ⬍ .01)
in the chemotherapy-only group. Risk of lung cancer was significantly
increased (P ⬍ .05) in patients treated with only radiotherapy (nine
cases, seven of whom received radiotherapy above and two below the
diaphragm). The risk was also increased in those patients treated with
only chemotherapy, but based on small numbers it was not increased
in those with mixed-modality treatment (three cases, for whom site of
radiotherapy is not known). The relative risk of lung cancer was
significantly raised in the CHOP subcohort (RR ⫽ 2.1; 95% CI, 1.1 to
3.7), but not in those patients treated with chlorambucil (RR ⫽ 1.1;
95% CI, 0.4 to 2.4). The risk of bladder and urethra cancers was

Table 4. Relative Risks of Second Primary Malignancy of Selected Sites, by Time Since First Treatment
Time Since First Treatment (years)
⬍5 5-9 10-14 ⱖ 15
No. of No. of No. of No. of
Cancer Site Cases SIR 95% CI Cases SIR 95% CI Cases SIR 95% CI Cases SIR 95% CI
ⴱ
Mouth and pharynx 1 1.4 0.03 to 7.7 2 3.3 0.4 to 11.8 0 0.0 0.0 to 9.9 2 8.6 1.0 to 31.2
Colon and rectum 6 1.6 0.6 to 3.6 3 0.8 0.2 to 2.5 4 1.5 0.4 to 3.9 4 1.9 0.5 to 5.0
Lung 9 1.6 0.7 to 3.0 11 2.1ⴱ 1.1 to 3.8 6 1.6 0.6 to 3.5 2 0.7 0.1 to 2.7
Breast (female) 2 0.3 0.04 to 1.2 3 0.6 0.1 to 1.8 4 1.3 0.4 to 3.3 2 1.0 0.1 to 3.7
Bladder and urethra 1 0.6 0.02 to 3.5 2 1.3 0.2 to 4.9 3 2.8 0.6 to 8.1 2 2.4 0.3 to 8.7
Leukemia† 9 14.0‡ 6.4 to 26.6 6 10.4‡ 3.8 to 22.7 2 5.0 0.6 to 17.9 0 0.0 0.0 to 11.9§
All solid cancers except nmsc㛳 27 0.9 0.6 to 1.3 34 1.2 0.9 to 1.7 27 1.4 0.9 to 2.1 15 1.1 0.6 to 1.8
All malignancies except nmsc 38 1.2 0.9 to 1.6 41 1.4ⴱ 1.0 to 2.0 29 1.5 1.0 to 2.1 15 1.0 0.6 to 1.7
and NHL¶

Abbreviations: SIR, standardized incidence ratio; nmsc, non-melanoma skin cancer; NHL, non-Hodgkin’s lymphoma; AER, absolute excess risks per 10,000
person-years.
ⴱ
P ⬍ .05.
†AERs: 9.6 for ⬍ 5 years, 9.7 for 5-9 years, 5.9 for 10-14 years, and ⫺2.2 for ⱖ 15 years.
‡P ⬍ .001.
§Ptrend ⫽ .01.
㛳AERs: ⫺3.9 for ⬍ 5 years, 12.0 for 5-9 years, 6.3 for 10-14 years, and 6.3 for ⱖ 15 years.
¶AERs: 7.3 for ⬍ 5 years, 22.6 for 5-9 years, 33.6 for 10-14 years, and 2.4 for ⱖ 15 years.

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 Mudie et al

Table 5. Relative Risks of Second Primary Malignancy of Selected Sites, by Treatment Modality
Chemotherapy Mixed Modalities Radiotherapy
No. of No. of No. of
Cancer Site Cases SIR 95% CI Cases SIR 95% CI Cases SIR 95% CI
ⴱ
Mouth and pharynx 0 0.0 0.0 to 3.8 3 5.7 1.2 to 16.6 2 4.6 0.6 to 16.5
Colon and rectum 12 2.1ⴱ 1.1 to 3.6 5 1.5 0.5 to 3.5 0 0.0 0.0 to 1.3
Lung 16 1.9ⴱ 1.1 to 3.1 3 0.6 0.1 to 1.7 9 2.3ⴱ 1.1 to 4.5
Breast (female) 1 0.12† 0.003 to 0.7 7 1.7 0.7 to 3.6 3 0.8 0.2 to 2.4
Bladder and urethra 3 1.2 0.3 to 3.6 0 0.0 0.0 to 2.6 5 4.5ⴱ 1.5 to 10.4
Leukemia 10 10.5‡ 5.0 to 19.3 7 13.0‡ 5.2 to 26.7 0 0.0 0.0 to 8.3
All solid cancers except nmsc 46 1.0 0.7 to 1.4 30 1.2 0.8 to 1.7 27 1.3 0.9 to 1.9
All malignancies except nmsc 58 1.3 0.9 to 1.6 37 1.4 1.0 to 2.0 28 1.3 0.9 to 2.0
and NHL

Abbreviations: SIR, standardized incidence ratio; nmsc, non-melanoma skin cancer; NHL, non-Hodgkin’s lymphoma.
ⴱ
P ⬍ .05.
†P ⬍ .01.
‡P ⬍ .001.

significantly raised only after radiation treatment (five cases, of
whom two received radiotherapy below and two above the dia-
phragm, and for one patient the site of radiotherapy was un-
known). All three cases of bladder and urethra cancer among the
chemotherapy-treated patients occurred within the CHOP subco-
hort (RR ⫽ 1.7; 95% CI, 0.3 to 4.9).
Overall, the risk of all malignancy was significantly raised in the
CHOP subcohort (RR ⫽ 1.6; 95% CI, 1.2 to 2.1), mainly due to the
raised risks of leukemia, lung, and colorectal cancers. The risk of
second malignancy overall in the chlorambucil subcohort was border-
line significantly raised (RR ⫽ 1.4; 95% CI, 1.0 to 1.9), primarily due to
the high risk of leukemia in this group.
The 15-year cumulative risk of second malignancy in the total
cohort was 11.2% (95% CI, 9.1 to 13.7). Cumulative risks were
greater for males (13.6%; 95% CI, 10.5 to 17.5) than females (8.3%;
95% CI, 5.8 to 11.3), and were much greater in patients who were first
treated at 50 years of age and older (17.5%; 95% CI, 13.6 to 22.3) than
for those who were treated at a younger age (7%; 95% CI, 5.0 to 9.9).
The main contributors to the overall 15-year risk were lung cancer
(2.8%), leukemia (1.5%), colorectal cancer (1.5%), and breast cancer
(1.2%; data not shown).
DISCUSSION
This cohort of British NHL patients had a 30% higher rate of second
malignancy than in the general population of England and Wales,
primarily due to elevated risks of leukemia and lung cancer. The
results may have been biased slightly upwards, because cancer regis-
tration in England and Wales is only approximately 90% complete,1
however, the results are comparable to the raised risks of 18% to 37%
in other large cohort studies.5-9 Also similar to previous reports among
NHL patients,5-7 the raised relative risk was greater in male than
female patients. Only a few studies have examined age at first treat-
ment in relation to risk of second malignancy following NHL, and the
evidence has been conflicting. An American study of childhood
NHL,23 based on 497 cases, reported a much higher relative risk of
malignancy overall (RR ⫽ 10.8; 95% CI, 6.1 to 16.9) than in adult
cohorts, whereas a smaller Italian study29 of children with NHL re-
ported no raised risk. An international cohort study7 found no differ-
ence in relative risk of malignancy overall between NHL patients aged
younger and older than 40 years at diagnosis, whereas a Swedish
study9 found greater relative risks at younger ages. Similar to the
Swedish study, we found that risk decreased significantly with increas-
ing age at first treatment.
Long-term risk of second malignancy after NHL has been exam-
ined previously by Travis et al,7 who found raised risks beyond 15 years
of follow-up. In this study, with a similar mean length of follow-up,
RRs of second malignancy were raised for the first 15 years, with no
evident raised risk thereafter. The 15-year cumulative risk of all second
malignancies in our study was a little lower than the one found in the
study by Travis et al7 (11% v 15%), probably reflecting the younger
mean age of our cohort (46.6 v 56.1 years).
Raised relative risks (two- to eight-fold) of leukemia among NHL
patients have been demonstrated previously in adult cohort
studies.6,7,9,11-13 The relative risk was even greater (200-fold) in chil-
dren.23 High relative risks have been linked to alkylating chemother-
apy, including chlorambucil and cyclophosphamide specifically,17
which were associated with raised risk in our data, and have been
shown to be leukemogenic when used to treat Hodgkin’s disease and
other malignancies.30-32 Involved-field radiation treatment did not
materially increase the risk of leukemia in previous studies of patients
treated for NHL12,17 and Hodgkin’s disease,4,32other than the risk
conferred by alkylating chemotherapy, but low-dose total-body irra-
diation did.15-18,33,34 In our study, radiotherapy-treated patients pre-
dominantly received involved-field treatments, and no cases of
leukemia occurred in the group treatedwith radiation only. The rela-
tive risks of leukemia were similarly raised in the chemotherapy- and
mixed-modality–treated groups. The high relative risk of leukemia
seen after CHOP and chlorambucil chemotherapies is of a similar
order of magnitude to the risks observed following treatment with
alkylating regimens such as MOPP (mechlorethamine, vincristine,
procarbazine, prednisone) in Hodgkin’s disease patients.4
As in previous reports,15-17 we found that patients who presented
with advanced stages of NHL were more likely to develop leukemia.
This reflects their treatment; it has been found that NHL stage was
not associated with leukemia after the risks were adjusted for the effect
of alkylating agents.17 The relative risk of leukemia in our study dimin-
ished with patient age at first treatment, as has been observed after

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Second Cancer After Non-Hodgkin’s Lymphoma

chemotherapy for Hodgkin’s disease.24 As is usual in chemotherapy-
induced leukemia,34 including leukemia after NHL,7 the risk of leuke-
mia was raised significantly during the 10 years after first treatment,
and then diminished.
In a large case-control study of bladder cancer after NHL,
Travis et al21 demonstrated that risk of this cancer is strongly
associated with cumulative dose of cyclophosphamide, with the
lowest doses (up to 20g) having a nonsignificant two-fold in-
creased risk. In this cohort, we found a not significantly increased
risk of bladder cancer in patients treated with CHOP, who were
generally administered between 6 to 9 cycles of treatment with no
long-term maintenance, which would give a cumulative cyclophosph-
amide dose of about 20g or less. We observed a significantly raised risk
of bladder cancer in the radiotherapy-only treated group, in accor-
dance with the elevated bladder cancer risks shown in radiotherapy-
treated NHL patients6 and other radiation-exposed cohorts.35,36
Several studies have shown lung cancer as the most common
second malignancy among NHL patients, with risks raised by 36% to
90%.5-7 We found a 60% raised risk of this cancer, and a significantly
raised risk after radiotherapy. Although previous studies6,12 of NHL
patients have not found a significantly increased risk of lung cancer
following radiation treatment, it is well established that exposure to
ionizing radiation can increase the risk of lung cancer.36 We do not
have comprehensive data on field of radiotherapy for the overall
cohort, and an additional limitation of our study is that data on
smoking was also unavailable.
Raised risks of lung cancer after chemotherapy for NHL have
been demonstrated in one US cohort,6 but not in another.12 A recent
French study14 found a significantly raised risk of this malignancy in
men following the CHOP-like regimen ACVBP (doxorubicin, cyclo-
phosphamide, vindesine, bleomycin, prednisone). Raised risks of lung
cancer have also been seen after alkylating chemotherapy for
Hodgkin’s disease.37,38 Risk of lung cancer in our cohort was signifi-
cantly elevated after CHOP but was not evident in chlorambucil-
treated patients. This warrants more detailed investigation, which we
plan to do with a nested case-control approach.
Modest nonsignificant increases in the risk of colorectal cancer
after NHL have been observed in some previous studies,6-8 but not all.9
In our study, the raised risk was only statistically significant when
following chemotherapy, specifically CHOP. To our knowledge, the
risk of colorectal cancer following chemotherapy in NHL has not been
reported before. A multicenter study of second malignancy after
Hodgkin’s disease showed a large significant risk of digestive and
peritoneal cancers following treatment with doxorubicin (RR ⫽ 23),
which is part of the CHOP regimen, but did not report the specific
cancer sites associated with this treatment.39 Two components of
CHOP, namely cyclophosphamide and doxorubicin, have been
shown to cause solid tumors in rodent models.40 The risk of colorectal
cancer in relation to chemotherapy for NHL, specifically CHOP,
needs further investigation.
Several NHL cohort studies have noted a reduction in breast
cancer risk,6-9,14 though only two studies found the diminution to
be statistically significant.6,9 Where examined, no significant rela-
tion was found to any specific type of treatment.6,12,14 We found a
significant diminution of risk for women treated with chemother-
apy. A significantly reduced risk of breast cancer has been shown
repeatedly in Hodgkin’s disease patients treated with alkylating
chemotherapy; the effect was greater with an increasing number of
cycles, and related to premature menopause as a consequence of
treatment.34 Drugs used to treat NHL are capable of causing pre-
mature menopause. Ovarian failure following treatment with cy-
clophosphamide is well documented, with most studies showing a
linear correlation between cumulative dose of cyclophosphamide
and reduction in age at menopause.41 It may therefore be the case
that for NHL, as for Hodgkin’s disease, chemotherapy can cause
reduced breast cancer risk via induction of premature menopause.
Significantly reduced risk of endometrial malignancy (RR ⫽ 0.51)
was found in a recent Swedish study of NHL patients,9 and we also
noted a deficit, which might perhaps relate to treatment-induced
premature menopause.
In conclusion, long-term follow-up of this cohort of British
NHL patients treated under the age of 60 years revealed an in-
creased risk of second malignancy, with a 15-year cumulative prob-
ability of 11.2%. After chemotherapy there was an elevated risk of
leukemia, as would be expected, but also of lung and colorectal
cancers and there was a diminution of the risk of breast cancer.
These potential effects of treatment need to be taken into account
during clinical follow-up.

REFERENCES
1. Swerdlow AJ, dos Santos Silva I, Doll R:
Cancer incidence and mortality in England and
Wales: Trends and risk factors. Oxford, United King-
dom, Oxford University Press, 2001
2. Swerdlow AJ: Epidemiology of Hodgkin’s dis-
ease and non-Hodgkin’s lymphoma. Eur J Nucl Med
Mol Imaging 30:S3-S12, 2003 (suppl 1)
3. National Cancer Institute: SEER Cancer Sta-
tistics Review, 1975-2001. http://seer.cancer.gov/
csr/1975_2001/
4. Swerdlow AJ, Van Leeuwen FE: Late effects
after treatment for Hodgkin lymphoma, in Dembo
AJ, Linch DC, Lowenberg B (eds): Textbook of
Malignant Hematology. Abingdon, United Kingdom,
Taylor & Francis, 2005, pp 753-768
5. Greene MH, Wilson J: Second cancer fol-
lowing lymphatic and hematopoietic cancers in
Connecticut, 1935-82. Natl Cancer Inst Monogr
68:191-217, 1985
6. Travis LB, Curtis RE, Boice JD Jr, et al:
Second cancers following non-Hodgkin’s lym-
phoma. Cancer 67:2002-2009, 1991
7. Travis LB, Curtis RE, Glimelius B, et al: Sec-
ond cancers among long-term survivors of non-
Hodgkin’s lymphoma. J Natl Cancer Inst 85:1932-
1937, 1993
8. Brennan P, Coates M, Armstrong B, et al:
Second primary neoplasms following non-Hodgkin’s
lymphoma in New South Wales, Australia. Br J
Cancer 82:1344-1347, 2000
9. Dong C, Hemminki K: Second primary neo-
plasms among 53 159 haematolymphoprolifera-
tive malignancy patients in Sweden, 1958-1996: A
search for common mechanisms. Br J Cancer
85:997-1005, 2001
10. MacDougall BK, Weinerman BH, Kemel S:
Second malignancies in non-Hodgkin’s lymphoma.
Cancer 48:1299-1301, 1981
11. Storm HH, Prener A: Second cancer following
lymphatic and hematopoietic cancers in Denmark,
1943-80. Natl Cancer Inst Monogr 68:389-409, 1985
12. Lavey RS, Eby NL, Prosnitz LR: Impact on
second malignancy risk of the combined use of
radiation and chemotherapy for lymphomas. Cancer
66:80-88, 1990
13. Lishner M, Slingerland J, Barr J, et al: Second
malignant neoplasms in patients with non-Hodgkin’s
lymphoma. Hematol Oncol 9:169-179, 1991
14. Andre M, Mounier N, Leleu X, et al: Second
cancers and late toxicities after treatment of aggres-
sive non-Hodgkin lymphoma with the ACVBP regi-
men: A GELA cohort study on 2837 patients. Blood
103:1222-1228, 2004
15. Greene MH, Young RC, Merrill JM, et al:
Evidence of a treatment dose response in acute
nonlymphocytic leukemias which occur after ther-
apy of non-Hodgkin’s lymphoma. Cancer Res 43:
1891-1898, 1983
16. Pedersen-Bjergaard J, Ersboll J, Sorensen
HM, et al: Risk of acute nonlymphocytic leukemia
and preleukemia in patients treated with cyclophos-
phamide for non-Hodgkin’s lymphomas: Compari-
son with results obtained in patients treated for

www.jco.org 1573

Downloaded from ascopubs.org by 106.199.123.120 on May 22, 2019 from 106.199.123.120

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Mudie et al

Hodgkin’s disease and ovarian carcinoma with other
alkylating agents. Ann Intern Med 103:195-200,
1985
17. Travis LB, Curtis RE, Stovall M, et al: Risk of
leukemia following treatment for non-Hodgkin’s
lymphoma. J Natl Cancer Inst 86:1450-1457, 1994
18. Travis LB, Weeks J, Curtis RE, et al: Leukemia
following low-dose total body irradiation and chemo-
therapy for non-Hodgkin’s lymphoma. J Clin Oncol
14:565-571, 1996
19. Hosing C, Munsell M, Yazji S, et al: Risk of
therapy-related myelodysplastic syndrome/acute leuke-
mia following high-dose therapy and autologous bone
marrow transplantation for non-Hodgkin’s lymphoma.
Ann Oncol 13:450-459, 2002
20. Pedersen-Bjergaard J, Ersboll J, Hansen VL,
et al: Carcinoma of the urinary bladder after treat-
ment with cyclophosphamide for non-Hodgkin’s
lymphoma. N Engl J Med 318:1028-1032, 1988
21. Travis LB, Curtis RE, Glimelius B, et al: Blad-
der and kidney cancer following cyclophosphamide
therapy for non-Hodgkin’s lymphoma. J Natl Cancer
Inst 87:524-530, 1995
22. Travis LB, Gonzalez CL, Hankey BF, et al:
Hodgkin’s disease following non-Hodgkin’s lym-
phoma. Cancer 69:2337-2342, 1992
23. Leung W, Sandlund JT, Hudson MM, et al: Sec-
ond malignancy after treatment of childhood non-
Hodgkin lymphoma. Cancer 92:1959-1966, 2001
24. Swerdlow AJ, Barber JA, Hudson GV, et al:
Risk of second malignancy after Hodgkin’s disease
in a collaborative British cohort: The relation to age
at treatment. J Clin Oncol 18:498-509, 2000
25. World Health Organisation.Manual of the In-
ternational Statistical Classification of Diseases, In-
juries, and Causes of Death (ed 9). Geneva,
Switzerland, World Health Organisation, 1978
26. Clayton D, Hills M: Statistical Models in Epi-
demiology. Oxford, Oxford University Press, 1993
27. Kaplan E, Meier P: Non-parametric estimation
from incomplete observations. J Am Stat Assoc
53:457-481, 1958
28. Breslow N, Day N: Statistical methods in
cancer research. Lyon, France, International Agency
for Research on Cancer, 1987
29. Pillon M, Di Tullio MT, Garaventa A, et al:
Long-term results of the first Italian Association of
Pediatric Hematology and Oncology protocol for the
treatment of pediatric B-cell non-Hodgkin lymphoma
(AIEOP LNH92). Cancer 101:385-394, 2004
30. Haas JF, Kittelmann B, Mehnert WH, et al: Risk of
leukaemia in ovarian tumour and breast cancer patients
following treatment by cyclophosphamide. Br J Cancer
55:213-218, 1987
31. Kaldor JM, Day NE, Pettersson F, et al: Leu-
kemia following chemotherapy for ovarian cancer.
N Engl J Med 322:1-6, 1990
32. Kaldor JM, Day NE, Clarke EA, et al: Leukemia
following Hodgkin’s disease. N Engl J Med 322:7-
13, 1990
33. Gomez GA, Aggarwal KK, Han T: Post-therapeutic
acute malignant myeloproliferative syndrome and acute
nonlymphocytic leukemia in non-Hodgkin’s lymphoma.
Cancer 50:2285-2288, 1982
34. Van Leeuwen FE, Travis LB: Second cancers,
in DeVita VT, Hellman S, Rosenberg SA (eds): Can-
cer: Principles and Practice of Oncology. Philadel-
phia, PA, Lippincott Williams & Wilkins, 2005, pp
2575-2602
35. Boice JD Jr, Land CE, Preston DL: Ionizing
radiation, in Schottenfeld D, Fraumeni JF Jr (eds):
Cancer Epidemiology and Prevention. New York,
NY, Oxford University Press, 1996, pp 319-354
36. UNSCEAR: Sources and effects of ionizing
radiation. UNSCEAR 2000 Report to the General
Assembly, with scientific annexes. New York, NY,
United Nations, 2000
37. Swerdlow AJ, Schoemaker MJ, Allerton R, et
al: Lung cancer after Hodgkin’s disease: A nested
case-control study of the relation to treatment. J Clin
Oncol 19:1610-1618, 2001
38. Travis LB, Gospodarowicz M, Curtis RE, et al:
Lung cancer following chemotherapy and radiother-
apy for Hodgkin’s disease. J Natl Cancer Inst 94:
182-192, 2002
39. Boivin JF, Hutchison GB, Zauber AG, et al:
Incidence of second cancers in patients treated for
Hodgkin’s disease. J Natl Cancer Inst 87:732-741,
1995
40. IARC working group on the evaluation of
carcinogenic risks to humans: Overall evaluation of
carcinogenicity: An updating of IARC Monographs
volumes 1-42. Lyon, France, IARC, 1987
41. Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI:
Gonadal disfunction, in DeVita VT, Hellman S, Rosenberg
SA (eds): Cancer: Principles and Practice of Oncolgy.
Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp
2560-2574

■ ■ ■

Acknowledgment
We thank the collaborators at the British National Lymphoma Investigation (BNLI) whose patients are included in this cohort.

Authors’ Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs
or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Anthony J. Swerdlow GlaxoSmithKline (A)
Dollar Amount Codes (A) ⬍ $10,000 (B) $10,000-99,999 (C) ⱖ $100,000 (N/R) Not Required

Author Contributions

Conception and design: Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins

Administrative support: Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins, Zongkai Qiao
Provision of study materials or patients: Barry W. Hancock, Peter J. Hoskin, David C. Linch
Collection and assembly of data: Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins, Paul Smith, Zongkai Qiao, David C. Linch
Data analysis and interpretation: Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins
Manuscript writing: Nadejda Y. Mudie, Anthony J. Swerdlow, David C. Linch
Final approval of manuscript: Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins, Paul Smith, Zongkai Qiao, Barry W. Hancock, Peter J. Hoskin,
David C. Linch
Other: Anthony J. Swerdlow [Grant application], David C. Linch [Grant application]

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
JOURNAL OF CLINICAL ONCOLOGY
Official Journal of the American Society of Clinical Oncology

Vol 24, No 10 C O N T E N T S April 1, 2006

Editorials
Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time
for Oncologists to Get to Know Their Cardiologists?
Willem J. van Heeckeren, Shyam Bhakta, Jose Ortiz, Jeff Duerk, Matthew M. Cooney, Afshin Dowlati,
Keith McCrae, and Scot C. Remick (see article on page 1491) ................................................................................................................... 1485

Developing a New Framework for Dose Calculation

Howard Gurney (see article on page 1499) ............................................................................................................................................................... 1489

Original Reports
PHASE I AND CLINICAL PHARMACOLOGY
Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting
Agent, ZD6126, in Patients With Solid Tumors
Laurens V. Beerepoot, Sandra A. Radema, Els O. Witteveen, Tawnie Thomas, Catherine Wheeler,
Sanford Kempin, and Emile E. Voest (see editorial on page 1485) ......................................................................................................... 1491

Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body
Surface Area Values
Walter J. Loos, Felix E. de Jongh, Alex Sparreboom, Ronald de Wit, Desiree M. van Boven-van Zomeren,
Gerrit Stoter, Kees Nooter, and Jaap Verweij (see editorial on page 1489) ..................................................................................... 1499

PEDIATRIC ONCOLOGY
High WT1 Expression After Induction Therapy Predicts High Risk of Relapse and Death
in Pediatric Acute Myeloid Leukemia
Hélène Lapillonne, Aline Renneville, Anne Auvrignon, Cyril Flamant, Annick Blaise, Christine Perot,
Jean-Luc Lai, Paola Ballerini, Françoise Mazingue, Sylvie Fasola, Axelle Dehée, Françoise Bellman,
Mircéa Adam, Myriam Labopin, Luc Douay, Guy Leverger, Claude Preudhomme,
and Judith Landman-Parker .................................................................................................................................................................................................. 1507

White Race As a Risk Factor for Hypothyroidism After Treatment for Pediatric
Hodgkin’s Lymphoma
Monika L. Metzger, Melissa M. Hudson, Grant W. Somes, Ron I. Shorr, Chin-Shang Li, Matthew J. Krasin,
John Shelso, Ching-Hon Pui, and Scott C. Howard ............................................................................................................................................ 1516

(continued on following page)

Journal of Clinical Oncology (ISSN 0732-183X) is published 36 times a year, three times monthly, by American Society of Clinical Oncology, 1900 Duke St, Suite 200, Alexandria,
VA 22314. Periodicals postage is paid at Alexandria, VA, and at additional mailing offices. Publication Mail Agreement Number 863289.
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Human Telomere Reverse Transcriptase Expression Predicts Progression and Survival in
Pediatric Intracranial Ependymoma
Uri Tabori, Jing Ma, Michael Carter, Maria Zielenska, James Rutka, Eric Bouffet, Ute Bartels, David Malkin,
and Cynthia Hawkins .................................................................................................................................................................................................................. 1522

Translocation Carcinomas of the Kidney After Chemotherapy in Childhood

Pedram Argani, Marick Laé, Edgar T. Ballard, Mahul Amin, Carlos Manivel, Brian Hutchinson,
Victor E. Reuter, and Marc Ladanyi ................................................................................................................................................................................. 1529

Skip Metastases in Osteosarcoma: Experience of the Cooperative Osteosarcoma

Study Group
Leo Kager, Andreas Zoubek, Ulrike Kastner, Beate Kempf-Bielack, Jenny Potratz, Rainer Kotz,
G. Ulrich Exner, Christiane Franzius, Susanna Lang, Rainer Maas, Heribert Jürgens, Helmut Gadner,
and Stefan Bielack ......................................................................................................................................................................................................................... 1535

Treatment Complications in Children Diagnosed With Neuroblastoma During a

Screening Program
Stéphane Barrette, Mark L. Bernstein, Jean-Marie Leclerc, Martin A. Champagne, Yvan Samson,
Josée Brossard, and William G. Woods ...................................................................................................................................................................... 1542

Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large

Prospective Study of Primary Neuroblastoma
Michelle Haber, Janice Smith, Sharon B. Bordow, Claudia Flemming, Susan L. Cohn, Wendy B. London,
Glenn M. Marshall, and Murray D. Norris .................................................................................................................................................................. 1546

Role of Radiotherapy in Supratentorial Primitive Neuroectodermal Tumor in Young

Children: Results of the German HIT-SKK87 and HIT-SKK92 Trials
Beate Timmermann, Rolf-Dieter Kortmann, Joachim Kühl, Stefan Rutkowski, Christof Meisner,
Torsten Pietsch, Frank Deinlein, Christian Urban, Monika Warmuth-Metz, and Michael Bamberg ............................. 1554

THORACIC ONCOLOGY
Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary
Hyperthermic Cisplatin Lavage for Mesothelioma
William G. Richards, Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, Pasi A. Jänne,
Lucian R. Chirieac, Beow Y. Yeap, Rene J. Dekkers, Phillip M. Hartigan, Leah Capalbo,
and David J. Sugarbaker .......................................................................................................................................................................................................... 1561

EPIDEMIOLOGY
Risk of Second Malignancy After Non-Hodgkin’s Lymphoma: A British Cohort Study
Nadejda Y. Mudie, Anthony J. Swerdlow, Craig D. Higgins, Paul Smith, Zongkai Qiao, Barry W. Hancock,
Peter J. Hoskin, and David C. Linch ................................................................................................................................................................................ 1568

HEMATOLOGIC MALIGNANCIES
Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen
for Patients With Previously Treated Chronic Lymphocytic Leukemia
Nicole Lamanna, Matt Kalaycio, Peter Maslak, Joseph G. Jurcic, Mark Heaney, Renier Brentjens,
Andrew D. Zelenetz, Denise Horgan, Alison Gencarelli, Katherine S. Panageas, David A. Scheinberg,
and Mark A. Weiss ........................................................................................................................................................................................................................ 1575

Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25

Years of Treatment Experience at The University of Texas M.D. Anderson Cancer Center
Qi Liu, Luis Fayad, Fernando Cabanillas, Fredrick B. Hagemeister, Gregory D. Ayers, Mark Hess,
Jorge Romaguera, M. Alma Rodriguez, Apostolia M. Tsimberidou, Srdan Verstovsek, Anas Younes,
Barbara Pro, Ming-Sheng Lee, Ana Ayala, and Peter McLaughlin ......................................................................................................... 1582

(continued on following page)

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Phase III Intergroup Study of Fludarabine Phosphate Compared With
Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed
Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin’s Lymphoma
Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin,
Christiane de Wolf-Peeters, Ken MacLennan, Elvira Staab-Renner, Joachim Kalmus, Astrid Schott,
Ivana Teodorovic, Anastassia Negrouk, Martine van Glabbeke, and Robert Marcus .............................................................. 1590

Prospective Study of Survival Outcomes in Non-Hodgkin’s Lymphoma Patients With

Rheumatoid Arthritis
Ted R. Mikuls, Justin O. Endo, Susan E. Puumala, Patricia A. Aoun, Natalie A. Black, James R. O’Dell,
Julie A. Stoner, Eugene C. Boilesen, Martin A. Bast, Debra A. Bergman, Kay M. Ristow, Melissa Ooi,
James O. Armitage, and Thomas M. Habermann ............................................................................................................................................... 1597

GASTROINTESTINAL CANCER
Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal
Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment
Emma Dotor, Miriam Cuatrecases, María Martínez-Iniesta, Matilde Navarro, Felip Vilardell, Elisabeth Guinó,
Laura Pareja, Agnés Figueras, David G. Molleví, Teresa Serrano, Javier de Oca, Miguel A. Peinado,
Víctor Moreno, Josep Ramón Germà, Gabriel Capellá, and Alberto Villanueva ......................................................................... 1603

Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment

of Advanced Esophageal Cancer Patients
Maarten L. Janmaat, Mariëlle I. Gallegos-Ruiz, José A. Rodriguez, Gerrit A. Meijer, Walter L. Vervenne,
Dick J. Richel, Cees Van Groeningen, and Giuseppe Giaccone ................................................................................................................ 1612

SUPPORTIVE CARE AND QUALITY OF LIFE

Randomized Trial of Peer Counseling on Reproductive Health in African American Breast
Cancer Survivors
Leslie R. Schover, Rosell Jenkins, Dawen Sui, Jennifer Harned Adams, Michelle S. Marion,
and Karen Eubanks Jackson ................................................................................................................................................................................................. 1620

NEUROONCOLOGY
Survival Prediction in Patients With Glioblastoma Multiforme by Human Telomerase
Genetic Variation
Luo Wang, Qingyi Wei, Li-E Wang, Kenneth D. Aldape, Yumei Cao, M. Fatih Okcu, Kenneth R. Hess,
Randa El-Zein, Mark R. Gilbert, Shiao Y. Woo, Sujit S. Prabhu, Greg N. Fuller, and Melissa L. Bondy .................... 1627

Review Article
Peripheral Neuropathy Induced by Microtubule-Stabilizing Agents
James J. Lee and Sandra M. Swain ................................................................................................................................................................................ 1633

Art of Oncology
Deliberate Deceit of Family Members: A Challenge to Providers of Clinical
Genetics Services
Jennifer T. Loud, Nancy E. Weissman, June A. Peters, Ruthann M. Giusti, Benjamin S. Wilfond,
Wylie Burke, and Mark H. Greene .................................................................................................................................................................................... 1643

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Correspondence
Chronic Eosinophilic Leukemia/Hypereosinophilic Syndrome and Acute Leukemia
Neil Abramson ................................................................................................................................................................................................................................. 1647

Errata .................................................................................................................................................................................................................................................... 1648

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