Second malignancies following cancer therapy

Second Malignancies

Following

Cancer Therapy

Mary C. Fraser and Margaret A. Tucker

T

HE MOST SERIOUS long-term consequence of cancer treatment is the development of a second malignancy. Several recent studies have quantified the risk of leukemias and solid tumors after treatment for childhood malignancies, Hodgkin’s disease, multiple myeloma, nonHodgkin’s lymphomas, gastrointestinal (GI) cancers, lung cancer, and gynecologic cancers.l-7 Acute nonlymphocytic leukemia following treatment with alkylating agents and solid tumors following radiotherapy comprise most of the secondary cancers.Treatment-relatedmalignanciesare of great concern because frequently they are fatal. However, these malignancies account for only a small portion of mortality in long-term survivors. Studying second malignancies after an initial cancer is somewhatcomplicated. Somewill occur by chance alone; others may occur because the first and secondcancerssharecommon etiologies. For example, it is not unexpectedthat patientswith bladder cancer also have an increasedrisk of lung cancer becauseboth are related to smoking. Some second tumors occur becauseof a genetic predisposition to develop secondcancers, such as sarcomasfollowing retinoblastoma,or breastcancerfollowing a sarcoma in families affected with the Li-Fraumeni syndrome.8,9 Finally, some second cancersmay be related to the treatmentof the first cancer. This article will focus on these treatmentinduced cancers and the related clinical implications . RATIONALE FOR STUDIES OF TREATMENTRELATED MALIGNANCIES

During the past severaldecades,the exposureof large numbers of patients to chemotherapyand/or radiotherapy that has carcinogenic potential has created a unique opportunity to (1) evaluate and quantify the risk of various malignanciesfollowing exposure to specific drugs and/or therapeutic regimens, (2) identify treatmentregimensthat are and those that are not associatedwith an increasedrisk of a treatment-related neoplasm, and (3) further elucidate mechanismsof radiation and drug carcinogenesis in humans.1,2*7The relationship between cancer therapies and second malignancies can only be explored systematically and scientifi&miners in Oncology Nursing, Vol 5, No 1 (February), 1989: pp 43-55

tally through epidemiologic studies. The major criteria of these analytic studies are listed in Table 1. EXPERIMENTAL EVIDENCE OF TREATMENTRELATED NEOPLASMS

By affecting DNA synthesisor function, antitumor agents kill and injure cells that are actively dividing, such as neoplastic cells. lo Unfortunately, the toxicity of these compounds also extends to actively dividing cells in normal tissues, such as bone marrow or the lining of the GI tract. The class of drugs most commonly implicated in long-term damageto normal cells is the alkylating agents, of which several are potent animal carcinogens.‘-7*1’ Alkylating agents bind directly to DNA, causing nicks, breaks, and rearrangementsin both neoplastic and normal cells. The process of alkylation is known to have significant cytotoxic, mutagenic, and carcinogenic effects.” Lethal damage is the desired effect in neoplastic cells. If the nonlethal damageto DNA in the normal cells can be accurately repaired, the cells will return to normal. If the cellular damagecannot be repaired, then malignant transformation and/or mutation may occur. Since 1971, the International Agency for Researchon Cancer (IARC) has sponsoreda program under which various chemicals are formally assessed to determine their carcinogenic risk in humans.l1 This review is a continuous process;the most recent review was published in 1987. As shown in Table 2, group 1 agentsare consideredto be carcinogenic to humans; group 2 agents are probably carcinogenic to humans; and group 3 agentscannot be classified with regard to their carcinogenicity to humans. Almost all of the drugs in groups 1 and 2 are alkylating agents. In contrast, From the Cancer Nursing Service and the Family Studies Section, Environmental Epidemiology Branch. National Cancer Institute, Bethesda, MD. Address reprint requests to Mary C. Fraser, RN, MA, Family Studies Section, Environmental Epidemiology Branch, National Cancer Institute, Executive Plaza North, Room 439, National Institutes of Health, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use. 0749-2081/89/0501-OOOt5$O.OOlO

43

FRASER AND TUCKER

44

Table 1. Characteristics of Aneiytic Epidemiologic of Treatment-Related Maiianancies Metastasis as an explanation ruled out through detailed pathology material.

Studies

for subsequent cancer must be histologic examination of

Chronology of tumors must be considered Latency period of at least 1 year between exposure to a carcinogenic treatment and the development of a second malignancy Cancers that occur within the first year are not included in analyses because there is not sufficient time between exposure to the potential carcinogen and development of the second cancer. Sample must be of sufficient size to permit detection of whatever magnitude of risk might be expected leg, if small risk anticipated, need large sample size). Analysis of subsequent cancers should consider different types of second cancers (leukemia, lung cancer, thyroid cancer, etc) rather than assigning ail second cancers to a single category, since the etiology of different types varies.

none of the antimetabolitesor vinca alkaloids have been classified as carcinogenic on the basis of available data for humans. TREATMENT-RELATED

LEUKEMIC CONDITIONS

The most frequently reported secondcancerfollowing aggressivechemotherapyis acute nonlymphocytic leukemia (ANL). Although there are occasional reports of other forms of leukemia occurring following anticancer therapy, ANL is the only type that has been systematically linked to the administration of cytotoxic chemotherapy,primarily alkylating agents.lM7There is also a much smaller risk associated with radiation therapy treatment.‘2-15The clinical characteristicsof spontaneousand treatment-inducedANL are shown in Table 3.7,‘6-20 EPIDEMIOLOGIC STUDIES OF CHEMOTHERAPY-RELATED LEUKEMIA

Most of the quantitative epidemiologic studies of the relationship between cytotoxic therapy and the development of secondary leukemias have beendesignedto evaluatethe risks following treatment for specific initial cancers. Secondaryleukemias occur excessively in conjunction with cytotoxic therapy after Hodgkin’s disease, multiple myeloma, ovarian cancer, non-Hodgkin’s lymphomas, certain childhood cancers, polycythemia

Vera, breast cancer, GI cancers, lung cancer, and testicular cancer.1-7,21Results of representative studieswith comparablerisk estimatesare summarized below and in Table 4. Acute Leukemia Following Hodgkin’s Disease

Hodgkin’s diseaseis a prototype for the successful managementof a previously incurable malignancy by the use of aggressive multimodal therapy. Dramatic improvement in the overall survival and cure rates has been achieved, regardless of stage.22Arseneauand associateswere the first investigators to report that the use of intensive chemotherapy and extensive radiotherapy could be consideredrisk factors for the developmentof new malignancies, especially ANL.23 Leukemia is the best-describedand most intensively studied secondcancer following Hodgkin’s disease.Most of the large clinical series and randomized trials have reported an increased incidence of leukemia, primarily ANL.4*21,24-41 The risks detailed in Table 4 are representativeof most of the published data. The data from Greene and Wilson24 represent a group of patients who received much less chemotherapy than modern groups of patients, which explains the lower risk. Most of the leukemias occur within the first 10 years. The relative risks in the first five- and 5to-lO-year periods are not significantly different. Studies to date indicate that after 10 years the relative risk of leukemia is clearly lower.26,32 The risk of leukemia by treatment category also has been examined (Table 5). The risk is greatest in the categories that include chemotherapy, but there also appearsto be an increased risk of leukemia following radiation therapy alone. The risk of leukemia is significantly higher in individuals receiving chemotherapy (in any of the subgroups) than in those receiving radiation therapy a10ne.25-27,3’732,36 Although based on small numbers of observedcasesof leukemia in the chemotherapy-alonegroups, most studies have not found significantly different risks of leukemia following combined modality therapy or chemotherapy alone. With respect to specific chemotherapy regimens, MOPP (mustargen, oncovin, procarbazine, and prednisone)is the combination for which most information is available, becauseit has been used for the longest period of time in the largest number

TREATMENT-RELATED

MALIGNANCIES

45

Table 2. Anticancer Drugs Classified According to International Agency for Reeearch on Cancer [IARC) Cercinogenicity Categoriee Group

Definition

Agent

1

2

3

is carcinogenic

Generic

to humans

2A

Agent is probably carcinogenic Higher degree of certainty

2B

Lower degree

of certainty

Agent cannot to humans.

be classified

Name

CIWS

Busulfan Chlornaphazinel Chlorambucil Cyclophosphamide Phenylalanine Mustard MOPPt Treosulphan SemustinelMethyl CCNU

Alkylating Alkylating Alkylating Alkylating Alkylating

agent agent agent agent agent

Alkylating Alkylating

agent agent

CarmustineBCNU Cisplatin Doxorubicin LomustineiCCNU Nitrogen mustard PipobromanS Procarbazine Triethylenethiophosphoramide Dacarbazine Uracil mustard Dactinomycin Methotrexatel 5-FluorouracilS

Alkylating agent Alkylating agent Antitumor antibiotic Alkylating agent Alkylating agent Alkylating agent Alkylating agent Alkylating agent Alkylating agent Alkylating agent Antitumor antibiotic Antimetabolite Antimetabolite

to humans

as to carcinogenicity

No longer used in clinical setting. t MOPP = nitrogen mustard (alkylating agent), vincristine, procarbazine (alkylating agent), prednisone. $ Not currently on IARC list, but should be added.’ § Data currently available suggest compound is not carcinogenic. Adapted from Table 1 in the article by Fraser and Tucker in the Oncology Nursing Forum (Vol 15, No. 1,1988) with permission the Oncology Nursing Press, July 1988; modifications from updated information presented in ref. 11. l

of patients. The data for other regimens are limited 2*25,26,29,31 Acute Leukemia Following Multiple Myeloma

There have been numerous reports of increased risk of ANL following multiple myeloma.2*42In general, the risks reported exceedthe risks associated with treatment for Hodgkin’s disease. The drug most frequently associatedwith the development of ANL in patients with multiple myeloma appears to be melphalan, with or without other alkylating agents.2One concern about the interpretation of studies of acute leukemia following treatment for multiple myeloma is that patients with multiple myeloma may have an underlying predisposition to the development of leukemia that is unrelated to therapy.* Acute Leukemia Following Ovarian Cancer

Studies of treatment-related malignancies in women with ovarian cancerhave beenparticularly

from

informative for three reasons.1,2,43First, unlike somecancers, an intrinsic predisposition to leukemia does not exist. Second, the leukemogenic effects of radiation, alkylating agents, and both modalities combined can be assessedbecauseeach is used in the treatment of this disease. Third, the incidence of ovarian cancer is higher than many other cancersin which aggressivetherapy is used, so that a large number of individuals are available for study. Early studies suggested that the elevated risk of leukemia and preleukemia following ovarian cancer was due to treatment with alkylating agents.44-46Subsequent studies have sought to quantify the risks associatedwith specific chemotherapy agents. In a large study of women treated with single-agent chemotherapy, the relative risk (RR) of leukemia was 11 for cyclophosphamide and 61 for melphalan.47The cumulative risks of leukemic disorders (including preleukemia) at 10 years were 5.4% (standard error, or SE + 3.2%) following cyclophosphamide and 11.2% (SE rt

46

FRASER AND TUCKER

Table 3. Characteristics of Treatment-Related Nonlymphocytic Leukemia IANL) Compared “Spontaneous” ANL Treatment-Related

“Svmtaneous”

ANL

Related to prior exposure to alkylating agents and/or radiotherapy Prolonged pancytopenia/ preleukemia prior to onset Latency period 2-5 yr after exposure, with peak incidence approximately 5 vr Dysplasia of one or more cell lines on marrow biopsy Specific cytogenetic abnormalities of chromosomes 3, 5, 7, 17. Approximately 90% have abnormalities of 5 and/or 7 Refractory

to treatment

Poor survival; almost uniformly fatal within few months

Acute With

a

Peak age varies depending on priman/ tumor; age of onset about 5 years after treatment for first cancer

ANL

Etiology largely unknown; small percentage related to chemical exposure leg, benzene) Approximately 30% present with preleukemia; rest sudden onset Not applicable

May show dysplasia or more cell lines

of one

Specific cytogenetic abnormalities of chromosomes 5, 7, 8, 11, 15, 18, 17, 21, (rarely 3, 4). Less than 5% have abnormalities of 5 and/or 7. Responsive to combination chemotherapy Approximately 50% l-year survival with some longterm survivors following bone marrow transplant Peak age onset in 50s

Duplicated from the article by Fraser and Tucker in the Onco/ogy Nursing Forum (Vol 15, No. 1, 1988) with permission from the Oncology Nursing Press, July 1988.

2.6%) following melphalan. All three leukemic disorders following cyclophosphamideoccurred in the highest dose group, and the risk of ANL following melphalan also was related to dose. In a comparison of incidence rates, the risk of leukemia following melphalan was 3.6 times that following cyclophosphamide. The median cumulative dosesover 12 months treatmentwere 19,500 mg of cyclophosphamideand 600 mg of melphalan; these dosagesrepresentedthe usual therapeutic regimens for this cancer. It is noteworthy that most of the leukemic disorders following melphalan occurred among women who had received more than 700 mg, whereasall the leukemias following cyclophosphamide arose among women who had received at least 27,ooOmg. These data

suggest that whenever possible, the lowest total drug dose compatible with therapeutic response should be administered.47This study is important becauseit is the first to demonstratethat there are clear differences in risk of leukemia following different alkylating agents.47 Acute Leukemia Following NonHodgkin’s Lymphoma Although non-Hodgkin’s lymphoma patients are frequently treated with similar therapeutic regimens as individuals with Hodgkin’s disease, this group has been much less intensively studied. One small study showed an increasedrisk of leukemia following either radiation alone (on the basis of one leukemia case) or after combined modality treatment (three cases).48 A larger study of leukemia following nonHodgkin’s lymphoma was reported by Greeneand associatesin 1983.49 Among 5 17 patients, nine developed ANL for an observed/expected ratio (O/E) of 105. Most of the leukemiasoccurred after multiple courses of treatment for indolent histology lymphomas. Six of the patients in this study who developed leukemia had been treated with combined modality therapy, and three had been treated with radiation therapy alone. The risk of ANL increasedsignificantly with increasing cumulative radiation dose to the bone marrow and with multiple courses of combined modality therapy. Thesedata suggestthat treatment regimens for indolent non-Hodgkin’s lymphoma should minimize both the duration and quantity of cytotoxic therapy in an effort to reduce the risk of ANL.1g2*49 Acute Leukemia Following Childhood Cancer Studies of second malignancies in long-term survivors of childhood cancerhave beenespecially valuable.4so-55Survival after childhood cancerhas dramatically improved, and these individuals may be at risk of developing complications for many years. In addition, children are exposed to fewer confounding environmental factors such as tobacco, alcohol, or occupational exposures. The risk of treatment-related leukemia among long-term survivors of childhood cancer has been evaluated.4*50-53*56 Among the 9,170 survivors followed by the Late Effects Study Group (LESG), a consortium of 13 pediatric oncology centers, secondary leukemia occurred in 22 patients, comparedwith 1.52 expected(O/E = 14).51Treatment

TREATMENT-RELATED

47

MALIGNANCIES

Table 4. Selected

Studies

Series

of Risk of Acute

Nonlymphocytic

Total Number of Patients

Hodgkin’s disease Kaldor et al, 1987” Greene and Wilson, 1985*“ Boivin et al, 1984’s Tucker et al, 1988*e Valagussa et al, 1988s7 Tucker et al, 19844 Bergsagel et al, 198230 Colman et al, 1988s’ Blayney et al, 198732 Multiple myeloma Bergsagel et al, 1979“’ Ovarian cancer Greene et al, 198246 Greene et al, 198647 Non-Hodgkin’s lymphoma Gomez et al, 1982@ Greene et al, 198349 Childhood cancer Tucker et al, 19875’ Polycythemia vera Berk et al, 198157 Brusamolino et al, 198458 Breast cancer Curtis et al, 1984c’ Fisher et al, 1985@ GI cancer Boice et al, 1980e4 Boice et al, 1983c5 Lung cancer Chak et al, 1984= Ratain et al, 1987c9 * Risk not statistically significant. t Includes myelodysplastic disorders. $ Cumulative risk among women treated -Data not available.

Leukemia

Number

in Patients

of Leukemias Observed

28,462 2,482 2,591

Treated

for Several

Relative

Risk

Types of Cancer Cumulative Risk (No. vrs Follow-UP)

.-

1,507 1,329 1,036 780 730 192

106 2 21 28 27 12 7 8 12t

89 42 86 96

364

14

214

1,399 3,363

12 28

117

4 9

341 105

7.9% -t 3.2% (10)

22

14

0.8% i 0.2% (20)

26 6

-

8.483

27 43t

2.1 -

1,402 3,633

6 17t

1.6'

158 119

3 4

517

9.170

431 100

59,115

with chemotherapy

with alkylating agents was associatedwith a significantly elevated risk of 4.8 for leukemia. A strong dose-responserelationship also was observed between leukemia risk and total dose of alkylating agentswith the relative risk reaching 23 in the highest dose category.51In this group, no effect of radiation therapy on leukemia risk could be detected. Basedon small numbers, there was a suggestion of a more than multiplicative interaction between doxorubicin and alkylating agents that may be more leukemogenic than one would expect, based on their independent risks. This

11

1.5* 29 66

67 23.5

.3.3% rt 0.6% (15) 3.6% f 0.9% 112) 4.2% r 1.9% (20)

10% r 3%

(15)

17% t 4%

(4)

4.7% + 1.6% (7) 8.4% -t 1.6% (10)tS

-

9% (71

<2% (10) 3.2% (7)

316 -

25% 2 13% (3.1) 44% t 24% (2.5)

only

finding is of particular importance becauseof the increasing use of alkylating agents and doxorubitin in many chemotherapycombinations. Acute Leukemia Following Polycythemia Vera In a clinical trial of 431 patients with polycythemia Vera, the risk of ANL in patients receiving chlorambucil was 13.5 times greater than that observedin patients treatedwith phlebotomy only, with a suggestionof a greater risk among patients receiving higher drug doses.57Basedon this study, the Polycythemia Vera Study Group has discontin-

48

FRASER AND TUCKER

Table 5. Risk of Leukemia Following Hodgkin’s Disease by Treatment Category Total No. of Patients

Number of Leukemias Observed

Relative Risk

Cumulative Risk

2,090 141 360

2 5 14

3 125 140

-

714 648

2 18

11 117

15yr 0.6% f 0.5% 4.9% It 1.2%

Salvage CT post XRT post gold + XRT CT

179 65 80

2 3 3

58 253 130

1.8% f 1.3% 12.3% + 6.8% 11.5% + 6.6%

Valagussa et al, 1988” XRT XRT + CT CT

307 926 96

Colman et al, 18883’ XRT XRT + CT CT

195 329 206

0 6 2

95 283 179 102

0 11 7 3

-

-

11 1

-

Series Boivin et al, 198425 XRT* Intensive XRT + CT Intensive CT Tucker et al, 1988’s XRT Adjuvant CT

Coltman and Dixon, XRT Adjuvant CT Salvage CT CT Blayney et al, 198732t XRT + MOPP MOPP alone

-

-

155 191

1982aa

15yr 0 5.9% + 1.4% 1.4% ? 1.6% 7v 6.4% f 2.1% 7.7% ? 2.9% 6.2% f 3.4% 15yr approximately <2%

23%

Abbreviations: XRT, radiation therapy; CT, chemotherapy. * Radiotherapy group includes XRT + nonintensive CT. t Includes myelodysplastic disorders. -Data not available.

ued the use of chlorambucil in the treatment of polycythemia Vera. Treatment with another alkylating agent, pipobroman, has also been associatedwith ANL following polycythemia vera.58The findings should be interpreted with caution becausepolycythemia vera has an inherent tendency to transform into ANL, regardlessof therapy. However, thesestudies are important because they provide the first quantitative data documenting that chlorambucil is a cause of human leukemia, and that the risk of ANL appears to be dose-related.’ In addition, pipobroman also may be leukemogenic. Acute Leukemia Following Breast Cancer An association of leukemia with breast cancer has frequently been noted.59-61The fiit study re-

porting quantitative evidence that women with breast cancer are at increased risk of ANL was basedon NC1 Surveillance Epidemiology and End Results (SEER) data from 59,115 women with breastcancerdiagnosedbetween 1973 and 1980.60 Twenty-seven patients developed ANL compared with 13.2 casesexpected(O/E = 2.1). Data were available only for initial treatment, but the risk was highest among women whose first treatment was chemotherapy(RR = 28). The most well-characterized study to date of the risk of leukemia following breast cancer was from the National Surgical Adjuvant Breast and Bowel Project (NSABP), in which 8,483 women with primary operable breast cancer participated in seven randomized clinical trials evaluating adjuvant chemotherapy.61The patients were treated either

TREATMENT-RELATED

49

MALIGNANCIES

by surgery alone, by surgery and radiation therapy, or by surgery and adjuvant chemotherapy. Most casesof leukemia (n = 36) and all sevencasesof myeloproliferative syndrome occurred in patients who had received adjuvant chemotherapythat included melphalan, but a small risk of leukemia was also observed in the patients treated with postoperative radiation therapy.61To date, an increased risk of leukemia has not been demonstrated in women receiving CMF (cyclophosphamide,methotrexate, and 5-fIuorouracil).62 Thesedata suggestthat women who receive adjuvant chemotherapywith melphalan or postoperative radiation therapy are at increasedrisk of leukemia. However, the risk is lower than that reported following chemotherapy for other solid tumors and hematologic malignancies, a difference that may be related to the total dose of melphalan received. Acute Leukemia Following Gastrointestinal Cancer Similar to ovarian cancer, there does not appear to be an intrinsic risk of leukemia following colorectal cancer.63There have been several clinical trials that included single alkylating agents; these have allowed the evaluation of leukemia risk following exposure to specific alkylating agents. Although an early study suggestedthat treatment with low-dose thiotepa did not confer an increasedrisk of leukemia,@ among the more than 2,000 individuals who received adjuvant methylCCNU for gastric, colon, or rectal cancer, nine casesof ANL were observed compared with 0.8 casesexpected (O/E = 10.8).65In contrast, only one patient who had not received methyl-CCNU developed ANL. The relative risk of ANL in patients exposed to methyl-CCNU compared with those unexposed was 15.9. Of note also is that eight patients developed myeloproliferative syndromes. The cumulative risk of leukemic conditions (3.2% at 7 years) is similar to that observed following exposure to other alkylating agents. This study demonstrated that chlorethyl nitrosourea drugs are leukemogenic in humans.65 A small study also has documented an increased risk of leukemia following treatment of brain cancer with BCNU, another chlorethyl nitrosourea drug.66

Acute Leukemia Following Lung Cancer ANL does not appear to be part of the natural history of lung carcinomatreatedonly with surgery and/or radiation therapy. In a randomized clinical trial of lung cancerreported in 1977, it is noteworthy that none of the 249 placebo-treatedpatients developed ANL compared with four of 243 patients receiving the alkylating agent busulfan.67 This study is significant because it provides the only quantitative human data regarding the leukemogenic potential of busulfan in humans. More recently, a survey of 158 patients receiving intensive combined-modality therapy for small cell carcinoma of the lung revealed three patients with ANL comparedwith 0.01 casesexpected (O/ E = 316)? The actuarial risk of ANL was 25% (? 13%) at 3.1 years. Of the drugs used in this trial, procarbazine,cyclophosphamide,and CCNU were the agents most likely to be related to the development of leukemia. The leukemia patients received high cumulative dosesof thesedrugs. Becauseof the small number of leukemia patients in this study, meaningful analysis of the leukemogenic potential of the various agents is not possible.68 An increasedrisk of leukemia also was reported following treatment of non-small-cell lung cancer with combinations including at least cisplatin and etoposide.69 The cumulative risk of leukemia among two-or-more-year survivors is 44% (+24%). Again, meaningful analysis of individual agents is not possible, but this study does find a significantly increasedrisk of leukemia in cisplatin-containing regimens. SUMMARY

In summary, all of these studies of leukemia as a second cancer have shown similar patterns of risk. The overwhelming risk factor for leukemia is treatmentwith alkylating agentchemotherapy.The time at greatestrisk appearsto be during the first 10 years after treatment.lV2Radiation therapy in the presenceof alkylating agentsconfers no detectable additional risk of leukemia,4’25*26*31s36.51 although in the absenceof chemotherapy, radiation therapy alone confers a small increasein risk. 12*13 The risk of leukemia rises with increasing dosesof alkylating agents, so that the risk is directly related to the total dose of drugs received. The risk of

50

FRASER AND TUCKER

leukemia also varies by the specific alkylating agents used, but few data currently exist to compare drugs. Future studies are needed to clarify theserisks. From the available data, leukemia contributes very little to the mortality of long-term survivors, and effective treatment should not be abandonedbecauseof the small risk of leukemia. Within the confines of successfultreatment, however, the total dose of alkylators should be minimized, and new treatmentsthat minimize exposure to these drugs should be explored.

with chemotherapyhas not been extensively evaluated, partially because many of the individuals who receive chemotherapy also receive radiation therapy. Large numbers of individuals surviving for extendedperiods of time are necessaryto start to disentangle the effects of both radiation and drugs. Only now are populations of individuals who have survived more than 10 to 15 years after childhood cancer, Hodgkin’s disease, breast cancer, and gynecologic cancersavailable for study. Hodgkin’s Disease

SOLID TUMORS FOLLOWING CANCER TREATMENT

Solid tumors following Hodgkin’s disease are somewhatcomplicated to study, becausemany individuals receive both radiation therapy and chemotherapy.25-27*31*36 Some receive radiation alone, but only a small number of individuals receive chemotherapyalone. Therefore, it is possible to estimate the risks of solid tumors associated with either radiation therapy or combined modality therapy, but not with chemotherapyalone, because there are not enough individuals in this category. Another important consideration in estimating the risks of second cancer is that individuals with Hodgkin’s diseasehave an underlying immunodeficiency that may have an impact on the type of tumors that develop.26 After 10 years, solid tumors predominate as the most important second cancer.26,70At 15 years, the cumulative risk of a second solid tumor is 13.2% (+3.1%) (Fig 1). Although the relative risks of solid tumors (two- to three-fold) are lower than the relative risks for leukemia, the actual numbersof solid tumors are much larger. The risk

The risk of solid tumors following exposure to ionizing radiation has been well described after multiple types of exposures including radium in radium dial painters, the atomic bombs in Hiroshima and Nagasaki,thorotrast usedas a contrast agent, multiple x-ray exposures such as in the treatment of ankylosing spondylitis, and repeated fluoroscopies for tuberculosis.12-t5These exposures,however, are different from the exposuresof therapeutic radiation for cancers. Only recently have the risks of second solid tumors associated with therapeutic-range radiation therapy been quantified and related to the actual dosesof radiation received. Most radiation-related cancersappear after 10 years, with an increasing risk with increasing duration of follow-up. The majority of radiation-related cancersoccur either within the direct field of radiation or near the field, in organs that receive radiation scatter.4,‘2-‘5*26*53 The risk of solid tumors following treatment 20-

c 3 z $

15 -

----.- -

All Cancers (17.6%) Solid Tumors (13.2%) Leukemia (3.3%) Lymphoma (1.6%)

lo-

0

E 8

5-

0

2

4

6

8

10

TIME (Years)

12

14

16

18

Fig 1. Actuarial risk of second cancers in 1,507 patients with Hodgkin’s disease treated at Stanford University Medical Center. The percentages in parentheses indicate the actuarial risk at 15 years. (Reprinted with permission of The New Eng/end Journal of Medicine, 318:78. 1988)

TREATMENT-RELATED

MALIGNANCIES

51

ation therapy and actinomycin D; that is, the risk of solid tumors increasesover time, which is conof thyroid cancer was much higher in those treated sistent with a radiation effect. In several studies with both radiation and actinomycin D than in eithat have reported the types of second solid tuther alone.56 For each of these tumors, the risk mors, the most common were cancersof the lung, increasedwith duration of follow-up, as long as 25 stomach, bone, and soft tissues, and melayears after the diagnosis of the first cancer. Breast cancer also appearsto noma.4721724-27,31,71 be increased.Most of these(lung, stomach,breast, bone, and soft tissue cancers) are known radioGynecologic Cancers genie cancers.No single study has sufficient numMost of the treatment-inducedsolid tumors folbers of any single type of solid tumor to examine lowing gynecologic cancers are radiationthe risks related to type of treatment. Several studrelated.‘2-‘5’43 Following radiation for cervical ies, however, have estimatedthe risks of all solid cancer, small excessesof bladder, rectum, uterine tumors related to type of treatment.25-27*36,4’ In corpus, connective tissue, and bone cancers were general, the risks are similar among studies, and seenin several studies. Among the organs that rethe risks do not significantly vary by type of treatceived more than 100 cGy (1 cGy = 1 rad), the ment. risk of secondcancer increasedover time, starting In addition to the solid tumors following at approximately 10 years and continuing for at Hodgkin’s disease,there is also an increasedrisk least 30 years.13.i4 of non-Hodgkin’s lymphoma.2’~24~26~30~31~72~73 Similar excessesof rectum, bone, and bladder Theselymphomas occur after either radiation thercancers were seen following radiation for endoapy or adjuvant chemotherapy.The pattern of secmetrial cancer.14X15 The risk rose with increasing ond cancers that includes non-Hodgkin’s lymtime after treatmentwith radiation therapy. Neither phoma is consistent acrossstudiesand is similar to endometrial nor cervical cancer is commonly the distribution of tumors after renal transplantatreated with chemotherapy. tion or other immunosuppression.The melanomas Women with ovarian cancer also are at inoccur in individuals with dysplastic nevi and hiscreasedrisk of solid tumors. Radiation therapy aptologically resemblethe melanomasthat occur afpearsto account for part of the excessrisk of recter renal transplantation.7’ There is also some evidence that there is an eftal, bladder, and connective tissue cancers.43The risk of thesecancersincreasesover time. The data fect of age at treatment. The pattern of second are too limited to evaluate the potential risks assotumors following childhood Hodgkin’s diseaseis ciated with chemotherapy. slightly different, with a higher risk of sarcomas and thyroid cancer.4 It is too early to assessthe risks of lung, breast, or stomach cancer in this Other Cancers group. In the early 196Os,Danish investigators reported Childhood Cancer a dramatic excessof carcinomaof the urinary bladSubstantialexcessesof several solid tumors also der among patients receiving chlomaphazine, a compound that is closely related to a well-known have been observedafter all childhood cancers.In bladder carcinogen.74Ten of 6 1 patients developed the previously cited survey by the Late Effects bladder carcinoma, and an additional five develStudy Group, excessesof bone (RR = 133), thyoped “abnormal urine cytology.” Based on these roid (RR = 53), and connective tissue malignanobservations, chlomaphazine was withdrawn from cies (RR = 41) were noted.4 For each of these clinical practice. tumors, an increasing risk with increasing radiaSeveral studies have demonstrated an excess tion dose was shown.53*56In addition, for bone risk of bladder cancer among patients receiving sarcomasthere was an independenteffect of treatment with alkylating agents.53Individuals who recyclophosphamidefor various malignant and nonmalignant conditions.75-77The effect appearsspeceived alkylating agents alone had a four-fold incific for this particular alkylating agent, which increasedrisk of bone sarcoma.This finding needs to be confirmed in other studies. For thyroid canduces acute toxic effects in the bladder mucosa. In summary, most of the available data to date cer, there appearedto be an interaction with radi-

FRASER AND TUCKER

have implicated radiation therapy as the more important risk factor for the development of solid tumors.4~‘4*26s3Many studies have shown evidenceof somedose response.In addition, there is some suggestiveevidence that chemotherapymay contribute to an increasedrisk of secondsolid tumors. These observations, however, must be confirmed and clarified with future studies. Longer follow-up of larger groups of long-term survivors is needed to disentangle the effects of radiation therapy and chemotherapy. CLINICAL IMPLICATIONS REGARDING TREATMENT-RELATED NEOPLASIA

Studies of treatment-relatedmalignancies have beenpossible becauseof the dramatic successesin therapy for several malignancies. The small risks of secondary malignancies should not be a deterrent to using current treatment modalities with proven therapeutic benefits in patients with advanced disease.78-80 Overall, few long-term survivors develop life-threatening treatment-relatedmalignancies. However, the use of chemotherapeutic agents and radiation therapy in the adjuvant therapy of cancerpatients at low risk of recurrenceand the treatment of nonneoplasticdiseasesis a different issue. Most of the literature suggestingthat chemotherapeutic drugs are related to second tumors is derived from experiencewith alkylating agents.Several clinical, laboratory, and epidemiologic studies suggestthat antimetabolites and several other anticancer drugs have little if any carcinogenic potential. Thus, broad generalizations about the safety or long-term toxicity of chemotherapeutic drugs as a whole should be avoided. The risks of solid second cancersfollowing radiotherapy are well documented,but the long-term safety of most cytotoxic drugs and combined modality treatment regimens remains to be established. Becausethe latency interval for many solid tumors may be 10 years or greater, careful longterm follow-up of patients is necessary.Any statement regarding the safety of treatment must be based on well-designed cohort studies conducted over a prolonged period of time. Clinical trials are important for assessingnot only the therapeutic results of various treatmentprograms, but also for evaluating the long-term complications of therapy in order to maximize the benefit of the treatment and improve the quality of life.

NURSING IMPLICATIONS

Oncology nurses are directing more attention to characterizing the late effects of cancer therapy.7~54755s1-83 With the longer survival that is experienced following many cancers, and with new and more intensive treatment regimens being planned, other long-term complications may emerge. Each patient must be observed regularly throughout his or her life by clinicians who are alert to the increasedrisk of a secondor even third malignancy. Guidelines have been published that assist nurses in obtaining a proper history and review of systems,and performing a physical examination in cancer survivors.54,55s1 Oncology nursesneed to know which patients are at highest risk for developing treatment-relatedmalignancies to ensurethat theseindividuals have accessto lifetime surveillance. Patients and their families need to be taught about the small, but potential, risk of a subsequent cancer. This is particularly important for those patients who have received cancer therapy that has placed them at increasedrisk of a treatment-related malignancy. Nursesshould also encouragepatients to practice health-promoting behaviors. For example, since individuals with Hodgkin’s diseaseare at increasedrisk of lung cancer, nursesshould play an important role in discouraging theseindividuals from smoking. The role and contributions of oncology nurses should be considered not only for an individual patient but also in a broader context.7’84Analytic epidemiologic studies that attempt to quantify the risk of treatment-relatedmalignancies require detailed information regarding the exposuredata, ie, treatmentsreceived. The patient’s chart is the original source of information available for studies of both acute and late effects of cancer therapy. Therefore, when nurses are documenting the type of chemotherapy administered, it is important to detail as closely as possible the name of the drug, as well as dosage, frequency, route, duration and other pertinent information. Documenting what the patient actually received increasesthe reliability of the exposure data and helps in determining if any variations or modifications to the medical order for chemotherapywere necessary. CONCLUSION

In the absenceof proper treatment, essentially all patients with disseminated malignancy and a

TREATMENT-RELATED

53

MALIGNANCIES

substantial number of those with more localized diseasewill die of their cancer. Unfortunately, effective cancer therapy usually results in exposure to treatment that, in itself, may be carcinogenic. The long-term risks attributed to such therapy, however, must be balancedagainstthe benefits of therapy for a life-threatening disease.The risk of treatment-related malignancies is under intensive

investigation. As the follow-up time increaseson various treatment regimens, our knowledge of these late effects will be advancedsignificantly. ACKNOWLEDGMENT The authors thank Ruth Craig, Robert Garcon, and CarshenaStone for expert technical assistance.

REFERENCES 1. Greene MH: Interaction between radiotherapy and chemotherapyin humanleukemogenesis,in Boice JD Jr, Fraumeni JF Jr (eds): Radiation Carcinogenesis:Epidemiology and Biological Significance. New York, Raven, 1984, pp 199-210 2. Greene MH: Epidemiologic studies of chemotherapyrelated acute leukemia, in Castellani A (ed): Epidemiology and Quantitation of Environmental Risk in Humansfrom Radiation and Other Agents. New York, Plenum, 1985, pp 499-514 3. Dorr FA, Coltman CA: SecondCancersFollowing Antineoplastic Therapy. Chicago, Year Book Medical, 1985 4. Tucker MA, MeadowsAT, Boice JD Jr, et al: Cancerrisk following treatmentof childhood cancer, in Boice JD Jr, Fraumeni JF Jr (eds): Radiation Carcinogenesis:Epidemiology and Biological Significance. New York, Raven, 1984, pp 21l-224 5. Li FP: Second cancers, in DeVita VT Jr, Hellman S, RosenbergSA (eds): Cancer: Principles and Practice of Oncology (ed 2). Philadelphia, Lippincott, 1985, pp 2040-2049 6. Kyle RA: Second malignancies associatedwith chemotherapy, in Perry MC, Yarbro JW (eds): Toxicity of Chemotherapy. Orlando, Grune & Stratton, 1984, pp 479-506 7. Fraser MC, Tucker MA: Late effects of cancer therapy: Chemotherapy-relatedmalignancies.Oncol Nurs Forum 15:6777, 1988 8. Abramson DH, Ellsworth RM, Kitchin TD, et al: Second nonocular tumors in retinoblastoma survivors: Are they radiation-induced?Ophthalmology 91:1351-1355, 1984 9. Li FP, Fraumeni JF Jr: Prospective study of a family cancer syndrome. JAMA 247:2692-2694,1982 10. Chabner BA, Myers CE: Clinical pharmacology of cancer chemotherapy,in DeVita VT Jr, Hellman S, RosenbergSA (eds):Cancer:Principles and Practiceof Oncology (ed 2). Philadelphia, Lippincott , 1985, pp 156-197 11. World Health Organization, International Agency for Researchon Cancer:Overall evaluationsof carcinogenicity: An updating of IARC Monographsvols l-42. IARC Monogr Eva1 Carcinog Risk Chem Hum [Suppl 71, 1987 12. Boice JD, Hutchison GB: Leukemia in women following radiotherapy for cervical cancer: Ten-year follow-up of an international study. JNCI 65:115-129, 1980 13. Boice ID Jr, Blettner M, Kleinerman RA, et al: Radiation doseand leukemia risk in patients treatedfor cancerof the cervix. JNCI 79:1295-1311, 1987 14. Boice JD Jr, Engholm G, Kleinerman RA, et al: Radiation dose and secondcancer risk in patients treated for cancer of the cervix. Radiat Res 116:3-55, 1988 15. Storm HH: Secondaryprimary cancerafter treatmentfor cervical cancer:Late effects after radiotherapy. Cancer61:679688, 1988

16. Pedersen-BjergaardJ, Philip P, Pederson NT, et al: Acute nonlymphocytic leukemia, preleukemia, and acute myelo-proliferative syndrome secondaryto treatment of other malignant diseases. II. Bone marrow cytology, cytogenetics, resultsof HLA typing, responseto antileukemic chemotherapy, and survival in a total seriesof 55 patients. Cancer 54:452-462, 1984 17. Bitter MA, LeBeau MM, Rowley JD, et al: Associations between morphology, karyotype, and clinical features in myeloid leukemias. Hum Pathol 18:21l-225, 1987 18. Yeomans AC: Myelodysplastic syndromes-A preleukemic disorder. Cancer Nurs 10:32-40, 1987 19. Whang-PengJ, Young RC, Lee EC, et al: Cytogenetic studies in patients with secondary leukemitidysmyelopoietic syndrome after different treatment modalities. Blood 71:403414, 1988 20. Bennett JM, Moloney WC, Greene MH, et al: Acute myeloid leukemia and other myelopathic disorders following treatment with alkylating agents. Hematol Path01 1:99-104, 1987 21. Kaldor JM, Day NE, Band P, et al: Secondmalignancies following testicular cancer, ovarian cancer and Hodgkin’s disease: An international collaborative study among cancer registries. Int J Cancer 39:571-585, 1987 22. DeVita VT Jr: The consequencesof the chemotherapyof Hodgkin’s disease: The 10th David A. Kamofsky Memorial Lecture. Cancer 47:1-13, 1981 23. Arseneau JC, Sponzo RW, Levin DL, et al: Nonlymphomatousmalignant tumors complicating Hodgkin’s disease: Possible association with intensive therapy. N Engl J Med 287~1119-1122,1972 24. Greene MH, Wilson J: Secondcancers following lymphatic and hematopoietic cancers in Connecticut 1935-1982. NC1 Monogr 68:191-217, 1985 25. Boivin JF, Hutchison GB, Lyden M, et al: Secondprimary cancersfollowing treatment of Hodgkin’s disease. JNCI 72:233-241, 1984 26. Tucker MA, Coleman CN, Cox RS, et al: Risk of second cancers after treatment for Hodgkin’s disease. N Engl J Med 318:76-81, 1988 27. Valagussa P, Santoro A, Fossati-Bellani F, et al: Hodgkin’s diseaseand secondmalignancies. Proc Am Sot Clin Oncol 7:227, 1988 28. ValagussaP, SantoroA, Fossati-Bellani F, et al: Second acute leukemia and other malignanciesfollowing treatment for Hodgkin’s disease.J Clin Oncol 4:830-837, 1986 29. Valagussa P, Santoro A, Fossati-Bellani F, et al: Ab-

54 sence of treatment induced secondneoplasmsafter ABVD in Hodgkin’s disease.Blood 59:488-494, 1982 30. Bergsagel DE, Alison RE, Bean HA, et al: Results of treating Hodgkin’s diseasewithout a policy of Iaparotomystaging. Cancer Treat Rep 66:717-731, 1982 31. Colman M, Easton DF, Horwich A, et al: Secondmalignancies and Hodgkin’s disease-The Royal MarsdenHospital experience. Radiother 0~01 11:229-238, 1988 32. Blayney DW, Longo DL, Young RC, et al: Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin’s disease. N Engl J Med 316:710-714, 1987 33. Pedersen-BjergaardJ, Larsen SO: Incidence of acute nonlymphocytic leukemia, preleukemia, and acute myeloproliferative syndrome up to 10 years after treatment for Hodgkin’s disease. N Engl J Med 307:9665-9671,1982 34. Coleman CN, Kaplan HS, Cox R, et al: Leukemias, non-Hodgkin’s lymphomas, and solid tumorsin patientstreated for Hodgkin’s disease.Cancer Surv 1:733-744, 1982 35. Glicksman AS, Pajak TF, Gottlieb A, et al: Secondmalignant neoplasmsin patientssuccessfullytreatedfor Hodgkin’s disease:A Cancer and Leukemia Group B study. CancerTreat Rep 66:1035-1044, 1982 36. Coltman CA Jr, Dixon DO: Secondmalignanciescomplicating Hodgkin’s disease:A SouthwestOncology Group loyear follow-up. Cancer Treat Rep 66:1023-1033, 1982 37. Coleman CN: Secondarymalignancy after treatment of Hodgkin’s disease:An evolving picture. J Clin Oncol 4:821824, 1986 38. Hemy-Amar M: Secondcancersafter radiotherapy and chemotherapy for early stages of Hodgkin’s disease. JNCI 71:911-916, 1983 39. Koletsky AJ, Bertino JR, Farber LR, et al: Secondneoplasms in patients with Hodgkin’s diseasefollowing combined modality therapy-The Yale experience. J Clin Oncol 4:31l317, 1986 40. Rubin P, Zagars G, ChuangC, et al: Hodgkin’s disease: Is there a price for successfultreatment?A 25year experience. J Radiat Oncol Biol Phys 12:153-166, 1986 41. Tester WJ, Kinsella TJ, Waller B, et al: Secondmalignant neoplasmscomplicating Hodgkin’s disease:The National Cancer Institute experience. J Clin Oncol 2:762-769, 1984 42. Bergsagel DE, Bailey AJ, Langley GR, et al: The chemotherapy of plasma cell myeloma and the incidence of acute leukemia. N Engl J Med 301:743-748, 1979 43. Tucker MA, Fraumeni JF Jr: Treatment-relatedcancers following gynecologic malignancy. Cancer 60:2 117-2122, 1987 44. Reimer RR, Hoover RN, Fraumeni JF Jr, et al: Acute leukemia after alkylating-agent therapy of ovarian cancer. N Engl J Med 297:177-181, 1977 45. Pedersen-BjergaardJ, Nissen NI, SorensenHM, et al: Acute non-lymphocytic leukemia in patients with ovarian carcinoma following long-term treatment with Treosulfan (= dihydroxybusulfan). Cancer 45:19-29, 1980 46. Greene MH, Boice JD Jr, Greer GE, et al: Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer. N Engl J Med 307:1416-1421,1982 47. GreeneMH, Harris EL, GershensonDM, et al: Melphalan may be a more potent leukemogenthan cyclophosphamide. AM Intern Med 105:360-367,1986

48. Gomez GA, Aggarwal KK, Han R: Post-therapeutic acute malignant myeloproliferative syndrome and acute nonlymphocytic leukemia in non-Hodgkin’s lymphoma: Correlation with intensity of treatment. Cancer 50:2285-2288, 1982 49. GreeneMH, Young RC, Merrill JR, et al: Evidence of a treatment dose responsein acute nonlymphocytic leukemias which occur after therapy on non-Hodgkin’s lymphoma. Cancer Res 43:1891-1898, 1983 50. MeadowsAT, Baum E, Fossati-Bellani F, et al: Second malignant neoplasmsin children: An update from the Late Effects Study Group. J Clin Oncol 3:532-538, 1985 51. Tucker MA, MeadowsAT, Boice JD Jr, et al: Leukemia after therapy with alkylating agents in childhood cancer. JNCI 78:459-464, 1987 52. Mike V, Meadows AT, D’Angio GJ: Incidence of second malignant neoplasms in children: Results of an intemational study. Lancet 2:1326-1331, 1982 53. Tucker MA, D’Angio GJ, Boice JD, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317:588-593, 1987 54. RuccioneK, FergussonJ: Late effects of childhood cancer and its treatment. Oncol Nurs Forum 11:54-64, 1984 55. McCalla J: A multidisciplinary approach to identification and remedial intervention for adverselate effects of cancer therapy. Nurs Clin North Am 20:117-130, 1985 56. Tucker MA, MeadowsAT, JonesPM, et al: Therapeutic radiation at young age linked to secondarythyroid cancer. Proc Am Sot Clin Oncol5:211, 1986 (abstr) 57. Berk PD, Goldberg JD, Silverstein MN, et al: Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 304441-447, 1981 58. Btusamolino E, SalvaneschiL, Canevari A, et al: Efficacy trial of pipobroman in polycythemia vera and incidence of acute leukemia. J Clin Oncol 2:558-561, 1984 59. Lemer HJ: Acute myelogenousleukemia in patients receiving chlorambucil as long-term adjuvant chemotherapyfor stage II breast cancer. Cancer Treat Rep 62:1135-1138, 1979 60. Curtis RE, Hankey BF, Myers MH, et al: Risk of leukemia associatedwith the first course of cancer treatment: An analysis of the Surveillance, Epidemiology, and End Results Program experience. JNCI 72:531-544, 1984 61. Fisher B, Rockette H, Fisher ER, et al: Leukemia in breastcancerpatientsfollowing adjuvant chemotherapyor postoperative radiation: The NSABP experience. J Clin Oncol 3:1640-1658, 1985 62. ValagussaP, Tancini G, BonadonnaG: Secondmalignancies after CMF for resectable breast cancer. J Clin Oncol 5:1138-1142, 1987 63. Hoar SK, Wilson J, Blot WJ, et al: Secondcancer following cancerof the digestive systemin Connecticut, 1935-82. NC1 Monogr 68:49-56, 1985 64. Boice JD Jr, GreeneMH, Keehn RJ, et al: Late effects of low dose adjuvant chemotherapyin colorectal cancer. JNCI 64501-511, 1980 65. Boice JD Jr, GreeneMH, Killen JY, et al: Leukemia and preleukemia after adjuvant treatment of gastrointestinalcancer with semustine(methyl-CCNU). N Engl J Med 309:1079-1084, 1983 66. Greene MH, Boice JD Jr, Strike TA: Carmustine as a cause of acute nonlymphocytic leukemia. N Engl J Med 313:579, 1985

TREATMENT-RELATED

MALIGNANCIES

67. Stott H, Fox W, Girling DJ, et al: Acute leukemia after busulphan. Br Med J 2:1513-1517, 1977 68. Chak LY, Sikic BL, Tucker MA, et al: Increased incidence of acute nonlymphocytic leukemia following therapy in patients with small cell carcinoma of the lung. J Clin Oncol 2:385-390, 1984 69. Ratain MJ, Kaminer LS, Bitran JD, et al: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 70:1412-1417, 1987 70. Coleman CN: Secondary neoplasms in patients treated for cancer: Etiology and perspective. Radiat Res 92: 188-200, 1982 71. Tucker MA, Misfeldt D, Coleman CN, et al: Cutaneous malignant melanoma after Hodgkin’s disease. Ann Intern Med 102:37-41, 1985 72. Krikorian JG, Burke JS, Rosenberg SA, et al: Occurrence of non-Hodgkin’s lymphoma after therapy for Hodgkin’s disease. N Engl J Med 300:452-458, 1979 73. Jacquillat C, Khayat D, Desprez-Curely JP, et al: NonHodgkin’s lymphoma occurring after Hodgkin’s disease: Four new cases and a review of the literature. Cancer 53:459-462, 1984 74. Thiede T, Christensen BC: Bladder tumours induced by chlomaphazine. A five-year follow-up study of chlomaphazinetreated patients with polycythaemia. Acta Med Stand 185: 133137, 1969

55 75. Wall RL, Clausen K: Carcinoma of the urinary bladder in patients receiving cyclophosphamide. N Engl J Med 293:271-273, 1975 76. Hoover RN, Fraumeni JF Jr: Drug-induced cancer. Cancer 47:1071-1080, 1981 (suppl) 77. Plotz PH, Klippel JH, Decker JL, et al: Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. AM Intern Med 91:221-223, 1979 78. Reimer RR: Risk of a second malignancy related to the use of cytotoxic chemotherapy. CA 32:286-292, 1982 79. Schottenfeld D: Cancer risks of medical treatment. CA 32:258-279, 1982 80. Canellos GP: Therapy-related leukemia: A necessary complication of successful systemic chemotherapy? J Clin Onco1 2: 1077-1078, 1984 (editorial) 81. Leonard MA, Waskerwitz MJ: Late effects in adolescent survivors of childhood cancer. Semin Oncol Nurs 2: 126-132, 1986 82. Quigley K, O’Rourke A: Cancer survivors: implications for nursing practice. Oncol Nurs Forum 13:95, 1986 (suppl, abstr) 83. Thomas C: Detecting second primaries in individuals with cancer. Oncol Nurs Forum 13:63, 1986 (suppl, abstr) 84. Brown LM, Pottem LM: Epidemiologic approaches to cancer research. Semin Oncol Nurs 2:146-153. 1986