Original Investigation | Oncology

Association of Radiotherapy for Rectal Cancer and Second GynecologicalMalignant NeoplasmsXu Guan, MD, PhD; Ran Wei, MD; Runkun Yang, MD; Zhao Lu, MD; Enrui Liu, MD; Zhixun Zhao, MD, PhD; Haipeng Chen, MD; Ming Yang, PhD; Zheng Liu, MD, PhD;Zheng Jiang, MD, PhD; Xishan Wang, MD, PhD

Abstract

IMPORTANCE Radiotherapy is a common treatment for rectal cancer, yet the risk of secondgynecological malignant neoplasms (SGMNs) in patients with rectal cancer undergoing radiotherapyhave not been adequately studied.

OBJECTIVE To investigate the association between radiotherapy and the risk of individual types ofSGMN in patients with rectal cancer and assess survival outcomes.

DESIGN, SETTING, AND PARTICIPANTS A large population-based cohort study was designed toidentify the risk of SGMNs in patients with rectal cancer diagnosed from January 1973 to December2015. The statistical analysis was conducted from September 2019 to April 2020. The study wasbased on the 9 cancer registries of Surveillance, Epidemiology, and End Results database. A total of20 142 female patients with rectal cancer in localized and regional stage were included.

EXPOSURE Receipt of neoadjuvant radiotherapy for rectal cancer.

MAIN OUTCOMES AND MEASURES The development of an SGMN defined as any type of GMNoccurring more than 5 years after the diagnosis of rectal cancer. The cumulative incidence of SGMNswas estimated by Fine-Gray competing risk regression. Poisson regression was used to evaluate theradiotherapy-associated risk for SGMNs in patients undergoing radiotherapy vs patients notundergoing radiotherapy. The Kaplan-Meier method was used to assess the survival outcomes ofpatients with SGMNs.

RESULTS Of 20 142 patients, 16 802 patients (83.4%) were White and the median age was 65 years(interquartile range, 54-74 years). A total of 5310 (34.3%) patients were treated with surgery andradiotherapy, and 14 832 (65.7%) patients were treated with surgery alone. The cumulative incidenceof SGMNs during 30 years of follow-up was 4.53% among patients who received radiotherapy and1.53% among patients who did not. In competing risk regression analysis, undergoing radiotherapywas associated with a higher risk of developing cancer of the uterine corpus (adjusted hazard ratio,3.06; 95% CI, 2.14-4.37; P < .001) and ovarian cancer (adjusted hazard ratio, 2.08; 95% CI, 1.22-3.56;P = .007) compared with those who did not receive radiotherapy. The dynamic radiotherapy-associated risks (RR) for cancer of the uterine corpus significantly increased with increasing age atrectal cancer diagnosis (aged 20-49 years: adjusted RR, 0.79; 95% CI, 0.35-1.79; P = .57; aged 50-69years: adjusted RR, 3.74; 95% CI, 2.63-5.32; P < .001; aged �70 years: adjusted RR, 5.13; 95% CI,2.64-9.97; P < .001) and decreased with increasing latency since rectal cancer diagnosis (60-119months: adjusted RR, 3.22; 95% CI, 2.12-4.87; P < .001; 120-239 months: adjusted RR, 2.72; 95% CI,1.75-4.24; P < .001; 240-360 months: adjusted RR, 1.95; 95% CI, 0.67-5.66; P = .22), but the dynamicRR for ovarian cancer increased with increasing latency since rectal cancer diagnosis (60-119 months:adjusted RR, 0.70; 95% CI, 0.26-1.89; P = .48; 120-239 months: adjusted RR, 2.26; 95% CI,

(continued)

Key PointsQuestion Is radiotherapy for rectal

cancer associated with the increasing

risk of second gynecological malignant

neoplasms and prognosis in women

with rectal cancer?

Findings In this cohort study of 20 142

patients with rectal cancer, radiotherapy

for rectal cancer was associated with an

increased risk of second cancer of the

uterine corpus and ovarian cancer.

Development of cancer of the uterine

corpus was associated with a worse

prognosis.

Meaning Results of this study suggest

that special attention is warranted to

reduce the risk of second gynecological

malignant neoplasms in the treatment

and follow-up of patients with rectal

cancer after radiotherapy.

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

1.09-4.70; P = .03; 240-360 months: adjusted RR, 11.84; 95% CI, 2.18-64.33; P = .004). The 10-yearoverall survival among patients with radiotherapy-associated cancer of the uterine corpus wassignificantly lower than that among matched patients with primary cancer of the uterine corpus(21.5% vs 33.6%; P = .01).

CONCLUSIONS AND RELEVANCE Radiotherapy for rectal cancer was associated with an increasedrisk of cancer of the uterine corpus and ovarian cancer. Special attention should be paid to reduceradiotherapy-associated SGMNs and improve their prognosis.

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Introduction

During the last decades, several large randomized trials have demonstrated that neoadjuvantradiotherapy plays a well-established role in the improvement of locoregional control of rectal cancerbut is not associated with increased long-term survival.1-3 Therefore, the benefits and adverse eventsof radiotherapy should be carefully balanced when considering all potential effects of radiotherapy.Radiotherapy-associated second primary cancer (SPC) is a rare but notable late complication ofcancer therapy.4

Studies assessing the risk of SPC are inconsistent regarding the role of radiotherapy for rectalcancer treatment.5-7 Although some studies have demonstrated an increased risk of overall SPCsafter radiotherapy for rectal cancer treatment, others have reported no obvious increased risk.8-10

Because of the likelihood of pelvic organs receiving a greater radiotherapy dose than organs innonpelvic areas, it is necessary to understand the risk of SPCs in organs within the irradiatedvolume.9,11,12 Assessments of the potential risk of radiotherapy-associated SPC for pelvic cancers,including malignant neoplasms of prostate and bladder, have verified the idea of an increased risk ofSPCs in patients undergoing pelvic radiotherapy.13-15 However, whether the risk of secondgynecological malignant neoplasms (SGMNs) is increased after radiotherapy for rectal cancer has notbeen well addressed.

Although previous studies8-10,16-20 have investigated the risk of SGMNs among patients withrectal cancer treated with radiotherapy, the current research on this topic is limited andcontradictory. Most studies oversimplified the risk estimation by grouping various types ofgynecological malignant neoplasms (GMNs) into 1 broad category, without consideration of the greattumor heterogeneity and differences in pathogenesis among SGMN entities.8-10,16-20 Theunderstanding of radiotherapy-associated SGMN has prognostic and therapeutic implications but hasbeen rarely studied. Therefore, we performed this study with the aims of investigating radiotherapyand the risk of individual types of SGMN and assessing patient survival outcomes.

Methods

Database and ParticipantsFemale patients diagnosed with rectal cancer as the first primary cancer were identified from 9registries of the Surveillance, Epidemiology and End Results (SEER) database between January 1,1973, and December 31, 2015. All primary cancer sites were coded according to the InternationalClassification of Diseases for Oncology, Third Edition. The patients included were pathologicallydiagnosed with rectal cancer (C19.9) or rectosigmoid cancer (C20.9). The tumor stage was restrictedto the localized and regional stage, and the details of tumor stage are shown in eTable 1 in theSupplement. The exclusion criteria included patients in whom rectal cancer were not their firstprimary cancer, patients who were aged younger than 20 years, patients with distant stage, patients

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who survived less than 5 years after rectal cancer diagnosis, patients who did not undergo surgery,and patients with missing data on radiotherapy, surgery, age, tumor stage, race, survival status orfollow-up information. This study has been approved by the Ethics Committee of Cancer Hospital,Chinese Academy of Medical Sciences. The access to and use of SEER data did not require informedpatient consent. This study followed the Strengthening the Reporting of Observational Studies inEpidemiology (STROBE) reporting guideline for cohort studies.

Treatment Interventions for Rectal CancerPatients with rectal cancer were classified into 2 groups according to initial treatment modality. Theradiotherapy group was composed of patients with rectal cancer who received surgery andneoadjuvant external-beam radiotherapy, and the no-radiotherapy group was composed of patientswho received surgery alone. We excluded patients who received other types of radiotherapy (ie,brachytherapy, combination therapy). The SEER database collected data only on the initial course ofcancer treatment, and the radiotherapy doses were not registered in the SEER database.

Definition and Follow-up of SGMNsThe primary outcome of this study was the development of an SGMN, which was defined as any typeof GMN occurring more than 5 years after the treatment of rectal cancer because of at least a 5-yearlatency period from radiotherapy exposure to solid tumor occurrence.21 The SEER program adheresto the International Classification of Diseases for Oncology, Third Edition guidelines to distinguishSPCs from recurrent disease. To obtain comprehensive estimations for the risk of SGMNs, we firstestimated the risk for all types of combined SGMNs and then separately estimated the risk indifferent types of female genital organs, including the cervix uteri (C53.0-C53.9), corpus and uterus(C54.0-C54.9, C55.9), ovary (C56.9) and other female genital organs as 1 group (C51.0-C51.9, C52.9,C57.0-C57.9, C58.9). The follow-up for SGMNs began 5 years after rectal cancer diagnosis and endedat the date of diagnosis of any SGMN, all-cause death, or after 30 years of follow-up, whicheveroccurred first. The cut-off point for follow-up was defined as January 1, 2016 (April 2019 SEERdata release).

Statistical AnalysisFine-Gray competing risk regression analysis was used to assess the cumulative incidence of SGMNdevelopment. Experiencing a non-SGMN and dying of all causes were considered competing eventsby calculating hazard ratios (HRs) and 95% CIs for SGMN occurrence. The multivariable risk modelwas built by using a backward selection procedure with variables with 2-sided P < .05 in univariableanalyses, which was considered statistically significant and included in multivariable analyses. χ2

tests were used to compare categorical data, or Fisher exact test when frequencies were below 5.Mann-Whitney test were used for analysis of continuous variables with a normal and nonnormaldistribution, respectively. This procedure was performed with R software, version 3.5.3 (R Project forStatistical Computing).

The radiotherapy-associated risk (RR) was estimated by using Poisson regression analysis withthe relative risk and 95% CIs of SGMN development for patients with rectal cancer who receivedradiotherapy compared with those who did not receive radiotherapy, and the RRs were calculatedwith R software version 3.5.3. Then, Poisson regression analysis was used to calculate thestandardized incidence ratio (SIR) and 95% CIs. The SIR was defined as the ratio of observedincidence SGMNs among rectal cancer survivors to the incidence of GMNs in the US generalpopulation. The SIRs were calculated with SEER*Stat 8.3.6. Both RRs and SIRs were adjusted for theage at rectal cancer diagnosis and the calendar year of rectal cancer diagnosis in our analysis. Thedetails of statistical methods are shown in eFigure 2 in the Supplement. To further evaluate thedynamic risks and incidence for SGMNs associated with radiotherapy, we calculated the RRs and SIRsstratified by latency time since rectal cancer diagnosis, age at rectal cancer diagnosis, and year ofrectal cancer diagnosis.

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To evaluate the prognosis of SGMNs, the Kaplan-Meier method was used to calculate the10-year overall survival for SGMNs and only primary GMN, and P values were calculated with thelog-rank test. Overall survival was defined as the time from SGMN diagnosis to death from any cause.The only primary GMN was defined as the patients diagnosed with only GMN and without any othercancers throughout their lifetime. Propensity score matching was used to reduce possible bias forsurvival comparison. These analyses were performed using R software (version 3.5.3).

Results

Patient CharacteristicsA total of 22 589 patients with rectal cancer were identified (eFigure 1 in the Supplement). Afterexcluding the patients with nonmatching data, 20 142 patients remained in final cohort, 16 802patients (83.4%) were White, and the median age was 65 years (interquartile range, 54-74 years).The median follow-up time was 140 months (interquartile range, 92-212 months). A total of 14 832patients (65.7%) were in the no-radiotherapy group and 5310 patients (34.3%) were in theradiotherapy group. The baseline characteristics of patients with rectal cancer by treatment modalityare shown in Table 1. After a latency of 5 years, 176 patients (1.2%) in the no-radiotherapy group and144 patients (2.7%) in the radiotherapy group developed SGMN. The baseline characteristics ofpatients who developed SGMN are shown in eTable 2 in the Supplement.

Cumulative Incidences of SGMNsThe cumulative incidence of combined SGMNs was 2.16% after rectal cancer diagnosis; theincidences were 1.53% in patients with no radiotherapy and 4.53% in patients receiving radiotherapy(P < .001) (Figure 1A). In organ-specific analyses, the cumulative incidences of cancer of the uterinecorpus, ovarian cancer, and other SGMNs were significantly higher in the radiotherapy group than theno-radiotherapy group, including cancer of the uterine corpus (1.00% vs 2.80%; P < .001), ovariancancer (0.29% vs 0.98%; P = .007), and other SGMNs (0.20% vs 0.62%; P = .007), but nodifference was observed for cervical cancer (Figure 1B-E).

Risk of SGMNs Attributable to RadiotherapyAll variables listed in Table 1 were selected for univariable competing risk regression analysis(eTables 3-7 in the Supplement). In multivariable analysis, radiotherapy was associated with a higherrisk of developing combined SGMNs (adjusted HR, 2.99; 95% CI, 2.23-4.02; P < .001). In analyses ofeach type of SGMN, increased risks were observed in cancer of the uterine corpus (adjusted HR,3.06; 95% CI, 2.14-4.37; P < .001) and ovarian cancer (adjusted HR, 2.08; 95% CI, 1.22-3.56;P = .007) but not in cervical cancer or other SGMNs (Table 2). In subgroup analyses, the increasedrisk of developing cancer of the uterine corpus and ovarian cancer was associated with radiotherapyin most subgroups with HRs greater than 1.00 (eTables 8-12, and eFigures 3 and 4 in theSupplement).

The RRs were calculated to confirm the risk of SGMNs attributable to radiotherapy. We foundthat the adjusted RR of additional risk for combined SGMNs was 2.82 (95% CI, 2.24-3.56, P < .001),and increased risk was also observed for cancer of the uterine corpus (adjusted RR, 3.19; 95% CI,2.39-4.26; P < .001), ovarian cancer (adjusted RR, 2.26; 95% CI, 1.30-3.91; P = .004), and otherSGMNs (adjusted RR, 2.72; 95% CI, 1.43-5.16; P = .002) (Table 2). We then found that the SIR forcombined SGMNs was 2.32 (95% CI, 1.95-2.73, P < .05) in patients who received radiotherapy, andthe SIRs for patients who underwent radiotherapy were significantly higher for cancer of the uterinecorpus (SIR, 2.88; 95% CI, 2.33-3.5; P < .05) and other SGMNs (SIR, 2.79; 95% CI, 1.65-4.41; P < .05)(Table 2).

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Dynamic Risk and Incidence Evaluation for SGMNsTo assess the risks of SGMNs attributable to radiotherapy, we established 3 dynamic RR plots basedon latency period, time of rectal cancer diagnosis, and age at rectal cancer diagnosis (Figure 2;eTables 13-17 in the Supplement). In the dynamic latency-RR plot, an increased risk of cancer of theuterine corpus was observed in the early latency, but this risk presented a downward trend in the latelatency (60-119 months: adjusted RR, 3.22; 95% CI, 2.12-4.87; P < .001; 120-239 months: adjustedRR, 2.72; 95% CI, 1.75-4.24; P < .001; 240-360 months: adjusted RR, 1.95; 95% CI, 0.67-5.66;P = .22) (Figure 2A; eTable 14 in the Supplement). In the dynamic age-RR plot, no increased risk ofcancer of the uterine corpus was observed in patients aged 20 to 50 years with rectal cancer, but therisk gradually increased and peaked at an age of older than 70 years (20-49 years: adjusted RR, 0.79;95% CI, 0.35-1.79; P = .57; 50-69 years: adjusted RR, 3.74; 95% CI, 2.63-5.32; P < .001; �70 years:

Table 1. Comparisons of Baseline Characteristics of Patients With Rectal Cancer by Treatment Modality

Characteristic

No. (%)

P valueRadiotherapy (n = 5310) No radiotherapy (n = 14 832)Age at rectal cancer diagnosis, median (IQR), y 61 (52-70) 66 (56-75) <.001a

Age at rectal cancer diagnosis, y

20-49 1047 (19.7) 1767 (12)

<.001b50-69 2886 (54.4) 7230 (48.7)

≥70 1377 (25.9) 5835 (39.3)

Year of rectal cancer diagnosis, median (IQR) 1999 (1991-2006) 1993 (1984-2002) <.001a

Year of rectal cancer diagnosis

1975-1984 503 (9.5) 4095 (27.6)

<.001b1985-1994 1228 (23.1) 4063 (27.4)

1995-2004 1984 (37.4) 3983 (26.9)

≥2005 1595 (30) 2691 (18.1)

Race

White 4449 (83.8) 12 353 (83.3)

<.001bBlack 352 (6.6) 1170 (7.9)

Otherc 509 (9.6) 1309 (8.8)

Tumor grade

Grade I/II 3992 (75.2) 9899 (66.7) <.001b

Grade III/IV 777 (14.6) 1141 (7.7)

Unknown 541 (10.2) 3792 (25.6)

Tumor stage

<.001bLocalized 1742 (32.8) 11 393 (76.8)

Regional 3568 (67.2) 3439 (23.2)

Tumor histology

Adenocarcinoma 4831 (91) 14 181 (95.6)

<.001bMucous tumor 360 (6.8) 490 (3.3)

Other 119 (2.2) 161 (1.1)

Tumor size, cm

<2 191 (3.6) 827 (5.6)

<.001b≥2 1306 (24.6) 1323 (8.9)

Unknown 3813 (71.8) 12 682 (85.5)

Chemotherapy

No 1293 (24.4) 13 892 (93.7)<.001b

Yes 4017 (75.6) 940 (6.3)

Follow-up time of patients with rectal cancer,mo, median (IQR)

120.5 (93-175) 154 (99-232) <.001a

Total person-years at risk 65 397 205 487

Latency between rectal cancer and SGMN,mo, median (IQR)

110 (69.3-156.5) 123.5 (63.3-137.8) <.001a

Patients who developed SGMN 144 (2.7) 176 (1.2) <.001b

Abbreviations: IQR, interquartile range; SGMN, secondgynecological malignant neoplasm.a P values were calculated using the Mann-Whitney

test for continuous variables and χ2 test.b P values were calculated using the Mann-Whitney

test for categorical variables.c Other includes American Indian/Alaska Native and

Asian/Pacific Islander.

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adjusted RR, 5.13; 95% CI, 2.64-9.97; P < .001) (Figure 2B; eTable 14 in the Supplement). In thedynamic diagnosis time-RR plot, a slightly increased risk of cancer of the uterine corpus was observedafter radiotherapy in the years from 1975 to 1984, and this risk remained elevated up to the yearsfrom 2005 to 2015 (1975-1984: adjusted RR, 2.67; 95% CI, 1.48-4.83; P = .001; 1985-1994: adjustedRR, 3.58; 95% CI, 2.21-5.79; P < .001; 1995-2004: adjusted RR, 2.72; 95% CI, 1.62-4.59; P < .001;�2005: adjusted RR, 5.00; 95% CI, 1.80-13.92; P = .002) (Figure 2C; eTable 14 in the Supplement).However, we observed 3 opposite risk trends in 3 RR plots of ovarian cancer compared with the

Figure 1. Comparisons of Cumulative Incidence of Second Gynecological Malignant Neoplasma (SGMNs) Between Patients Who Received Radiotherapy (RT)and Patients Who Did Not Receive RT

0

No. at risk

120 180 240 300 360

5.00

4.00

Cum

ulat

ive

inci

denc

e, %

Time after rectal cancer diagnosis, mo

3.00

2.00

1.00

60

10 860 8608 7153 6222 574614 7243889 3242 2885 2699 26185274

10 860 8608 7153 6222 574614 7243889 3242 2885 2699 26185274

10 860 8608 7153 6222 574614 7243889 3242 2885 2699 26185274

After no RTAfter RT

After no RT

After RT

Cumulative incidences of SGMNs combinedA

0

No. at risk

120 180 240 300 360

1.20

1.00

Cum

ulat

ive

inci

denc

e, %

Time after rectal cancer diagnosis, mo

0.80

0.40

0.20

60

After no RTAfter RT

Cumulative incidences of ovarian cancer C

0

No. at risk

120 180 240 300 360

1.20

1.00

Cum

ulat

ive

inci

denc

e, %

Time after rectal cancer diagnosis, mo

0.80

0.40

0.60

0.20

60

After no RTAfter RT

Cumulative incidences of other SGMNsE

0

No. at risk

120 180 240 300 360

3.00

Cum

ulat

ive

inci

denc

e, %

Time after rectal cancer diagnosis, mo

2.50

1.00

1.50

2.00

0.50

60

10 860 8608 7153 6222 574614 7243889 3242 2885 2699 26185274

10 860 8608 7153 6222 574614 7243889 3242 2885 2699 26185274

After no RTAfter RT

Cumulative incidences of CUCB

0

No. at risk

120 180 240 300 360

0.30

0.25

Cum

ulat

ive

inci

denc

e, %

Time after rectal cancer diagnosis, mo

0.20

0.15

0.10

0.05

60

After no RTAfter RT

Cumulative incidences of cervical cancerD

Cumulative incidence:1.53% vs 4.53%; P <.001

Cumulative incidence:1.00% vs 2.80%; P <.001

Cumulative incidence:0.29% vs 0.98%; P = .007

Cumulative incidence:0.20% vs 0.62%; P = .007

Cumulative incidence:0.08% vs 0.11%; P = .60Cumulative incidence:0.08% vs 0.11%; P = .60

After RTAfter RT

After no RT

After no RT

After RT

After no RTAfter no RT

After RT

After no RT

After RT

P values were calculated with the Fine-Gray test. CUC indicates cancer of the uterine corpus.

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trends in cancer of the uterine corpus, such as in the latency-RR plot (60-119 months: adjusted RR,0.70; 95% CI, 0.26-1.89; P = .48; 120-239 months: adjusted RR, 2.26; 95% CI, 1.09-4.70; P = .03;240-360 months: adjusted RR, 11.84; 95% CI, 2.18-64.33; P = .004; Figure 2D, Supplement Table 15),age-RR plot (20-49 years: adjusted RR, 4.63; 95% CI, 0.40-54.17; P = .22; 50-69 years: adjusted RR,

Table 2. Risk of Developing SGMNs in Patients With Rectal Cancer by Statistical Methoda

SGMNs

Multivariable competing riskregression(RT vs NRT)

Poisson regression(RT vs NRT)

Poisson regression(RT vs US general population)

Poisson regression(NRT vs US general population)

Adjusted HR (95% CI) P value Adjusted RR (95% CI) P value Adjusted SIR (95% CI) P value Adjusted SIR (95% CI) P valueCombined SGMNs 2.99 (2.23-4.02) <.001 2.83 (2.24-3.60) <.001 2.32 (1.95-2.73) <.05 0.80 (0.69-0.93) <.05

Cancer of the uterinecorpus

3.06 (2.14-4.37) <.001 3.19 (2.39-4.26) <.001 2.88 (2.33-3.50) <.05 0.93 (0.76-1.12) NS

Ovarian cancer 2.08 (1.22-3.56) .007 2.26 (1.30-3.91) .004 1.34 (0.85-2.01) NS 0.54 (0.38-0.75) <.05

Cervical cancer NA NA 1.44 (0.48-4.30) .52 1.12 (0.37-2.62) NS 0.65 (0.33-1.17) NS

Other SGMNs 2.02 (0.71-5.57) .180 2.72 (1.43-5.16) .002 2.79 (1.65-4.41) <.05 0.98 (0.63-1.46) NS

Abbreviations: HR, hazard ratio; NRT, no radiotherapy; NA, not applicable; NS, nosignificance; RC, rectal cancer; RR, radiotherapy-associated risk; RT, radiotherapy; SGMN,second gynecological malignant neoplasm; SIR, standardized incidence ratio.a Fine-Gray competing risk regression analyses were used to calculate the HRs and 95%

CIs for SGMN in patients with rectal cancer treated with RT vs patients not treated withRT. Covariables that were significant in univariable competing risk regression analysis(P < .05) are included in the multivariable analysis. The HR (RT vs NRT) for cervical

cancer in univariable competing risk regression was not significant (P > .05), so thecervical cancer data were left blank in multivariable competing risk regression. Poissonregression analyses were used to calculate the RR and 95% CIs of SGMNs for patientswith RT vs patients with NRT. Similarly, Poisson regression analyses were used tocalculate the SIR and 95% CIs of SGMNs for patients with RT and NRT vs the US generalpopulation. Both RR and SIR were adjusted for age at RC diagnosis and calendar yearof RC diagnosis in our analysis.

Figure 2. Dynamic Radiotherapy-Associated Risk (RR) Plots

0

6

4

5

RR 3

2

1

60 180 240 300 360

Time after diagnosis, mo120

Corpus uteri cancer by rectal cancer latencyA

65

RR

25

30

35

40

45

50

55

60

10

15

20

5

060 180 240 300 360

Time after diagnosis, mo120

Ovarian cancer by rectal cancer latencyD

0

10

4

5

6

7

8

9

RR

3

2

1

20 40 50 60 70 80

Age, y30

Corpus uteri cancer by age at rectal cancerdiagnosis

B

55

RR 25

30

35

40

45

50

10

15

20

5

020 40 50 60 70 80

Age, y30

Ovarian cancer by age at rectal cancer diagnosisE

15

5

7

9

11

13RR

3

1

1975 1995 2005 2015

Year1985

Corpus uteri cancer by year of rectal cancerdiagnosis

C

32

RR

0

4

8

12

16

20

24

28

1975 1995 2005 2015

Year1985

Ovarian cancer by year of rectal cancer diagnosisF

Adjusted RRs and 95% CIs of developing cancer of the uterine corpus and ovarian cancer in patients treated with radiotherapy vs patients treated without radiotherapy are plotted.

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2.19; 95% CI, 1.13-4.21; P = .02; �70 years: adjusted RR, 2.02; 95% CI, 0.67-6.12; P = .21; Figure 2E,Supplement Table 15) and diagnosis time-RR plot (1975-1984: adjusted RR, 5.06; 95% CI, 1.46-17.55;P = .01; 1985-1994: adjusted RR, 3.05; 95% CI, 1.34-6.96; P = .008; 1995-2004: adjusted RR, 1.02;95% CI, 0.41-2.52; P = .97; �2005: adjusted RR, 1.93; 95% CI, 0.12-31.02; P = .64) (Figure 2D-F;eTable 14 and eTable 15 in the Supplement).

In addition, we evaluated the dynamic SIRs for patients treated with radiotherapy and patientsnot treated with radiotherapy. For patients not treated with radiotherapy, no increased incidencesof cancer of the uterine corpus (eFigure 5A-C in the Supplement) were observed compared with theincidence in the US general population in 3 plots. For patients who underwent radiotherapy, the SIRsfor cancer of the uterine corpus presented similar findings as the RR plots (eFigure 5A-C in theSupplement). In analyses of SIRs for ovarian cancer, we found that SIRs for ovarian cancer in patientswho did not receive radiotherapy were significantly lower than those in the US general populationin 3 plots (eFigure 5D-F in the Supplement), but no significant increased incidence of ovarian cancerwas observed for patients treated with radiotherapy compared with the US general population(eFigure 5D-F in the Supplement). The details of RRs and SIRs were shown in eTables 18-22 in theSupplement.

Survival Outcome of SGMNsWe compared survival between patients with cancer of the uterine corpus after radiotherapy and noradiotherapy, and the 10-year overall survival of patients who developed cancer of the uterine corpusafter radiotherapy was significantly lower than that of patients after no radiotherapy, both beforepropensity score matching (Figure 3A) and after propensity score matching (Figure 3B). We thenused matched only primary cancer of the uterine corpus patients as a control group by usingpropensity score matching. We observed that the 10-year overall survival for patients who developedcancer of the uterine corpus after radiotherapy was significantly lower than that for matched patientswith only primary cancer of the uterine corpus (10-year overall survival, 21.5% vs 36.6%; P = .01)(Figure 3C), and no difference was observed between patients without radiotherapy and matchedpatients with only primary cancer of the uterine corpus (Figure 3D). Information on only primaryGMNs and survival analyses for combined SGMNs, ovarian cancer, cervical cancer and other SGMNswere shown in eTables 23-27, and eFigures 6-9 in the Supplement.

Discussion

This is, to our knowledge, the first large population-based study to present the risk dynamics andprognosis of individual types of SGMN after radiotherapy among patients with rectal cancer. In ourstudy, the key findings are as follows. First, radiotherapy was considered an important risk factor forthe development of cancer of the uterine corpus and ovarian cancer in patients with rectal cancer.Second, the incidence of cancer of the uterine corpus after radiotherapy was higher than that in theUS general population. Third, the risks for developing cancer of the uterine corpus after radiotherapyincreased with age, increased with diagnosis time, and decreased with latency, but the oppositetrends were observed for ovarian cancer. Fourth, cancer of the uterine corpus after radiotherapypresented a poor prognosis.

Previous studies8-10,16 assessing the risk of SGMNs after radiotherapy treatment for rectalcancer showed conflicting results (eTable 28 in the Supplement); there are several reasons for thesevariations in results, including the definition of SGMNs, latency period selection, length of follow-upduration, methodology and sample size of the cohort population. Birgisson et al9 and Wiltink et al8

found that radiotherapy was not associated with an increased risk of developing SGMNs in patientswith rectal cancer. However, only 8 and 10 SGMNs were observed in these 2 studies, which lackedstatistical power to support their conclusions. Rombouts et al10 reported that SGMNs (combinedmalignant neoplasms of the corpus uteri, cervix uteri, ovary, vulva, and vagina) occurred morefrequently in patients with rectal cancer who received radiotherapy, but this study did not perform

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risk analyses for each type of SGMN. In addition, Kendal et al17 found that an increased risk ofdeveloping SGMNs, including cancer of the uterine corpus and cervical cancer as 1 group, afterradiotherapy treatment, but they did not consider the great heterogeneity among different types ofGMNs. To better address this issue, we separately estimated the risk for each type of SGMN inour study.

The issue of latency cut-off point was determined to be associated with the risk of SPCoccurrence after radiotherapy, which may be the main reason for the conflicting results regarding therisk of developing ovarian cancer from different studies.21 Wang et al19 reported that preoperativeradiotherapy increased the risk of SPCs in the uterus but not the cervix or ovary after a latency periodof more than 1 year. Similarly, Warschkow et al16 performed a cohort study to evaluate the risk forSPCs with a 1-year latency after radiotherapy treatment for rectal cancer and found that an increasedrisk of SGMNs after rectal cancer involved malignant neoplasms of the endometrium only, not theovary, cervix, or vulva. In our study, we identified SGMNs that occurred after a 5-year latency becausethe 5-year latency period from radiotherapy exposure to solid tumor occurrence allowed for a morereasonable conclusion to be drawn.4 To further confirm the latency influence on risk evaluation, werepeatedly analyzed the risk of SGMN using a 1-year cut-off latency, and found that the risk for cancerof the uterine corpus after radiotherapy continued to be increased, but no risk for other typesof SGMNs.

Figure 3. Survival Outcome of Second Gynecological Malignant Neoplasms

0

No. at risk

20 40 60 80 100 120

1.00

0.80

OS

Time, mo

0.60

0.40

0.20

0

77 65 48 36 30 2510644 28 20 17 14 1398

After no RTAfter RT

After no RT

After RT

Patients who developed CUC after RT vs after no RTA

10-y OS: 39.2% vs 21.5%HR, 1.79 (95% CI, 1.25-2.57); P = .002

0

No. at risk

20 40 60 80 100 120

1.00

0.80

OS

Time, mo

0.60

0.40

0.20

0

57 47 34 25 20 178140 24 17 15 12 1181

After no RTAfter RT

After no RT

After RT

Propensity score–matched patients who developed CUC after RTvs after no RT

B

10-y OS: 32.8% vs 20.9%HR, 1.68 (95% CI, 1.12-2.51); P = .01

020 40 60 80 100 120

1.00

0.80

OS

Time, mo

0.60

0.40

0.20

0

44 28 20 17 14 1398

278 204 155 128 108 96490

No. at riskCUC after RTMatched onlyprimary CUC

CUC after RT

Matched onlyprimary CUC

Patients who developed CUC after RT vs patients with onlyprimary CUC

C

10-y OS: 21.5% vs 36.6%HR, 1.42 (95% CI, 1.08-1.87); P = .01

020 40 60 80 100 120

1.00

0.80

OS

Time, mo

0.60

0.40

0.20

0

77 65 48 36 30 25106

398 309 262 209 162 137530

No. at riskCUC after no RTMatched onlyprimary CUC

CUC after no RT

Matched onlyprimary CUC

Patients who developed CUC after no RT vs patients with onlyprimary CUC

D

10-y OS: 39.2% vs 45.0%HR, 1.21 (95% CI, 0.90-1.62); P = .20

Hazard ratios (HRs) were calculated using Cox proportional hazards regression models. CUC indicates cancer of the uterine corpus; OS, overall survival; RT,radiotherapy.

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The statistical methods used for analysis are essential for the interpretation of the results. Weused both competing risk regression and Poisson regression to assess the risk of SGMNs. Herein, weassessed the increased risks of cancer of the uterine corpus and ovarian cancer after radiotherapy,but other types of SGMNs presented conflicting results according to different statistical method. Wecompared the incidence of SGMNs in patients who survived rectal cancer to the US generalpopulation, which could provide a more comprehensive understanding of the association betweenradiotherapy and the incidence of SGMNs.

In our analyses, we assessed the dynamic risk and incidence of SGMNs. The highestradiotherapy-associated risk for developing ovarian cancer was found after a latency of more than 20years, but for cancer of the uterine corpus, the highest risk was within 5 to 10 years. This findingsuggests that long-term follow-up may be warranted for the detection of ovarian cancer afterradiotherapy, but follow-up for cancer of the uterine corpus should be considered in the early latency.An increased risk of cancer of the uterine corpus was observed with increasing age at diagnosis butwas significantly decreased for ovarian cancer. This finding showed that both young patients andpatients aged 50 years or older with rectal cancer who underwent radiotherapy faced a high risk ofcancer of the uterine corpus. The mechanism underlying these opposite results between cancer ofthe uterine corpus and ovarian cancer warrants further study. Despite the improvements inradiotherapy treatment for rectal cancer in recent decades associated with better local control, ourfindings showed that the risk of cancer of the uterine corpus increased to 2.7-fold from 1975 to 1984and gradually increased to 5.0-fold after 2005. This finding may be associated with changes inradiotherapy dose and radiotherapy modality over time. During the study period from 1973 to 2015,radiotherapy treatment modality has shifted toward hypofractionation, which may underlie thehigher incidence of cancer of the uterine corpus in more recent years.

Compared with nonradiotherapy-associated GMNs, the clinical phenotype and prognosis ofradiotherapy-associated SGMNs may present great heterogeneity. In our study, we found thatpatients with radiotherapy-associated cancer of the uterine corpus had worse survival than matchedcontrol patients with only primary cancer of the uterine corpus. However, no survival differencesbetween radiotherapy-associated GMNs and only primary GMNs were observed for other types ofGMNs. This finding suggests that the occurrence of radiotherapy-associated cancer of the uterinecorpus might be due to the induction of other genetic signaling pathways after radiotherapyexposure, which is different from the normal genetic pathway of only primary cancer of the uterinecorpus development. Owing to the varied genetic phenotype, radiotherapy-associated cancer of theuterine corpus is resistant to conventional treatment and presents worse prognosis. However, nogenomic data in the SEER database could be used to interpret the genetic features of cancer of theuterine corpus after radiotherapy exposure.

Strengths and LimitationsThe strengths of the present study include a long follow-up period to discover potential SGMNs aswell as a large observation population with relatively homogenous treatment exposure identifiedfrom the SEER database. This study has limitations. First, a lack of randomization of the initialtreatment for rectal cancer may be associated with potential biases. However, the occurrence ofSGMNs may not only be associated with radiotherapy exposure but may also be affected by othercrucial risk factors, such as lifestyle, genetic background, environmental factors, and other cancer-related treatments.22 Therefore, it is impossible to balance all factors between the 2 treatment types.Instead, we adjusted all confounding risk factors using a multivariable risk competing model toreduce the potential bias associated with the lack of randomization. Second, we could not determinethe associations between modality of radiotherapy, radiotherapy dose, and number ofadministrations and the risk of SGMNs. Third, the SEER database records only the initial treatmentinformation of rectal cancer, and whether patients with rectal cancer received delayed radiotherapyin subsequent treatment is unknown, which may potentially misclassify the patients in theradiotherapy group into the no-radiotherapy group. However, this limitation is unlikely to affect our

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main conclusion but reflects only an underestimation of the increased risk attributable toradiotherapy.

Conclusions

In this cohort study, several methodologies were used together to assess an increased risk ofdeveloping cancer of the uterine corpus and ovarian cancer in female patients with rectal cancer whoreceived radiotherapy, and the risk of SGMN was evaluated from several dimensions, which togethercould provide a meaningful reference for the treatment and follow-up of SGMNs in patients withrectal cancer after radiotherapy.

ARTICLE INFORMATIONAccepted for Publication: October 25, 2020.

Published: January 8, 2021. doi:10.1001/jamanetworkopen.2020.31661

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Guan X et al.JAMA Network Open.

Corresponding Authors: Xishan Wang, MD, PhD (wxshan1208@126.com), and Zheng Jiang, MD, PhD(812818858@qq.com), Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, ChineseAcademy of Medical Sciences & Peking Union Medical College, Beijing, China, 100021.

Author Affiliations: National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & PekingUnion Medical College, Beijing, China (Guan, Wei, Lu, E. Liu, Zhao, Chen, M. Yang, Z. Liu, Jiang, Wang); The SecondAffiliated Hospital of Harbin Medical University, Harbin, China (R. Yang, Wang).

Author Contributions: Drs Wang and Jiang had full access to all of the data in the study and take responsibility forthe integrity of the data and the accuracy of the data analysis. Drs Guan and Wei contributed equally to this workas first co–authors.

Concept and design: Guan, Wei, Jiang, Wang.

Acquisition, analysis, or interpretation of data: Wei, R. Yang, Lu, E. Liu, Zhao, Chen, M. Yang, Z. Liu, Jiang, Wang.

Drafting of the manuscript: Guan, Wei, Lu, Zhao, Z. Liu, Jiang.

Critical revision of the manuscript for important intellectual content: Wei, R. Yang, E. Liu, Chen, M. Yang,Jiang, Wang.

Statistical analysis: Guan, Wei, R. Yang, Lu, E. Liu, M. Yang, Z. Liu, Jiang, Wang.

Obtained funding: Wei, Jiang.

Administrative, technical, or material support: Chen, Jiang.

Supervision: Jiang, Wang.

Conflict of Interest Disclosures: None reported.

Additional Contributions: The authors thank Fahad Mukhtar MD, MPH (Department of Epidemiology andBiostatistics, College of Public Health, University of South Florida), for insightful comments and valuablesuggestions that have inspired us to further improve our manuscript. No compensation was received.

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SUPPLEMENT.eFigure 1. Flow DiagrameFigure 2. Statistical Methods AnnotationeFigure 3. Subgroup Analyses of Competing Risk Regression for the Risk of Developing Corpus Uteri CancereFigure 4. Subgroup Analyses of Competing Risk Regression for the Risk of Developing Ovarian CancereFigure 5. Dynamic Standardized Incidence Ratios

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eFigure 6. Survival Comparisons Between RC Patients Who Developed SGMseFigure 7. Survival Comparisons Between RC Patients Who Developed OCeFigure 8. Survival Comparisons Between RC Patients Who Developed CCeFigure 9. Survival Comparisons Between RC Patients Who Developed Other Types of SGMseTable 1. The Description of Tumor Stage of Rectal Cancer in SEER ProgrameTable 2. Comparisons of Baseline Characteristics of RC Patients Who Developed SGMs by Treatment TypeeTable 3. Univariable and Multivariable Competing Risk Regression Analysis of Risk of Developing Combined SGMsin RC PatientseTable 4. Univariable and Multivariable Competing Risk Regression Analysis of Risk of Developing Corpus UteriCancer in RC PatientseTable 5. Univariable and Multivariable Competing Risk Regression Analysis of Risk of Developing Ovarian Cancerin RC PatientseTable 6. Univariable and Multivariable Competing Risk Regression Analysis of Risk of Developing Cervical Cancerin RC PatientseTable 7. Univariable and Multivariable Competing Risk Regression Analysis of Risk of Developing Other SGMs inRC PatientseTable 8. Subgroup Analyses of Hazard Ratios of Developing Combined SGMs in RC Patients Who Received RTVersus RC Patients Who Did Not Receive RTeTable 9. Subgroup Analyses of Hazard Ratios of Developing Corpus Uteri Cancer in RC Patients Who Received RTVersus Those Who Did Not Receive RTeTable 10. Subgroup Analyses of Hazard Ratios of Developing Ovarian Cancer in RC Patients Who Received RTVersus Those Who Did Not Receive RTeTable 11. Subgroup Analyses of Hazard Ratios of Developing Cervical Cancer in RC Patients Who Received RTVersus Those Who Did Not Receive RTeTable 12. Subgroup Analyses of Hazard Ratios of Developing Other SGMs in RC Patients Who Received RT VersusThose Who Did Not Receive RTeTable 13. Radiation-attributed Risk of Combined SGMs by Age at RC Diagnosis, Latency and Year of RC DiagnosiseTable 14. Radiation-attributed Risk of Corpus Uteri Cancer by Age at RC Diagnosis, Latency and Year of RCDiagnosiseTable 15. Radiation-attributed Risk of Ovarian Cancer by Age at RC Diagnosis, Latency and Year of RC DiagnosiseTable 16. Radiation-attributed Risk of Cervical Cancer by Age at RC Diagnosis, Latency and Year of RC DiagnosiseTable 17. Radiation-attributed Risk of Other SGMs by Age at RC Diagnosis, Latency and Year of RC DiagnosiseTable 18. Standardized Incidence Ratio of Combined SGMs by Age at RC Diagnosis, Latency and Year of RCDiagnosiseTable 19. Standardized Incidence Ratio of Corpus Uteri Cancer by Age at RC Diagnosis, Latency and Year of RCDiagnosiseTable 20. Standardized Incidence Ratio of Ovarian Cancer by Age at RC Diagnosis, Latency and Year of RCDiagnosiseTable 21. Standardized Incidence Ratio of Cervical Cancer by Age at RC Diagnosis, Latency and Year of RCDiagnosiseTable 22. Standardized Incidence Ratio of Other SGMs by Age at RC Diagnosis, Latency and Year of RC DiagnosiseTable 23. Patients Characteristics of Corpus Uteri Cancer and Matched Only Primary Corpus Uteri CancereTable 24. Patients Characteristics of Ovarian Cancer and Matched Only Primary Ovarian CancereTable 25. Patients Characteristics of Cervical Cancer and Matched Only Primary Cervical CancereTable 26. Patients Characteristics of Other SGMs and Matched Other Only Primary SGMseTable 27. Patients Characteristics of Corpus Uteri Cancer Before and After PSM MatchingeTable 28. Studies of The Risk of Developing SGMs After Radiation Therapy Among RC Patients

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