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Keywords:

  • radiotherapy;
  • second primary cancer;
  • rectal cancer;
  • prostatic cancer

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

External beam radiation therapy (EBRT) for rectal cancer unavoidably delivers significant radiation dose to the prostate gland. The effect of this incidental exposure on subsequent prostate cancer diagnosis was investigated using the Surveillance, Epidemiology, and End Results (SEER) cancer registry.

METHODS.

Men diagnosed with localized or regional (L/R) rectal cancer from 1988–1997 and treated with EBRT and sphincter-sparing surgery (SSS) were identified. Men treated for L/R rectal cancer with SSS who did not receive EBRT, and men with L/R colon cancer who did not receive EBRT, were studied for comparison. Multiple Primary Standardized Incidence Ratios of observed to expected (O/E) cases of prostate cancer were calculated using SEER*Stat.

RESULTS.

In all, 1574 men with L/R rectal cancer treated with EBRT and SSS were identified. The median age at diagnosis was 64 and median survival was 76 months. Twenty were subsequently diagnosed with prostate cancer, a number significantly less than expected compared with the general population of similar age and race. The ratio of O/E cases was 0.28 (95% confidence interval [CI], 0.17, 0.43). In contrast, 3114 men diagnosed with rectal cancer undergoing SSS who were not treated with EBRT and 24,578 men diagnosed with colon cancer who were not treated with EBRT were subsequently diagnosed with prostate cancer at rates similar to the general population (O/E of 0.94 and 1.09).

CONCLUSIONS.

EBRT for L/R rectal cancer was associated with a 72% decrease in the frequency of subsequent prostate cancer diagnosis when compared with men of similar age and race. Possible mechanisms that may explain this observation are discussed. Cancer 2008. © 2007 American Cancer Society.

Approximately 218,890 new cases of prostate cancer and 23,840 new cases of rectal cancer will be diagnosed in men living in the US in 2007.1 National Comprehensive Cancer Network guidelines recommend local radiation as a component of rectal cancer treatment in patients with T3 or T4 disease, in patients with N1 or N2 nodal disease, and in patients with incompletely resected disease.2 Traditional treatment in the US includes approximately 45 Gy to the posterior pelvis, generally supplemented by additional boost dose delivered to the tumor or resection bed.3, 4 Consequently, the prostate and bladder unavoidably receive a significant radiation dose.

The impact of inadvertent prostate radiation on subsequent prostate cancer diagnosis is unknown. Diagnosis may be increased if radiation induces new prostate cancers, analogous to the increased incidence of rectal cancer detected after prostate irradiation.5, 6 Alternatively, diagnosis may be decreased if radiation sterilizes occult preexisting prostate cancer or if radiation reduces the utility of prostate-specific antigen (PSA) as a screening tool.7, 8

Using data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, we evaluated the frequency of subsequent prostate cancer diagnosis in men who received external beam radiation therapy (EBRT) for rectal cancer, in men who did not receive EBRT for rectal cancer, and in men who did not receive EBRT for colon cancer.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Subjects

Three populations diagnosed with colon or rectal cancer between 1988 and 1997 were identified in the SEER cancer registry (9 Registries Public Use Data, 1973–2003)9: 1) men with local or regional rectal cancer treated with sphincter-sparing surgery (SSS) and EBRT; 2) men with local or regional rectal cancer treated with SSS not receiving EBRT; and 3) men with local or regional colon cancer not receiving EBRT.

The SEER program of the National Cancer Institute assembles information on cancer incidence and survival in the US. The SEER program registries routinely collect data on patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status. The public use data contains information on whether or not a subject received radiation. However, it contains neither the radiation details (such as dose) nor information on systemic treatment. The catchment for the 9 registries used in this analysis included 10% of the US population.

SSS permits digital rectal exam (DRE) for prostate evaluation. After abdominoperineal resection, this is no longer feasible. Men treated with local tumor destruction, local tumor excision, wedge or segmental resection, or pull through with sphincter preservation were defined as having SSS. DRE and PSA are used for prostate cancer diagnosis. DRE is an important tool, given its ease, lack of cost, high specificity, and ability to detect cancer in men with normal PSA levels.10–12 This study potentially included men screened for prostate cancer in the PSA era. Men with a prior cancer diagnosis, including prostate cancer, and men who underwent abdominoperineal resection were excluded. The 1988–1997 date range allowed at least 6 years for diagnosis of subsequent prostate cancer. Among those with localized or regional prostate cancer, the extent of the disease was classified as: 1) incidental diagnosis of prostate cancer (not palpated clinically); 2) prostate confined disease; 3) disease extension beyond the prostate; and 4) disease that invaded into or was fixed to adjacent organs. Pathologic extent of disease classification was used when men had both clinical and pathologic extent of disease information. Radiation treatment and surgical treatment for prostate cancer were categorized as: i) recommended or performed and ii) not recommended or performed. If the subject refused treatment, it was assumed treatment was recommended. Cause of death was determined by International Classification of Diseases (ICD) codes.

Statistical Analysis

Multiple Primary Standardized Incidence Ratios of observed to expected (O/E) cases of prostate cancer were calculated using SEER*Stat. SEER*Stat is statistical software for the analysis of SEER and other cancer-related databases.13 The defined cohort of men diagnosed with colorectal cancer was followed through time to compare their subsequent prostate cancer experience to the number of prostate cancers that would be expected based on incidence rates for the general population. The expected rates were calculated taking into account age, race, and year. For this analysis each person in the cohort was followed until they developed prostate cancer, were lost to follow-up, death, or until the study cutoff date of 2003.14

Prostate cancer mortality, prostate cancer treatment, and prostate cancer distribution by stage, grade, and extent of disease were compared using chi-square or Fisher exact tests between: 1) men treated for rectal cancer with EBRT and men treated for rectal cancer without EBRT, and 2) men treated for rectal cancer with EBRT and men treated for colon cancer without EBRT.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 1574 men with local or regional rectal cancer treated with SSS and EBRT were identified (Table 1); 589 (37%) of these cases were localized and 985 (63%) were regional. Median age at diagnosis was 64. Median survival after rectal cancer diagnosis was 76 months. Twenty men subsequently developed prostate cancer (Table 2), a number significantly less than expected based on the general population. The ratio of observed to expected cases was 0.28 (95% confidence interval [CI], 0.17, 0.43) (Fig. 1). Prostate cancer was diagnosed 2 months to 10 years after rectal cancer diagnosis (median, 5.4 years) and median age at prostate cancer diagnosis was 75. Sixteen of 17 (94%) prostate cancers with staging information were localized or regional at diagnosis and 1 had distant disease at diagnosis. Among those with localized or regional disease, 3 (19%) were classified as having an incidental diagnosis of prostate cancer (not palpated clinically), 12 (75%) had prostate-confined disease, and 1 (6%) had disease extension beyond the prostate. Twelve of 19 cases (63%) with grade information were moderately differentiated and the other 7 were poorly differentiated. The risk of a prostate cancer diagnosis was significantly less than expected in both 1 to 5 year (O/E 0.15; 95% CI, 0.05, 0.34) and 5 to 10 year (O/E 0.44; 95% CI, 0.21, 0.80) intervals since rectal cancer diagnosis. On the basis of ICD-9 and ICD-10 codes, of the 20 men diagnosed with prostate cancer after rectal cancer, 3 died from prostate cancer, 5 died from colorectal cancer, 1 died of malignancy not otherwise specified, 2 died of other causes, and 9 were alive at last follow-up.

thumbnail image

Figure 1. Ratio of prostate cancer cases diagnosed after treatment for colorectal cancer to the expected frequency of prostate cancer diagnosis based on the age and race adjusted general population. EBRT indicates external beam radiation treatment; vertical bars are 95% confidence intervals.

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Table 1. Characteristics of Colorectal Cancer Cases Identified in the SEER 9 Cancer Registry
 Men with L/R rectal cancer treated using SSS and EBRTMen with L/R rectal cancer treated using SSS without EBRTMen with L/R colon cancer treated without EBRT
  1. L/R indicates local regional; SSS, sphincter-sparing surgery; EBRT, external beam radiation therapy.

No. of men with rectal or colon cancer meeting inclusion criteria1574311424,578
Rectal or colon cancer stage589 (37%) local2588 (83%) local12,535 (51%) local
985 (63%) regional526 (17%) regional12,043 (49%) regional
Median age at diagnosis of rectal or colon cancer646870
Median survival after rectal or colon cancer diagnosis76 mo89 mo83 mo
Table 2. Characteristics of Prostate Cancer Diagnosed After Treatment for Colorectal Cancer
 Men with L/R rectal cancer treated using SSS and EBRT (n = 1574)Men with L/R rectal cancer treated using SSS without EBRT (n = 3114)Men with L/R colon cancer treated without EBRT (n = 24,578)
  • L/R indicates local regional; SSS, sphincter-sparing surgery; EBRT, external beam radiation therapy.

  • *

    Percentage of cases with stage information.

  • Cases with grade information.

No. of men subsequently diagnosed with prostate cancer201641526
Median age at prostate cancer diagnosis757575
Prostate cancer stage*16 (94%) L/R134 (91%) L/R1284 (93%) L/R
1 (6%) distant13 (9%) distant101 (7%) distant
3 unknown17 unknown141 unknown
Prostate cancer differentiation7 (36%) poor43 (28%) poor325 (21%) poor
12 (63%) moderate93 (60%) moderate885 (58%) moderate
 18 (12%) well147 (10%) well

In all, 3114 men with local or regional rectal cancer treated with SSS who did not receive radiation therapy were identified (Table 1); 2588 (83%) of these cases were localized and 526 (17%) were regional. The median age at diagnosis was 68. Median survival after rectal cancer diagnosis was 89 months and 164 men subsequently developed prostate cancer (Table 2). This number was similar to the general population, with an O/E of 0.94 (95% CI 0.80, 1.10) (Fig. 1). Prostate cancer was diagnosed 9 months to 16 years after rectal cancer diagnosis (median, 3.5 years) and median age at prostate cancer diagnosis was 75. In all, 134 of 147 (91%) prostate cancers with staging information were localized or regional at diagnosis and 13 (9%) had distant disease at diagnosis. Among those with localized or regional disease, 31 (23%) were classified as having an incidental diagnosis of prostate cancer (not palpated clinically), 87 (65%) had prostate-confined disease, 12 (9%) had disease extension beyond the prostate, and 4 (3%) had disease that invaded into or was fixed to adjacent organs. Eighteen of 154 (28%) cases with grade information were well differentiated, 93 (60%) were moderately differentiated, and 43 (28%) were poorly differentiated. The risk of a prostate cancer diagnosis was similar to the general population in both 1 to 5 year (O/E 0.94; 95% CI, 0.74, 1.18) and 5 to 10 year (O/E 0.84; 95% CI, 0.62, 1.11) intervals since rectal cancer diagnosis. On the basis of ICD-9 and 10 codes, of the 164 men diagnosed with prostate cancer after rectal cancer, 17 died of prostate cancer, 14 died of colorectal cancer, 9 died of cancer not otherwise specified, 1 died of unknown causes, 41 died of other medical causes, and 82 were alive at last follow-up.

A total of 24,578 men with local or regional colon cancer who did not receive radiation therapy were identified (Table 1); 12,535 (51%) of these cases were localized and 12,043 (49%) were regional. The median age at diagnosis was 70. Median survival after colon cancer diagnosis was 83 months and 1526 men subsequently developed prostate cancer (Table 2). This number was slightly higher than expected compared with the general population, with an O/E of 1.09 (95% CI, 1.03, 1.14) (Fig. 1). Prostate cancer was diagnosed 2 months to 15 years after colon cancer diagnosis (median, 4 years) and median age at prostate cancer diagnosis was 75. In all, 1284 of 1385 (93%) prostate cancers with staging information were localized or regional at diagnosis and 101 (7%) had distant disease at diagnosis. Among those with localized or regional disease, 383 (30%) were classified as having an incidental diagnosis of prostate cancer (not palpated clinically), 774 (60%) had prostate-confined disease, 107 (8%) had disease extension beyond the prostate, and 20 (2%) had disease that invaded into or was fixed to adjacent organs. In all, 147 of 1357 (10%) cases with grade information were well differentiated, 885 (58%) were moderately differentiated, and 325 (21%) were poorly differentiated. On the basis of ICD-9 and 10 codes, of the 1526 men diagnosed with prostate cancer after colon cancer, 130 died of prostate cancer, 106 died of colorectal cancer, 15 died of cancer not otherwise specified, 11 died of unknown causes, 457 died of other medical causes, and 807 were alive at last follow-up.

Men treated for rectal cancer with EBRT and men treated for rectal cancer without EBRT had similar prostate cancer grade distribution (poor, moderate, or well; P = .293), similar prostate cancer stage distribution (local/regional vs distant; P = .359), and among those with localized or regional disease, similar T-stage distribution (incidentally found disease, disease confined to the prostate, extension beyond the prostate, or extending into or fixed to adjacent organs or bone; P = .945). Likewise, men treated for rectal cancer with EBRT and men treated for colon cancer without EBRT had similar prostate cancer grade distribution (poor, moderate, or well; P = .187), similar prostate cancer stage distribution (local/regional vs distant; P = 1.0), and among those with localized or regional disease, similar T-stage distribution (incidentally found disease, disease confined to the prostate, extension beyond the prostate, or extending into or fixed to adjacent organs or bone; P = .945).

Men treated for rectal cancer with EBRT were less likely to receive radiation or to have radiation therapy recommended for their subsequent localized or regional prostate cancer than men treated for rectal cancer without EBRT (16.7% vs 55.7%, P = .031) and men treated for colon cancer without EBRT (16.7% vs 39.4%, P = .037). Men treated for rectal cancer with EBRT underwent surgery or had surgery recommended for their subsequent localized or regional prostate cancer at rates similar to men treated for rectal cancer without EBRT (75.0% vs 72.4%, P = 1.0) and men treated for colon cancer without EBRT (75.0% vs 63.1%, P = .437).

Men treated for rectal cancer with EBRT and men treated for rectal cancer without EBRT had similar prostate cancer mortality (0.19% vs 0.55%, P = .097). Likewise, men treated for rectal cancer with EBRT and men treated for colon cancer without EBRT had similar prostate cancer mortality (0.19% vs 0.53%, P = .067).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

These results demonstrate that EBRT for rectal cancer was associated with a 72% reduction in the subsequent diagnosis of prostate cancer compared with the observed frequency in men of similar age and race. No reduction was found in men with rectal cancer who did not receive EBRT or in men with colon cancer who did not receive EBRT. Although posttreatment surveillance, including medical imaging, may have changed over the 15 years of this study, these 3 groups of men with colorectal cancer could be expected to have similar prostate cancer risk factors, similar posttreatment medical imaging, similar general medical assessments, and similar longitudinal contact with physicians and access to screening. This finding is in marked contrast to the increase in rectal cancer diagnosis observed after radiation for prostate cancer previously demonstrated using a similar SEER database analysis.5

Rectal and prostate cancers are diagnosed at a similar time in life. The median age of rectal cancer diagnosis in males is 66 and the median age of prostate cancer diagnosis is 68.15 In this study the diagnosis of prostate cancer decreased after EBRT for rectal cancer. The potential explanations for this observation fall into 2 broad categories. Either radiation therapy for rectal cancer reduces the ability to detect prostate cancer or radiation therapy reduces the development or progression of cancer within the prostate.

Screening for prostate cancer has become commonplace in the US since the early 1990s. The standard tools are the PSA test and the DRE. Inadvertent irradiation given during the treatment of bladder or rectal cancer can significantly reduce PSA levels. The reduction is 50% on average and lasts for many years.7, 8 This ‘ascertainment bias’ may reduce the utility of PSA as a screening tool in this population. If PSA utility were reduced, prostate cancer diagnosis could be delayed, which could result in more advanced disease at diagnosis. However, in this study the extent of prostate cancer at diagnosis after EBRT for rectal cancer was similar to the extent of disease after treatment for colorectal cancer without EBRT. In the face of another serious disease, it is also possible that physicians are less aggressive in their search for prostate cancer. Yet a decrease in prostate cancer diagnosis was still demonstrated 5 years after rectal cancer treatment, a timepoint when many patients are considered ‘cured.’

The second potential explanation for this observed decline in prostate cancer detection rates is biologic. Inadvertent irradiation of the prostate during treatment for rectal cancer may sterilize or cytoreduce subclinical prostate cancer or precancerous intraepithelial lesions. Support for this concept can be found from data reporting a decrease in the incidence of lumbar spine metastasis in prostate cancer patients who received prophylactic paraortic lymph node treatment.16 In addition, radiation may impede cancer progression by altering the local hormonal or stromal milieu. Such effects may decrease the risk of subsequent clinically significant prostate cancer and could be analogous to radiation's efficacy in reducing the incidence of subsequent invasive breast cancer in patients irradiated for ductal carcinoma in situ of the female breast.17, 18

EBRT could differentially affect subclinical prostate cancer or precancerous intraepithelial lesions based on their degree of histologic differentiation and increase the risk of poorly differentiated tumors. However, in this study the histologic grade of prostate cancer diagnosed after EBRT for rectal cancer was similar to the grade distribution after treatment for colorectal cancer without EBRT. The number of men diagnosed with prostate cancer after EBRT for rectal cancer was small, so a subtle difference in grade distribution may not have been apparent.

Treatment options for prostate cancer diagnosed after EBRT for rectal cancer include radical prostatectomy, reirradiation with brachytherapy, and hormonal therapy. Higher complication rates would be expected for surgery and reirradiation than in those without prior radiation. As anticipated, men who received EBRT for rectal cancer were less likely to receive radiation or have radiation therapy recommended for subsequent prostate cancer than men who did not receive EBRT for colorectal cancer. Although prior radiation therapy may have limited their treatment options, men who received EBRT for rectal cancer did not have increased prostate cancer mortality compared with men who did not receive EBRT for colorectal cancer.

Patients who received EBRT for rectal cancer in the Swedish rectal cancer trial and the Uppsala trial had an increased risk of second cancer in organs within or adjacent to the irradiated volume compared with those who did not receive radiation. However, the relative risk of subsequent prostate cancer diagnosis was not significantly increased or decreased.19 There are several potential explanations for why there was a decrease in subsequent prostate cancer diagnosis after EBRT in this study but not after EBRT in the Uppsala and Swedish trials. In the US, standard treatment for rectal cancer delivers doses in the range of 45 to 54 Gy in 1.8 to 2 Gy fractions in conjunction with chemotherapy.3, 4 Most patients enrolled in the Swedish and Uppsala trials received EBRT delivered to 25 Gy in 5 Gy fractions without chemotherapy.20, 21 Thus, the difference in findings may reflect a treatment effect. Patients who received EBRT in the Uppsala and Swedish trials did not commonly undergo PSA testing for early detection of prostate cancer and a large portion of the men who received surgery and radiation underwent an abdominoperineal resection, prohibiting a DRE for prostate cancer screening (243 of 454 men and women in the Swedish trial20 and 127 of 382 men and women in the Uppsala trial21 underwent an APR). Therefore, prostate cancer in those individuals probably would have been diagnosed after it had become symptomatic within the prostate or through metastasis. All men selected for this SEER study had SSS, permitting DRE. It is likely that some men who received EBRT for rectal cancer in this study underwent PSA screening, because PSA screening was common after 1990 in the US.

We acknowledge that this study has several limitations. The SEER cancer registry does not provide information regarding chemotherapy received, hormonal therapy received, radiation dose and fractionation, or the method of prostate cancer diagnosis. However, the national radiation and chemotherapy practice from this time period are known from patterns of care studies and clinical experience. This study was a hypothesis-generating effort and cannot identify the basis for the observed difference in prostate cancer diagnosis. A prospective study would be required to clarify the mechanism. The mean follow-up after EBRT for rectal cancer was 6.2 years (maximum, 15.8 years); it is possible that with the passage of more time the prostate cancer risk after rectal radiotherapy could increase from the late induction of new cancers.

Long-term follow-up after radiation treatment for cervix, breast, prostate, pediatric, and other cancers have shown an increased risk of second cancers within or adjacent to the radiation field.5, 6, 22–26 This is the only study of which we are aware that focused on the frequency of prostate cancer detection after EBRT for rectal cancer in the US. The substantial decrease in diagnosis may be the result of a reduced ability to detect prostate cancer or may be a true biologic effect. Either way, when discussing EBRT with patients as part of the multimodality treatment of rectal cancer it is reassuring to know that EBRT does not appear to increase the risk of subsequent clinically significant prostate cancer over the first decade of follow-up.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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