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Two secondary malignancies after radiotherapy for seminoma: case report and review of the literature
CASE REPORT
TWO SECONDARY MALIGNANCIES AFTER RADIOTHERAPY FOR SEMINOMA: CASE REPORT AND REVIEW OF THE LITERATURE MICHAEL A. HUGHES, ALICE WANG,
AND
THEODORE L. DEWEESE
ABSTRACT We report a case of a 50-year-old man with two synchronous second malignancies 25 years after orchiectomy and adjuvant radiotherapy for seminoma. An annual health examination revealed an elevated prostatespecific antigen level. A biopsy was performed revealing Gleason score 9 adenocarcinoma of the prostate. Computed tomography of the abdomen revealed a 2-cm solid mass in the right kidney consistent with renal cell carcinoma. Both of these lesions were within the nonstandard radiation field for seminoma with which this patient was treated. Second malignancies, including prostate cancer, are a very uncommon occurrence but an important consideration in long-term survivors of seminoma treated with radiotherapy. UROLOGY 62: 748i–748iii, 2003. © 2003 Elsevier Inc.
I
t is generally accepted that exposure to radiation places patients at risk of second malignant neoplasms. Secondary neoplasms are very uncommon but are a serious sequela of radiotherapy, with the potential for significant health problems in a patient cured of a primary neoplasm. The risk is increased in diseases in which treatment produces long-term disease-free survival, such as Hodgkin’s disease or seminoma. The incidence increases with increasing time after treatment and with increasing dose. Although the contemporary management of seminoma includes treatment with relatively low doses of radiation, the doses used previously were higher and fields were larger than those used today. Moreover, patients are usually young, and the cure rate is high. This combination makes the development of a secondary malignancy, particularly in or near the radiation fields, an important consideration. In this report, we present a case of prostate and renal cell cancer found in a patient at an annual examination 25 years after orchiectomy and radiotherapy for seminoma.
From the Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Address for correspondence: Theodore L. DeWeese, M.D., Department of Radiation Oncology, 401 North Broadway, Suite 144, Baltimore, MD 21231 Submitted: April 17, 2003, accepted (with revisions): June 10, 2003 © 2003 ELSEVIER INC. ALL RIGHTS RESERVED
CASE REPORT A 50-year-old man presented to his primary care physician for his annual physical examination. He reported a several-year history of decreased urinary stream and incomplete emptying of his bladder. In the prior several weeks, the patient had noted increased urinary frequency and nocturia, but no other symptoms. His past medical history was remarkable for early-stage seminoma 25 years earlier, which had been treated with orchiectomy and adjuvant radiotherapy at an outside institution to a total dose of 30 Gy to the bilateral pelvis and para-aortic lymph nodes. The physical examination revealed an absent right testis and a mildly atrophic left testis. The rectal examination revealed a 30-g prostate that was mildly tender, firm, with induration of the apex bilaterally, and intact sulci. The fecal occult blood test was negative. Laboratory studies revealed a prostate-specific antigen level of 12.0 ng/mL. He was diagnosed with prostatitis and began taking ciprofloxacin. He was also scheduled for a biopsy of his prostate. After 2 weeks of antibiotic treatment, his prostatitis symptoms resolved. The biopsy of his prostate revealed Gleason score 4 ⫹ 5 ⫽ 9 adenocarcinoma involving 70% of multiple fragmented cores, with perineural invasion identified. A whole body bone scan was negative for metastatic disease. Computed tomography of the abdomen and pelvis revealed no evidence of metastatic disease but showed a 2-cm, ill-defined 0090-4295/03/$30.00 doi:10.1016/S0090-4295(03)00669-1 748i
TABLE I. Selected recent studies of second malignancy in seminoma
Ruther et al.,1 2000 Bachaud et al.,2 1999 Bauman et al.,3 1998 Akimoto et al.,4 1997 Travis et al.,5 1997 Chao et al.,6 1995
n
Median/Mean Follow-up (yr)
839 131 212 94 15,602 128
3.9 11 7.5 12 10.2 11.7
Second Cancers (n) 9 14 6 7 1,033 9
(1.1) (10.7) (2.8) (7.4) (6.6) (7.0)
Relative Risk (95% CI)
P Value
2.1 (1.0–4.0) 2.81 (1.54–4.72) — 2.3 (0.5–2.4) 1.42 2.09 (0.4–3.4)
0.05 ⬍0.001 — NS ⬍0.05 NS
KEY: CI ⫽ confidence interval; NS ⫽ not significant. Numbers in parentheses are percentages, unless noted otherwise. Number of secondary cancers included all solid tumors, both inside and outside the treatment field, and leukemias, but excluded the contralateral testis.
mass in the mid-pole of the right kidney. Ultrasonography of the right kidney showed a 2.1 ⫻ 1.8 ⫻ 1.7-cm hypoechoic mass compatible with a solid renal neoplasm—likely renal cell carcinoma. Given the small size and the usual slow growth rate of renal call carcinoma of this size, treatment was deferred while he was treated for his high-grade prostate cancer. He subsequently underwent definitive three-dimensional, conformal radiotherapy, in combination with androgen suppression, for adenocarcinoma of the prostate. COMMENT Several studies have examined the rate of development of second malignancies after orchiectomy and radiotherapy for seminoma1– 6 (Table I). The number of secondary cancers included all solid tumors both inside and outside the treatment field and leukemias but excluded the contralateral testis. The data show that the absolute risk varies from 1.1% to 10.7% and increases with longer followup. Interestingly, the relative risk for all the studies was approximately 2, although not all reached statistical significance. However, overall, the data support the concept that the risk of a second malignancy with radiotherapy for seminoma is small but increased. Specifically, the risk of renal cell cancer was significantly increased in one study1 (relative risk ⫽ 12.5, 95% confidence interval 1.5 to 45.1). In another, the observed/expected ratio in irradiated patients was 1.65 at 20 or more years after therapy.5 One case of secondary prostate cancer was reported in each of two recent studies.2,3 In the largest study,5 no excess risk of prostate cancer was detected. It is possible that both the renal cell carcinoma and the prostate cancer occurred spontaneously and were not directly related to the radiotherapy this patient received for his seminoma. Interestingly, however, it has been previously described that radiation-induced malignancies tend to occur at the margin region of the treatment fields, as seen 748ii
FIGURE 1. Coronal computed tomography scan obtained at time of simulation for radiotherapy for prostate cancer. Red line denotes previous radiation field used for treatment of this patient’s seminoma and its relation to the new cancers. Orange rectangle represents patient’s present renal cell carcinoma. Blue structure in low pelvis indicates location of patient’s prostate.
in this case,7,8 and often take years from the radiotherapy to become evident. In addition, the age of this patient when his clinically symptomatic prostate cancer was diagnosed (50 years) was far younger than the median age at diagnosis of most patients with prostate cancer in the United States, in whom the disease is frequently asymptomatic and found only by screening serum prostate-specific antigen. Finally, to understand more completely whether this patient’s renal cell and prostate carcinomas were induced by radiotherapy would require knowledge about the incidence of UROLOGY 62 (4), 2003
such malignancies in men who have a history of early-stage seminoma but who did not receive radiation or chemotherapy and were followed up for many years. To our knowledge, no such data exist. Thus, given the timing of second tumor presentation, the relationship of these tumors to previous radiation portals, the patient’s age, and the lack of history of an inherited familial syndrome known to increase risk, we believe one can reasonably conclude that these second tumors were a result of the patient’s previous radiotherapy for seminoma. Standard radiotherapy fields for early-stage seminoma include the ipsilateral pelvic (common, external, and internal iliac) and para-aortic lymph nodes. This patient’s fields included the whole pelvis and the para-aortic and ipsilateral inguinal nodes (Fig. 1). These fields included his prostate, which would be excluded in current standard fields for seminoma, as well as the site of his present renal cell carcinoma in his right kidney. The benefit of postorchiectomy radiotherapy significantly outweighs the risk of a second malignancy. Furthermore, previous radiotherapy for seminoma does not necessarily preclude the use of radiotherapy for another malignancy in the treated region, such as prostate cancer, particularly when using three-dimensional and intensity-modulated radiation techniques. Given the increased risk of a
UROLOGY 62 (4), 2003
second malignancy, it may be prudent to perform computed tomography of the abdomen and pelvis even for patients with early-stage prostate cancer who have previously been irradiated for seminoma. REFERENCES 1. Ruther U, Dieckmann K-P, Bussar-Maatz R, et al: Second malignancy following pure seminoma. Oncology 58: 75–82, 2000. 2. Bachaud J-M, Berthier F, Soulie M, et al: Second nongerm cell malignancies in patients treated for stage I-II testicular seminoma. Radiother Oncol 50: 191–197, 1999. 3. Bauman GS, Venkatesan VM, Ago CT, et al: Postoperative radiotherapy for stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 42: 313–317, 1998. 4. Akimoto T, Takahashi I, Takahashi M, et al: Long-term outcome of post orchiectomy radiation therapy for stage I and II testicular seminoma. Anticancer Res 17: 3781–3785, 1997. 5. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long term survivors of testicular cancer. J Natl Cancer Inst 89: 1429 –1439, 1997. 6. Chao CKS, Lai PP, Michalski JM, et al: Secondary malignancy among seminoma patients treated with adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 33: 831–835, 1995. 7. Dorr W, and Herrmann T: Cancer induction by radiotherapy: dose dependence and spatial relationship to irradiated volume. J Radiol Prot 22: A117–A121, 2002. 8. Ruther U, Dieckmann K, Bussar-Maatz R, et al: Second malignancies following pure seminoma. Oncology 58: 75–82, 2000.
748iii
TWO SECONDARY MALIGNANCIES AFTER RADIOTHERAPY FOR SEMINOMA: CASE REPORT AND REVIEW OF THE LITERATURE MICHAEL A. HUGHES, ALICE WANG,
AND
THEODORE L. DEWEESE
ABSTRACT We report a case of a 50-year-old man with two synchronous second malignancies 25 years after orchiectomy and adjuvant radiotherapy for seminoma. An annual health examination revealed an elevated prostatespecific antigen level. A biopsy was performed revealing Gleason score 9 adenocarcinoma of the prostate. Computed tomography of the abdomen revealed a 2-cm solid mass in the right kidney consistent with renal cell carcinoma. Both of these lesions were within the nonstandard radiation field for seminoma with which this patient was treated. Second malignancies, including prostate cancer, are a very uncommon occurrence but an important consideration in long-term survivors of seminoma treated with radiotherapy. UROLOGY 62: 748i–748iii, 2003. © 2003 Elsevier Inc.
I
t is generally accepted that exposure to radiation places patients at risk of second malignant neoplasms. Secondary neoplasms are very uncommon but are a serious sequela of radiotherapy, with the potential for significant health problems in a patient cured of a primary neoplasm. The risk is increased in diseases in which treatment produces long-term disease-free survival, such as Hodgkin’s disease or seminoma. The incidence increases with increasing time after treatment and with increasing dose. Although the contemporary management of seminoma includes treatment with relatively low doses of radiation, the doses used previously were higher and fields were larger than those used today. Moreover, patients are usually young, and the cure rate is high. This combination makes the development of a secondary malignancy, particularly in or near the radiation fields, an important consideration. In this report, we present a case of prostate and renal cell cancer found in a patient at an annual examination 25 years after orchiectomy and radiotherapy for seminoma.
From the Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Address for correspondence: Theodore L. DeWeese, M.D., Department of Radiation Oncology, 401 North Broadway, Suite 144, Baltimore, MD 21231 Submitted: April 17, 2003, accepted (with revisions): June 10, 2003 © 2003 ELSEVIER INC. ALL RIGHTS RESERVED
CASE REPORT A 50-year-old man presented to his primary care physician for his annual physical examination. He reported a several-year history of decreased urinary stream and incomplete emptying of his bladder. In the prior several weeks, the patient had noted increased urinary frequency and nocturia, but no other symptoms. His past medical history was remarkable for early-stage seminoma 25 years earlier, which had been treated with orchiectomy and adjuvant radiotherapy at an outside institution to a total dose of 30 Gy to the bilateral pelvis and para-aortic lymph nodes. The physical examination revealed an absent right testis and a mildly atrophic left testis. The rectal examination revealed a 30-g prostate that was mildly tender, firm, with induration of the apex bilaterally, and intact sulci. The fecal occult blood test was negative. Laboratory studies revealed a prostate-specific antigen level of 12.0 ng/mL. He was diagnosed with prostatitis and began taking ciprofloxacin. He was also scheduled for a biopsy of his prostate. After 2 weeks of antibiotic treatment, his prostatitis symptoms resolved. The biopsy of his prostate revealed Gleason score 4 ⫹ 5 ⫽ 9 adenocarcinoma involving 70% of multiple fragmented cores, with perineural invasion identified. A whole body bone scan was negative for metastatic disease. Computed tomography of the abdomen and pelvis revealed no evidence of metastatic disease but showed a 2-cm, ill-defined 0090-4295/03/$30.00 doi:10.1016/S0090-4295(03)00669-1 748i
TABLE I. Selected recent studies of second malignancy in seminoma
Ruther et al.,1 2000 Bachaud et al.,2 1999 Bauman et al.,3 1998 Akimoto et al.,4 1997 Travis et al.,5 1997 Chao et al.,6 1995
n
Median/Mean Follow-up (yr)
839 131 212 94 15,602 128
3.9 11 7.5 12 10.2 11.7
Second Cancers (n) 9 14 6 7 1,033 9
(1.1) (10.7) (2.8) (7.4) (6.6) (7.0)
Relative Risk (95% CI)
P Value
2.1 (1.0–4.0) 2.81 (1.54–4.72) — 2.3 (0.5–2.4) 1.42 2.09 (0.4–3.4)
0.05 ⬍0.001 — NS ⬍0.05 NS
KEY: CI ⫽ confidence interval; NS ⫽ not significant. Numbers in parentheses are percentages, unless noted otherwise. Number of secondary cancers included all solid tumors, both inside and outside the treatment field, and leukemias, but excluded the contralateral testis.
mass in the mid-pole of the right kidney. Ultrasonography of the right kidney showed a 2.1 ⫻ 1.8 ⫻ 1.7-cm hypoechoic mass compatible with a solid renal neoplasm—likely renal cell carcinoma. Given the small size and the usual slow growth rate of renal call carcinoma of this size, treatment was deferred while he was treated for his high-grade prostate cancer. He subsequently underwent definitive three-dimensional, conformal radiotherapy, in combination with androgen suppression, for adenocarcinoma of the prostate. COMMENT Several studies have examined the rate of development of second malignancies after orchiectomy and radiotherapy for seminoma1– 6 (Table I). The number of secondary cancers included all solid tumors both inside and outside the treatment field and leukemias but excluded the contralateral testis. The data show that the absolute risk varies from 1.1% to 10.7% and increases with longer followup. Interestingly, the relative risk for all the studies was approximately 2, although not all reached statistical significance. However, overall, the data support the concept that the risk of a second malignancy with radiotherapy for seminoma is small but increased. Specifically, the risk of renal cell cancer was significantly increased in one study1 (relative risk ⫽ 12.5, 95% confidence interval 1.5 to 45.1). In another, the observed/expected ratio in irradiated patients was 1.65 at 20 or more years after therapy.5 One case of secondary prostate cancer was reported in each of two recent studies.2,3 In the largest study,5 no excess risk of prostate cancer was detected. It is possible that both the renal cell carcinoma and the prostate cancer occurred spontaneously and were not directly related to the radiotherapy this patient received for his seminoma. Interestingly, however, it has been previously described that radiation-induced malignancies tend to occur at the margin region of the treatment fields, as seen 748ii
FIGURE 1. Coronal computed tomography scan obtained at time of simulation for radiotherapy for prostate cancer. Red line denotes previous radiation field used for treatment of this patient’s seminoma and its relation to the new cancers. Orange rectangle represents patient’s present renal cell carcinoma. Blue structure in low pelvis indicates location of patient’s prostate.
in this case,7,8 and often take years from the radiotherapy to become evident. In addition, the age of this patient when his clinically symptomatic prostate cancer was diagnosed (50 years) was far younger than the median age at diagnosis of most patients with prostate cancer in the United States, in whom the disease is frequently asymptomatic and found only by screening serum prostate-specific antigen. Finally, to understand more completely whether this patient’s renal cell and prostate carcinomas were induced by radiotherapy would require knowledge about the incidence of UROLOGY 62 (4), 2003
such malignancies in men who have a history of early-stage seminoma but who did not receive radiation or chemotherapy and were followed up for many years. To our knowledge, no such data exist. Thus, given the timing of second tumor presentation, the relationship of these tumors to previous radiation portals, the patient’s age, and the lack of history of an inherited familial syndrome known to increase risk, we believe one can reasonably conclude that these second tumors were a result of the patient’s previous radiotherapy for seminoma. Standard radiotherapy fields for early-stage seminoma include the ipsilateral pelvic (common, external, and internal iliac) and para-aortic lymph nodes. This patient’s fields included the whole pelvis and the para-aortic and ipsilateral inguinal nodes (Fig. 1). These fields included his prostate, which would be excluded in current standard fields for seminoma, as well as the site of his present renal cell carcinoma in his right kidney. The benefit of postorchiectomy radiotherapy significantly outweighs the risk of a second malignancy. Furthermore, previous radiotherapy for seminoma does not necessarily preclude the use of radiotherapy for another malignancy in the treated region, such as prostate cancer, particularly when using three-dimensional and intensity-modulated radiation techniques. Given the increased risk of a
UROLOGY 62 (4), 2003
second malignancy, it may be prudent to perform computed tomography of the abdomen and pelvis even for patients with early-stage prostate cancer who have previously been irradiated for seminoma. REFERENCES 1. Ruther U, Dieckmann K-P, Bussar-Maatz R, et al: Second malignancy following pure seminoma. Oncology 58: 75–82, 2000. 2. Bachaud J-M, Berthier F, Soulie M, et al: Second nongerm cell malignancies in patients treated for stage I-II testicular seminoma. Radiother Oncol 50: 191–197, 1999. 3. Bauman GS, Venkatesan VM, Ago CT, et al: Postoperative radiotherapy for stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 42: 313–317, 1998. 4. Akimoto T, Takahashi I, Takahashi M, et al: Long-term outcome of post orchiectomy radiation therapy for stage I and II testicular seminoma. Anticancer Res 17: 3781–3785, 1997. 5. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long term survivors of testicular cancer. J Natl Cancer Inst 89: 1429 –1439, 1997. 6. Chao CKS, Lai PP, Michalski JM, et al: Secondary malignancy among seminoma patients treated with adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 33: 831–835, 1995. 7. Dorr W, and Herrmann T: Cancer induction by radiotherapy: dose dependence and spatial relationship to irradiated volume. J Radiol Prot 22: A117–A121, 2002. 8. Ruther U, Dieckmann K, Bussar-Maatz R, et al: Second malignancies following pure seminoma. Oncology 58: 75–82, 2000.
748iii