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Advances in the Screening, Diagnosis and Treatment of

Testicular and Prostate Cancer

Leon McCrea II, MD MPHAssociate Professor of Family Medicine

Drexel University College of Medicine

Director, Family Medicine Residency Program

Disclosure

• No financial interest• No conflict of interest

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Learning Objectives

• Understand how prostate‐specific antigen (PSA) is used in the monitoring of prostate cancer, and controversies regarding use of PSA as a cancer screening test

• Know how to evaluate the use of genomic testing in the management of prostate cancer

• Be able to provide patients with effective options for adjuvant treatment of stage 1 seminoma.

Case Study

A 17‐year‐old male presents to your office for a college entrance physical examination. He learned about testicular cancer in health class, and asks you about screening. He has no history of cryptorchidism and no physical symptoms.

Screening for Testicular Cancer. American Family Physician. Volume 84, Number 4. August 15, 2011

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Which one of the following statements about testicular cancer is correct?❏ A. Most cases of testicular cancer are discovered during the clinical examination.

❏ B. Testicular cancer is the most common type of cancer in men older than 50 years.

❏ C. Testicular cancer is common compared with other types of cancer.

❏ D. In most cases, testicular cancer is managed surgically; treatment also may include radiation therapy or chemotherapy.

❏ E. Less than 40 percent of newly diagnosed cases of testicular cancer are curable.


According to the U.S. Preventive Services Task Force (USPSTF), how should you respond to your patient’s question about whether he should be screened for testicular cancer?

❏ A. Tell him he should be screened for testicular cancer when he is 50 years of age.❏ B. Explain why a clinical screening examination and self‐examinations for testicular cancer would not be of benefit to him.❏ C. Inform him that regular self‐examinations have been shown to reduce the risk of death from testicular cancer.❏ D. Recommend that he be checked today for testicular cancer, as part of a routine physical examination.❏ E. Perform a clinical screening examination for testicular cancer if he is currently sexually active.


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Which of the following statements about screening for testicular cancer are correct?❏ A. Clinical examination for testicular cancer has a 95 percent sensitivity rate for detecting disease.

❏ B. Regular self‐examination of the testicles has been shown to detect more early stage cancer than diagnosis on the basis of symptoms.

❏ C. Potential harms associated with screening for testicular cancer include anxiety and harms from diagnostic tests or procedures.

❏ D. The benefits of screening asymptomatic men for testicular cancer with clinical examination or patient self‐examination are small to none.Screening for Testicular Cancer. American Family Physician. Volume 84, Number 4. August 15, 2011

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PDQ® Adult Treatment Editorial Board. PDQ Testicular Cancer Treatment. Bethesda, MD: National Cancer Institute.

How Many People Survive 5 Years or More After Diagnosis of Testicular Cancer?


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How Common is this Cancer?


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Who Gets Testicular Cancer?

PDQ® Adult Treatment Editorial Board. PDQ Testicular Cancer Treatment. Bethesda, MD: National Cancer Institute

Who Dies From Testicular Cancer?


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Trends in Rates for Testicular Cancer


Am Fam Physician. 2018;97(4):261-26

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According to current guidelines, at what age does the USPSTF recommend that should you consider initiating prostate cancer screening with PSA for an average risk man?

a) 40

b) 45

c) 50

d) USPSTF guidelines do not recommend offering prostate cancer screening.

Physician Education and Assessment Center. The Johns Hopkins Hospital Dept. of Medicine. 2002‐2018

Incidence and Mortality

• Estimated new cases and deaths from testicular cancer in the United States in 2018

• New cases: 9,310.• Deaths: 400.

•Highly treatable, usually curable• Young and middle‐aged men

• For patients with low‐stage seminoma or nonseminoma, the cure rate approaches 100%

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Risk Factors

•An undescended testis (cryptorchidism)

•A family history of testis cancer (particularly in a father or brother)

•A personal history of testis cancer.• Surgical correction of an undescended testis (orchiopexy) before puberty MAY to lower the risk of testis cancer

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Classification of Testicular Tumors

Germ cell tumors (95% of all testicular cancers)

• Seminomas.

• Embryonal carcinomas.

• Teratomas.

• Yolk sac tumors.

• Choriocarcinomas

Sex cord–stromal tumors (< 5% of all testicular cancers)

• Leydig cell tumor

• Sertoli cell tumor

• Granulosa cell tumor

• Mixed and unclassified sex cord–stromal tumors

Tumors that are 100% seminoma are considered seminomas. All other tumors, including those that have a mixture of seminoma and nonseminomacomponents, are considered and should be managed as nonseminomas.

What Should I Order? (After the ultrasound)

• Chemistry panel

• LFTs• Tumor markers (beta human chorionic gonadotropin, lactate dehydrogenase (may be elevated in seminoma), and alpha fetoprotein (may be elevated in nonseminoma).

• Chest radiography (would get CT Chest if anything abnl)• Abdominal/pelvic computed tomography (CT)

• Brain MRI (based on history)

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Serum Tumor Markers• AFP

• Elevation of serum AFP in 40% to 60% of nonseminomas

• Seminomas do not produce AFP

• beta‐hCG• Elevation in approximately 14% with stage I seminoma prior to orchiectomy

• Elevation about 50% with metastatic seminoma

• 40% to 60% with nonseminomas have an elevated level

• LDH• Seminomas and nonseminomas may have elevated LDH but values are of less clear prognostic significance because LDH may be elevated in many different conditions unrelated to cancer

Nonseminomas - tumor-marker elevation after the cancerous testicle has been removed is one of the most significant predictors of prognosis. Serum tumor markers are also very useful for monitoring all stages of nonseminomas and for monitoring metastatic seminomas because elevated marker levels are often the earliest sign of relapse.

Staging

• Histology (seminoma vs. nonseminoma).

• Extent of spread (testis only vs. retroperitoneal lymph node involvement vs. pulmonary or distant nodal metastasis vs. nonpulmonary visceral metastasis).

• For nonseminomas ‐ serum tumor marker are elevation

• For disseminated seminomas, the main adverse prognostic variable is the presence of metastases to organs other than the lungs

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Treatment ‐ Good PrognosisNonseminoma:

• Testis/retroperitoneal primary, and no nonpulmonary visceral metastases

• Good markers–all of:Alpha‐fetoprotein(AFP) less than 1,000 ng/mL

• Human chorionic gonadotropin (hCG) less than 5,000 IU/mL (1,000 ng/mL)

• Lactate dehydrogenase (LDH) less than 1.5 × the upper limit of normal

• 56%–61% of nonseminomas

• 5‐year progression‐free survival (PFS) is 89%; 5‐year survival is 92%–94%

Seminoma:

• Any primary site and no nonpulmonary visceral metastases

• Normal AFP, any hCG, any LDH

• 90% of seminomas

• 5‐year PFS is 82%; 5‐year survival is 86%.

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Treatment – Intermediate PrognosisNonseminoma:

• Testis/retroperitoneal primary, no nonpulmonary visceral metastases, and

• AFP 1,000 ng/mL or more and 10,000 ng/mL or less, or

• hCG 5,000 IU/L or more and 50,000 IU/L or less, or

• LDH 1.5 or more × N* and less than 10 ×N*


• 5‐year PFS is 75%; 5‐year survival is 80%–83%.

Seminoma:

• Any primary site

• Nonpulmonary visceral metastases, and

• Normal AFP, any hCG, any LDH10% of seminomas

• 5‐year PFS is 67%; 5‐year survival is 72%

Treatment – Poor Prognosis

Nonseminoma:

• Mediastinal primary, or nonpulmonary visceral metastases,

• AFP more than 10,000 ng/mL, or

• hCG more than 50,000 IU/mL (10,000 ng/mL), or

• LDH more than 10 × the upper limit of normal


• 5‐year PFS is 41%; 5‐year survival is 71%.

Seminoma:

• No patients are classified as poor prognosis.

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Am Fam Physician. 2018;97(4):261-26

Stage I seminoma has a cure rate that approaches 100% regardless of whether postorchiectomy adjuvant therapy is given

Standard treatment options:

• Radical inguinal orchiectomy with no retroperitoneal node radiation therapy

• Followed by chest x‐rays and computed tomographic (CT) scans of the abdomen and pelvis (surveillance).

• Studies are typically performed every 4 months for the first 3 years, then every 6 months for 3 years, and then annually for an additional 4 years.

Results of multiple clinical series, including more than 1,200 patients with stage I seminoma managed by postorchiectomy surveillance, have been reported

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Standard Treatment Option Results

• The overall 10‐year tumor recurrence rate is 15% to 20%

• Nearly all patients whose disease recurred were cured by radiation therapy or chemotherapy.

• Thus, the overall cure rate is indistinguishable from that achieved with adjuvant radiation therapy or carboplatin chemotherapy

Adjuvant Therapy – Because We Can’t Just Watch and Wait!!!Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy

• 5‐year relapse‐free survival (RFS) rate of 95% to 96%

• 5‐year disease‐specific survival rate in excess of 99%

• no longer favored ‐ associated with an increased risk of secondary malignancies and an increased risk of death from secondary malignancies

Data from multiple large series and randomized controlled tria

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There is another option…

• Radical inguinal orchiectomy followed by either one or two doses of carboplatin adjuvant therapy

• In a large, randomized, controlled, noninferiority trial, 1,477 men with stage I seminoma were randomly assigned to undergo para‐aortic radiation therapy or to receive a single dose of carboplatin after radical inguinal orchiectomy, study participants were followed up for a median of 6.5 years.

• The RFS rate at 5 years was 94.7% in the carboplatin arm and 96.0% in the radiation therapy arm [nonsignificant trend in favor of radiation therapy];

• The one death from seminoma occurred in the radiation therapy arm.

• There was a reduced number of contralateral testicular germ cell tumors in the carboplatin arm.

N Engl J Med 2014;371:2005-16.

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The Aftermath

• Fertility• Chemo – likely unaffected, 3 mos

• Radiation – likely affected, 1‐2 yrs

• Secondary Leukemia• Radiation and Chemo

• Renal Function• Chemo

• Lung Function• Chemo

• Hearing• Chemo

• Cardiovascular Disease• Radiation and Chemo

A pleasant 75‐year‐old Caucasian man with poorly controlled type 2 diabetes comes to see you as a new patient. He last had a PSA done ten years ago and it was 2.0ng/ml. He is asking if it should be repeated. He has occasional nocturia but otherwise is healthy. You recommend which of the following?

a) No further PSA testing

b) PSA testing and digital rectal exam

c) PSA testing alone

d) Digital rectal exam alone


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A 54‐year‐old man presents to your office for establishment of primary care. His wife is present and raises concern for his prostate‐specific antigen (PSA) increasing with each year it was tested. She presents test results for your review from the past several years outlining a PSA four years previously of 1.0 ng/mL. A result from two years ago shows a PSA of 1.8 ng/mL and from six months prior of 2.3 ng/mL. The gentleman’s wife, in particular, is concerned and asks whether a biopsy may be indicated here. What is your recommendation?

a) Repeat a PSA now and if any higher refer to Urology

b) Refer for prostate biopsy

c) Continue annual PSA testing

d) Refer to urology now


Cancer and the Prostate

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How Many People Survive 5 Years or More After Diagnosis of Prostate Cancer?



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How Common is this Cancer?


Who Gets Prostate Cancer?

PDQ® Adult Treatment Editorial Board. PDQ Testicular Cancer Treatment. Bethesda, MD:National Cancer Institute

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Who Dies from Prostate Cancer?

PDQ® Adult Treatment Editorial Board. PDQ Testicular Cancer Treatment. Bethesda, MD:National Cancer Institute

Trends in Rates for Prostate Cancer


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Inadequate Evidence of Benefit Associated With Screening for Prostate Cancer Using Prostate‐Specific Antigen (PSA) or Digital Rectal Exam (DRE)

• Screening tests are able to detect prostate cancer at an early stage• Results from two randomized trials showed no effect on mortality through 7 years but are inconsistent beyond 7 to 10 years

• Based on solid evidence, screening with PSA and/or DRE results in overdiagnosis of prostate cancers, and detection of some prostate cancers that would never have caused significant clinical problems

• 20% to 70% of men who had no problems before radical prostatectomy or external‐beam radiation therapy will have reduced sexual function and/or urinary problems

Incidence and Mortality

• Prostate cancer is the most common cancer diagnosed in North American men, excluding skin cancers

• Estimated that in 2018, approximately 164,690 new cases and 29,430 prostate cancer–related deaths will occur in the United States

• Second leading cause of cancer death in men, exceeded by lung cancer

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Screening by Serum PSA

• Multifunctional Test• Initial diagnosis of disease, Tool in monitoring for recurrence and for prognosis of outcomes after therapy

• Benefits• Simplicity, objectivity, reproducibility, relative lack of invasiveness, and relatively low cost

• Concern• Despite potential for early diagnosis, we cant avoid overdiagnosis and overtreatment

Follow‐up After Treatment

• Optimal follow‐up strategy for men treated for prostate cancer is uncertain

• Using surrogate endpoints for clinical decision making is controversial

• Current evidence to support changing therapy based on such endpoints translates into clinical benefit is weak

• Rates of PSA change are thought to be markers of tumor progression

• Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor and of very limited utility in making therapeutic decisions

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Although the PSA test is nearly universally used to follow patients, diversity of recommendations on the provision of follow‐up careD'Amico AV, Moul JW, Carroll PR, et al.: Surrogate end point for prostate cancer‐specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95 (18): 1376‐83, 2003.

Prelim Results: Retrospective cohort of 8,669 patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short post‐treatment PSA doubling time (<3 months in this study) fulfills some criteria as a surrogate endpoint for all‐cause mortality and prostate cancer‐specific mortality after surgery or radiation therapy

Other Retrospective Analysis…

Petrylak DP, Ankerst DP, Jiang CS, et al.: Evaluation of prostate‐specific antigen declines for surrogacy in patients treated on SWOG 99‐16. J Natl Cancer Inst 98 (8): 516‐21, 2006.

Results: Retrospective analysis (SWOG‐S9916 [NCT00004001]) showed that PSA declines of 20% to 40% (but not 50%) at 3 months and 30% or more at 2 months after initiation of chemotherapy for hormone‐independent prostate cancer, and fulfilled several criteria of surrogacy for overall survival

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Follow‐up after radical prostatectomy

• Detectable PSA level identifies patients at elevated risk of local treatment failure or metastatic disease

• Substantial proportion of patients with an elevated or rising PSA level after surgery remain clinically free of symptoms for extended periods

• Evidence of failure on the basis of elevated or slowly rising PSA alone, therefore, may not be sufficient to initiate additional treatment

What does the evidence support…

• Retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is considered evidence of biochemical recurrence.

• 103 (34%) developed clinical evidence of recurrence• Median time to the development of clinical metastasis after biochemical recurrence was 8 years

• After the men developed metastatic disease, the median time to death was an additional 5 years

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Follow‐up after radiation therapy

• Combination of clinical tumor stage, Gleason score, and pretreatment PSA level is often used to estimate the risk of relapse

• PSA is often followed for signs of tumor recurrence after radiation therapy

• Elevated or rising PSA may be a prognostic factor for clinical disease recurrence

• American Society for Therapeutic Radiology and Oncology Consensus Panel – “prostate re‐biopsy is not necessary as standard follow‐up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication”

• However, the long‐term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%

Follow‐up after hormonal therapy

• After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression‐free status

• Decreases in PSA of less than 80% may not be very predictive

• PSA expression is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response.

• Clinicians cannot rely solely on the serum PSA level to monitor a patient’s response to hormonal therapy; they must also follow clinical criteria

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Genetics and Prostate Cancer• Inheritance and Risk

• Multiple affected first‐degree relatives (FDRs) with prostate cancer• Early‐onset prostate cancer (age ≤55 years)• Prostate cancer with a family history of other cancers (e.g., breast, ovarian, pancreatic).

• Associated Genes and Single‐Nucleotide Polymorphisms (SNPs)• BRCA1, BRCA2, the mismatch repair genes, and HOXB13• Genome‐wide association studies

• Clinical Management• Targeted screening based on genetic profile

• Psychosocial and Behavioral Issues• Risk Perception, Screening Behaviors, Interest in genetic testing

The case for genetics…

• The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patient’s life) is greater than the number of men with clinically detected disease.

• Our challenge is why some prostate carcinomas remain clinically silent, while others cause serious, even life‐threatening illness

• Risk Factors• Age (rarely seen <40); Ancestry (Black>>White>>Japanese); Family history

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Hereditary Prostate CA

•Hopkins Criteria• Three or more affected first‐degree relatives (father, brother, son).

• Affected relatives in three successive generations of either maternal or paternal lineages.

• At least two relatives affected at age 55 years or younger.• Linkage Studies

• Linkage to chromosome 17q21‐22 and subsequent fine‐mapping and targeted sequencing have identified recurrent pathogenic variants in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early‐onset prostate cancer

Genome‐wide Association Studies

• Able to leverage knowledge of a connection between Androgen Receptor (AR) Positive and aggressive forms of prostate CA

• Investigators targeted SNPs that reside at sites where the AR binds to DNA

• Based on previous mapping of thousands of AR binding sites

• Localized a SNP (KRT8) locus at 12q13.13—a locus previously implicated in cancer development—associated with prostate cancer risk, with an OR of 1.22

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Genes and Prostate CA Risk

• Based on data from the Breast Cancer Linkage Consortium ‐ a review of the relationship between germline pathogenic variants in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role

Screening in carriers of BRCA pathogenic variantsBancroft EK, Page EC, Castro E, et al.: Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. EurUrol 66 (3): 489‐99, 2014

• Prostate cancer screening in carriers of BRCA1/BRCA2 pathogenic variants versus noncarriers

• Study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2carriers, 428 BRCA2 noncarriers)

• 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy

• Overall cancer detection rate was 36.4%

• Using published stage and grade criteria for risk classification, intermediate‐ or high‐risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%)

• Ninety‐five percent of the men were white; therefore, the results cannot be generalized to all ethnic groups

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Risk Perception

• Overall, knowledge of hereditary prostate cancer was low, especially concepts of genetic susceptibility, indicating a need for increased education

• Some studies found that men with a family history of prostate cancer considered their risk to be the same as or less than that of the average man

• A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer

Anticipated Interest in Genetic Testing for Risk of Prostate Cancer• Advice of their primary care physician

• Combination of emotional distress and concern about prostate cancer treatment effects

• Having children

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Psychosocial outcomes of screening in individuals at increased familial risk• Concern about developing prostate cancer

• Baseline distress levels

• Distress experienced during prostate cancer screening

Thank you for you attention

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