Testicular Cancer: Detection, Prevention, and Therapeutics by Jeanne Keith, PharmD Introduction
T
esticular cancer is rare, accounting for approximately 1% of all male cancers. In contrast, it is the most common cancer seen in men between the ages of 15 and 35. Because testicular cancer strikes men in their most productive years, its effects are much more devastating. The prognosis and management of testicular cancer have changed dramatically in the past 10 years. Major advances have been made in the techniques used to diagnose, stage, and monitor testicular cancer. The most important improvement has been in the management of disseminated disease with antineoplastic drug regimens. These improvements have changed a disease once considered to be uniformly fatal, to one that can now be cured in most patients. This article summarizes the epidemiology and etiology of this disease, its signs and symptoms, appropriate diagnostic and staging techniques, prognosis, and treatment. In addition, early and late complications of therapy and detection and screening techniques will be discussed.
Epidemiology and Etiology Pproximately 5,500 cases oftesA ticular cancer are diagnosed in the United States each year, which
Jeanne Keith, PharmD, is professional services associate manager, Amgen, 1840 Dehavilland Dr., Thousand Oaks, CA 91320. American Pharmacy's cancerscreening series guest editor is Celeste Lindley, PharmD, ofthe University of North Carolina School of Pharmacy. Received and accepted November 1989. 46
yield an estimated incidence of 5.9 per 100,000 men. For unknown reasons, the incidence of this disease has increased over the past several decades, particularly in white urban populations. Testicular cancer is four times more common in whites than blacks, and is seen more frequently in higher social classes. Little is known about the etiology of testicular cancer, although some risk factors for its development have been identified. The single most important risk factor is a history of cryptorchidism or undescended testes. During normal development, the testes are formed near the kidneys and descend into the scrotum shortly after birth. If this fails to occur or if it occurs after the age of six, the incidence of testicular cancer increases from 1% to 15%. Approximately 12% of all testicular cancer patients have a history of cryptorchidism. Although other studies have suggested a number of possible risk factors, none is as dramatic or as well documented as cryptorchidism. Additional risk factors include testicular trauma, mumps orchitis, elevated testicular temperature, inguinal hernia, and atrophic testes. There is some evidence that heredity and genetic disorders may play a role in this disease. The number of cases of familial occurrence, although small, is well defined, particularly with bilateral disease. In addition, an increased incidence of testicular cancer has been associated with genetic abnormalities. Specifically, mediastinal germ cell tumors (testicular cancer arising at some point along the mediastinum, rather than the testes) have been associated with Klinefelter's syndrome. Finally, those patients diagnosed with testicular cancer have
a much higher risk (1,000 times greater) of developing cancer in the other testicle than healthy individuals have of developing testicular cancer; however, the overall risk is still low.
Clinical Presentation nfortunately most patients U who develop testicular cancer suffer no early symptoms that would encourage them to contact their physicians. The age group this disease strikes is often healthy, and most young men do not practice testicular self-examination (TSE). When symptoms occur, they are often vague and nonspecific. The first sign is usually a change in the consistency of the testicle, with some enlargement. A heavy or dragging, aching feeling in the abdomen can develop. If rapid growth with hemorrhaging occurs, then sharp testicular pain is reported. For those men who practice TSE (see "Screening and Early Detection"), the first sign of disease is usually a painless testicular mass. The most common site of metastasis is in the retroperitoneal lymph nodes. From there, it can spread through the blood to the lungs, liver, brain, viscera, and bone; however, brain, viscera, and bone metastases are rare. Signs and symptoms related to metastases include abdominal masses, adenopathy, gynecomastia, and headaches.
Diagnosis and Initial Evaluation hen a patient has a testicular W mass (with or without any other symptoms), the physician should perform a complete history and physical, including palpation of the testes and surrounding struc-
American Pharmacy, Vol. NS30, No.7 July 1990/414
tures. Once this mass is documented, orchiectomy with complete excision of the spermatic cord is usually performed through an inguinal incision (see figure). If the incision is done using a trans scrotal (through the scrotum) approach, the risk of disease spreading through the lymphatic system is increased. Orchiectomy provides the tissue necessary for a definitive diagnosis and is the first step in effective treatment. The tissue must be carefully examined to determine its cell of origin. Of all testicular cancers, 96% are of germ cell origin (germinal neoplasms). There are four types of testicular cancer: embryonal, teratocarcinoma, choriocarcinoma, and seminoma. These types can also be found ·in combination. Seminoma is the most common, accounting for approximately 40% of cases. Teratocarcinomas occur in 20%-25% of the cases, embryonal, in 150/0-20%, and pure choriocarcinoma, rarely (1%). For treatment, the four types of testicular cancer are categorized as either seminomas or nonseminomas. This distinction is important, as treatment differs markedly. The stage of testicular cancer at diagnosis is the single most important factor affecting prognosis. Numerous staging classifications have been developed, with the simplest using three stages for nonseminomas and four stages for seminomas. For both seminomas and nonseminomas, Stage I is when the cancer is confined to the testes; at Stage II the cancer involves the retroperitoneal lymph nodes. (Stage II is often further subdivided on the basis of size and number of nodes involved and whether a palpable abdominal mass is present.) For nonseminomas, Stage III is any disease found above the diaphragm. For seminomas, Stage III represents diseased mediastinal or cervical lymph nodes, and Stage IV represents viceral (lung, bone, liver, and! or brain) metastases. Because teSticular cancer usually metastasizes first to the retroperitoneal lymph nodes, many physicians opt for a retroperitoneal lymph node dissection (RPLND) to both assess the stage of the cancer and remove any diseased nodes.
spermatic cord
collecting tubules Internal Structure
Male reproductive organs. Source: American Cancer Society.
When attempting to determine t4e stage of a seminoma, an RPLND may not be performed initially because subdiaphragmatic radiation therapy (as described under "Treatment") has been used successfully to treat Stage II disease. Other tests, such as retroperitoneal lymphangiography or computed tomography (CT) are used to stage the patient's disease. However, these methods are not as sensitive as surgery in detecting micrometastases. For this reason, the exact incidence of retroperitoneal involvement in seminomas is not known for certain but is thought to be approximately 10%-15%. Other tests used to stage testicular cancer include chest x-ray, chest CT, whole lung tomography, CT of the abdomen, and studies of the retroperitoneallymph nodes such as CT or bipedal lymphangiography (if RPLND is not performed). Testicular cancer is unique in that it is associated with reliable serum markers. Alpha fetal protein (AFP) is a glycoprotein produced by endodermal sinus cells that originate in the yolk sac of the fetus and is normally undetectable in the adult circulation. When it is found in the serum of a testicular cancer patient, it denotes the presence of nonseminomatous elements, even if these elements are not detected histologically. Patients with pure seminomas will not secrete AFP.
American Pharmacy, Vol. NS30, No. 7 July 1990/415
Elevated AFP levels are also associated with hepatitis, hepatomas, and other malignant gastrointestinal, biliary, or pancreatic diseases. Human chorionic gonadotropin (HCG), also a glycoprotein, is normally secreted by the human placenta and is elevated in patients with nonseminomatous testicular tumors, as well as li ver, breast, stomach, pancreatic, and lung cancers. Unlike AFP, B-HCG can be elevated slightly in patients with seminomas. However at higher levels, nonseminomatous elements are thought to be present. The development of sensitive assays for B-HCG and AFP has markedly improved the management of testicular cancer. Serial measurement of these markers is useful in diagnosing the type of testicular cancer and monitoring response to therapy and disease recurrence. Of patients with disseminated nonseminomatous tumors, 80% to 85% will have either or both serum markers elevated. AFP has a biological half-life offive days and methods to use this value in following a patient's response to therapy have been developed. If these levels remain elevated despite treatment, persistent disease is known to be present, even if there is no radiographic evidence of disease. B-HCG levels should decrease by at least one log (90%) every three weeks following each treatment. If this does not occur, then alternate treatment modalities should be considered.
Prognosis he prognosis for this disease has T changed drastically over the past two decades. While the majority of nonseminomatous patients used to die within 1 to 2 years of diagnosis, today even those patients with Stage III disease have a 70% to 80% chance of cure. Those patients with Stage I or II nonseminomatous cancer have a greater than 90% chance of cure. Patients with seminoma have a 90% to 100% five-year survival prognosis. Because the majority of patients who relapse will do so within two years . of diagnosis, testicular cancer is considered to be cured if the patient is free of disease at the two-year
47
mark. Recently, however, a number of late recurrences (occurring after more than 10 years) have been reported. The most important prognostic factor in testicular cancer is the stage of disease at diagnosis. Most investigators agree that age, mode oftreatment, histology, or elevation oftumor markers are not important prognostic factors and do not help predict the 100/0-15% who will relapse. Once a patient relapses, the prognosis is again primarily determined by the patient's extent of disease at relapse.
Treatment Seminomas Seminoma accounts for 30%-40% of testicular cancer. Unlike nonseminomatous patients, the majority (600/0-80%) of these patients present with clinical Stage I disease, due to the slow-growing nature of seminoma. Any patient whose histology indicates pure seminoma but who has an elevated AFP should be treated as a nonseminomatous patient. An elevated B-HCG is more controversial. Seminomas are highly radiosensitive, and local (subdiaphragmatic) radiation therapy with 2,000 to 3,000 rads over three to four weeks will cure 99% of patients with Stage I disease. It is likely that the majority of Stage I patients will be cured with orchiectomy alone (without radiation treatment). Even though radiation treatment is well tolerated, it would be optimal to limit therapy to only those who will clearly benefit. As a result, some clinicians advocate a surveillance-only policy after orchiectomy in patients with Stage I seminoma. The disadvantage to this approach is the intensive and meticulous follow-up required, primarily because the serum markers used to follow nonseminomatous patients are not helpful in this situation. When both the patient and physician are highly motivated, this approach seems reasonable in Stage I seminomas. Recurrences after treatment of Stage I or II seminoma tend to occur in a small number of patients within two years in the mediastinal, retroperitoneal, or supraclavicular 48
regions. While radiation therapy is effective for isolated recurrences, prophylactic mediastinal or supraclavicular irradiation has not been found to improve the three-year disease-free survival. Prophylactic radiation in Stages I and II seminoma is, therefore, no longer recommended. The treatment of patients with advanced Stage II (bulky disease) seminoma is controversial. Some clinicians advocate radiation treatment followed by chemotherapy for relapses or progressive disease, while others recommend initial treatment with chemotherapy followed by radiation for disease progression. Both approaches have been associated with high cure rates. The use of radiation, however, can limit the doses and intensity of future chemotherapy if it becomes necessary. Advanced seminomas (Stages III and IV) are currently treated with chemotherapy because radiation therapy alone is associated with a low cure rate.
Nonseminomas Standard treatment for patients diagnosed with nonseminomatous testicular cancer postorchiectomy includes RPLND to further stage the patient and, more important, to remove any diseased lymph nodes. Those diagnosed with Stage I or early Stage II disease are then followed postoperatively with monthly serum markers and chest x-rays for the first year and then every other month during the second year for disease recurrence. This approach, while still considered standard by many investigators, is controversial. Because only 25%-35% of patients with clinical Stage I disease will be found to have Stage II disease after RPLND, clinicians have questioned the value of subjecting all clinical Stage I patients to RPLND. This is an important question, considering the success of chemotherapy for patients who progress or relapse, and the fact that 650/0-70% of patients will lose antegrade ejaculatory function after a traditional RPLND as a result of severing the sympathetic plexus during surgery. On the other hand, those patients
who relapse after orchiectomy alone will be subjected to chemotherapy with cisplatin when they may have been cured with RPLND. In addition, patients who may have relapsed with pulmonary disease only following RPLND will relapse with pulmonary disease and moderate retroperitoneal disease - increasing the tumor burden and lessening the chance for cure with chemotherapy. Finally, new techniques, including unilateral modified nerve-sparing RPLNDs have been reported to preserve antegrade ejaculatory function in as much as 80% of patients. Studies have demonstrated the benefits of surveillance only, particularly in patients without certain risk factors thought to increase their risk of relapse, such as vascular invasion of the primary tumor or embryonic histology. These studies have led several centers to adopt a surveillance-only program, similar to that discussed for seminomas. Intense monitoring and follow-up are essential because antineoplastic therapy is highly successful if tumor burden is low. The optimal schedule for follow-up is not known but should include frequent visits with measurement of serum markers and computed tomography scans of the chest and abdomen during the first year, and less frequent monitoring for the second and third years. Both methods of treatment (RPLND or surveillance-only) are accepted today. Whichever course of treatment is undertaken, both the patient and physician must understand the risks involved and the importance of monitoring. Of patients initially diagnosed with Stage II disease, treatment with orchiectomy and RPLND will cure 50%. However, between 40% and 50% of patients will relapse and, if carefully monitored, postsurgery tumor burden will be minimal. Treatment with chemotherapy cures 900/0-100% of these patients upon relapse. Treatment to prevent relapse usually consists of four courses of chemotherapy. Another approach is to treat patients postoperatively with two courses of adjuvant chemotherapy. This substantially decreases the rate of relapse, and is less toxic because two courses rather than four are administered.
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Chemotherapy Standard Initial Chemotherapy For patients with advanced Stage II or III nonseminomatous testicular cancer, or Stage III or IV seminoma, initial treatment postorchiecto my should be combination chemotherapy. Ten to twenty years ago, patient prognosis was very poor. The improvement seen in the prognosis of disseminated testicular cancer treated with chemotherapy drugs has been attributed to the careful, thorough, and well-organized approach of investigators at major cancer centers. The treatment of testicular cancer with antineoplastic therapy began in the 1960s with dactinomycin combinations. While the rate of complete remissions was low (100/0-20%) and only half of those achieving complete remission were cured, it did mean that a cure for testicular cancer was possible with chemotherapy. In the 1970s it was discovered that vinblastine and bleomycin in combination were synergistic against testicular cancer. While the number of patients achieving complete remission increased to 40%, it was the discovery of cisplatin's activity against testicular cancer that made the major difference in the number of patients now cured. Cisplatin is considered the most active single agent against testicular cancer. Two effective regimens used over the past 10 to 15 years are PVB (consisting of cisplatin, vinblastine, and bleomycin) and VAB (initially consisting of vinblastine, dactinomycin, and bleomycin) (see Table 1). Six VAB protocols have been developed, with the most recent (VABVI) consisting of cyclophosphamide, dactinomycin, vinblastine,. bleomycin, and cisplatin. Both regimens are considered effective treatment in Stages II, III, and IV of the disease and result in more than 70% long-term complete remISSIons. VAB-VI causes more mucosal, dermatologic, and otologic toxicity, whereas PVB produces significantly more severe leukopenia. In an attempt to decrease toxicity while maintaining high cure rates, vinblastine in the PVB regimen was replaced with etoposide (PEB). PEB has been found as effective as
PVB with a lower incidence of complications (see "Complications of Chemotherapy") and has replaced PVB as first-line treatment at some institutions. Maintenance therapy with vinblastine and/or other agents for one to two years has been studied and found to have no benefit, and is associated with increased toxicity. Further studies directly comparing these regimens are necessary to better evaluate comparative efficacy and toxicity. Studies are also ' underway attempting to further decrease toxicity by eliminating certain agents, decreasing duration of treatment, and/or substituting agents (e.g., carboplatin for cisplatin to ease outpatient administration).
More intensive treatment includes the addition of more drugs (vinblastine plus etoposide) and/or higher doses of the drugs used (most frequently cisplatin) and/or bone marrow transplants. Few patients, fortunately, are presenting with advanced disease because of better
Poor-Prognosis Patients Approximately 30% of patients will fail primary chemotherapy or will relapse at some point after treatment. A subset of patients will require additional courses of standard initial chemotherapy regimens. However, most patients who do not enter complete remission or who relapse after chemotherapy has been completed will receive salvage regimens. These regimens consist of cisplatin and other antineoplastics that the patients have not been exposed to previously. Salvage regimens often contain etoposide for those not exposed previously and/or ifosfamide (a recently approved cyclophosphamide derivative that has shown synergy with etoposide against testicular cancer in preclinical trials). Highdose carboplatin and etoposide with autologous bone marrow transplant are also being studied for persistent disease, with promising preliminary results. As mentioned previously, the most important factor predicting likelihood of successful response to treatment is the bulk of disease at presentation. For those patients with advanced disease, prognosis is still poor with standard treatment. Researchers are studying the effect of more intensive treatment on advanced disease. These studies have been difficult to evaluate because the criteria used to define advanced disease or poor-prognosis patients have varied among institutioJ;ls.
American Pharmacy, Vol. NS30, No.7 July 1990/417
49
public and professional awareness. Those who present with advanced disease should be enrolled in a clinical trial until more definitive recommendations can be made. Not all germ cell neoplasms arise in the testicle. Some can arise from the mediastinum, retroperitoneum, or less commonly other sites. Obviously in these cases, unless a mass is also detected in the testicle, orchiectomy is not indicated. Any young male patient presenting with a retroperitoneal or mediastinal mass should have serum markers drawn to aid in diagnosis. Treatment and prognosis may be the same as that seen with disseminated germ cell cancer arising in the testicle. However, several more aggressive regimens are available and advocated by some authorities.
Complications of Chemotherapy Of the first-line chemotherapy regimens currently available, all share the same dose-limiting toxicity of leukopenia. Because granulocytopenic fevers are life-threatening, minimizing this toxicity in a curable neoplasm is extremely important. Replacing vinblastine with etoposide in PVB has significantly decreased the incidence of these fevers. With the long-term survival of testicular cancer patients, study of the chronic toxicity of various treatments used has been possible. Much concern has centered around the effect of treatment on fertility. For unknown reasons 750/0-80% of patients will have low sperm counts or sperm with abnormal motility following orchiectomy even if the remaining testicle appears clinically normal. As discussed, bilateral RPLND results in major fertility problems due to resection of the thoracolumbar sympathetic plexus. This effect is usually permanent, but treatment with sympathomimetic agents has been successful in reversing the problem in some patients. Newer unilateral techniques have helped in preserving antegrade ejaculation. A common side effect of radiation treatment of seminomas is oligospermia or azospermia due to the contralateral testis exposure to 1.50/0-2% of the treatment dose. This effect is usually transient as 50
the sperm count returns to pretreatment levels 1.5 to 2 years after treatment. New techniques for shielding the contralateral testis during radiation reportedly decrease the exposure to 0.1%, eliminating reductions in sperm counts. The effects of antineoplastics on fertility are not as clear. It is known that current treatment regimens, which include the alkylating agent cisplatin, are associated with oligospermia, azospermia, and decreased leydig cell functions. This effect peaks approximately one year after treatment but reverses in at least 50% of patients within the following two years. Men less likely to recover from these effects incl ude those older than 30, those receiving abdominal radiation therapy, and those receiving treatment for more than 6 months. Two other side effects occurring in men receiving treatment for ger-
minal neoplasms include Raynaud's phenomenon and peripheral paresthesia. Raynaud's can occur with those receiving bleomycin alone. However, it increases in frequency when vinblastine is added, and occurs in approximately 50% of patients receiving these drugs in combination with cisplatin. In 50% of patients, this effect is reversible over time, but it can be permanent. Persistent paresthesia is more commonly seen in patients on regimens containing vinblastine, with an incidence of 400/0-50%. This effect has decreased in frequency since etoposide has been used to replace vinblastine. Cisplatin is associated with a number of other serious side effects including severe nausea and vomiting (which can be partially to totally alleviated with metoclopramide therapy), ototoxicity (which is related to dose and schedule of ad-
American Pharmacy, Vol. NS30, No.7 July 1990/418
ministration of cisplatin), electrolyte abnormalities (such as hypomagnesemia), and nephrotoxicity (which can be minimized with adequate saline hydration). Bleomycin administration is associated with fever, chills, cutaneous striae, alopecia, weight loss, and pulmonary fibrosis. Discontinuing bleomycin therapy when symptoms of lung dysfunction first occur can help to minimize pulmonary fibrosis. Always of concern in long-term survivors of antineoplastic therapy is the risk of secondary malignancies. Fortunately, the risk of this as a result of treatment appears to be low with testicular cancer. There have been a number of reports of leukemia, particularly acute megakaryocytic leukemia. These reports are most commonly seen in patients with a primary mediastinal germ cell tumor and may be related to the presence of this rather than to the treatment. In addition, there have been few reports of soft tissue sarcoma and transitional cell bladder cancer, possibly secondary to radiation and/or chemotherapy.
Screening and Early Detection he chances for cure are best when the disease is caught in T the early stages. Studies have shown that patients often delay going to their physician for several months after detecting a scrotal mass. The better educated this
population is, the more likely this behavior will change. Physicians, particularly those responsible for the health of young men in large groups such as sports teams, armed forces, and schools, should be aware of the prevalence and proper handling of testicular cancer in this age group. Most important for the early treatment of testicular cancer is the testicular self-examination (see box). If any mass is detected, a physician should be contacted as soon as possible. Pharmacists can help increase their patients' awareness of this dis-
ease by providing free pamphlets on testicular cancer, which are available from the American Cancer Society. Two such pamphlets are currently available: Facts on Testicular Cancer and For Men Only- Testicular Cancer and How to Do TSE (a Self Exam). The National Cancer Institute also has a patient pamphlet available, What You Need to Know About Cancer of the Testes. In addition, by increasing their knowledge of the current concepts in treatment of testicular cancer and its side effects, pharmacists can better counsel and monitor their patients ..®
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American Pharmacy, Vol. NS30, No.7 July 1990/419
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51
T
esticular cancer is rare, accounting for approximately 1% of all male cancers. In contrast, it is the most common cancer seen in men between the ages of 15 and 35. Because testicular cancer strikes men in their most productive years, its effects are much more devastating. The prognosis and management of testicular cancer have changed dramatically in the past 10 years. Major advances have been made in the techniques used to diagnose, stage, and monitor testicular cancer. The most important improvement has been in the management of disseminated disease with antineoplastic drug regimens. These improvements have changed a disease once considered to be uniformly fatal, to one that can now be cured in most patients. This article summarizes the epidemiology and etiology of this disease, its signs and symptoms, appropriate diagnostic and staging techniques, prognosis, and treatment. In addition, early and late complications of therapy and detection and screening techniques will be discussed.
Epidemiology and Etiology Pproximately 5,500 cases oftesA ticular cancer are diagnosed in the United States each year, which
Jeanne Keith, PharmD, is professional services associate manager, Amgen, 1840 Dehavilland Dr., Thousand Oaks, CA 91320. American Pharmacy's cancerscreening series guest editor is Celeste Lindley, PharmD, ofthe University of North Carolina School of Pharmacy. Received and accepted November 1989. 46
yield an estimated incidence of 5.9 per 100,000 men. For unknown reasons, the incidence of this disease has increased over the past several decades, particularly in white urban populations. Testicular cancer is four times more common in whites than blacks, and is seen more frequently in higher social classes. Little is known about the etiology of testicular cancer, although some risk factors for its development have been identified. The single most important risk factor is a history of cryptorchidism or undescended testes. During normal development, the testes are formed near the kidneys and descend into the scrotum shortly after birth. If this fails to occur or if it occurs after the age of six, the incidence of testicular cancer increases from 1% to 15%. Approximately 12% of all testicular cancer patients have a history of cryptorchidism. Although other studies have suggested a number of possible risk factors, none is as dramatic or as well documented as cryptorchidism. Additional risk factors include testicular trauma, mumps orchitis, elevated testicular temperature, inguinal hernia, and atrophic testes. There is some evidence that heredity and genetic disorders may play a role in this disease. The number of cases of familial occurrence, although small, is well defined, particularly with bilateral disease. In addition, an increased incidence of testicular cancer has been associated with genetic abnormalities. Specifically, mediastinal germ cell tumors (testicular cancer arising at some point along the mediastinum, rather than the testes) have been associated with Klinefelter's syndrome. Finally, those patients diagnosed with testicular cancer have
a much higher risk (1,000 times greater) of developing cancer in the other testicle than healthy individuals have of developing testicular cancer; however, the overall risk is still low.
Clinical Presentation nfortunately most patients U who develop testicular cancer suffer no early symptoms that would encourage them to contact their physicians. The age group this disease strikes is often healthy, and most young men do not practice testicular self-examination (TSE). When symptoms occur, they are often vague and nonspecific. The first sign is usually a change in the consistency of the testicle, with some enlargement. A heavy or dragging, aching feeling in the abdomen can develop. If rapid growth with hemorrhaging occurs, then sharp testicular pain is reported. For those men who practice TSE (see "Screening and Early Detection"), the first sign of disease is usually a painless testicular mass. The most common site of metastasis is in the retroperitoneal lymph nodes. From there, it can spread through the blood to the lungs, liver, brain, viscera, and bone; however, brain, viscera, and bone metastases are rare. Signs and symptoms related to metastases include abdominal masses, adenopathy, gynecomastia, and headaches.
Diagnosis and Initial Evaluation hen a patient has a testicular W mass (with or without any other symptoms), the physician should perform a complete history and physical, including palpation of the testes and surrounding struc-
American Pharmacy, Vol. NS30, No.7 July 1990/414
tures. Once this mass is documented, orchiectomy with complete excision of the spermatic cord is usually performed through an inguinal incision (see figure). If the incision is done using a trans scrotal (through the scrotum) approach, the risk of disease spreading through the lymphatic system is increased. Orchiectomy provides the tissue necessary for a definitive diagnosis and is the first step in effective treatment. The tissue must be carefully examined to determine its cell of origin. Of all testicular cancers, 96% are of germ cell origin (germinal neoplasms). There are four types of testicular cancer: embryonal, teratocarcinoma, choriocarcinoma, and seminoma. These types can also be found ·in combination. Seminoma is the most common, accounting for approximately 40% of cases. Teratocarcinomas occur in 20%-25% of the cases, embryonal, in 150/0-20%, and pure choriocarcinoma, rarely (1%). For treatment, the four types of testicular cancer are categorized as either seminomas or nonseminomas. This distinction is important, as treatment differs markedly. The stage of testicular cancer at diagnosis is the single most important factor affecting prognosis. Numerous staging classifications have been developed, with the simplest using three stages for nonseminomas and four stages for seminomas. For both seminomas and nonseminomas, Stage I is when the cancer is confined to the testes; at Stage II the cancer involves the retroperitoneal lymph nodes. (Stage II is often further subdivided on the basis of size and number of nodes involved and whether a palpable abdominal mass is present.) For nonseminomas, Stage III is any disease found above the diaphragm. For seminomas, Stage III represents diseased mediastinal or cervical lymph nodes, and Stage IV represents viceral (lung, bone, liver, and! or brain) metastases. Because teSticular cancer usually metastasizes first to the retroperitoneal lymph nodes, many physicians opt for a retroperitoneal lymph node dissection (RPLND) to both assess the stage of the cancer and remove any diseased nodes.
spermatic cord
collecting tubules Internal Structure
Male reproductive organs. Source: American Cancer Society.
When attempting to determine t4e stage of a seminoma, an RPLND may not be performed initially because subdiaphragmatic radiation therapy (as described under "Treatment") has been used successfully to treat Stage II disease. Other tests, such as retroperitoneal lymphangiography or computed tomography (CT) are used to stage the patient's disease. However, these methods are not as sensitive as surgery in detecting micrometastases. For this reason, the exact incidence of retroperitoneal involvement in seminomas is not known for certain but is thought to be approximately 10%-15%. Other tests used to stage testicular cancer include chest x-ray, chest CT, whole lung tomography, CT of the abdomen, and studies of the retroperitoneallymph nodes such as CT or bipedal lymphangiography (if RPLND is not performed). Testicular cancer is unique in that it is associated with reliable serum markers. Alpha fetal protein (AFP) is a glycoprotein produced by endodermal sinus cells that originate in the yolk sac of the fetus and is normally undetectable in the adult circulation. When it is found in the serum of a testicular cancer patient, it denotes the presence of nonseminomatous elements, even if these elements are not detected histologically. Patients with pure seminomas will not secrete AFP.
American Pharmacy, Vol. NS30, No. 7 July 1990/415
Elevated AFP levels are also associated with hepatitis, hepatomas, and other malignant gastrointestinal, biliary, or pancreatic diseases. Human chorionic gonadotropin (HCG), also a glycoprotein, is normally secreted by the human placenta and is elevated in patients with nonseminomatous testicular tumors, as well as li ver, breast, stomach, pancreatic, and lung cancers. Unlike AFP, B-HCG can be elevated slightly in patients with seminomas. However at higher levels, nonseminomatous elements are thought to be present. The development of sensitive assays for B-HCG and AFP has markedly improved the management of testicular cancer. Serial measurement of these markers is useful in diagnosing the type of testicular cancer and monitoring response to therapy and disease recurrence. Of patients with disseminated nonseminomatous tumors, 80% to 85% will have either or both serum markers elevated. AFP has a biological half-life offive days and methods to use this value in following a patient's response to therapy have been developed. If these levels remain elevated despite treatment, persistent disease is known to be present, even if there is no radiographic evidence of disease. B-HCG levels should decrease by at least one log (90%) every three weeks following each treatment. If this does not occur, then alternate treatment modalities should be considered.
Prognosis he prognosis for this disease has T changed drastically over the past two decades. While the majority of nonseminomatous patients used to die within 1 to 2 years of diagnosis, today even those patients with Stage III disease have a 70% to 80% chance of cure. Those patients with Stage I or II nonseminomatous cancer have a greater than 90% chance of cure. Patients with seminoma have a 90% to 100% five-year survival prognosis. Because the majority of patients who relapse will do so within two years . of diagnosis, testicular cancer is considered to be cured if the patient is free of disease at the two-year
47
mark. Recently, however, a number of late recurrences (occurring after more than 10 years) have been reported. The most important prognostic factor in testicular cancer is the stage of disease at diagnosis. Most investigators agree that age, mode oftreatment, histology, or elevation oftumor markers are not important prognostic factors and do not help predict the 100/0-15% who will relapse. Once a patient relapses, the prognosis is again primarily determined by the patient's extent of disease at relapse.
Treatment Seminomas Seminoma accounts for 30%-40% of testicular cancer. Unlike nonseminomatous patients, the majority (600/0-80%) of these patients present with clinical Stage I disease, due to the slow-growing nature of seminoma. Any patient whose histology indicates pure seminoma but who has an elevated AFP should be treated as a nonseminomatous patient. An elevated B-HCG is more controversial. Seminomas are highly radiosensitive, and local (subdiaphragmatic) radiation therapy with 2,000 to 3,000 rads over three to four weeks will cure 99% of patients with Stage I disease. It is likely that the majority of Stage I patients will be cured with orchiectomy alone (without radiation treatment). Even though radiation treatment is well tolerated, it would be optimal to limit therapy to only those who will clearly benefit. As a result, some clinicians advocate a surveillance-only policy after orchiectomy in patients with Stage I seminoma. The disadvantage to this approach is the intensive and meticulous follow-up required, primarily because the serum markers used to follow nonseminomatous patients are not helpful in this situation. When both the patient and physician are highly motivated, this approach seems reasonable in Stage I seminomas. Recurrences after treatment of Stage I or II seminoma tend to occur in a small number of patients within two years in the mediastinal, retroperitoneal, or supraclavicular 48
regions. While radiation therapy is effective for isolated recurrences, prophylactic mediastinal or supraclavicular irradiation has not been found to improve the three-year disease-free survival. Prophylactic radiation in Stages I and II seminoma is, therefore, no longer recommended. The treatment of patients with advanced Stage II (bulky disease) seminoma is controversial. Some clinicians advocate radiation treatment followed by chemotherapy for relapses or progressive disease, while others recommend initial treatment with chemotherapy followed by radiation for disease progression. Both approaches have been associated with high cure rates. The use of radiation, however, can limit the doses and intensity of future chemotherapy if it becomes necessary. Advanced seminomas (Stages III and IV) are currently treated with chemotherapy because radiation therapy alone is associated with a low cure rate.
Nonseminomas Standard treatment for patients diagnosed with nonseminomatous testicular cancer postorchiectomy includes RPLND to further stage the patient and, more important, to remove any diseased lymph nodes. Those diagnosed with Stage I or early Stage II disease are then followed postoperatively with monthly serum markers and chest x-rays for the first year and then every other month during the second year for disease recurrence. This approach, while still considered standard by many investigators, is controversial. Because only 25%-35% of patients with clinical Stage I disease will be found to have Stage II disease after RPLND, clinicians have questioned the value of subjecting all clinical Stage I patients to RPLND. This is an important question, considering the success of chemotherapy for patients who progress or relapse, and the fact that 650/0-70% of patients will lose antegrade ejaculatory function after a traditional RPLND as a result of severing the sympathetic plexus during surgery. On the other hand, those patients
who relapse after orchiectomy alone will be subjected to chemotherapy with cisplatin when they may have been cured with RPLND. In addition, patients who may have relapsed with pulmonary disease only following RPLND will relapse with pulmonary disease and moderate retroperitoneal disease - increasing the tumor burden and lessening the chance for cure with chemotherapy. Finally, new techniques, including unilateral modified nerve-sparing RPLNDs have been reported to preserve antegrade ejaculatory function in as much as 80% of patients. Studies have demonstrated the benefits of surveillance only, particularly in patients without certain risk factors thought to increase their risk of relapse, such as vascular invasion of the primary tumor or embryonic histology. These studies have led several centers to adopt a surveillance-only program, similar to that discussed for seminomas. Intense monitoring and follow-up are essential because antineoplastic therapy is highly successful if tumor burden is low. The optimal schedule for follow-up is not known but should include frequent visits with measurement of serum markers and computed tomography scans of the chest and abdomen during the first year, and less frequent monitoring for the second and third years. Both methods of treatment (RPLND or surveillance-only) are accepted today. Whichever course of treatment is undertaken, both the patient and physician must understand the risks involved and the importance of monitoring. Of patients initially diagnosed with Stage II disease, treatment with orchiectomy and RPLND will cure 50%. However, between 40% and 50% of patients will relapse and, if carefully monitored, postsurgery tumor burden will be minimal. Treatment with chemotherapy cures 900/0-100% of these patients upon relapse. Treatment to prevent relapse usually consists of four courses of chemotherapy. Another approach is to treat patients postoperatively with two courses of adjuvant chemotherapy. This substantially decreases the rate of relapse, and is less toxic because two courses rather than four are administered.
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Chemotherapy Standard Initial Chemotherapy For patients with advanced Stage II or III nonseminomatous testicular cancer, or Stage III or IV seminoma, initial treatment postorchiecto my should be combination chemotherapy. Ten to twenty years ago, patient prognosis was very poor. The improvement seen in the prognosis of disseminated testicular cancer treated with chemotherapy drugs has been attributed to the careful, thorough, and well-organized approach of investigators at major cancer centers. The treatment of testicular cancer with antineoplastic therapy began in the 1960s with dactinomycin combinations. While the rate of complete remissions was low (100/0-20%) and only half of those achieving complete remission were cured, it did mean that a cure for testicular cancer was possible with chemotherapy. In the 1970s it was discovered that vinblastine and bleomycin in combination were synergistic against testicular cancer. While the number of patients achieving complete remission increased to 40%, it was the discovery of cisplatin's activity against testicular cancer that made the major difference in the number of patients now cured. Cisplatin is considered the most active single agent against testicular cancer. Two effective regimens used over the past 10 to 15 years are PVB (consisting of cisplatin, vinblastine, and bleomycin) and VAB (initially consisting of vinblastine, dactinomycin, and bleomycin) (see Table 1). Six VAB protocols have been developed, with the most recent (VABVI) consisting of cyclophosphamide, dactinomycin, vinblastine,. bleomycin, and cisplatin. Both regimens are considered effective treatment in Stages II, III, and IV of the disease and result in more than 70% long-term complete remISSIons. VAB-VI causes more mucosal, dermatologic, and otologic toxicity, whereas PVB produces significantly more severe leukopenia. In an attempt to decrease toxicity while maintaining high cure rates, vinblastine in the PVB regimen was replaced with etoposide (PEB). PEB has been found as effective as
PVB with a lower incidence of complications (see "Complications of Chemotherapy") and has replaced PVB as first-line treatment at some institutions. Maintenance therapy with vinblastine and/or other agents for one to two years has been studied and found to have no benefit, and is associated with increased toxicity. Further studies directly comparing these regimens are necessary to better evaluate comparative efficacy and toxicity. Studies are also ' underway attempting to further decrease toxicity by eliminating certain agents, decreasing duration of treatment, and/or substituting agents (e.g., carboplatin for cisplatin to ease outpatient administration).
More intensive treatment includes the addition of more drugs (vinblastine plus etoposide) and/or higher doses of the drugs used (most frequently cisplatin) and/or bone marrow transplants. Few patients, fortunately, are presenting with advanced disease because of better
Poor-Prognosis Patients Approximately 30% of patients will fail primary chemotherapy or will relapse at some point after treatment. A subset of patients will require additional courses of standard initial chemotherapy regimens. However, most patients who do not enter complete remission or who relapse after chemotherapy has been completed will receive salvage regimens. These regimens consist of cisplatin and other antineoplastics that the patients have not been exposed to previously. Salvage regimens often contain etoposide for those not exposed previously and/or ifosfamide (a recently approved cyclophosphamide derivative that has shown synergy with etoposide against testicular cancer in preclinical trials). Highdose carboplatin and etoposide with autologous bone marrow transplant are also being studied for persistent disease, with promising preliminary results. As mentioned previously, the most important factor predicting likelihood of successful response to treatment is the bulk of disease at presentation. For those patients with advanced disease, prognosis is still poor with standard treatment. Researchers are studying the effect of more intensive treatment on advanced disease. These studies have been difficult to evaluate because the criteria used to define advanced disease or poor-prognosis patients have varied among institutioJ;ls.
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public and professional awareness. Those who present with advanced disease should be enrolled in a clinical trial until more definitive recommendations can be made. Not all germ cell neoplasms arise in the testicle. Some can arise from the mediastinum, retroperitoneum, or less commonly other sites. Obviously in these cases, unless a mass is also detected in the testicle, orchiectomy is not indicated. Any young male patient presenting with a retroperitoneal or mediastinal mass should have serum markers drawn to aid in diagnosis. Treatment and prognosis may be the same as that seen with disseminated germ cell cancer arising in the testicle. However, several more aggressive regimens are available and advocated by some authorities.
Complications of Chemotherapy Of the first-line chemotherapy regimens currently available, all share the same dose-limiting toxicity of leukopenia. Because granulocytopenic fevers are life-threatening, minimizing this toxicity in a curable neoplasm is extremely important. Replacing vinblastine with etoposide in PVB has significantly decreased the incidence of these fevers. With the long-term survival of testicular cancer patients, study of the chronic toxicity of various treatments used has been possible. Much concern has centered around the effect of treatment on fertility. For unknown reasons 750/0-80% of patients will have low sperm counts or sperm with abnormal motility following orchiectomy even if the remaining testicle appears clinically normal. As discussed, bilateral RPLND results in major fertility problems due to resection of the thoracolumbar sympathetic plexus. This effect is usually permanent, but treatment with sympathomimetic agents has been successful in reversing the problem in some patients. Newer unilateral techniques have helped in preserving antegrade ejaculation. A common side effect of radiation treatment of seminomas is oligospermia or azospermia due to the contralateral testis exposure to 1.50/0-2% of the treatment dose. This effect is usually transient as 50
the sperm count returns to pretreatment levels 1.5 to 2 years after treatment. New techniques for shielding the contralateral testis during radiation reportedly decrease the exposure to 0.1%, eliminating reductions in sperm counts. The effects of antineoplastics on fertility are not as clear. It is known that current treatment regimens, which include the alkylating agent cisplatin, are associated with oligospermia, azospermia, and decreased leydig cell functions. This effect peaks approximately one year after treatment but reverses in at least 50% of patients within the following two years. Men less likely to recover from these effects incl ude those older than 30, those receiving abdominal radiation therapy, and those receiving treatment for more than 6 months. Two other side effects occurring in men receiving treatment for ger-
minal neoplasms include Raynaud's phenomenon and peripheral paresthesia. Raynaud's can occur with those receiving bleomycin alone. However, it increases in frequency when vinblastine is added, and occurs in approximately 50% of patients receiving these drugs in combination with cisplatin. In 50% of patients, this effect is reversible over time, but it can be permanent. Persistent paresthesia is more commonly seen in patients on regimens containing vinblastine, with an incidence of 400/0-50%. This effect has decreased in frequency since etoposide has been used to replace vinblastine. Cisplatin is associated with a number of other serious side effects including severe nausea and vomiting (which can be partially to totally alleviated with metoclopramide therapy), ototoxicity (which is related to dose and schedule of ad-
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ministration of cisplatin), electrolyte abnormalities (such as hypomagnesemia), and nephrotoxicity (which can be minimized with adequate saline hydration). Bleomycin administration is associated with fever, chills, cutaneous striae, alopecia, weight loss, and pulmonary fibrosis. Discontinuing bleomycin therapy when symptoms of lung dysfunction first occur can help to minimize pulmonary fibrosis. Always of concern in long-term survivors of antineoplastic therapy is the risk of secondary malignancies. Fortunately, the risk of this as a result of treatment appears to be low with testicular cancer. There have been a number of reports of leukemia, particularly acute megakaryocytic leukemia. These reports are most commonly seen in patients with a primary mediastinal germ cell tumor and may be related to the presence of this rather than to the treatment. In addition, there have been few reports of soft tissue sarcoma and transitional cell bladder cancer, possibly secondary to radiation and/or chemotherapy.
Screening and Early Detection he chances for cure are best when the disease is caught in T the early stages. Studies have shown that patients often delay going to their physician for several months after detecting a scrotal mass. The better educated this
population is, the more likely this behavior will change. Physicians, particularly those responsible for the health of young men in large groups such as sports teams, armed forces, and schools, should be aware of the prevalence and proper handling of testicular cancer in this age group. Most important for the early treatment of testicular cancer is the testicular self-examination (see box). If any mass is detected, a physician should be contacted as soon as possible. Pharmacists can help increase their patients' awareness of this dis-
ease by providing free pamphlets on testicular cancer, which are available from the American Cancer Society. Two such pamphlets are currently available: Facts on Testicular Cancer and For Men Only- Testicular Cancer and How to Do TSE (a Self Exam). The National Cancer Institute also has a patient pamphlet available, What You Need to Know About Cancer of the Testes. In addition, by increasing their knowledge of the current concepts in treatment of testicular cancer and its side effects, pharmacists can better counsel and monitor their patients ..®
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American Pharmacy, Vol. NS30, No.7 July 1990/419
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![[Elastography shows promise in testicular cancer detection].](/assets/img/hold.png)
