Chapter 110:  Neoplasms of the Testis

Incidence

An age-related incidence curve of testicular cancer reveals a bimodal distribution. The major peak occurs between ages 15 and 35 years, due almost exclusively to tumors of germ cell origin, which account for approximately 95% of all testicular cancer. Within the subclass of germ cell neoplasms is another bimodal distribution, with embryonal carcinoma representing the predominant histopathologic diagnosis up to the age of 35 years, after which seminoma is more common up to the age of 75 years. The incidence of testicular cancer declines steadily beyond the age of 40 years, but a small rise beyond the age of 75 years can be attributed primarily to an increase in the incidence of testicular lymphoma.

Demographic analysis of testicular cancer worldwide reveals a number of interesting trends. The incidence of the disease varies markedly on the basis of geographic distribution, with the highest incidence in northern Europe and North America, and the lowest in Asia and Africa. There is also a striking influence of race, with the incidence among black and Hispanic males worldwide far less than that for their Caucasian counterparts.^4,5 The incidence of testicular cancer rises with increasing socioeconomic status,⁶ but even when stratified by this parameter, the racial differences persist, with blacks having a lower incidence than Caucasians in each class.

The incidence of testicular cancer is increasing among young Caucasian males in the Scandinavian countries, the United Kingdom, and the United States. In Denmark, from 1945 to 1970, the age-adjusted incidence for testicular cancer nearly doubled to 6.4 per 100,000. During that period, the percentage of malignant neoplasms in the 15- to 34-year age range attributable to testicular cancer increased from 17 to 29%.^7,8 A similar doubling in incidence in younger age groups in England and Wales over the same period has also been observed.^9,10 In the United States, from 1937 to 1976, the age-adjusted incidence for testicular cancer in Caucasian males rose from 2 to 3.8 per 100,000, while the rate for African American males remained constant at 0.9 per 100,000.^9,11–13 The American Cancer Society projected that in 1999, 6,900 cases of testicular cancer would be diagnosed in the United States, with approximately 300 persons dying of the disease.

Risk Factors

Cryptorchidism is the major identifiable risk factor associated with the development of testicular cancer, with a risk ratio variably reported between 2.5 and 14 in case-control studies.^14–17 The location of the maldescended testicle appears to be an important cofactor in the subsequent development of cancer, since those patients with intra-abdominal retention have a four-fold higher incidence of malignancy than do those with the testicle retained in the inguinal canal. For a number of reasons, it seems unlikely that maldescent, in and of itself, represents the initiating event in the development of germ cell tumors: only 10% of testicular tumors are associated with cryptorchidism; at least 25% of the malignancies in patients with cryptorchidism occur in the contralateral, normally descended testicle; prepubertal orchiopexy fails to prevent the subsequent development of malignancy in the undescended testicle;¹⁸ and first-degree male relatives of patients with testicular cancer exhibit an increased incidence of cryptorchidism, hydroceles, and inguinal hernias, as well as testicular cancer.¹⁹ These data suggest that some genetic predisposition and/or in utero environmental event may result in several urothelial developmental abnormalities, including maldescent and germ cell neoplasia. Interestingly, an increase in the frequency of cryptorchidism has been observed and appears to parallel the timing and magnitude of the increase in incidence of testicular cancer.²⁰

The use of exogenous estrogens during pregnancy in the mothers of testicular cancer patients has been analyzed by a number of investigators. Interest in this as a possible etiologic factor is based on a series of observations: murine testicular tumors can be produced experimentally by administration of estrogen,²¹ male offspring of mothers treated with diethylstilbesterol (DES), a synthetic, nonsteroidal estrogen, exhibit a number of urogenital developmental abnormalities, including testicular hypoplasia and maldescent,^22–24 female offspring of mothers using DES during the first 2 months of gestation have shown an increased frequency of clear cell adenocarcinoma of the vagina, with a peak incidence in the middle to late teens;²⁵ use of exogenous estrogens by pregnant women was a common practice from 1940 to 1960 for a number of conditions, including threatened abortion; and the risk of testicular cancer is increased 40-fold in testicular feminization syndromes.²⁶ Three case control studies have been performed, and show a relative risk of 2.8 to 5.3 in the offspring of mothers who were administered exogenous sex steroids during gestation,^8,14,23 although differences between index and control cases have, in general, failed to reach statistical significance. It is unlikely that exogenous steroids contribute to a major degree to the incidence of testicular cancer in the United States. Their lack of use in other endemic areas with rising incidence rates (Denmark) underscores their relatively minor role (if any) in the etiology of this disease.

Carcinoma in situ of the testis (intratubular germ cell neoplasia) appears to represent a true premalignant condition for the development of invasive germ cell tumors. On the basis of observations by Skakkebaek and colleagues, the appearance of these cytologically abnormal cells can be detected in a small percentage of men undergoing infertility work-ups, and a significant number of those individuals subsequently develop invasive germinal malignancies.^27,28 Carcinoma in situ may appear in up to 10% of contralateral testes in patients with a prior germ cell malignancy.^29,30 Although the premalignant potential of such lesions is no longer in doubt, general agreement on the clinical approach to this histopathologic finding has not been established.

Patients with a history of unilateral testicular cancer are at risk for developing cancer in the other testicle. In a large Danish series, 2.7% of 2,338 patients developed a contralateral testicular tumor during the period of follow-up.³¹ Patients with nonseminoma had a higher overall relative risk of developing contralateral tumors than did those with seminoma. Investigators at the Royal Marsden Hospital reported a similar rate of 2.75% for developing contralateral tumors among 760 men in an interval as long as 15 years. (248). These observations underscore the importance of continued follow-up after treatment. Recommendations for the investigation and management of carcinoma in situ in patients with a diagnosis of testicular cancer ranges from close clinical observation to biopsy of the contralateral testicle and, if carcinoma in situ is identified, radiation therapy to the testicle.

Seminoma

Overall, the diagnosis of pure seminoma accounts for approximately 47% of all testicular cancers, but interestingly, its incidence is increased in cryptorchid testes, where it accounts for more than 60% of neoplasms.^43,44 Currently, seminoma is subclassified as either classic or spermatocytic. Formerly, a third category of anaplastic seminoma was distinguished histologically, on the basis of a large number of mitoses per high-power field, an absence of trophoblastic elements, and a tumor appearing less well organized on low-power examination than its classic counterpart. Although patients with this anaplastic variant may present with more advanced disease, when stratified by stage of disease, survival rates are no different than those for patients with classic seminoma, and ultrastructural characteristics are identical.^45–47 On the basis of these findings, an international panel in 1980 suggested that this term be deleted from pathologic classification.⁴⁸

Classic Seminoma

This subtype accounts for approximately 93% of all seminomas. On gross examination, the tumor is generally rounded and well demarcated, although no formal capsule exists. On cut sections, distinct lobulation is apparent, with nodules separated by dense fibrous bands. Areas of necrosis and hemorrhage may also be observed but, typically, are neither numerous nor large.

Figure 110.1

Small nests of seminoma are separated by a lymphoid (more...)

Figure 110.1

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Small nests of seminoma are separated by a lymphoid infiltrate and a focal granulomatous reaction.

Microscopically, there is a monotonous distribution of uniform, rounded cells with large, centralized nuclei and nucleoli. The cytoplasm may be either clear or granular and will frequently stain positively for glycogen, lipid, and/or alkaline phosphatase. Stromal elements are equally characteristic, with a lymphocytic infiltration that can proceed to granuloma formation containing Langerhans’-like giant cells (Fig. 110.1). These areas may predominate histologically and mimic granulomatous orchitis. Approximately 7% of classic seminomas contain true syncytial trophoblastic giant cells (as distinct from Langerhans’ cells) that stain positively for human chorionic gonadotropin (hCG), and that may account for the low-level elevation of serum hCG in some patients with pure seminoma.

Clinically, classic seminoma presents in the fourth or fifth decade, most commonly as an enlarging, painless testicular mass. Only one quarter of seminomas present with metastatic disease; in a review of over 2,300 cases, Smith documented that 74.7% of patients presented with stage I disease, 19.5% with stage II, and only 5.8% with stages III and IV.⁴³ Lymphatic spread is to the para-aortic lymph nodes, then to the mediastinal or supraclavicular lymph nodes, usually only after the development of significant infradiaphragmatic disease. Hematogenous dissemination to the lung, liver, bone, or adrenal is a late occurrence in the natural history of this disease. Low-level hCG elevation can be seen in 5 to 10% of pure seminomas and is likely a result of the presence of syncytial trophoblastic elements within the tumor.⁴⁹ The presence of such hCG elevation, however, does not appear to negatively influence prognosis.^49–51 Seminoma does not secrete alpha-fetoprotein (AFP), however, and elevation of this serum marker denotes the presence of nonseminomatous elements.

Spermatocytic Seminoma

Figure 110.2

Spermatocytic seminoma. There is a diffuse, sheet-like (more...)

Figure 110.2

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Spermatocytic seminoma. There is a diffuse, sheet-like arrangement of neoplastic cells that vary in size.

Spermatocytic seminoma accounts for approximately 7% of all seminomas. On gross examination, this variant has a grayish appearance and tends to be softer than the classic variety, containing cystic areas without necrosis or hemorrhage. Microscopically, these tumors tend to form tubular clusters and are composed of round cells of highly variable size that are closely related morphologically to the three types of cells in the normal spermatocytic series (Fig. 110.2). In contrast to classic seminoma, stromal lymphocytic infiltration does not occur in spermatocytic seminomas. Clinically, this variant tends to occur in an older population than does classic seminoma, with a median age of 65 years. The prognosis is excellent, as this tumor grows extremely slowly. The appearance of metastases is anecdotal, and orchiectomy alone may be the only treatment necessary when this diagnosis is made.⁵²

Embryonal Carcinoma

Embryonal carcinoma accounts for 20% of all testicular tumors. Macroscopically, pure embryonal carcinomas tend to be small (even in the presence of widespread metastases), although larger tumors can efface the normal testicular tissue. The cut surface is less homogeneous than seminoma, with frequent areas of necrosis and hemorrhage. Direct invasion of the spermatic cord, epididymis, and tunica albuginea is common.

Figure 110.3

Embryonal carcinoma. Irregularly shaped glands and (more...)

Figure 110.3

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Embryonal carcinoma. Irregularly shaped glands and papillae are lined by pleomorphic cells with vesicular, crowded nuclei and poorly defined cytoplasmic membranes.

Fig. 110.3

Clinically, these are aggressive tumors with a high metastatic potential. Embryonal carcinoma may contain differentiated components of extraembryonic structures, such as trophoblastic or yolk sac elements, with corresponding elevation of the serum levels of hCG or AFP, respectively.

Yolk Sac Carcinoma

While yolk sac elements are frequently found in embryonal carcinoma, this pattern can also appear in a pure form. Formerly referred to as endodermal sinus tumor, it is the most common testicular malignancy in infants and young children.^37,53,54 In children, it is occasionally designated as infantile embryonal carcinoma or orchidoblastoma and carries an excellent prognosis.⁵⁵ Macroscopically, lesions may be large and on cut sections appear yellowish, with areas of cystic degeneration.

Figure 110.4

Yolk sac tumor. Numerous microcysts occur in the most (more...)

Figure 110.4

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Yolk sac tumor. Numerous microcysts occur in the most common pattern of yolk sac tumor.

Fig. 110.4

In adults, pure yolk sac tumor is a virulent neoplasm with early hematogenous dissemination and a particular affinity for the development of hepatic metastases. Primary mediastinal germ cell tumors are especially prone to exhibiting this type of extraembryonic differentiation, with the incidence in one series approaching 50%.⁵⁶ Serologically, patients with pure yolk sac tumors have elevated serum levels of AFP, usually with a normal serum level of hCG.

Choriocarcinoma

Although trophoblastic components are common components of mixed germ cell tumors, pure choriocarcinoma of the adult testis is rare. On gross examination, the appearance of the tumor is variable because of the common appearance of other germ cell elements. In pure form, however, choriocarcinoma is characterized on cut sections by frequent focal hemorrhages.

Figure 110.5

Choriocarcinoma. Syncytiotrophoblastic cells (more...)

Figure 110.5

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Choriocarcinoma. Syncytiotrophoblastic cells “cap” islands of mononucleated cytotrophoblast. Note the hemorrhagic background.

Fig. 110.5

Choriocarcinoma of the testis represents the most aggressive pathologic variant of germ cell tumors in adults, characteristically with early hematogenous and lymphatic spread. Large-volume visceral metastases may be observed at presentation with an occult primary lesion. A poorer prognosis in these patients may result from the average volume of disease at presentation, rather than as an inherent resistance to therapy with this pathologic pattern. These patients characteristically have extreme elevations of serum levels of hCG, with a normal serum level of AFP.

Teratocarcinoma

The term “teratocarcinoma” refers to a germ cell tumor containing elements of mature teratoma mixed with other germ cell elements. Macroscopically, there is a variegated appearance, with cystic areas of the mature teratoma admixed with areas of solid tumor representing the malignant elements. Microscopically, separate areas of obviously malignant germinal elements (i.e., embryonal carcinoma) are in proximity to mature, adult-like structures. Clinically, the aggressiveness of this tumor lies somewhere in between that of mature teratoma and pure embryonal carcinoma.

Teratoma

The term “teratoma” refers to a germ cell tumor that contains elements of all three germ layers (endoderm, mesoderm, and ectoderm), present with varying degrees of differentiation. Although technically no malignant tissue exists in these terminally differentiated tumors, metastases can occur, and death can result from slowly progressive, unresectable disease. Therefore, the label “benign” is misleading and should be avoided when referring to these tumors. Teratoma does not secrete either β-hCG or AFP and is not responsive to chemotherapy. Subcategories include mature teratoma, immature teratoma, and teratoma with malignant transformation. Surgical extirpation represents the only known therapeutic option.

Macroscopically, primary lesions in the testicle tend to be large, replacing normal epithelium. Cut surfaces show large multi-loculated cystic areas, with cysts containing serosanguinous fluid. If solid areas are noted grossly, they should be analyzed histologically, as other malignant germinal elements may be present.

Mature Teratoma

Figure 110.6

Mature teratoma. There are mature-appearing, small (more...)

Figure 110.6

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Mature teratoma. There are mature-appearing, small glands, a portion of a pilosebaceous unit, and bundles of smooth muscle.

Microscopically, mature (adult) teratoma is easily distinguished, with obvious epithelial-lined structures, as well as mature cartilage, and striated or smooth muscle (Fig. 110.6). Although each component is histologically mature, the distribution of the elements appears haphazard. Overall, testicular teratomas are much less well organized at an organ level than are their ovarian counterparts.

Immature Teratoma

Figure 110.7

Immature teratoma. An island of immature neuroepithelium (more...)

Figure 110.7

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Immature teratoma. An island of immature neuroepithelium is present adjacent to a nodule of hyaline cartilage.

Several histologic features may result in a teratoma being labeled as immature. The presence of a highly cellular stroma exhibiting mitotic figures is sufficient to make this diagnosis (Fig. 110.7). More commonly, immature teratoma has areas of primitive mesoderm, endoderm, or ectoderm mixed with the more mature elements.

Gonadal Stromal Tumors

Tumors arising from stromal tissue account for only 4% of all adult testicular tumors but represent almost 20% of childhood testicular tumors.⁶⁰ These tumors are thought to arise from primitive gonadal mesenchyme and have been subcategorized as Leydig’s cell tumor, Sertoli’s cell tumor, gonadoblastoma, and granulosa-theca cell tumor.⁶¹

Diagnosis

The diagnostic process begins with the physical examination. The examination of the testis is performed by grasping the gonad between the thumb and first two fingers and carefully palpating the testis, epididymis, and cord. Tumors of the testis can present with a discrete nodular density or as diffuse infiltration of the entire testis (particularly seminoma and lymphoma). The other testis serves as a useful reference standard to make comparisons.

On occasion, it is difficult to distinguish between a mass within the body of the testis and a small tense hydrocele; a large hydrocele may obscure complete palpation. In such instances, trans-scrotal ultrasound may be useful in discriminating the diagnostic possibilities. Inguinal orchiectomy remains the standard approach for definitive pathologic diagnosis, as well as for ensuring local control of a primary testicular cancer.

Extragonadal germ cell tumors arising within the retroperitoneum or mediastinum require specialized management. At institutions with experienced cytopathologists, fine-needle aspiration coupled with elevated tumor markers is sufficient. If there is no marker elevation or the cytology is insufficient, a formal biopsy is required. For mediastinal germ cell tumors, an anterior median sternotomy is favored for diagnosis. Since chemotherapy is the primary modality of treatment, attempts at debulking or total removal of mediastinal germ cell tumors as initial management are inappropriate. Primary retroperitoneal germ cell tumors are more commonly associated with an occult testicular primary. Such patients should have a thorough evaluation of the gonads, including the use of testicular ultrasonography. If a previously unsuspected testicular tumor is found, orchiectomy can serve as the diagnostic procedure. Otherwise, fine-needle aspiration of the abdominal mass or exploratory laparotomy is required to provide tissue for diagnosis.

Management of patients who have had a scrotal violation depends on the procedure performed and the anticipated treatment of the malignancy. If, at the time of scrotal orchiectomy, the surgeon identified the tumor and removed the testis in toto, then the only additional procedure that need be accomplished is removal of the inguinal portion of the spermatic cord. This can be done at the time of the retroperitoneal lymphadenectomy or through a separate inguinal incision. If a testicular biopsy was performed, management of the hemiscrotum depends on the primary treatment modality. Patients who are receiving primary chemotherapy do not need hemiscrotectomy. Patients managed with surgery alone should have a hemiscrotectomy performed at the time of retroperitoneal lymphadenectomy. Inguinal lymphadenectomy is reserved for patients with palpable inguinal lymphadenopathy. For patients with early-stage seminoma who have had a scrotal violation, about 5 to 10% will experience local failure. Extending the field to include the groin and scrotum diminishes these prospects but is associated with increased infertility. Such patients should be managed on a case-by-case basis, depending on such issues as the desire to have a family and compliance with follow-up.

Tumor Markers

Management of testicular cancer has come to depend on the accurate determination of levels of serum tumor markers and the interpretation of these values in the clinical context. The most sensitive and specific markers are AFP and the beta subunit of hCG. AFP is a glycoprotein normally produced by the fetal yolk sac and is derived from the yolk sac or embryonal carcinoma elements of germ cell cancers. Levels of AFP are not detectable in normal adults. The half-life of this protein in the serum is about 5 days. hCG is a smaller glycoprotein that is normally produced by trophoblastic tissues. In germ cell cancers, syncytiotrophoblastic components elaborate hCG. The protein comprises an alpha subunit and a beta subunit, each of which is antigenically distinct. The serum half-life of the entire protein is 18 to 24 hours.

Clinical decisions in patients with germ cell cancer frequently depend on precise measurement of serum tumor markers: beta subunit hCG, AFP, and lactate dehydrogenase (LDH). Overall, hCG and/or AFP is elevated in 85% of patients with disseminated testicular and primary retroperitoneal nonseminomatous germ cell tumors. AFP alone is elevated in 40% of patients, and hCG alone is elevated, which is somewhat more common, in 50 to 60% of patients with disseminated testicular cancer. Elevated LDH is a less specific marker and is probably a correlate of disease bulk. Mediastinal nonseminomatous germ cell tumors more commonly have elevation of AFP (80%) and less commonly of hCG (40%).

Pure seminoma is most frequently associated with normal AFP and hCG, but about 10% of all cases, and up to 30 to 50% of patients with advanced disease, may have low-level elevation of hCG (usually less than 100 mIU/mL).⁶⁷ Any elevation of AFP in patients with seminoma must be viewed as evidence of nonseminomatous disease and management should proceed as such.

The role of preorchiectomy determination of markers is limited, particularly since as many as one-third of patients with early-stage disease have normal markers.⁶⁸ AFP and hCG should be determined before and after orchiectomy, but the absence of marker elevation should not influence the decision to undertake the procedure. Likewise, normalization of serum markers after orchiectomy does not ensure that all disease has been removed, although persistence of marker elevation implies residual disease.

The rate of disappearance of elevated tumor markers is very useful in determining response to treatment. hCG is the most useful in this regard; the most clinically helpful guideline is that a 10-fold decrease in the hCG level over a 3-week period is consistent with disease eradication. Less steep declines of hCG levels may correlate with the emergence of drug-resistant disease in the case of chemotherapy, or residual disease in the case of surgery. Likewise, the reappearance of marker elevation often predates the radiographic appearance of recurrent disease and, as such, is an invaluable method of detecting early relapse.

While the presence of tumor markers and their accurate determination serve as a luxury in the management of patients with germ cell cancer, the presence of these markers also can lead to errors in clinical management, if not interpreted with caution. First, hCG determination can be nonspecific, and there is some cross-reactivity in the radioimmunoassay with luteinizing hormone. Also, hCG can be falsely elevated in patients who use marijuana. Low levels of hCG elevation consequently are difficult to interpret. A conservative approach to this dilemma is to repeat the hCG determination to ensure that the elevation is not a laboratory error. If the level is still high, the patient should be queried regarding drug usage. Testosterone should be given to ensure that a hypogonadal state with resultant high levels of luteinizing hormone is not interfering with the determination of hCG. If the level remains increased, restaging procedures and investigation of sanctuary sites are in order.

A recent example of how blind dependence on predicted hCG declines can lead to treatment errors was demonstrated at Indiana University in the retrospective review of management strategies in patients with very high hCG levels. Forty-one patients with an hCG greater than 50,000 mIU/mL were included. All patients received modern cisplatin-based chemotherapy. As expected 40 of 41 had advanced disease by the Indiana prognostic classification system. The overall results reveal that 22 patients (54%) are continuously free of disease, and 8 more are currently free of disease with additional therapies. Only 2 of these 41 patients had normal hCG levels at the time of the fourth course of chemotherapy. Eight additional patients had normalized the hCG within 1 month of the fourth course of therapy. Of these patients, 7 remain continuously free of disease, and 3 are currently disease free with salvage therapy. Thirty-one patients had an abnormal hCG > 1 month after completing the fourth course of primary chemotherapy. Fifteen of these patients are continuously disease free, despite no further treatments. An additional 5 patients are currently disease free with salvage treatments. The median level of hCG for these 15 patients at 1 month was 24 mIU/mL (range 2–77). The median time to normalization was 149 days (range 114–230 days). This review highlights a subset of patients with very high hCG levels that do not have a consistent predictable decline of hCG with treatment. Absolute dependence on predicted patterns of decline in these patients would have resulted in overtreatment or inappropriate initiation of salvage therapy.

False-positive elevation of AFP is quite rare. Differential considerations include laboratory error, other tumor types (such as hepatocellular carcinoma), and liver inflammation from cirrhosis or hepatitis.

Nonseminoma: Early Stage

There is an ongoing controversy regarding the management of early-stage nonseminomatous germ cell tumors. This controversy has been spurred, in part, by the phenomenal success of chemotherapy in disseminated disease and increasing concern regarding the acute and long-term toxicities of curative therapy.

Knowledge of the natural history of testicular primary lesions and their lymphatic drainage patterns is key to understanding the therapeutic options available. Testicular lymphatics arise in proximity to the embryonic origin of the testicle, in the genital ridge in the high lumbar region. Although the afferent lymphatic channels accompany testicular descent into the scrotum, draining lymph nodes remain in the retroperitoneum, including first-echelon lumbar nodes and second-echelon iliac chain nodes.

The specific patterns of lymphatic drainage for testicular tumors have been known for over 80 years. In 1910, Jamieson and Dobson demonstrated that the drainage pattern differed according to the side of the primary lesion, with right-sided lesions draining to the paracaval, interaortocaval, and preaortic nodes, and left-sided lesions to the paraaortic and preaortic nodes.⁷⁵

Retroperitoneal Lymph Node Dissection

On the basis of the knowledge of a predictable pattern of spread of testicular tumors, multiple reports of retroperitoneal lymph node dissections (RPLND) surfaced from 1907 through 1950,^76–78 with a significant improvement in the 5-year survival to 46%. A number of surgical techniques have been described to expose and resect retroperitoneal lymph nodes. Radical lymphadenectomy via a thoracoabdominal (extraperitoneal) approach was described in 1950,⁷⁹ while reports of pure abdominal (anterior) approaches dominated the 1970s,^80–82 with each approach having intrinsic advantages. The extraperitoneal approach allows easy exposure on the ipsilateral side, whereas the anterior approach is preferable when bilateral dissections are undertaken. An extension of the anterior approach, which included bilateral renal suprahilar dissection, was pioneered by Donohue.⁸³

In experienced hands, the classic, bilateral RPLND, as described, is associated with minimal perioperative morbidity and virtually no mortality.⁸⁴ A major side effect of this approach, however, is the loss of antegrade ejaculation, with resultant infertility in over 90% of patients, a significant factor in young men in the 15- to 34-year age group. Several “nerve-sparing” modifications of the classic node dissection have been described, in an attempt to minimize ejaculatory dysfunction and maintain the staging and/or therapeutic benefit of the procedure. An anatomic basis for such modified procedures has been provided by several meticulous mapping studies of retroperitoneal node involvement in early-stage disease.^85–87 In the study by Donohue and colleagues, patients with grossly negative, microscopically involved nodes (stage B1) were analyzed separately.⁸⁵ In right-sided primary lesions, no patient had involvement of the suprahilar regions, and only 4% had left para-aortic (contralateral) node involvement. Similarly, in left-sided B1 disease, no patient exhibited right paracaval or precaval involvement. These studies suggested that full bilateral dissection is unnecessary in patients with grossly negative nodes at the time of surgery.

Unilateral lymph node dissections have, therefore, become popular for treating early-stage disease, both in the United States^88,89 and in Europe.^87,90,91 Modifications to the classic dissection have generally involved complete dissection of lymph nodes on the same side as the primary lesion, with limited (if any) intervention on the contralateral side, thus preserving the contralateral sympathetic efferents and ejaculatory function in 75 to 90% of patients. Particular emphasis is given to avoidance of the region anterior to the aortic bifurcation, as nerves exiting the thoracolumbar sympathetic trunk cross this region and become the hypogastric plexus. Preservation of these fibers appears to be particularly important in the maintenance of ejaculatory function. In a more recently described procedure by Donohue and colleagues, postganglionic sympathetic fibers from lumbar ganglia are prospectively identified and preserved prior to lymphadenectomy.⁹² Of 75 patients treated in this manner, all are alive and disease free at 2 years, and 100% have preservation of antegrade ejaculation. Retroperitoneal recurrences occurred in 3 of 14 stage B patients, and in none of the 61 pathologic stage A patients. An updated experience with clinical stage A patients (and nerve-sparing RPLND) has confirmed the early results with the procedure. Ejaculation is reliably maintained, retroperitoneal recurrence is rare, and more than 99% of patients ultimately are cured.⁸³ Thus, it appears that the majority of patients can have their ejaculatory function preserved following retroperitoneal node dissection for early-stage disease, without a sacrifice in terms of retroperitoneal relapse or survival.

Radiotherapy

While RPLND has been a mainstay of therapy for early-stage nonseminomatous germ cell tumors in the United States for the past 40 years, radiation therapy has been used in similar clinical situations in Europe, particularly in the United Kingdom and Denmark. Data from the Royal Marsden Hospital were reported for both clinical stage A (with negative lymphangiogram) and clinical stage B (positive lymphangiogram).⁹³

Patients with clinical stage A disease received 4,000 cGy to the retroperitoneum, experienced a 17% relapse rate (including 4.7% in the retroperitoneum), and a 2-year disease-free survival of 84%. Radiation therapy was well tolerated with minimal acute toxicity, although a later report from the same institution suggested an increased incidence of peptic ulcer disease in irradiated patients, a finding now confirmed by other groups.⁹⁴ In patients with clinical stage B disease, 4,500 cGy was given to the retroperitoneum, as well as 4,000 cGy to the mediastinum and the supraclavicular regions bilaterally. Radiotherapy was much less effective in this clinical setting, with a relapse rate of 52% (42% in the retroperitoneum) and an overall survival of only 58% on follow-up of 3 to 12 years.

Extensive experience with radiotherapy has also been reported by the Danish Testicular Carcinoma Study Group (DATECA). Prior to 1980, patients with clinical stage A disease were treated with infradiaphragmatic radiotherapy, as well as adjuvant chemotherapy with bleomycin and vincristine. The 2-year disease-free survival of 87% was found to be statistically significantly better than that of 74% in a group of patients treated off-study with radiotherapy alone.⁹⁵ In a subsequent randomized DATECA study on clinical stage A disease, patients received either orchiectomy alone or orchiectomy followed by infradiaphragmatic radiotherapy.⁹⁶ The group receiving radiotherapy had a significantly lower overall relapse rate, with complete elimination of retroperitoneal relapses.

Although data from the United States on radiotherapy in early-stage disease have been sparse⁹⁷ they have, in general, supported the European trials. Today, the use of radiotherapy in this clinical situation is limited, on the basis of both the success of cisplatin-based combination chemotherapy in distant metastatic disease and the prevalence of “surveillance” as a treatment option in clinical stage A disease.

Pathologic Stage A

Patients with disease clinically limited to the testicle who undergo staging RPLND and are found to have pathologically negative lymph nodes are classified as pathologic stage A. Relapse rates and 5-year survivals in these surgically staged patients have been reported from a number of institutions.^{81,91,98–101} With relatively few changes in the surgical technique of RPLND from 1950 to 1980, relapse rates, and particularly intra-abdominal recurrences, have remained at a constant level. The overall relapse rate for these patients is approximately l0%, with the great majority of relapses occurring in the lungs, since the surgical procedure has effectively removed the retroperitoneum as a significant site of relapse. However, with a significant improvement in the therapy for distant metastatic disease and clinical staging techniques over that same period, 5-year survival rates improved from 77% in 1969¹⁰² to almost 98% in 1987.¹⁰³

In the largest prospective study of observation in pathologic stage A nonseminomatous disease, the Testicular Cancer Intergroup Study enrolled 264 patients after RPLND.¹⁰³ With a median follow-up of 45 months, 28 patients (10.5%) had recurred, 25 of whom developed a first relapse within 24 months of node dissection. Six patients (2.3%) died, although only 2 of the 6 died of drug-resistant cancer. At the time of the report, 97.7% of patients were alive and disease free.

The current recommendation for patients with pathologic stage A nonseminomatous disease is for no further therapy to be administered following RPLND. This recommendation is based on the high surgical cure rate with orchiectomy and RPLND alone (90%), the favorable relapse pattern in patients who recur (lung only), and the effectiveness of chemotherapy for small-volume metastatic disease in relapsing patients.

Clinical Stage A

As the vast majority of testicular cancer patients are cured today even in the presence of minimal to moderate distant metastatic disease, attention has been focused on a reduction in the toxicity of curative therapy. For nonseminomatous disease clinically limited to the testicle, this has resulted in a reconsideration of the need for RPLND and its attendant morbidity. This type of surveillance policy has been quickly accepted but must be considered in the context of its effect on the natural history of the disease, the implications for patient follow-up, fertility, the potential need for chemotherapy, and ultimately patient survival.

The accurate diagnosis of clinical stage A disease is critical to the consideration of less interventional therapy. Following inguinal orchiectomy and the diagnosis of nonseminoma, serum levels of β-hCG and AFP must return to normal (if elevated before orchiectomy), and abdominal CT, chest radiography, and chest CT must all be negative for metastatic disease before a patient can be labeled as having clinical stage A disease. In this clinical setting, approximately 30% of patients will suffer a relapse if no other therapy is administered, with the retroperitoneum remaining as the area at highest risk.

Table 110.6

Studies of Surveillance Following Orchiectomy in Clinical (more...)

Table 110.6

Studies of Surveillance Following Orchiectomy in Clinical Stage A Nonseminomatous Germ Cell Tumors

Series (reference)	Patients	Relapse (%)	Alive/NED post-relapse	Follow-up (median), months
(234)	67	14(21)	13	12-60 (NR)
(205)	85	23(27)	22	24-64 (42)
(83)	259	70(27)	67	NR (30)
(64)	93	28(30)	NR	12-61 (34)
(219)	85	23(28)	23	60 (NR)
(250)	69	15(22)	13	2-63 (31)
(210)	46	13(28)	11	6-88 (40)
(196)	109	30(28)	30	6-66 (30)
(212)	45	11(24)	11	6-39 (NR)
(191)	14e	3 (21)	3	NR (16)
(258)	20	8(40)	8	NR (14)
(269)	36	12(33)	10	14-92 (36)
(114)	24	5(21)	3	33-27 (NR)
(195)	41	9(22)	9	11-127 (37)
Total	993	264(26.6%)

While the excellent results with surveillance in centers with great expertise in the treatment of testicular cancer are clear, there are some inherent dangers with this approach, making its applicability on the community level somewhat less clear. Patients selected for this approach in reported studies have, in general, been highly motivated individuals, able logistically and psychologically to comply with mandated follow-up procedures. Accuracy of clinical staging is critical and is proportional to the number of cases seen. This staging may be inferior at institutions seeing only a handful of cases per year. The optimal frequency of visualization of the retroperitoneum (the most frequent site of relapse) has not been determined. The schedule of intensive follow-up (normally 2 years) may be insufficient, as relapses have continued (4% a year) in the third and fourth years of follow-up in the MRC trial. Patients have the potential to relapse with larger-volume disease than after RPLND. Such patients may have an inferior response to chemotherapy and reduced survival. The presence of occult teratoma in the retroperitoneum that is not removed at staging RPLND may predispose to late relapse (see “Special Considerations” below).

Pathologic Stages B1, B2

There is controversy regarding the optimal management of patients with clinical stage A disease who are found at RPLND to have nodal metastases, either microscopically (B1) or grossly (B2) involved. Approximately 50% of patients with nodal involvement at RPLND relapse, if no additional therapy is given. Surgical series have shown that pathologic B1 patients recur at the 10 to 25% level, if managed by observation after RPLND, whereas pathologic stage B2 patients recur 50% of the time, if observed after RPLND.^120,121 In light of the effectiveness of chemotherapy in disseminated disease, investigators have logically addressed the possibility of using it as a postoperative adjuvant in resected stage B patients or even as a substitute for surgery in clinical stage B disease.

A number of nonrandomized studies using single-agent or low-dose chemotherapy have been reported and have had little impact on the relapse rate in resected patients.^80,122

Significant improvements in relapse rates following adjuvant chemotherapy were not seen until cisplatin-based regimens were introduced. At the Memoral Sloan-Kettering Cancer Center (VAB-3), use of an early cisplatin-containing regimen in 29 patients with resected B disease completely eliminated relapses, with a median follow-up of 24 months.¹²² Similarly striking results were noted in two nonrandomized trials in patients with low-volume retroperitoneal metastases using cisplatin, vinblastine, and bleomycin.^123,124

A large, prospective, randomized, multi-national trial in this clinical setting was the Testicular Cancer Intergroup Study.¹²⁵ In this study, 195 pathologic stage B patients were randomly assigned to no further therapy after RPLND, or to two immediate postoperative courses of adjuvant chemotherapy, either PVB (cisplatin, vinblastine, bleomycin) or VAB-6 (cisplatin, vinblastine, bleomycin, actinomycin-D, cyclophosphamide). Results were reported in 1987, with a median follow-up of 4 years. Predictably, there was a significant difference in relapse-free survival, with 49% of the observation group relapsing, compared with 6% of patients assigned to receive adjuvant chemotherapy. However, the difference is even more striking, as only 1 of the 6 relapsing patients in the adjuvant arm actually received his assigned therapy, and 1 patient on retrospective analysis had an inadequate RPLND. Thus, two courses of cisplatin-based therapy in completely resected stage B patients effectively eliminated the possibility of relapse. No specific histopathologic features were predictive of relapse, although there was a nonstatistically significant trend toward a higher relapse rate with increasing nodal stage. This contrasts with previous reports suggesting that relapse was highly correlated with the degree of nodal involvement. In terms of survival, there was no significant difference between the two groups, indicating that either approach should result in a greater than 95% cure rate, provided that complete surgical resection is undertaken and meticulous follow-up observed.

More recently, Motzer and colleagues have investigated the use of two cycles of etoposide and cisplatin at 3-week intervals in the setting of pathologic stage II nonseminomatous germ cell tumor.¹²⁶ Fifty patients were treated. All remain alive and disease free. The small number of patients in the study and the fact that a large number of patients were likely cured with surgery alone raises the question regarding the power of the study to detect a small nagative impact on outcome of the two-drug combination. Behnia and colleagues at Indiana University reviewed 86 patients treated with two cycles of bleomycin, etoposide, and cisplatin at 4-week intervals.¹²⁷ Again, all patients remained cancer free in long-term follow-up. In keeping with the principles of adjuvant therapy for other diseases in which the best therapy for metastatic disease makes the best adjuvant therapy, we currently recommend two cycles of BEP in this setting.

Clinical Stage B2

In patients undergoing clinical staging and those found to have nonbulky abdominal disease (nonpalpable, mass < 5 cm on CT scan, or fewer than five nodes involved on CT scan), traditional therapy has included RPLND with complete resection, followed by either observation until relapse or adjuvant chemotherapy (as above), with excellent results. More recently, some investigators have advocated the use of primary chemotherapy for these clinical stage B patients, with the hope that many of them would achieve a radiographic complete remission and thus be spared the morbidity and expense of subsequent RPLND. In a report from the M.D. Anderson Cancer Center,¹⁰⁰ 50 patients with clinical stage B disease were treated with primary chemotherapy, and 96% of patients achieved complete remission. Only 22% of patients required RPLND following chemotherapy for resection of a residual mass or for persistent marker elevation. A number of factors were analyzed in an attempt to define which patients would subsequently be likely to undergo resection of residual disease, and only the presence of teratomatous elements in the primary tumor was predictive. In patients with pure embryonal carcinoma in the testicle, only 8% subsequently required RPLND, compared with 36% of patients with elements of teratoma in the testicle. This approach clearly reduces the percentage of patients requiring RPLND, with results comparable with those of the traditional approach. However, approximately 50% of patients in this clinical setting are cured by RPLND alone. The relative merits and toxicities of RPLND versus chemotherapy have been the subject of much debate, although long-term side effects from using either a nerve-sparing RPLND or a short course of chemotherapy are negligible, and therapy should be tailored to the individual patient.

Clinical Stage B3

The presence of large-volume abdominal disease that prohibits surgical removal (palpable abdominal mass, lymph nodes > 5 cm, more than five nodes involved on CT) should be treated with primary chemotherapy. After achievement of a serologic complete remission (normalization of serum β-hCG and AFP), restaging with abdominal CT is performed followed by, if necessary, surgical resection of residual radiographic abnormalities, as discussed below.

Seminoma Early Stage

Orchiectomy and postoperative radiation therapy have constituted the standard of care for early-stage seminoma patients during most of the 20th century.^128–131 A properly performed radical orchiectomy by an inguinal approach is highly effective therapy for controlling disease at the primary tumor site. Occult or gross para-aortic lymphatic tumor deposits can be eradicated with high probability after low doses of radiation therapy, owing to the extreme radiosensitivity of seminoma. More recently, success in surveillance trials in stage A nonseminomatous testicular cancers has naturally led to similar investigations for seminoma. These trials, while still ongoing, have afforded the opportunity to learn more about the natural history of early-stage seminoma. Regardless of whether surveillance becomes a standard part of clinical practice for seminoma, these scientific trials are providing information that will undoubtedly affect clinical practice. With a large majority of patients experiencing prolonged disease-free survival in early-stage seminoma, long-term quality-of-life end points will assume increasing significance in evaluating treatment strategies.

Stage I Seminoma: Postorchiectomy Surveillance

Cure rates are very high, and the risk of serious complications is relatively low with standard modest-dose postorchiectomy radiation therapy in patients with stage I seminoma. Although it is unlikely that alternative management schemes will significantly improve these results, progress can be made toward decreasing the morbidity of therapy. Standard postorchiectomy radiation therapy is associated with acute morbidity, such as nausea, as well as with more problematic late complications, such as peptic ulcer disease and second malignant neoplasms. Modifications in the fields and dose of adjuvant radiation therapy and considerations for alternative adjuvant chemotherapy aimed at decreasing treatment morbidity have been presented above. Another option aimed at decreasing morbidity in stage I patients is to omit adjuvant therapy altogether, that is, to adopt a policy of postorchiectomy surveillance.

As with nonseminoma, there is a strong rationale for a policy of postorchiectomy surveillance in clinical stage I seminoma. Four criteria for an effective surveillance program in seminoma after orchiectomy have been established: (1) the incidence of occult metastatic disease should be low, (2) follow-up should be carried out such that relapses are detected early, (3) relapses should be readily curable, and (4) the morbidity of the follow-up policy and salvage therapies should be less than that produced by initial adjuvant therapy of all patients. Although the actual incidence of occult metastatic disease in clinical stage I seminoma patients was not known prior to the inception of surveillance trials, it was felt to be as low as 8% and as high as 20 to 30%.^144,145 If follow-up policies were properly designed, relapsing patients could be identified early with low-stage disease, which could be treated with radiation therapy appropriate for nonbulky stage II initial presentations. Modern cisplatin-containing multi-agent chemotherapy has been recognized as a highly effective systemic therapy for both salvage and initially extensive presentations of seminoma. While these regimens include a significant risk of complications, including early toxic deaths,¹⁴⁶ the expected low rate of relapsing patients ultimately requiring systemic therapy theoretically would translate into an overall highly acceptable toxicity profile, given that the majority of patients would be cured by orchietomy alone and spared adjuvant therapy altogether.

Table 110.7

Results of Stage I Seminoma Surveillance Trials

Table 110.7

Results of Stage I Seminoma Surveillance Trials

	Royal Marsden Hospital*	Princess Margaret Hospital†	Danish Test‡	Totals
Number of patients	113	148	261	522
Median follow-up, months	62	47	48	50.8
Range of follow-up, months	14-141	7-87	6-67	6-141
No. of follow-up examsd in 3 years	10	15	11	12††
No. of CT/US examse in 3 years	5	9	8	7.3††
No. of relapses (% of all patients)	17 (15%)	23(16%)	49 (19%)	89(17%)
Median interval to relapse, months	18	15	14	15.2**
Range of interval to relapse, months	8-55	2-61	2-37	2-61
No. with non-bulky infradiaphragmatic nodal first relapse# (% of relapsing patients)	14 (82%)	NR	37 (75%)	51/66(77)
No. salvaged with radiation therapy alone (% of relapsing patients)	8 (47%)	16 (70%)	33 (67%)	57 (64%)
No. with second relapse	4 (24%)	4 (17%)	4 (8%)	12 (13%)
No. patients requiring chemotherapy (% of relapsing patients)	9 (53%)	7 (30%)	16 (33%)	32 (36%)
No. deaths from seminoma or seminoma therapy (% of all patients)	0 (0%)	1 (0.7%)	3 (1%)	4 (0.8%)

NR = not reported.

*

From Horwich et al.

†

From Wood et al.

‡

From von der Masse et al.140

§

Including history and physical examination, tumor markers, and chest x-ray.

||

Refers to computed tomography (CT) and/or ultrasound (US) of the abdomen.

#

Maximum nodal dimension less than 5 cm (Royal Marsden stage IIA/IIB).

**

Weighted mean based on number of patients per study.

††

Simple average.

The experiences from three surveillance studies with more than 100 patients and long-term follow-up have been reported.^139–141 As seen in Table 110.7, 17% of enrolled patients eventually relapsed in the cumulative experience after orchiectomy alone, which is significantly higher than the < 5% relapse rate seen in series with similar follow-up employing postorchiectomy radiation therapy. Despite fairly intensive follow-up, including frequent abdominal imaging, 22% of relapsing patients had either bulky abdominal, supradiaphragmatic, or disseminated disease. Additional patients had a second relapse after salvage radiation therapy, such that a higher than expected 36% of relapsing patients (6% of all patients enrolled) ultimately required systemic chemotherapy for salvage. Unlike nonseminoma surveillance trials, where the median time to relapse is < 6 months,¹⁴⁷ seminoma relapses occur much later, with a median interval of 15 months, as well as several late relapses up to 5 years. The vast majority of relapsing patients were eventually salvaged so that less than 1% of patients died of seminoma or seminoma therapy.

Each of these large studies used multivariate analysis to identify subset characteristics associated with higher relapse. The Danish study examined several variables but only identified higher relapse with larger primary testicular tumors and recommended avoiding surveillance when the primary tumor is larger than 6 cm (a small minority of patients). Blood vessel and/or lymphatic vessel invasion was associated with higher relapse in the Royal Marsden Hospital study, but not in the others. The investigators from the Princess Margaret Hospital study were the only group to identify younger patient age as a variable associated with higher relapse. Since there is no reliable tumor marker for seminoma, there is currently no effective method to identify patients more prone to relapsing up front who might best be treated with postorchiectomy radiation therapy as opposed to surveillance.

As predicted, ultimate control and survival for patients enrolled in surveillance trials are equivalent to the excellent results obtained with postorchiectomy radiation therapy. Around 20% of patients will relapse, and 40% of these patients subsequently will get more cancer therapy than if treated after orchiectomy. Overall, more than twice as many patients will ultimately require systemic chemotherapy in surveillance trials, compared with those treated with postorchiectomy radiation therapy. This must be balanced by the fact that 80% of patients are cured in surveillance programs without any adjuvant therapies and their associated toxicities. The merits of surveillance, then, rest on the degree of associated toxicity and the potential ability to decrease that toxicity. To avoid chemotherapy, the relapse must be detected early. As shown in Table 110.7, follow-up examinations were the least frequent in the Royal Marsden Hospital trial, and the required use of chemotherapy was the most frequent. More frequent follow-up, including abdominal imaging, may allow the earlier detection of small-volume disease but clearly will add to the costs of surveillance. Quality-of-life end points, such as psychologic stress associated with surveillance and fear of second malignant neoplasms, have not been carefully examined in either postorchiectomy adjuvant therapy or surveillance reports. Careful long-term toxicity follow-up in patients treated with surveillance will be necessary before surveillance gains widespread acceptance. Currently, it should still be considered an investigational approach.

Chemotherapy: Precisplatin

A broad spectrum of chemotherapeutic agents was tested from 1952 to 1972 in disseminated germ cell tumors, and virtually all were found to have some degree of activity in chemotherapy-naive patients. In the early 1960s, the Vinca alkaloids were finally tested in testicular cancer after demonstrating activity in non–Hodgkin’s lymphoma and Hodgkin’s disease. Vinblastine, as a single agent, was able to induce complete remissions in 4 of 30 treated patients.^87,154 Although these were of short duration, they provided investigators with a rational component of subsequent combination regimens.

Several antitumor antibiotics were also found to have single-agent activity, including the least (actinomycin-D) and most (mithramycin) extensively studied compounds.^155,156 Ultimately, a third antitumor antibiotic, bleomycin, was reported in 1970 to have significant activity, including the ability to induce complete remissions.¹⁵⁷

An early combination regimen reported by Li and colleagues in 1960, which contained methotrexate, actinomycin-D, and chlorambucil, remained popular throughout the rest of the decade.¹⁵⁸ Li reported an objective response rate of 52%, with over half of those being complete responses. More importantly, they represented the first durable remissions, with 5 patients alive at 9 to 39 months after treatment at the time of the report.

A major advance in the development of effective chemotherapy for metastatic disease occurred when vinblastine and bleomycin were used in combination, as reported by Samuels and colleagues at the M.D. Anderson Cancer Center.^154,159,160 These regimens used either biweekly bolus (VB-1) or continuous infusion (VB-3) bleomycin, with a reported response rate for VB-3 of 95%, with 65% of patients achieving a complete remission and most responses being enduring.

The most important event in the development of curative therapy for disseminated disease was the 1965 report by Rosenberg and colleagues of the antibacterial effect of platinum coordination compounds.¹⁶¹ One of these compounds, cis-diamminedichloroplatinum (II) (cisplatin), was found also to have significant antitumor activity. Preclinical studies revealed testicular atrophy as a side effect in the dog model, prompting some investigators to predict activity for this compound against human testicular malignancies in the clinical setting. Cisplatin was soon reported to be the single most active agent against testicular germ cell tumors, with response rates of 70% and complete remission rates of 50%.¹⁶² Twenty years later, it remains the most active drug in germ cell tumors. The relatively unique toxicities of cisplatin, including renal dysfunction, made it an excellent candidate for incorporation into combination regimens containing drugs which had myelosuppression as their primary side effect. Existing data on the use of intensive combination chemotherapy regimens for lymphomas and leukemia provided the background for similar approaches to the treatment of testicular cancer. Such combination regimens were subsequently developed at both Memorial Sloan-Kettering Cancer Center and Indiana University.

Vab Regimens: Memorial Sloan-Kettering Cancer Center

In the first of a series of combination regimens, investigators at Memorial Hospital added actinomycin-D to the combination of vinblastine and bleomycin. This regimen, termed VAB-I, was used from 1972 to 1974, and had a response rate of 34%, including 15% complete responses, results that were no better than those for vinblastine plus bleomycin alone.¹⁶³ In the first VAB regimen to contain cisplatin, VAB-II, 50 patients were treated from 1974 to 1976, with an 84% response rate and 50% complete remissions. Of the complete remissions, 46% were disease free at 16 to 33 months.¹⁶⁴ From 1975 to 1976, 80 patients were treated on a complicated protocol (VAB-3), which added chlorambucil, doxorubicin, and cyclophosphamide to a VAB regimen that lasted 24 to 30 months. The rate of response to this protocol was 81%, with 61% complete remissions, and a relapse from complete remission rate that fell to 31%.⁸⁹

Several changes in the schedule of administration of drugs were undertaken with VAB-4 in an attempt to decrease the frequency of early relapses. From 1976 to 1978, 41 evaluable patients were treated, with a response rate of 85% and a 61% complete remission rate; with a median follow-up of 27 months, only 12% of complete responders had relapsed.¹⁶⁵ In 1980, several modifications were made in this protocol to yield VAB-6. These changes increased the emphasis on the intensity of induction therapy (with administration of cycles every 3 to 4 weeks) and simultaneously decreased the duration of the maintenance phase of therapy to 1 year. At the time of the report, 91% of patients had achieved a complete remission, with an 18% relapse rate from complete remission with more than 24 months’ median follow-up.¹⁶⁶ There were also significant improvements in terms of toxicity, as this regimen eliminated the mucositis, renal insufficiency, and pulmonary fibrosis that had been seen with prior regimens.

Indiana University Studies

In 1974, investigators at Indiana University began studies using cisplatin, vinblastine, and bleomycin (PVB) in patients with disseminated testicular cancer. The initial study of 50 patients remains a landmark study in modern oncology.¹⁶⁷ This study incorporated principles of combination chemotherapy, as well as the concept of surgically resecting residual disease after the completion of chemotherapy. Induction chemotherapy was brief (three to four courses), and maintenance chemotherapy was given for 2 years after induction therapy. Three patients died within 2 weeks of the initiation of treatment. Of the remaining group of 47 patients, 33 (70%) obtained a complete remission with chemotherapy. Of the remaining 14 patients, 5 obtained a complete remission with resection of residual disease after the completion of chemotherapy. Six of the patients attaining remission have relapsed, but now with follow-up exceeding 10 years, it is gratifying to note that there seems to be little evidence of long-term toxicity from chemotherapy.

The initial study proved that PVB was remarkably effective, and yet there was substantial toxicity. The next study was designed to compare the original PVB program with a similar regimen with a lower dose of vinblastine (0.4 mg/kg versus 0.3 mg/kg). A third arm was added to assess the possible therapeutic benefit of adding doxorubicin to the PVB combination.³ Seventy-eight patients were entered into this three-arm study. The therapeutic results in all three arms were identical, with 70% of all patients remaining continuously free of disease. As expected, however, the reduction in the vinblastine dose was associated with fewer episodes of sepsis and granulocytopenic fever. Thus, on the basis of equivalent therapeutic results with lesser toxicity, the lower dose of vinblastine, along with cisplatin and bleomycin, became the standard regimen.

A third-generation study was begun at Indiana University in 1978 in conjunction with the Southeastern Cancer Study Group (SECSG).¹⁶⁸ The previous studies had used maintenance therapy with monthly vinblastine for 2 years after the completion of induction therapy. This trial tested the contribution of maintenance chemotherapy. In this study, patients with disseminated testicular cancer were given four courses of induction chemotherapy with PVB with or without doxorubicin. Patients obtaining a complete remission with chemotherapy, or after resection of teratoma, were randomized to receive maintenance vinblastine or no further therapy. This study failed to demonstrate an advantage for those patients randomized to the maintenance therapy arm, with a relapse rate of 12% for those receiving treatment versus 7% for patients receiving induction therapy only.

Confirmation of the results of these trials at Indiana University has been obtained in a large EORTC trial of chemotherapy for disseminated testicular cancer.¹⁶⁹ This trial tested the contribution of high-dose vinblastine (0.4 mg/kg) versus lower-dose vinblastine (0.3 mg/kg) and the value of maintenance vinblastine. The trial of 214 patients failed to demonstrate any advantage for patients assigned to high-dose vinblastine therapy or for those assigned to maintenance vinblastine.

Initial studies at Indiana University demonstrated the benefit of the addition of cisplatin to the combination of vinblastine and bleomycin, and subsequently refined the PVB protocol by randomized comparisons of dose and schedule. In addition, the earlier studies provided the framework for identifying patients with disseminated germ cell cancer who had excellent prospects of obtaining complete response to cisplatin-based treatment and those with a relatively poor chance of benefiting from treatment.

In the next study, Indiana University, in conjunction with the SECSG, designed a randomized trial comparing cisplatin plus bleomycin and either vinblastine (PVB) or etoposide (BEP).¹⁷⁰ Two hundred and sixty-one patients with disseminated germ cell cancer were entered and 244 were evaluable for response. Of these, 123 were randomly allocated to receive BEP, and 83% achieved a disease-free status. One hundred and twenty-one patients were assigned to receive PVB, and 74% attained a disease-free status. In the combined subgroups of patients with minimal or moderate disease by the Indiana classification system, 90% achieved a disease-free status, with no difference between the two treatment arms. Whereas PVB and BEP gave equally good therapeutic results, there was a marked difference in neuromuscular toxicity, with the PVB patients experiencing significantly more paresthesias, myalgias, and abdominal cramping. Since BEP had substantially less neuromuscular toxicity with equal or superior therapeutic results, four courses of cisplatin, etoposide, and bleomycin became the new standard.

Prognostic Factors in Disseminated Disease

With more clinical experience in germ cell tumors, investigators have become increasingly able to identify patients with good-risk features suitable for therapies of decreased intensity, as well as less fortunate patients presenting with poor-risk features for whom more intense, higher-risk approaches are reasonable. In the evolution of therapy for poor-risk disease, therapy is becoming more complex and intense and is associated with increased short- and long-term complications. Therefore, the imperative to properly identify a patient’s risk category has taken on increased importance.

Prognostic Classifications

Table 110.8

IGCCC Prognosis

Table 110.8

IGCCC Prognosis

GOOD PROGNOSIS
Nonseminoma	Seminoma
Testis/retroperitoneal primary and	Any primary site and
No nonpulmonary visceral metastases and	No nonpulmonary
Good markers – all of:	Normal AFP, any hCG, any LDH
AFP < 1000 ng/ml and
hCG < 5000 iu/l
LDH < 1.5 × upper limit of normal
56% of nonseminomas	90% of seminomas
5-year PFS 89%	5-year PFS 82%
5-year survival 92%	5-year survival 86%
INTERMEDIATE PROGNOSIS
Nonseminoma	Seminoma
Testis/retroperitoneal primary and	Any primary site and
No nonpulmonary visceral metastases and	Nonpulmonary visceral metastases and
Intermediate markers – any of:	Normal AFP, any hCG, any LDH
AFP ≥ 1000 and ≤ 50,000 iu/l or
hCG ≥ 5000 iu/l and ≤ 50 000 iu/l
LDH ≥ 1.5 × N and ≤ 10 × N
28% of nonseminomas	10% of seminomas
5-year PFS 75%	5-year PFS 67%
5-year survival 80%	5-year survival 72%
POOR PROGNOSIS
Nonseminoma	Seminoma
Mediastinal primary or	No patients classified and poor prognosis
Nonpulmonary visceral metastases or
Poor markers – any of:
AFP > 10,000 ng/mL or
hCG > 50,000 IU/L (10000ng/mL) or
LDH > 10 × upper limit of normal
16% of nonseminomas
5-year PFS 41%
5-year survival 48%

AFP = alpha-fetopretein; hCG = human choriionic gonadotropin; LDH = ; PFS = progression-free survival.

Most recently, an international consortium collected clinical data on patients receiving platinum-based therapy for metatastic germ cell tumor to develop a new prognostic model for disseminated disease.¹⁷¹ Data on 5,202 patients with nonseminomatous germ cell tumor and 660 patients with seminoma were analyzed, and it was found that independent predictors of outcome in univariate analysis included mediastinal primary site, degree of AFP, hCG, and LDH elevation, and the presence of nonpulmonary visceral metastasis. Using these factors, prognostic categories were derived. Good-risk patients with nonseminomatous disease were those with a testicular or retroperitoneal primary, favorable markers, and no nonpulmonary visceral metastases (anticipated progression-free survival 90%). Poor prognosis included those patients with mediastinal primary nonseminoma, patients with nonpulmonary visceral metastases, or those with unfavorable elevation of tumor markers (anticipated progression-free survival 40%). An intermediate group had an anticipated progression-free survival rate of 75%. For seminoma, only good- and intermediate-risk groups were identified, with good and intermediate risks being discriminated by the absence or presence of nonpulmonary visceral metasases (Table 110.8). This classification should be the standard classification system for comparing results of clinical studies done at various institutions.

Biologic Predictors of Outcome

The current ability to assign risk on the basis of currently available clinical parameters has been maximized. One can argue as to which system is the most accurate, but most commonly employed systems can assign prognosis correctly in the vast majority of patients. Current efforts at developing an internationally defined prognostic system may assist in supplementing local prognostic schemes and allow for accurate comparison of results across studies. However, the next level of prognostication will likely come from the measurement of currently available and some experimental biologic predictors of outcome. None of these biologic parameters have been investigated thoroughly enough to recommend widespread use, but future prognostic systems will almost certainly incorporate one or more of the parameters.

Ploidy and proliferative index have been investigated as prognostic parameters in a variety of tumors, including germ cell tumors.^176,177 In the advanced-disease category, as defined by the Indiana University staging system, Sledge and colleagues have analyzed ploidy and proliferative index as predictors of outcome.¹⁷⁸ In this study, ploidy was not predicative of survival. Proliferative index appeared to be a strong predictor of outcome. In the group of patients with a proliferative index above the mean, survival was 37.7 plus or minus 11.0 months, compared with a mean survival of 85.6 plus or minus 7.6 months for patients below the mean. In a multivariate analysis, proliferative index remained as the most significant variable in the model (p < .001 compared with log (hCG) (p = .016), histology (p = .045), treatment employed (p = NS), or DNA index (p = NS). Further attempts to validate these preliminary findings in the recently completed Eastern Cooperative Oncology Group (ECOG) study of cisplatin and etoposide with either bleomycin or ifosfamide in advanced germ cell tumors are ongoing.

Other groups are using similar approaches to assess the impact of cytogenetic findings and oncogene expression in determining outcome. The appearance of a nonrandom chromosomal abnormality in the majority of germ cell tumors has renewed the hope that a new understanding of the molecular mechanisms of this disease may be attainable in the near future, with an attendant benefit for the therapy of patients with advanced disease. The identification of an isochromosome of the short arm of chromosome 12 (i [12p]) was initially reported by Atkin and Baker and is present in as many as 90% of germ cell tumor specimens.^179,180 Its identification in numerous cell types, including seminoma, nonseminoma, and mature teratoma, as well as in both testicular and extragonadal primary lesions, and even in carcinoma in situ of the testis, all strongly suggest a role for this chromosomal event in the process of transformation.^{134,181–185}

Additionally, Bosl et al. have suggested that the number of copies of i (12p) present has prognostic importance.¹⁸¹ In their analysis, 4 of 11 patients (36%) with a normal karyotype or fewer than two additional copies of i (12p) had residual viable carcinoma after chemotherapy or failed induction therapy, compared with 6 of 6 patients with more than three copies (p = .035). Importantly, 3 of these latter 6 patients had been categorized as good risk by the Memorial Sloan-Kettering Cancer Center prognostic model. Further confirmation of these observations in large clinical trials in advanced disease will be required. However, this cytogenetic abnormality may ultimately prove to be an independent prognostic factor.

Investigators have begun to analyze host-related factors as predictors of outcome. In no other malignancy is the identification of resistance to a single chemotherapeutic agent so closely related to poor outcome as cisplatin in germ cell tumors. The ability to identify inherent (de novo) resistance to this agent at the time of diagnosis would allow the identification of patients destined to fail standard treatment, and allow early entry of such patients into clinical trials of novel therapeutic approaches. The analysis of potential mechanisms of cisplatin resistance can be broadly grouped into studies of platinum adduct formation, excision/repair capacity, and endogenous thiol content. Recently completed and ongoing investigations of the role of cisplatin resistance in predicting poor outcome offers some hope of identification of such patients early in the course of treatment.^186,187 It is hoped that such studies will lead to a biologically based prognostic system or a hybrid classification with clinical and biologic parameters accurately explaining the diversity of response seen in patients with germ cell tumors.

Current Studies

Other ongoing trials on poor-risk patients have incorporated high-dose cisplatin therapy along with newer agents or high-dose therapy with bone marrow transplantation. While preliminary results are encouraging, randomized comparisons of these new therapies with standard-dose cisplatin-based therapy are needed to evaluate the role of these innovative approaches.

Several groups are investigating the addition of other active agents to the traditional three-drug regimen, or modest dose escalation with the addition of growth factors or stem cells. At Indiana University, a pilot trial of the five-drug regimen VIP/VB (standard-dose VIP plus vinblastine 0.18 mg/kg on day 1 and bleomycin 30 units weekly plus G-CSF).¹⁹⁷ In this phase II trial, 20 patients were entered. Toxicity was significant, but manageable. There was only 1 therapy-related death in a patient who died of bleomycin lung disease during postchemotherapy surgery. Twelve of the 18 patients evaluable for response had a complete remission, and 2 additional patients obtained a marker-negative partial remission with residual, but minimal, radiogaphic abnormalities (101 months).⁶³ At a minimum follow-up of 3 months, 10 patients remain progression free.

The French trial for poor-risk disease compares BEP with the M.D. Anderson Cancer Center regimen of cisplatin, cycyclophosphamide, Adriamycin, CISCA/VB. Accrual to both these important trials has been completed, and analysis is pending.

Investigators in Hanover and at other institutions in Germany have attempted to intensify therapy for poor-risk patients by incorporating growth factors and peripheral blood progenitor cell support to give high-dose, repetitive chemotherapy cycles. In the most recent update of this phase I/II trial, patients with poor-risk disseminated germ cell tumors were given repetitive cycles of cisplatin 25 to 30 mg/m² on days 1 to 5, etoposide 100 to 250 mg/m² on days 1 to 5, and ifosfamide 2 g/m² on days 1 to 5 every 22 days for four cycles. At the highest dose levels, support with growth factors and peripheral blood progenitor cells was required. With these supportive care techniques, this high-dose therapy was tolerated with no dose-limiting myelosuppression, mucositis, renal toxicity, or neurotoxicity. Three of the 32 patients at the highest dose levels have died of causes related to therapy. Of the 23 evaluable for response, 20 (87%) have attained disease-free status, and 3 patients have relapsed. Accrual to this important exploratory trial is ongoing.

Investigators at the M.D. Anderson Cancer Center have incorporated some of the principles of alternating therapy and have attempted to intensify therapy by shortening the interval between cycles of individually effective therapies.¹⁹⁸ In a small pilot trial, poor-risk patients received rapidly alternating cycles of BOP (7 days’ delay), CISCA (14 days), POMB (10 days), and ACE (14 days). In 17 patients, remission was achieved after an average of 3.5 cycles. Of 11 patients evaluable for response, 8 achieved a disease-free status (73%). Toxicity was substantial, with significant requirements for red blood cell and platelet transfusions. There were no therapy-related deaths. Accrual is continuing.

This series of phase II trials suggest that more intensive, nonmyeloablative chemotherapy can be given safely. Therapeutic results are not obviously better than with less intense, standard therapy. The impact of such approaches will require randomized comparisons with standard treatment.

High-Dose Chemotherapy as Primary Treatment of Poor-Risk Disease

A randomized trial from the Institut Gustave Roussey has been reported, wherein poor-risk patients were randomized to receive conventional therapy with cisplatin, vinblastine, etoposide, and bleomycin versus similar therapy followed by a single cycle of high-dose cisplatin, etoposide, and cyclophosphamide.¹⁹⁹ Patients were further randomized to receive either the double-dose cisplatin, vinblastine, bleomycin, and etoposide regimen described by Ozols and colleagues or a modified regimen with etoposide 100 mg/m² on days 1 to 5, vinblastine 0.2 mg/kg on day 1, cisplatin 40 mg/m² on days 1 to 5, and bleomycin 20 units continuous infusion on days 1 to 5 followed by bolus injections on days 8, 15, and 22 of each cycle. Two such cycles were given, followed by high-dose consolidation with cisplatin 40 mg/m² on days 1 to 5, etoposide 350 mg/m² on days 1 to 5, and cyclophosphamide 1.6 g/m² on days 1 to 4 with autologous bone marrow support.

Between 1988 and 1991, 115 patients who were poor risk according the Institut Gustave Roussey prognostic model were enrolled. One patient was incorrectly determined to have poor-risk features and was ineligible. Fifty-seven patients were randomized to each arm. In the conventional arm, 7 patients failed to complete treatment, due to progressive disease (4), refusal (2), and toxic death (1). In the high-dose arm, 13 patients did not complete treatment, due to early death prior to transplant (6), refusal (3), toxic death (2), poor performance status (1), and HIV infection (1). In a long follow-up, 40 of 57 (70%) of patients are progression free on the standard therapy arm, compared with 33 of 57 (58%) on the high-dose arm.

This trial failed to demonstrate any advantage for the high-dose arm. As with many emerging new treatments, however, the high-dose arm of this trial would be considered substandard according to modern criteria, and different prognostic factors have emerged as important predictors of outcome. Accordingly, a large-scale trial is being conducted on very-poor-risk patients that will compare standard therapy (BEP) with brief conventional therapy followed by two cycles of very-high-dose carboplatin, etoposide, and cyclophosphamide. The trial is being conducted jointly by the Memorial Sloan-Kettering Cancer Center, the SWOG, and the ECOG. It is hoped that it will ascertain definitively the role of high-dose chemotherapy as primary therapy for poor-risk disease. This trial concept is based on the preliminary experience with high-dose chemotherapy as primary treatment at the Memorial Sloan-Kettering Cancer Center for patients with poor-predicted complete remission rates (,0.5) and treated with VAB-6 and for those patients exhibiting marker decline consistent with a prolonged half-life (more than 7 days AFP, more than 3 days hCG).²⁰⁰ Twenty-eight patients were entered, and 22 patients proceeded to two cycles of high-dose carboplatin, etoposide, and cyclophosphamide plus (ABMT). Overall, 12 of the 22 patients (55%) receiving high-dose therapy and 15 of 27 (56%) overall achieved a disease-free status—two via resection of residual carcinoma. Eleven patients remain continuously free of disease at a median follow-up of 31 months.

Postchemotherapy Surgery

Depending on the stage at diagnosis, 20 to 50% of patients who undergo induction chemotherapy for disseminated germ cell tumor have significant residual radiographic abnormalities. In this subset of patients, postchemotherapy resection of residual disease is often performed to remove residual teratoma or viable cancer. Several points bear emphasis in this setting. First, postchemotherapy surgery should be considered only if serum AFP and hCG have normalized. Patients with persistently elevated serum markers should be considered for salvage chemotherapy rather than surgical debulking. Second, postchemotherapy resection of residual abnormalities is rarely urgent, and sufficient time should be taken to allow the patient to recover from the effects of induction chemotherapy. Typically, patients are taken to surgery 6 weeks after the last round of treatment. Third, repeat imaging of the areas of abnormality should be performed prior to surgery. In many patients, continued involution of residual masses occurs after the completion of therapy, and surgical resection is not necessary.

Patients with persistent retroperitoneal disease undergo resection using either a midline or thoracoabdominal approach. Patients with unilateral disease in the pulmonary parenchyma or mediastinum can have resection of this supradiaphragmatic disease performed through a thoracotomy incision. Patients with combined thoracic and abdominal disease frequently require a median sternotomy as well as a midline abdominal approach. Patients who have received bleomycin as part of induction chemotherapy require specialized management. These patients may have subtle restrictive pulmonary disease and diminished DLCO. Care should be taken during anesthesia to avoid overhydration and to use colloid fluid replacement rather than crystalloid. Of most importance, inspired oxygen concentration should not exceed 25% in either the intraoperative or postoperative recovery period.

Resection of residual radiogaphic abdominal abnormalities after induction chemotherapy for disseminated nonseminomatous germ cell cancer has a complication rate significantly different from that of RPLND done for low-stage disease.^201,202 The only significant morbidity of the nerve-sparing RPLND in low-stage disease is a 1% chance of a subsequent small bowel obstruction secondary to postoperative adhesions. On the other hand, RPLND after chemotherapy is associated with a complication rate of 20% and a mortality of 0.8%. The most significant source of morbidity in this postchemotherapy group is pulmonary toxicity related to prior chemotherapy, especially bleomycin. In addition, RPLND is technically demanding, requiring frequent use of the techniques of vascular surgery, vena caval resection/repair, and varied incisions and approaches.

Overall, significant morbidity is rare and operative mortality almost nonexistent. However, the majority of patients undergoing bilateral radical retroperitoneal lymphadenectomy will be rendered infertile as a result of retrograde ejaculation. Recent developments in urologic surgery have allowed for the preservation of the sympathetic fibers that control ejaculation, while maintaining the therapeutic template of the cancer surgery. Depending on the extent of residual disease, some patients can retain ejaculatory function after undergoing resection of residual disease after chemotherapy.

The histopathologic findings in postchemotherapy surgical specimens help define the need for further treatment. In earlier reports, about 40% of cases revealed teratoma, 40% showed fibrous necrotic debris, and 20% of patients had residual viable germ cell cancer. Analysis of recent series suggests that the incidence of persistent cancer is decreasing. In a recent study of optimal duration of chemotherapy in minimal-extent disseminated germ cell cancer, 14 of 107 patients were found to have residual teratoma in the postchemotherapy specimen, and no patient was found to have viable carcinoma.¹⁸⁸ In the same study, 19 of 77 patients with moderate-volume disease were found to have teratoma, whereas only 6 had residual cancer. In a recent study of 153 advanced-disease patients, 30 patients were found to have residual teratoma, and only 6 had persistent germ cell cancer.¹⁹⁴ This apparent decrease in the incidence of residual cancer has been reported by others and is, in part, due to a better selection of patients for surgery and improvements in primary chemotherapy.

Those patients with persistent cancer which is identified and totally removed at postchemotherapy surgery require special management. If the surgical margins are free of tumor, all sites of known disease are removed, and the serum tumor markers remain normal, patients should receive two postoperative cycles of cisplatin-based therapy similar to induction therapy. Those patients with unresectable disease, positive surgical margins, or elevated tumor markers should be considered for full salvage therapy using new agents and more prolonged courses of therapy. About two-thirds of patients receiving additional postoperative cisplatin-based chemotherapy after total resection of residual viable cancer will remain free of disease.²⁰³

Chemotherapy of Seminoma

Modern chemotherapy series involving patients with nodally confined disseminated seminoma report cure rates of over 90%. Compared with earlier studies of radiotherapy in this setting where cure rates ranged from 20 to 60%, cisplatin-based chemotherapy is clearly the treatment of choice in this clinical presentation.

The rare patient who presents with advanced extranodal disease involving such sites as bone, lung parenchyma, or, less commonly, the liver or the central nervous system (CNS) fare less well. Recent results of the trial conducted by Indiana University, the SECSG, and SWOG, where 21 patients with far-advanced seminoma were entered, showed that only 13 of these 21 patients (62%) obtained complete remission.¹⁹⁴ As such, patients with advanced visceral involvement with seminoma cannot universally be considered to be good-risk patients, and entry into clinical trials of intense treatments is appropriate. Other investigators have challenged this approach and consider all patients with seminoma, despite the distribution or disease volume, to be good risk and enter such patients into trials designed to reduce toxicity.²⁰⁴

An additional area of controversy is the management of patients with residual radiographic abnormalities after completion of cisplatin-based combination chemotherapy. Motzer and colleagues report results of 41 patients with bulky stage II, stage III, or stage IV disease treated with cisplatin-based combination chemotherapy.²⁰⁵ At the completion of therapy, 23 patients had significant residual radiographic abnormalities, including 14 patients with masses ≥ 3 cm in size. Of these 23 patients, 19 underwent surgical exploration, and 5 were found to have significant findings other than fibrosis (4 viable seminoma and 1 teratoma). The authors recommend biopsy of residual radiographic abnormalities after chemotherapy for seminoma, if the residual disease measures ≥ 3 cm.

At Indiana University and other centers, a different policy has been adopted. The experience at this institution suggests that surgery in this setting is extremely difficult since the surgeon commonly encounters a dense desmoplastic reaction that makes resection difficult. Also, these patients are older, have commonly had extensive radiotherapy as well as chemotherapy, and, as in several series, are prone to operative catastrophes.²⁰⁶ Most compelling, however, is the recent review of seminoma from Indiana that reports only a 10% incidence of significant pathologic findings in the setting of residual radiographic disease.²⁰⁷ At Indiana University, close observation is the recommended approach in this setting.

Most recently, an analysis from a large trial has added some information in this controversial area. A detailed retrospective analysis of 45 patients with residual mass was done.²⁰⁸ Several findings were reported. If the pretreatment mass was > 5 cm, there was a higher chance of finding residual radiographic abnormalities (78% versus 15%, p = .0009). Of 33 patients with residual mass after chemotherapy, 4 had surgery (all fibrosis), 15 were treated with adjuvant radiation (2 recurrences), and 14 were treated with observation (2 recurrences). There was no evidence that risk of recurrence was related to diameter of residual mass.

Salvage Chemotherapy

Despite the dramatic successes of chemotherapy in disseminated germ cell tumors, 20 to 30% of all such patients will fail to achieve complete remission with first-line therapy.²⁰⁹ These individuals, as well as those who relapse from complete remission, are candidates for salvage chemotherapy. Because of the decreased efficacy and increased toxicity of second-line chemotherapy, this represents an important decision in the treatment of such patients and requires the expertise of individuals well versed in the intricacies of careful assessment of patients with germ cell tumors and of therapeutic options for this stage of testicular cancer.

Patient Selection

Table 110.9

Stage Grouping

Table 110.9

Stage Grouping

Stage 0	PTis	N0	M0	S0, SX
Stage I	pT1-4	N0	M0	SX
Stage IA	pT1	N0	M0	S0
Stage IB	pT1	N0	M0	S0
	pT2	N0	M0	S0
	pT3	N0	M0	S0
	pT4	N0	M0	S0
Stage IS	Any pT/TX	N0	M0	S1-3
Stage II	Any pT/TX	N1-3	M0	SX
Stage IIA	Any pT/TX	N1	M0	S0
	Any pT/TX	N1	M0	S1
Stage IIB	Any pT/TX	N2	M0	S0
	Any pT/TX	N2	M0	S1
Stage IIC	Any pT/TX	N3	M0	S0
	Any pT/TX	N3	M0	S1
Stage III	Any pT/TX	Any N	M1, M1a	SX
Stage IIIA	Any pT/TX	Any N	M1, M1a	S0
	Any pT/TX	Any N	M1, M1a	S1
Stage IIIB	Any pT/TX	N1-3	M0	S2
	Any pT/TX	Any N	M1, M1a	S2
Stage IIIC	Any pT/TX	N1-3	M0	S3
	Any pT/TX	Any N	M1, M1a	S3
	Any pT/TX	Any N	M1b	Any S
				S3
				Any S

There are several clinical situations that may mimic persistent, progressive, or recurrent disease (Table 110.9). One such situation involves the appearance of nodular lesions on the chest radiograph or chest CT scan at the end of chemotherapy or soon after completion of such therapy.²¹⁰ These nodules usually represent bleomycin-induced pulmonary injury and are characteristically located in a subpleural region. This possibility should be considered in a patient who is otherwise responding serologically or radiographically.

Another clinical situation frequently mistaken for progressive disease is the syndrome of growing teratoma.²¹¹ Radiographically enlarging metastatic lesions during chemotherapy concurrently with appropriately declining serologic markers are likely to represent the presence of teratomatous elements in these growing lesions. Appropriate management of such a patient includes completion of induction chemotherapy, with subsequent surgical resection of residual radiographic abnormalities and not administration of salvage chemotherapy.

The causes of misinterpretation of tumor markings are detailed above in the section on “Tumor Markers.” Assuming an elevation of hCG, restaging procedures and investigation of sanctuary sites are in order. False-positive elevation of AFP is quite rare. Differential considerations would include laboratory error; other tumor types, such as hepatoma; or liver inflammation caused by cirrhosis, hepatitis, or drug abuse.

In general, a conservative policy is to reserve the initiation of salvage therapy until there is a demonstration of rising markers on serial determinations. The vagaries of interpretation of low-level marker elevation makes such a policy necessary to ensure that patients are not treated with intense salvage chemotherapy on the basis of a false-positive marker elevation.

The possibility of occult CNS metastasis should be considered in the setting of systemic remission and persistent or new elevation of serum tumor markers. In this situation, CT scans of the brain should be performed, along with evaluations for a testicular sanctuary site. The CNS evaluation should proceed even in the absence of clinical signs or symptoms.

The other important sanctuary site from chemotherapy in germ cell cancer is the testis. In most settings, the primary in the testis has been removed in the initial diagnostic process. However, in some patients presenting with advanced disease, chemotherapy is initiated without a tissue diagnosis. In such cases, the testis must be removed at the completion of chemotherapy, even if the primary tumor is no longer evident.

The possibility of a metachronous testicular primary or an occult testicular primary must, at times, be entertained. In the setting of complete radiographic remission of systemic disease and a persistent or new elevation of serum tumor markers, the remaining testicle should be carefully examined and a testicular ultrasound be performed to rule out an occult primary in the remaining testis. Primary retroperitoneal germ cell tumors are commonly associated with occult testicular primaries, particularly in the setting of a retroperitoneal mass that is not midline in origin.

In some instances, very late relapses may be responsible for marker elevation. This unusual situation is discussed in more detail below.

Standard Salvage Therapy

The therapeutic results with salvage chemotherapy have not been as dramatic as those for initial therapy, due primarily to the paucity of active single agents in patients refractory to cisplatin. During the two decades since the introduction of cisplatin, only two agents, etoposide (VP-16) and ifosfamide, have demonstrated a 25% or higher response rate in this setting. The recent evaluation of paclitaxel in the setting of less cisplatin-resistant disease demonstrates that this, too, is an active agent with a 26% response rate as second-line treatment in patients who did not attain disease-free status with primary chemotherapy.²¹²

The current standard salvage chemotherapy that serves as a basis for comparison is the regimen of vinblastine, ifosfamide, and cisplatin (VeIP) reported at Indiana University.²¹³ Patients received cisplatin 20 mg/m² daily for 5 days, ifosfamide 1.2 g/m² daily for 5 days, vinblastine 0.11 mg/kg on days 1 and 2. One hundred and thirty-five patients who had not progressed on cisplatin and etoposide-based therapy received VeIP as initial salvage chemotherapy. Patient characteristics reflected this poor-risk population. Advanced disease by the Indiana classification system was present in 81 patients at initial presentation and 59 (48%) at the time of VeIP. Thirty-six patients had extragonadal primary site. Toxicity of the regimen in this pretreated population was significant, with 71% developing granulocytopenic fever. Transfusions of platelets (27%) and red blood cells (49%) were common. Renal insufficiency (serum creatinine > 4 mg %) was observed in 7% of patients. Three patients died of causes related to treatment. Despite the formidable toxicity, the therapeutic results were gratifying. Fifty-six patients (45%) achieved a disease-free status with either chemotherapy alone (34 patients) or by resection of teratoma (15 patients, 12%) or viable carcinoma (7 patients, 6%). Twenty-nine of these patients are continuously disease free, and 37 (30%) are currently disease free (minimum follow-up, 27 months). Among the patients with extragonadal primaries, only 6 of 31 attained disease-free status, and only 1 is continuously disease free. Outcome related to response to primary therapy is as follows: of the 77 patients who never attained a disease-free status with primary BEP, 17 became disease-free with VeIP, and 11 (14%) are continuously free of disease. These results have been confirmed by other investigators.²¹⁴

Separate information suggests that recurrent seminoma may be uniqually sensitive to salvage chemotherapy. Miller and colleagues at Indiana University reported the results of VeIP in patients with seminoma recurring after primary cisplatin/etoposide-based treatment.²¹⁵ Of these 23 patients, 19 (83%) achieved disease free status, and 13 (56%) are continuously free of disease.

High-Dose Chemotherapy for Multiply Recurrent Germ Cell Cancer

Investigations into the use of high-dose carboplatin (CBCDA) and etoposide (VP-16) with autologous bone marrow support began at Indiana University in 1986. Initial investigations were on patients who were heavily pretreated and for whom no other curative therapeutic options existed. Subsequent studies have explored modification of the initial regimen in refractory patients and the efficacy of this regimen in patients in first relapse after conventional therapy. Important insights have been gained into the need for patient selection, the particular problem of primary nonseminomatous mediastinal germ cell tumors, and the value of intervention early in the course of the disease for these toxic, expensive, yet potentially curative modes of therapy.

The initial phase I/II dose escalation study examined the use of two courses of high-dose CBDCA and VP-16 in patients with germ cell tumors refractory to cisplatin (defined as progression after or within 4 weeks of the last cisplatin dose) or recurrent after primary therapy with cisplatin-based therapy and a salvage therapy with an ifosfamide-cisplatin combination.²²⁰ Thirty-three patients were entered into the trial. Overall, 7 (21%) of the patients died as a consequence of treatment. Deaths were primarily due to infection, although 1 patient died of veno-occlusive disease of the liver. Of note, this was a very heavily pretreated patient population with over half the patients having received three or more prior chemotherapy regimens, and 67% of patients were cisplatin refractory. Eight patients obtained a complete remission and 6 a partial remission, for an overall response rate of 44% (95% confidence interval, 27 to 63%). Of the 8 patients attaining complete remission, 3 are long-term disease-free survivors, and a fourth patient died at 22 months, free of germ cell cancer, from a therapy-related acute myeloid leukemia.²²¹ More recently, an overview of the experience at Indiana University with the first 40 patients with multiply relapsed and refractory germ cell cancer treated with double autologous transplantation demonstrated a 15% long-term disease-free survival.²²² These results have been confirmed in a similar multi-institutional trial performed by the ECOG.²²³

Other Investigations

Other investigators have reported similar results using high-dose chemotherapy in patients with multiply relapsed testicular cancer.^{217,224–227} Taken as a whole, several conclusions can be drawn. First, high-dose chemotherapy can cure 15 to 20% of patients experiencing multiple relapses of germ cell cancer. Patients with germ cell cancer who are overtly cisplatin refractory have a significantly diminished chance of permanent disease control (less than 5%). Second, therapy-related mortality in this heavily treated patient population is substantial (10 to 20% therapy-related deaths). Third, there is no standard high-dose salvage regimen, and similar results have been achieved with high-dose carboplatin/etoposide with double autologous transplantation, cisplatin (or carboplatin), etoposide, and cyclophosphamide with single transplantation, or combinations including ifosfamide. Last, in all these studies, patients with mediastinal nonseminomatous primary tumors fared particularly poorly and represent a group of patients who do not benefit from high-dose chemotherapy.

Salvage Surgery

Indiana University has performed a retrospective review of all patients who were felt to have chemotherapy-refractory disease and were submitted to surgery for attempts at curative resection.²²⁸ All patients had serologic or other evidence of progressive cancer. A total of 48 patients were reviewed, the majority of whom underwent isolated retroperitoneal lymphadenectomy (33 patients). Of these patients, 38 patients (79%) were rendered free of gross disease by surgery, and 29 (60%) attained a serologic remission. Ten patients (21%) remain continuously free of disease with follow-up ranging from 31 to 89 months. Six additional patients are currently disease free, with additional surgery (4 patients) or high-dose chemotherapy with autologous bone marrow transplantation. Clinical benefit was obtained only in that group of patients with a solitary site of disease at the time of surgery. Patients with multiple sites of metastasis, although resectable, were not cured. In carefully selected patients with chemotherapy-incurable disease, salvage surgery does offer a significant prospect of long-term disease-free survival. Such decisions about surgeries should be made at centers with significant experience in germ cell tumor management.

New Agents

The development of new active compounds offers the best hope of truly changing the prospect for cure in recurrent or resistant germ cell tumors, as well as better therapy for patients presenting with poor-risk features. Several classes of drugs are being investigated, including the taxanes and the topoisomerase I inhibitors. Preliminary information suggests a possible role for pacitaxel in germ cell tumors, and other phase II studies have been reported.^212,229,230

Late Relapse

Of the 8 to 16% of patients with disseminated testicular cancer who relapse after achieving a complete remission, most will suffer a recurrence within the first year following therapy, and the overwhelming majority within 2 years. A late relapse in this disease is generally accepted to be one that appears after a disease-free interval of more than 24 months. As an increasing number of case reports of late relapses appeared, retrospective analysis of several large series was undertaken in an attempt to determine the true rate of late relapse, as well as to define any potential predictive factors for this outcome. These series consistently describe a relapse rate following complete remission of 2 to 4%, with recurrences as late as 16 years following complete remission. Those patients who have had recurrences with isolated mature teratoma in general have done well following excision, whereas those with marker-positive carcinoma have tended to recur with large-volume disease and have had less favorable responses to additional chemotherapy.

At Indiana University, 81 patients were analyzed retrospectively who had recurrence of germ cell tumor after 2 or more years of being disease free.²³¹ Sixty percent of these patients had recurrences after > 5 years (maximum was 32 years). Serum marker elevation was seen, with 56% of patients having an elevated AFP and 27% of patients an elevated hCG. Fifteen patients (19%) had a recurrence of teratoma, 8 are continuously free of disease, and 4 patients are currently free of disease after further surgery (271 to 1,021 months). Seven patients experienced recurrence with sarcomatous elements (with or without teratoma); 4 are currently disease-free. Fifty-nine patients had germ cell carcinoma as their initial late recurrence. Only 10 of these patients (17%) are continuously disease free (101 to 781 months). Nine other patients are currently disease free. Aggressive surgery was required in almost all these patients. Overall, 65 patients received cisplatin-based chemotherapy, and 17 (26%) achieved a disease-free status with chemotherapy with or without adjunctive surgery. Twelve of the 17 have relapsed. Only 2 patients treated with chemotherapy alone are continuously free of disease (neither of these patients had received previous chemotherapy). A second, smaller series demonstrated similar findings.⁸⁸

A biologic basis for the appearance of rapidly progressive, marker-positive carcinoma after an extended disease-free interval has been difficult to determine. One possibility is that residual, slowly growing mature teratoma might retain the ability to “de-differentiate” into malignant germ cell elements after extended periods of time. In the Indiana University series, the presence of teratoma was a statistically significant predictor of late relapse. The tendency toward large-volume disease at the time of relapse may be the result of infrequent follow-up after 2 years. If a relationship between teratoma and late relapse exists, there are clear implications for the policy of surveillance in clinical stage A nonseminomatous disease. Some patients with unresected, microscopic retroperitoneal teratoma may be at risk for relapse at a time when follow-up is being performed on a yearly basis. Although the appearance of late relapses is relatively rare and supports current recommendations for intensive follow-up for 2 years, 2 to 4% of complete responders will experience recurrences, indicating that some form of follow-up is necessary for an indefinite period.

Nephrotoxicity

The acute effects of cisplatin on both renal glomerular and tubular functions are well documented, with decreases in both glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), accompanied by magnesium wasting and elevated levels of b2-microglobulin, indicative of proximal tubule dysfunction. Most investigators have reported that the acute decreases in GFR and ERPF do not deteriorate further (or improve) during the months to years following completion of chemotherapy, while tubular function returns to normal.^232–234 There are other isolated reports in the literature of a further decline,¹¹⁸ or even improvement,²³⁵ in GFR in the years following chemotherapy.

Vascular Toxicity

Raynaud’s phenomenon is the most common vascular toxicity seen in patients following chemotherapy for testicular cancer. Although anecdotally reported after therapy with single-agent bleomycin, it is much more common following combination therapy with vinblastine and bleomycin. Vogelzang and colleagues reported a 21% incidence of this phenomenon in patients treated with vinblastine plus bleomycin, compared with 41% when cisplatin was added to these two drugs.²³⁶ Studies employing provocative testing suggest that even asymptomatic individuals may exhibit an exaggerated vasospastic response to cold stimuli.²³⁷ The onset of the phenomenon tends to be delayed, with a median time to appearance of symptoms of 10 months.²³⁶ Symptoms persist indefinitely, with 49% of patients in one series reporting continued symptoms at a median of 8.5 years from completion of therapy.²³⁸ The vasospasm has, in general, been refractory to therapy, although some success has been reported with the calcium channel blocker nifedipine.²³⁹ Interestingly, the replacement of vinblastine by VP-16 in combination therapy with cisplatin and bleomycin has not reduced the incidence of Raynaud’s phenomenon.¹⁷⁰

The relationship of cisplatin-based chemotherapy to large-vessel ischemic events is less clear. There have been case reports of myocardial ischemia and infarction, as well as cerebrovascular accidents, following vinblastine administration as a single agent or combined with bleomycin. Several anecdotal reports of major cardiovascular events in young men receiving chemotherapy for testicular cancer suggested a causal association between chemotherapeutic treatments and these events.^240–242 To evaluate the true risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer, questionnaires to assess cardiovascular toxicity were distributed to all participants in the Testicular Cancer Intergroup Study, and toxicity reviews from the chemotherapy flow sheets were conducted.²⁴³

Patients with pathologic stage I testicular cancer were registered in the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receiving two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who experienced a recurrance after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy.

A review of toxicity of treatment in those patients receiving adjuvant chemotherapy (N = 97) or chemotherapy for recurrent disease (N = 83) revealed no cases of acute cardiovascular toxicity. When the median follow-up after study enrollment was 5.1 years, 459 questionnaires were mailed, and 270 were returned. The percentage of returns was equal among the observed, adjuvant, and recurrent groups (59%, 54%, 64%, respectively). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in 2 patients in the observation group, and 1 nonfatal infarct was reported in the adjuvant treatment group. No patient in any group reported stroke. Three patients in the observation group and 1 patient in the recurrent group experienced a thromboembolic event. Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.

Neurotoxicity

The peripheral neuropathy and ototoxicity observed in treated testicular cancer patients are attributable primarily to cisplatin, with a somewhat lesser contribution by vinblastine. The peripheral effects became manifest clinically as a distal sensory neuropathy, with paresthesias and dysesthesias, disturbances of position and vibratory sensation, and relative sparing of motor units.²⁴⁴ Subjectively, these symptoms may be present for prolonged periods, with 43% of patients in one study reporting persistent symptoms 6 to 12 years after completion of therapy.²³⁸ Recent objective studies have confirmed the irreversibility of the neuropathy and have suggested that the dorsal root ganglion represents the primary target of cisplatin-induced damage.²⁴⁵ The substitution of etoposide for vinblastine in combination chemotherapy has been shown to reduce the incidence of neurologic side effects.¹⁷⁰

The ototoxicity associated with cisplatin administration is represented primarily by high-frequency hearing loss and is related not only to the cumulative dose of cisplatin, but also to the rate of infusion.^246,247 Other risk factors for the development of ototoxicity include a serum creatinine level higher than 1.5 mg/dL, increased age, and pre-existing hearing impairment.

Second Malignancies

Case reports and clinical alerts have suggested that treatment with high-dose etoposide can result in the development of a unique secondary leukemia.²⁴⁸ To estimate the risk for developing leukemia in the more common clinical setting of patients receiving conventional doses of etoposide along with cisplatin and bleomycin, we reviewed records of patients with germ cell cancer entering clinical protocols using etoposide at Indiana University.²²¹ Between 1982 and 1991, 538 patients entered serial clinical trials, with planned etoposide doses from 1,500 mg/m² to 2,000 mg/m² in combination with cisplatin plus either ifosfamide or bleomycin. Of these, 348 patients received an etoposide combination as initial chemotherapy, and 190 patients received etoposide as part of salvage treatment. In all, 315 patients are alive, and 337 patients have been followed up beyond 2 years. The median follow-up for patients still alive is 4.9 years. Two patients (0.37%) developed leukemia. One patient developed acute undifferentiated leukemia with a t(4:11)(q21:q23) cytogenetic abnormality 2.3 years after starting etoposide-based therapy, and 1 patient developed acute myelomonoblastic leukemia with normal chromosome studies 2 years after beginning chemotherapy. During this period, a number of patients were seen outside clinical trials, and we are aware of several hematologic abnormalities in this group, including 1 patient with acute monoblastic leukemia with a t(11:19)(q13:p13) abnormality. Secondary leukemia after treatment with chemotherapy including conventional-dose etoposide does occur. However, this low incidence of secondary leukemia does not alter the risk-benefit ratio of etoposide-based chemotherapy for germ cell cancer.

Fertility

Before the effects of therapy on fertility are examined, it must be realized that up to 80% of testicular cancer patients will be oligospermic at diagnosis, prior to the initiation of any therapy.²⁴⁹ Although the etiology of this oligospermia is unknown, several mechanisms have been proposed, including an autoimmune process,²⁵⁰ or a primary endocrine dysfunction resulting in impaired spermatogenesis.²⁵¹

In terms of therapy-related infertility, most patients with nonseminomatous disease in the past have undergone RPLND, either as a staging procedure or during postchemotherapeutic resection of residual disease. As described above, the classic RPLND is associated with almost universal ejaculatory dysfunction and resultant infertility secondary to the resection of thoracolumbar sympathetic fibers. The current trend toward observation instead of staging RPLND in clinical stage A nonseminomatous disease will reduce the incidence of infertility attributable to this modality of therapy.

The chemotherapy administered for testicular cancer has acute effects on both spermatogenesis and Leydig’s cell function; most patients remain azoospermic with elevated serum gonadotropins for the first 12 months following therapy. These toxic effects are reversible in a significant number of patients, however, as approximately 50% will see a return of both spermatogenesis and Leydig’s cell function during the second year after completion of therapy.^252,253 Several factors have been shown to decrease the likelihood of the return of spermatogenesis, including age over 30 years, treatment duration of more than 6 months, and prior abdominal radiotherapy.^254,255 In the Indiana University experience, at least one-third of patients treated with chemotherapy alone have been able to father children without congenital anomalies,²³⁸ confirming previous data.²⁵⁵

Pulmonary Toxicity

Bleomycin is solely responsible for the pulmonary toxicity observed in chemotherapy-treated testicular cancer patients. Pulmonary fibrosis develops in approximately 5% of individuals and is fatal in approximately 2%.²⁵⁶ This toxicity is directly related to cumulative dose, with a significant increase above 450 units. The earliest physical finding of bleomycin-induced pulmonary injury is an inspiratory lag and should prompt immediate discontinuation of the drug. Subsequent signs and symptoms include bibasilar rales, nonproductive cough, and exertional dyspnea. Laboratory abnormalities include decreases in DLCO and late changes, including hypoxia and hypercapnea. Radiographic abnormalities include the appearance of subpleural-based nodules, visible on the chest radiograph or chest CT scan.

The risk of developing symptomatic bleomycin-induced lung disease increases with age > 70 years,²⁴ prior or concomitant chest radiotherapy,^257,258 decreased renal function,^31,259 and high concentrations of inspired oxygen.¹¹⁶ Since the mortality or this condition approaches 50% and therapeutic interventions, such as corticosteroids, are ineffective,²⁶⁰ early diagnosis of asymptomatic patients and subsequent discontinuation of the drug are particularly important.

Cardiopulmonary Toxicity

An excess of cardiac deaths, especially in individuals over 40 years old at the time of treatment, has been observed in patients receiving mediastinal radiation therapy for seminoma.^136,261 Although this effect is likely deterministic, a dose threshold has not been observed within the ranges historically used to treat the mediastinum. Mediastinal radiation therapy is associated with double the risk of cardiac death, compared with that experienced in the general population. Along with the heart and pericardium, a moderate amount of the lung is included in a typical mediastinal field. A few cases of lethal pulmonary fibrosis have been reported, usually associated with bleomycin chemotherapy.^136,149 The recognition of cardiopulmonary toxicity has led to the general abandonment of mediastinal radiation therapy for most testicular cancer presentations.

Gastrointestinal Toxicity

Transient nausea generally accompanies abdominal radiation therapy for testicular cancer but seldom persists beyond a few months.²⁶² The doses typically used in seminoma are apparently below the threshold for late small bowel toxicity, such as obstruction secondary to adhesions, at least in patients without previous abdominal surgery or whole abdomen fields. Dyspepsia and peptic ulcer disease have been reported in 3 to 6% of patients after abdominal radiation therapy for testicular cancer.^263,264 Although these patients were treated with doses of 35 to 40 Gy, no late gastrointestinal toxicity was retrospectively reported when a dose of 25 Gy was used in 1.25-Gy fractions at the Princess Margaret Hospital.⁷³ In general, radiation therapy is predominantly associated with peptic ulcer disease in patients with a prior history of ulcers or abdominal surgery.²⁶⁴

Fertility

Transient sterility may occur in normal males at a single dose level of only 15 cGy, whereas permanent sterility will result at 350 to 600 cGy to the testicles.²⁶⁵ The induction of sterility at these dosage ranges rarely results in significant changes in hormone balance, libido, or ability to have erections. In fact, fractionated doses as large as 20 Gy to the testicle do not result in hormonal failure owing to the relative radioresistance of the Leydig’s (interstitial) cells, compared with the sensitive spermatogonial cells.²⁶⁶ With proper shielding of the remaining testicle, only transient azospermia should occur due to internally scattered dose from standard abdominal radiation therapy fields. Increased sterility may result from ipsilateral scrotal irradiation, and pretreatment sperm banking should be considered. Unfortunately, the majority of patients with testicular cancer will present with markedly decreased sperm counts and infertility before therapy for unknown reasons.²⁴⁹ While some will experience recovery of sperm cell production after radiation therapy, nearly half will continue to be infertile years after therapy.²⁶³

Second Malignancies

The carcinogenic potential of radiation therapy has long been recognized as a stochastic effect, with no completely safe threshold dose. The exact incidence of occurrence of radiation-induced malignancy in patients treated with radiation therapy for testicular cancer is difficult to determine as it requires a long, careful follow-up on very large numbers of similarly treated patients. After an incidence of second malignant neoplasms is determined, an appropriate comparison of risk with a similar control group of patients not receiving radiation therapy must be carried out. The general population may be a poor control group as patients with testicular cancer may be inherently more at risk for developing other cancers, either spontaneously or on exposure to known carcinogens. While the majority of reports of second malignant neoplasms in patients treated with radiation therapy for testicular cancer lack statistical power, adequate follow-up, or appropriate controls for risk assessment, they do form a potential basis for the comparison of different treatment modalities.

The majority of second malignant neoplasms occurring during the first 5 years after radiation therapy for testicular seminoma are contralateral second testicular cancers,²⁶⁷ which may be radiation induced or reflect an inherent predisposition. By 15 years after treatment, between 8 and 16% of treated patients will have experienced a second malignant neoplasm, with an increase in relative risk of 2.0 to 3.3 over the general population.^136,268 Radiation-induced second malignant neoplasms would be expected to occur mostly in the primarily irradiated volume. However, two reports show no difference in the rates of second malignant neoplasms within the treated volume, compared with outside the volume.^136,267 Extended-field radiation therapy including the mediastinum was found to be associated with an increase in second malignancies in a large series from the Norwegian Radium Hospital.²⁶⁹ Kleinerman et al. compared irradiated and nonirradiated groups of patients treated for testicular cancer in a large series from the Connecticut Tumor Registry and found a similar increase in second malignant neoplasms in both groups.²⁷⁰ Overall, there appears to be a small but real increase in second malignant neoplasms following radiation therapy for testicular cancer. This information should motivate radiation oncologists to minimize the dose and volume of radiation therapy for patients with testicular cancer, as long as control and overall cure rates are maintained.

Sanctuary Sites and CNS Metastases

It is quite uncommon for patients to present with CNS metastasis as an initial manifestation of metastatic testicular cancer. In a recent study of patients with far-advanced disease (Indiana University class 7, 8, 9), only 6 of 159 (4%) patients had CNS involvement at the time of the original diagnosis.¹⁹⁴ The rarity of this presentation makes CNS prophylaxis inappropriate for any subset of patients with advanced germ cell cancer. In patients with advanced hematogenous metastases or large-volume choriocarcinoma, however, clinical suspicion should be heightened and careful investigation of even minor CNS symptoms is warranted.

Patients with CNS involvement, either as a part of the initial presentation or as a manifestation of relapse, should be approached with curative intent. Chemotherapy penetrates poorly into the CNS and so is not the mainstay of therapy. Patients with CNS disease accompanying other systemic involvement should receive whole-brain radiotherapy (5,000 cGy in 5 weeks) along with appropriate systemic chemotherapy.²⁷¹ Patients relapsing with a solitary CNS metastasis without involvement of other sites undergo resection followed by CNS radiotherapy and two postoperative courses of “adjuvant” cisplatin-based chemotherapy.

The possibility of occult CNS metastasis should be considered in the setting of complete systemic remission and persistent or new elevation of serum tumor markers. In this situation, CT scans of the brain should be performed along with an evaluation for a testicular sanctuary site (see below). The CNS evaluation should proceed even in the absence of clinical signs or symptoms.

The other important sanctuary site from chemotherapy in germ cell cancer is the testis. In most settings, the testicular primary was removed in the initial diagnostic process. However, in some patients presenting with advanced disease, chemotherapy is initiated without a tissue diagnosis. In such cases, the testis must be removed at the completion of chemotherapy even if the primary tumor is no longer evident.

The possibility of a metachronous contralateral testis primary must, at times, be entertained. In the setting of complete radiographic remission of systemic disease and a persistent or new elevation of serum tumor markers, the remaining testicle should be carefully examined and a testicular ultrasound be performed to rule out an occult primary in the remaining testis. Primary retroperitoneal germ cell tumors are commonly associated with occult testicular primaries, particularly in the setting of a retroperitoneal mass that is not midline in origin.