NIH CONFERENCE

Testicular Germ-Cell Neoplasms: Recent Advances in Diagnosis and Therapy Moderator: TOM ANDERSON, M.D. Discussants: THOMAS A. WALDMANN, M.D.; and ELI GLATSTEIN, M.D.; Bethesda, Maryland The diagnosis and treatment of testicular neoplasms have been facilitated by identification of the tumor-associated proteins alpha-fetoprotein and human chorionic gonadotropin. These circulating tumor markers, present in 8 5 % to 9 0 % of patients with nonseminomatous testicular cancer, reflect tumor presence and reliably indicate response to therapy. Alpha-fetoprotein is produced by embryonal carcinoma and yolk-sac tumors; human chorionic gonadotropin is produced by syncytiotrophoblastic giant cells and the syncytiotrophoblastic component of choriocarcinoma. Refinements in staging techniques and definitions have improved prognostication. Effective therapy for seminoma (cure rate, greater than 9 0 % ) , early-stage (stage I, stage UN, 2) testicular carcinoma (cure rate, 6 5 % to 8 7 % ) , and advanced (stage IIN M stage III) testicular carcinoma (complete remission rate, 5 0 % to 7 4 % ) has been shown in clinical trials. Adjuvant chemotherapy/radiotherapy trials for limited stages of testicular carcinoma, and further experience with intensive chemotherapy-based trials for advanced stages may further improve the prognosis for all testicular germ-cell neoplasms.

D R . T O M A N D E R S O N (Senior Investigator, Medicine Branch, Clinical Oncology Program, Division of Cancer Treatment): Testicular tumors are relatively rare neoplasms, occurring with an estimated incidence of 2.2 per 100 000 patients and comprising only 1% to 2% of male malignant disease (1). These neoplasms, therefore, do not have a large impact on survival statistics, or are they felt to represent a major therapeutic problem for society. Such statistics are misleading, however, because these tumors affect young men in the prime of life, and are the most common cause of death by cancer in men between the ages of 29 and 35. Although they are more common in the white population than in the other races (2), the only known predisposition is the history of cryptorchism, which increases the risk of developing a testicular germcell tumor. The exact magnitude of this increased risk, estimated at anywhere from 10-to 1000-fold, has not yet been clarified (3, 4). Because orchiopexy after the age of 6 years does not appear to prevent a subsequent development of a malignant tumor, debate continues as to whether orchiopexy at any age protects against such an event, or whether some basic abnormality of the cryptorchid testis may exist, which both interferes with its nor• A n edited transcription of a Combined Clinical Staff Conference at the Clinical Center, Bethesda, Maryland, 16 February 1978, by the National Cancer Institute, National Institutes of Health, U.S. D e p a r t m e n t of Health, Education, and Welfare. • A u t h o r s who wish to cite a section of this conference and specifically indicate its a u t h o r can use this example for the form of reference: W A L D M A N N T A : T u m o r markers in the diagnosis and management of patients with testicular germ-cell neoplasms, pp. 374-377 in A N D E R S O N T (moderator): Testicular germ-cell neoplasms: recent advances in diagnosis and therapy. Ann Intern Med 90:373-385, 1979

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M.D.; NASSER JAVADPOUR,

mal development and anatomical placement and predisposes it to a subsequent neoplastic transformation (5-7). Questions regarding diagnosis, natural history of disease, and response to therapy have been difficult to answer because of the complexity and variety of histologic patterns of disease. The first comprehensive effort to classify these tumors was published by Friedman and Moore (8) in 1946, then modified by Dixon and Moore (9) in 1952. These investigators proposed that the vast majority of testicular tumors originate from totipotential germ cells, which can give rise to neoplasms that can be classified as testicular seminoma or as a subgroup of the testicular carcinomas including embryonal carcinoma, teratoma, or choriocarcinoma (8, 9). In 1964, Collins and Pugh (10) reviewed the cases registered with the British Testicular Tumor Registry and published a different classification scheme often referred to as the "British Classification." Although they accepted that seminomas were of germ-cell origin, they believed that the testicular carcinomas were of unknown histogenesis and preferred to use the terminology of teratoma differentiated, malignant teratoma intermediate (initially subdivided into subtypes A and B), malignant teratoma anaplastic, and malignant teratoma trophoblastic. In a 1976 revision, malignant teratoma intermediate subtype B and malignant teratoma anaplastic were combined to form a new category, malignant teratoma undifferentiated (11). Although this system is somewhat comparable to the American classification system, the histologic subcategories are not strictly equivalent, making comparison of treatment results difficult. The terminology using the phrase teratoma to include the entire spectrum of disease from mature teratoma, with its good prognosis, to choriocarcinoma, with its poor prognosis, has not been helpful in understanding the natural history of these diseases. The classification system currently used at the National Cancer Institute is the modification of the Dixon and Moore System proposed by Mostofi (12) and similar to that used by the World Health Organization (13) (Table 1). This system has expanded the histologic subtypes in both the germinal and nongerminal tumor categories and also provides a general category for those tumors with combinations of histologic elements. This system recognizes the complexity of the histologic patterns of disease and can be used to better understand the natural history of these diseases and appreciate the effects of the application of therapeutic interventions in these diseases. Diagnosis and histologic classification of germ-cell neoplasms have been further advanced by the develop373

Table 1. Histopathologic Classification of Testicular Tumors* Germinal cell origin Seminoma Spermatocyte Anaplastic Typical Embryonal carcinoma Adult type Infantile type (yolk-sac tumor or endodermal sinus tumor) Polyembryoma Teratoma Mature Immature With malignant transformation Choriocarcinoma Compound tumors Embryonal carcinoma with teratoma (teratocarcinoma) Any other combination of the above elements (14 possible combinations) Nongerminal-cell origin Insterstial cell tumor Sertoli cell tumor Gonadal-stromal tumor Compound tumors (four possible combinations) * References 12, 13.

ment of sensitive and specific immunologic techniques that can be used to quantitatively measure elevated blood levels of the tumor-associated polypeptides, alpha-fetoprotein and human chorionic gonadotropin, and to identify their cellular source by immunohistochemical staining of biopsy material, including formalin-fixed tissues. Using such investigative tools, the origin of the various germ-cell tumors can be verified, pathologic classifications systems validated and clarified, testicular germ-cell neoplasms more rapidly diagnosed, and treatment efficacy more accurately evaluated. Thus, although testicular germ-cell tumors are relatively rare, they are an important group of diseases to study because they provide a model for both laboratorybased and clinically oriented scientific research. New techniques have improved our ability to diagnose and stage such patients. Advances in the treatment indicate that long-term survival of many of these patients can be dramatically enhanced. This conference reviews the developments and impact of these advances. Tumor Markers in the Diagnosis and Management of Patients with Testicular Germ-Cell Neoplasms

Dr. Thomas A. Waldmann (Chief, Metabolism Branch, Division of Cancer Biology and Diagnosis): The placental protein, human chorionic gonadotropin, and the oncofetal protein, alpha-fetoprotein, are products of the normal placenta and normal fetal tissues respectively. Although present in fetal biologic fluids and in patients with certain forms of cancer, they are either absent or present in exceedingly low concentrations in the serum of normal adults. Because one or both of these proteins can be produced by malignant germ-cell neoplasms, radioimmunoassays for these proteins are valuable tools in diagnosing a testicular mass, in staging germ-cell tumors of the testis, and especially for monitoring the efficacy of therapy of patients with this form of cancer. 374

Alpha-fetoprotein was the first of the oncofetal proteins to be widely studied. It is a protein with a molecular weight of 70 000 and an alpha electrophoretic mobility (14-16). It is synthesized by the parenchymal cells of the liver, yolk sac, and gastrointestinal tract of the fetus (1719) and is the major serum protein of the human fetus, reaching levels up to 3 000 000 ng/ml by the 12th to 15th week of gestation (15, 17, 19). The serum concentration of alpha-fetoprotein diminishes with further fetal development, falling to 10 000 to 150 000 ng/ml at birth. At 1 year of age it has dropped to adult levels and is normally not detectable by the original relatively insensitive immunoprecipitation methods of measurement. In 1963, Abelev and coworkers (20) first associated alpha-fetoprotein with a tumor, finding it in the serum of mice and rats with chemically induced hepatomas. In the next year, Tartarinov (21) found alpha-fetoprotein in the serum of human patients with hepatocellular carcinoma. Subsequently, elevated alpha-fetoprotein levels have also been found in a high percentage of patients with germ-cell tumors of the testis (15) and in a lower percentage of patients with non-germ-cell tumors of endodermal origin (24, 25). Relatively simple and specific agar-gel precipitation tests were used to detect alpha-fetoprotein levels in initial studies. Unfortunately, these tests have a low level of sensitivity (3000 ng/ml) inadequate for monitoring the effectiveness of therapy. Subsequently, we (26) and others (2729) developed radioimmunossays and enzyme immunoassays that are sufficiently sensitive to detect the 1 to 16 n g / ml of alpha-fetoprotein present in normal serum (27). Using the radioimmunossay for alpha-fetoprotein, we have defined any value greater than 40 ng/ml as abnormally elevated, because all sera from 190 normal control subjects had a value below this level; only one of 500 samples from control subjects or patients with benign nonhepatic disease whom we studied had a value greater than 40 n g / ml. That one patient with an elevated value (52 ng/ml) had documented ulcerative colitis. Thus, with the discriminate of 40 ng/ml, there are very few false-positive values for alpha-fetoprotein in patients with benign nonhepatic disease. It should be noted, however, that modest elevations of alpha-fetoprotein are noted in patients with hepatocellular disease, particularly when active liver-cell regeneration is present (30-34). We then screened the sera of patients with malignancy and found elevated alpha-fetoprotein levels in association with certain tumors. More than 70% of the 130 patients with hepatocellular carcinoma had a level of greater than 40 ng/ml; a smaller number of patients with other endodermally derived tumor also had abnormally high alphafetoprotein levels. Sixteen of 91 patients with gastric carcinoma (17%), 10 of 44 patients with pancreatic carcinoma (23%), 10 of 193 patients with colonic carcinoma (5%), and 10 of 150 patients with bronchogenic carcinoma (7%) had elevated alpha-fetoprotein levels. Seventyfive of the 101 patients (75%) with nonseminomatous testicular germ-cell tumors had an elevated alpha-fetoprotein level (26). Three quarters of these 75 patients had values that were greater than 40 ng/ml as assessed by

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radioimmunoassay, but were less than 2000 ng/ml, the lower limit of detection of the precipitation in agar techniques, and thus would have been missed by these relatively insensitive procedures. The second important marker for testicular germ-cell tumors is human chorionic gonadotropin, a hormone secreted by the syncytiotrophoblastic cells of the normal placenta. Serum elevations of this marker occur in essentially all patients with gestational trophoblastic disease, in a majority of patients with testicular and ovarian germ-cell tumors, and in a smaller percentage of patients with other malignancies. Human chorionic gonadotropin is a glycoprotein with a molecular weight of approximately 45 000 containing two dissimilar polypeptide subunits designated alpha and beta. This hormone shares a common structure with other human glycoprotein hormones, such as luteinizing hormone. The amino-acid sequence of the alpha subunit is essentially identical among these trophic hormones, although significant differences in the amino-acid sequences of the beta chains confer specificity (35). Thus, the carboxy terminus of the human chorionic gonadotropin beta chain contains a unique sequence of 28 to 30 amino acids not found in luteinizing hormone. Antibodies prepared against the whole human chorionic gonadotropin molecule will cross-react with luteinizing hormone. Antibodies produced against the beta chain of human chorionic gonadotropin, however, do not significantly cross-react and therefore can be used to accurately measure serum levels of human chorionic gonadotropin. Vitukaitus and her co-workers (36) developed a radioimmunoassay for human chorionic gonadotropin using antibodies to the beta chain. They showed that normal persons have serum levels of human chorionic gonadotropin below 1 ng/ml. Virtually all patients with benign disorders have normal chorionic gonadotropin levels; certain patients with non-germ-cell malignancies, especially those with cancer of the stomach and pancreas, have had elevated values (36). In our studies, 73 of 100 patients with testicular nonseminomatous germ-cell tumors had an elevated human chorionic gonadotropin level. When both chorionic gonadotropin and alpha-fetoprotein were measured, a higher percentage of patients had an elevated level of a marker than when either marker was used alone. Thus, 59 of the first 100 patients we studied had an elevation of both markers, 16 had an elevation of alpha-fetoprotein alone, 14 had an elevation of human chorionic gonadotropin alone, and 11 had neither marker elevated. Thirty percent of the patients had an elevation of one but not the other marker, and 89% of the patients had an elevation of one or both marker proteins. We next applied these two serum marker tests to a prospective study to ascertain whether these tests could be helpful in diagnosing a testicular mass. Sixty-nine men who had testicular lesions requiring orchiectomy were studied. Fifty-five of these 69 patients either had a benign lesion or a non-germ-cell testicular tumor. None of these patients had an elevated marker. In contrast, 11 of the 14 patients with a testicular nonseminomatous germ-cell

tumor had an elevated marker. Thus there were no falsepositive values for these markers, but false-negative values did occur (21%). Therefore, although a negative hormone assay does not exclude a testicular tumor, a positive marker appears to be diagnostic of a testicular germ-cell tumor. Such a positive test can assist in the diagnosis of malignancy and could lead to a shortened interval between initial evaluation and appropriate therapy. These alpha-fetoprotein and human chorionic gonadotropin assays were then evaluated for their accuracy in clinical staging of nonseminomatous testicular tumors. It is important to emphasize that one should not expect the markers to disappear immediately after entire tumor removal. A tumor marker level at any given time after effective therapy is related to the original pretreatment level and the physiologic degradation rate of that marker. Thus, the significance of markers elevated after surgery can only be appreciated by obtaining additional marker assays over a period of time. After complete removal of a tumor, the marker should ultimately reach a normal value at a specific time depending on its half-life. The survival half-life of human chorionic gonadotropin is 12 to 20 hours; of alpha-fetoprotein, 3.5 to 6 days. Thus, if one completely removes a testicular tumor from a patient with a serum alph-fetoprotein concentration of 100 000 ng/ml, the alpha-fetoprotein, with its half-time of approximately 5 days, would not decline below 40 ng/ml (the upper limit of the normal range) for a period of approximately 50 days. If the marker's rate of decline is significantly lower than that predicted by the normal half-time, or stabilizes at a level greater than 40 ng/ml, residual tumor is presumably present. With this in mind, alpha-fetoprotein and human chorionic gonadotropin radioimmunoassays were evaluated for accuracy in clinical staging of nonseminomatous testicular germ-cell tumor in cooperation with Dr. Peter Scardino. Thirty-seven patients were studied after orchiectomy, but before a retroperitoneal lymph node dissection (37). Thirty-one of the 37 patients in this study were considered to have stage I disease on the basis of lymphangiogram and other clinical variables; six of the patients were thought to have stage II disease. Eleven of the 31 patients with nonseminomatous tumors considered clinically to be in stage I were found to have positive nodes at the time of retroperitoneal lymphadenectomy (stage IB old classification, or stage II, N p in the newer classification) or had negative nodes but developed a distant metastasis within 6 months of orchiectomy. Six of these patients had an elevated alpha-fetoprotein or human chorionic gonadotropin value, or both, at the time of clinical staging, which correctly indicated the presence of these occult nodal or nonnodal metastases. The remaining five patients with nodal metastases had normal marker levels or marker levels that were declining at a rate consistent with the known half-life of the marker in the circulation. The staging discrepancy was therefore reduced from 35% (11 of 31) based on clinical and lymphangiogram data alone to 16% (5 of 31) based on the additional information provided by the markers. Six patients were conAnderson

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Figure 1 . Changes in the markers, human chorionic gonadotropin (hCG) and alpha-fetoprotein (aFP), with therapy and in recurrence in the 12 patients with widely disseminated testicular nonseminomatous germ-cell tumors who showed rises in both markers with recurrence. ACT/VCR/BLEO = dactinomycin, vincristine, bleomycin; MITH = mithramycin; PLAT = platinum; ADRAI = doxorubicin.

sidered to have clinical stage II (stage II, N 2 4 ) disease; that is, the lymphangiograms suggested nodal metastases. At operation only four of these six patients had positive nodes. These four patients had had positive markers before the node dissection, whereas the two patients with negative nodes, who also remained free of tumor throughout the period of follow-up, had negative markers before surgery. Consequently, the discrepancy in clinical staging in these six patients was reduced from 33% (2 of 6) based on clinical data to 0% (0 of 6) based on the marker level. Thus, although some false-negative values

occurred in this study, the tumor markers proved to be more reliable indicators than the standard staging procedures (37). The serial measurement of alpha-fetoprotein and human chorionic gonadotropin by radioimmunoassay appears to be of special value in monitoring the effectiveness of therapy of these testicular nonseminomatous germ-cell tumors (37-41). We investigated the value of doing serial assays for human chorionic gonadotropin and alpha-fetoprotein during and following therapy in 34 patients with widely disseminated testicular nonseminomatous germcell tumors who had elevations of both human chorionic gonadotropin and alpha-fetoprotein. A number of patterns emerged: In 9% of the patients there was no clinical response to therapy and the alpha-fetoprotein and human chorionic gonadotropin levels increased until the patient's death. In 9% of the patients, both markers declined to normal after surgery and chemotherapy and remained within the normal range throughout the period of observation. These patients did not have a recurrence of their tumor, and again, the alpha-fetoprotein and human chorionic gonadotropin levels paralleled the clinical course of the disease. In two patients, representing 6% of the group, tumor masses failed to diminish during chemotherapy, but both human chorionic gonadotropin and alpha-fetoprotein marker levels fell to the normal range. At subsequent surgery one patient had a mature teratoma, and the other a mature teratoma with a microscopic focus of embryonal carcinoma. Thus, in these patients, those elements of the malignant tumor producing markers were largely ablated with chemotherapy, leaving elements that did not produce these markers, at least at levels detectable by these sensitive radioimmunoassays. Both markers declined dramatically after chemotherapy in 36% of the patients but remained above the upper limit of the normal range. Rising levels of both markers accompained tumor recurrence (Figure 1). In 40% of the patients, however, after an initial marked decline of both markers, one marker fell to within normal range and remained at a normal level even though tumor recurrence was documented. The other marker either remained elevated at all times or returned to normal levels only tran-

Figure 2 . Changes in the markers, human chorionic gonadotropin (hCG) and alpha-fetoprotein (aFP), with therapy and in recurrence in the 2 2 patients with widely disseminated testicular nonseminomatous germ-cell tumors who showed rises in recurrence only of human chorionic gonadotropin. NED = no evidence of disease; ACT-D/CHLORAM/MTX = dactinomycin, chlorambucil, methotrexate; CIS-PLAT/ BLEO = c / s - d i - c h l o r o d i a m m i n e platinum, bleomycin; ADRIA/VELBAN/INAPSIN = doxorubicin, vinblastine, droperidol. 376

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siently. This second marker returned to a very high level with tumor recurrence (Figure 2). This discordant behavior of these two tumor-associated proteins suggested that their cells of origin were probably different. This hypothesis was confirmed using an indirect immunoperoxidase technique to define the cellular localization of alpha-fetoprotein and human chorionic gonadotropin in germ-cell tumors of the testes (42). Alpha-fetoprotein was seen in embryonal cells and endodermal sinus tumor elements, whereas human chorionic gonadotropin was identified within synctiotrophoblastic giant cells. In no case was the same cell shown to produce both markers. Of greatest interest is the value of elevated tumor markers in those patients with no clinical evidence of disease after therapy. After initial therapy for germ-cell malignancy of the testis, 28 of the 34 patients in our series have had an elevated alpha-fetoprotein or human chorionic gonadotropin marker level, or both, at a time when they had no clinical evidence of disease. Each of these patients has had a clinically documented recurrence of their tumor within the subsequent 2-to-14-month period of observation. Thus, although false-negative estimates of tumor presence have been observed in approximately 10% of patients, false-positive values have not been noted. Clearly these studies indicate that sensitive tests for both alpha-fetoprotein and human chorionic gonadotropin are of great value in following the treatment of patients with testicular germ-cell tumors, especially in those patients who have no other clinical evidence of disease. In summary, serum levels of alpha-fetoprotein and human chorionic gonadotropin are elevated in the majority of patients with non-seminomatous germ-cell tumors of the testes. Evaluation of both of these markers is required, because some tumors only produce one of the markers. Even if both markers were present initially, only one marker may persist after therapy. To take full advantage of these tumor markers, it is essential to have a sufficiently sensitive assay, to detect and measure the alpha-fetoprotein level (less than 40 ng/ml) and human chorionic gonadotropin level (less than 1 ng/ml) found in normal serum; this means either radioimmunoassays or enzymeimmunoassays are required. These markers have been of value as an adjunct to the diagnosis of a testicular mass and in staging germ-cell tumors of the testis, and of special value in following patients after surgery, radiation, chemotherapy, or a combination of these. Although we have noted that approximately 10% of patients with nonseminomatous germ-cell tumors have normal marker levels, no false-positive values have been observed in our study of more than 300 patients; that is, there have been no persistently elevated alpha-fetoprotein or human chorionic gonadotropin levels in this group of patients in the absence of residual tumor. Therefore, we believe that an increasing serum alpha-fetoprotein level in a patient who previously had an alpha-fetoprotein-secreting tumor is indicative of recurrent tumor unless the patient has developed an intercurrent hepatic disease. Measurement of serum alpha-fetoprotein and human chorionic gonadotropin has become a necessary compo-

Figure 3. Cell origin of testicular tumor markers. HCG = human chorionic gonadotropin, AFP = alpha-fetoprotein.

nent of the evaluation and management of patients with nonseminomatous germ-cell malignancies of the testis. Immunocytochemistry of Testicular Tumors

Dr. Nasser Javadpour (Senior Investigator, Surgery Branch, Clinical Oncology Program, Division of Cancer Treatment): The histopathologic classification currently applied at the National Cancer Institute (NCI) is based on using intracellular localization of the tumor markers, human chorionic gonadotropin and alpha-fetoprotein, in various tumor cells by the immunoperoxidase histochemical technique. One of the major advantages of this technique is that it can be applied to either a prospective or retrospective study, because the tissue to be studied can be fixed in formaldehyde. Testicular germ-cell tumors may contain multiple cellular components with variable growth and metastatic patterns. Intracellular localization of these markers in various cancer cells has improved the diagnosis and understanding of the histopathology of testicular cancer. To correlate various types of neoplasms with the presence of these tumor markers in the tissue and serum, a study was undertaken of 40 patients with germ-cell tumors of the testis, all of whom had measurements of serum levels of chorionic gonadotropin and alpha-fetoprotein. Alpha-fetoprotein was found within the cells of embryonal carcinoma and endodermal sinus tumor (Figure 3) but not in the syncytiotrophoblastic giant cells occasionally found in seminomas, or in syncytiotrophoblastic components of choriocarcinoma. In contrast, human chorionic gonadotropin was found in syncytiotrophoblastic components of choriocarcinoma and in some cells of some cases of embryonal carcinoma, and only rarely in endodermal sinus tumors and seminoma. Thus, adult-type embryonal carcinoma is frequently associated with both alpha-fetoprotein and human chorionic gonadotropin; endodermal sinus tumor is associated with alpha-fetoprotein; and choriocarcinoma is associated with human chorionic gonadotropin. Pure seminoma and teratoma are unlikely to be associated with either marker as previously reported (Figure 3) (42). We have also prospectively studied 130 patients with pure seminoma in whom we had made serial quantitative measurements of human chorionic gonadotropin and alpha-fetoprotein using specific radioimmunoassays (43). Ten of the 130 patients had elevated serum human chorionic gonadotropin levels ranging from 2.8 to 428 n g / Anderson

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Table 2. Staging Methods for Testicular Cancer* A. Accepted staging method Stage U: tumor confined to the testis Stage IB : microscopic involvement of retroperitoneal lymph nodes Stage II: macroscopic involvement of retroperitoneal lymph nodes Stage III: extension beyond retroperitoneal lymph nodes B. Surgical pathologic staging method f Stage I: Local spread Pi—Confined to testis P2—Involves testicular adnexa P3—Involves scrotal wall Stage II: Confined to retroperitoneal lymphatics Ni—Microscopic N2—Gross involvement without capsular invasion N3—Gross involvement with capsular invasion N4—Massive involvement of retroperitoneal structures Stage III: Beyond retroperitoneum Mi—Solitary metastasis M2—Multiple metastases * Reference 45. t P = primary, N = node, M = distant metastasis.

ml. In serial sectioning of the tumor specimens, one of the ten patients had an element of choriocarcinoma in tissue obtained at the time of a retroperitoneal lymphnode dissection. After surgery and chemotherapy, the serum human chorionic gonadotropin level dropped to normal. All but one of the patients had normal levels of alpha-fetoprotein. However, in one patient the serum alpha-fetoprotein level was 152 ng/ml. Serial sectioning of the original testicular tumor showed an element of embryonal carcinoma; this patient subsequently developed metastatic involvement of aortocaval lymph nodes. At the time of a retroperitoneal lymphadenectomy, histopathologic examination showed an element of embryonal carcinoma. In this prospective study we have observed that an elevated serum alpha-fetoprotein level in patients with seminoma suggests the presence of an element of embryonal carcinoma. The frequency of an elevated human chorionic gonadotropin level in the serum of patients with apparently pure seminoma is about 7.5% (10 out of 130). Although the giant tumor cell occasionally found in "pure seminoma" is capable of secreting human chorionic gonadotropin, an elevated serum human chorionic gonadotropin level raises a possibility of the presence of elements of choriocarcinoma or embryonal carcinoma, or both, as illustrated by the case described above. The cases reported in the literature of seminoma with elevated levels of human chorionic gonadotropin have lacked serial sectioning of tumor specimens or localization (or both) of cellular human chorionic gonadotropin. Therefore, it is not clear whether they are indeed pure seminoma with syncytiotrophoblastic giant cells producing human chorionic gonadotropin or whether they have undetected foci of choriocarcinoma or embryonal carcinoma. As previously noted, because the immunoperoxidase techniques are applicable to formalin-fixed tissues, such cases could be retrospectively studied if tissues were still available. Such an investigation could also be carried out on tissue from large series of patients with seminoma 378

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in which, invariably, some patients relapse with nonseminomatous elements. In addition, patients with seminoma undergoing therapy should have their serum human chorionic gonadotropin and alpha-fetoprotein levels measured. Findings of nonseminomatous elements in their tumor or a different subsequent clinical course, or both, would provide the basis for possible alteration of the classic radiation therapy used so effectively for the "typical" seminoma patient. To date, neither study has been done, but results of such a study could significantly alter our approach to these patients in the future. STAGING OF TESTICULAR TUMORS

The staging of testicular tumors, as for other tumors, must accurately reflect the extent of the patient's disease and should equally reflect the natural history of disease progression. The physician can then make an accurate assessment of the disease, select the appropriate treatment, and gain some insight as to the patient's prognosis. The conventional staging of testicular tumors was described by Boden (44) and modified by Maier (Table 2A) (45). Although it does allow prognostication and reflects tumor extent to some degree, it does not provide a precise evaluation of the dissemination and natural history of this disease. The major problems with this staging method include lack of discrimination between varying degrees of local and metastatic spread within the category of stage I disease. This results in lumping patients with disease localized within the testis with those having microscopic retroperitoneal disease, with or without documented spermatic lymphatic involvement. The stage II designation also does not adequately reflect the variable degree of regional lymphatic involvement, thus combining patients with minimal, potentially surgically curable disease with patients who have massive, surgically incurable disease. The stage III category lacks the provision for describing single or multiple metastases, and does not distinguish between pulmonary and other sites of parenchymal metastases. In view of these observations, I would like to propose a new staging classification; although somewhat more complex it has the potential to define more accurately the extent of disease, assist in determining appropriate therapy, and improve our prognostic skills (Table 2B). This staging method for testicular cancers more fully takes into consideration the factors that are essential in modern therapy and prognosis of these diseases. In addition to the conventional laboratory and radiologic procedures used in clinically staging patients with testicular tumors, we have investigated the efficacy of chest tomograms, computerized tomography of the retroperitoneum, tumor markers, inferior vena-cavography, and lymphangiography. By using such procedures, one can more reliably distinguish between the various stages and substages of disease. Thus, a persistently elevated alpha-fetoprotein or human chorionic gonadotropin level, or both, in a patient with testicular tumor treated by inguinal orchiectomy indicates stage II or stage III disease. Similarly, inferior venacavography, computerized tomography, and lymphangiography can be used to dis-

tinguish patients with minimal stage II (NU2) disease from others characterized by obstruction or invasion, or both, of the inferior vena cava and the ureters (stage II, N 3 . 4 ). Using these diagnostic modalities for testicular carcinomas, we have reduced the staging error to 14% (46). SURGICAL M A N A G E M E N T OF TESTICULAR CANCER

Because a number of cases of testicular germ-cell tumors may be initially seen by nonurologists, it is important to reiterate the appropriate approach to a scrotal mass. First of all, unless the clinical history indicates otherwise, any scrotal mass in a young male patient should be suspect. As noted in Dr. Waldmann's presentation, a serum sample to measure human chorionic gonadotropin and alpha-fetoprotein levels should be obtained. Depending on the history, examination, tumor marker results, or a combination of these, an immediate exploration is advisable. The high inguinal incision allows delivery of the testis with control of vascular and lymphatic channels. Direct inspection of the testis, after opening the tunica vaginalis testis, usually settles the question and orchiectomy may be done if necessary. In cases where a small hematoma or an interstitial tumor or other disease can confuse identification of the testicular lesion, the wound may have to be carefully packed and a biopsy done by opening the testis and its covering away from the operative field. Because tumor cells can seed the scrotum with its separate lymphatic drainage, there is little justification for trans-scrotal biopsy of a scrotal mass. After a radical orchiectomy, the specimen is examined by the pathologist and subsequent treatment depends on the cell type and stage of the cancer. Briefly, the subsequent treatment of seminoma relies on radiotherapy, and pure choriocarcinoma requires chemotherapy. Patients with pure embryonal carcinoma, embryonal carcinoma

plus elements of seminoma or teratoma, or choriocarcinoma plus other elements routinely undergo retroperitoneal lymphadenectomy, both for therapy and as part of the staging evaluation, unless obvious stage IIN 4 or stage III disease is identified clinically. Before consideration of lymphadenectomy, it is essential to understand the embryologic basis of testicular lymphatic dissemination. Embryologically, the gonads arise from tissue in the genital ridge near the vicinity of the renal blastema; thus, testicular tumors usually involve the aortic, caval, and renal lymphatic system. The lymphatics of the testis drain to nodes located around the aorta from the level of the ipsilateral renal vein to the common iliac vein, including the lymphatics located around the region of the inferior mesenteric artery. Other infrequently involved sites include the lower periaortic nodes; thus, adequate lymphadenectomy must encompass the renal, aortic, caval, and ipsilateral common, external and internal iliac lymphatics (Figure 4A and B). The advent of tumor markers may well change the future treatment of testicular cancer (47-49). However, the conventional treatment for clinical stage I and II embryonal carcinoma and "teratocarcinoma" is retroperitoneal lymphadenectomy after radical orchiectomy. In a recent series of highly selected patients, Staubitz (48) reported 5-year disease-free survival rates for patients with stage I and "selected" stage II, presumably stage HN 2 , nonseminomatous testicular tumors of 87% and 83%, respectively. Our data on survival also agree with these figures. However, the major problem in evaluating the efficacy of current therapy for patients with testicular tumor has been lack of prospective randomized clinical trials. Role of Radiation Therapy in Testicular Tumors

Dr. Eli Glatstein (Chief, Radiation Oncology Branch,

Figure 4A. Bilateral lymph-node dissection for left-sided testis tumor. B. Bilateral lymph-node dissection for right-sided testis tumor. Anderson

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Clinical Oncology Program, Division of Cancer Treatment): In planning curative radiation therapy for a malignant testicular tumor, one must account for the tendency of these diseases to spread into regional lymphatics. The normal lymphatic drainage of the testis to the perirenal (particularly with left-sided tumor), periaortic (both high and low), as well as the ipsilateral iliac nodes must be included in the radiation field, just as it must be included in the field of dissection when surgical intervention is indicated (50). Atypical lymphatic drainage may occur in patients in whom an inappropriate trans-scrotal biopsy of malignant tumor was done or in patients who develop a malignant tumor subsequent to previous inguinal or scrotal surgery. In such patients the usual radiation portal may have to be expanded to include the scrotum itself or nodes inferior to the inguinal ligament, or both. For most patients requiring radiation therapy, however, a large volume incorporating the periaortic and ipsilateral iliac nodes (referred to as a "hockey-stick field") will suffice. The periaortic portion of the field is centered slightly eccentrically to include the ipsilateral renal hilum. This region should be carefully identified by injecting contrast media intravenously when the patient is in the treatment position at the time of localization by the radiation simulator. Identification of the exact location of the kidneys in this treatment position permits their exclusion from the radiation field and virtually eliminates the chance of radiation nephritis, because radiation nephritis occurs only if a generous portion of renal parenchyma is irradiated with a dose in excess of 2500 rad. In planning radiation therapy for testicular seminoma, two features dominate our thinking: One is the marked proclivity for lymphatic spread; the other is the remakable radioresponsiveness of this tumor. A relatively modest dose of 2500 or 3500 rad of megavoltage radiation at the midplane level is usually tumoricidal for this^ neoplasm. This dose usually eradicates the tumor within the treatment volume and seldom causes major long-term complications. Whenever lymphatic spread to the periaortic region is recognized radiographically, a supradiaphragmatic field of irradiation is usually added to treat the mediastinal and lower-neck nodes on a "prophylactic" basis. Ideally, one shapes the mediastinal field in the same way that one fashions the central portion of a mantle field for Hodgkin's disease; that is, to conform to the mediastinal and hilar contours of a specific patient in the treatment position (51). With massive periaortic involvement, the intraabdominal field is usually expanded to treat the entire abdomen with 2000 rad before boosting the dosage to 3500 for the involved region. For patients who have stage I or II disease, primary radiation therapy results in excellent survival rates (52, 55). Treatment of the periaortic, ipsilateral renal hilar, and ipsilateral iliac nodes usually results in 5-year survival data approaching 100% for patients who have a negative lymphangiogram. In most patients having a detectable abnormality of the lymphangiogram (stage IIN 2 4 ), the results of treatment are almost as good, with the stage 380

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IIN2_3 probability of freedom from relapse at 5 years generally being between 80% and 90%. Even in those patients who have massive intra-abdominal disease or supradiaphragmatic involvement, cure is often achieved with primary radiation therapy alone, if a large-enough volume has been treated with an adequate dose (53, 55). Primary radiation therapy for the treatment of nonseminomatous testicular carcinoma is also an effective tool, although more popular in England and Europe than in this country. Treatment strategy is, again, predicated on the propensity for lymphatic spread. However, there is a significant risk of hematogenous spread to the lung, often abruptly diagnosed within a few months of presentation. In addition, the tumoricidal dose of radiation required for embryonal carcinoma or "teratocarcinoma" is probably 4500 to 5000 rad, a dose approaching the radiation tolerance of the small bowel. The use of 5000 rad to the hockey-stick region for clinical stage I testicular carcinoma has resulted in long-term disease-free survival in approximately 80% to 85% of such cases. These results are comparable to those achieved by radical lymphadenectomy alone (52, 53, 56). Similarly, in patients who have stage IIN 2 . 4 nonseminomatous testicular carcinoma with a positive lymphangiogram, the results of such highdose irradiation (55% to 60% free of disease at 5 years) are also comparable to those results achieved by radical lymphadenectomy (52, 53, 56). These data for radiation therapy include patients who have tumor involvement above the level of the renal arteries, a group of patients frequently excluded from many series undergoing radical retroperitoneal node dissection. However, it should also be emphasized that the disease of patients having massive periaortic node disease with nonseminomatous testicular cancer is clearly difficult to control with radiation-therapy alone (57, 58). In addition, high-dose radiation therapy using doses of 5000 rad does carry a significant risk of morbidity, primarily radiation injury to the small bowel in approximately 5% to 10% of patients. On the other hand, many of these patients have fathered offspring after completion of treatment (59). Results obtained with primary radiation therapy alone have been compared with those obtained using radiation therapy as well as radical lymphadenectomy in a prospective randomized study at Walter Reed Army Hospital. The results showed no significant advantage in combining these two treatment modalities, because approximately 90% of stage I patients and 80% of stage II patients were disease free after 3 years on both arms of the study (60). Use of routine left supraclavicular lymph-node biopsies to rule out occult stage III disease was an important study feature. The results of primary radiation therapy alone in stage II nonseminomatous testicular cancer have been exceedingly poor (52, 53). Consequently, the use of "prophylactic" supradiaphragmatic field irradiation in clinical stage II patients remains controversial. The use of multiagent chemotherapy, either as a routine adjuvant to the subdiaphragmatic irradiation for stage II disease, or as part of a combined modality approach to selected patients who present with massive subdiaphragmatic disease, remains

Table 3. Activity of Chemotherapy Regimens Based on Alkylating Agents and Antibiotics

Drugs*

CLB + DaCT + MTX CLB + DaCT + MTX f CLB + DaCT HN 2 + DaCT HN 2 + MTX C T X ( L - P A M ) + MTX + VCR

CTX + DaCT + VCR

Patients

no. 23 90 31 14 15 28 10

* CLB = chlorambucil, DaCT = dactinomycin, mide), L - P A M = L-phenylalanine mustard. t Includes patients from Li and associates.

Responses

References

Complete Responses

Partial Responses

Total

no. (%) 7(30) 11 (12) 5(16) 1 (7) 2(13) 2 (7) 100)

no. (%) 5(22) 24 (27)

no. (%) 12 (52) 35 (39)

3(18) 3(20) 15(54) 4(40)

4(29) 5(33) 17 (61) 5(50)

Li and associates (61) Mackenzie (63) Muggia, Jacobs (62) Jacobs, Johnson, Wood (64) Jacobs, Johnson, Wood (64) Jacobs (65) Jacobs (65)

MTX = methotrexate, VCR = vincristine, HN 2 = nitrogen mustard, CTX = Cytoxan®

investigational but appears promising. Advances in Chemotherapy of Testicular Neoplasms

Dr. Anderson: The previous discussions emphasize that with an appropriate judicious approach patients with localized testicular neoplasms are potentially curable. Unfortunately, in a significant proportion of patients with advanced (stage II, N 3 or N 4 ) or widespread disease (stage III), or both, surgery or radiotherapy is inadequate to eradicate all disease. Potentially, however, such patients still may be rendered disease free for prolonged periods due to the tremendous advances in chemotherapy. These advances parallel those achieved with the chemotherapy of acute lymphocytic leukemia, Hodgkin's disease, Burkitt's lymphoma, and Wilms' tumor. Because various chemotherapeutic regimens are in a state of rapid evolution, it is not yet clear whether any one program is superior to the others. This discussion reviews the evolution of these chemotherapeutic regimens and indicates what important factors must be considered in evaluating the results of current treatment programs. The chemotherapy of testicular neoplasms represents the first successful combination chemotherapy in humans. In 1960, Li and associates (61) reported their results with various chemotherapeutic regimens in 36 patients with metastatic testicular tumors. Of 23 patients treated with a combination of chlorambucil, dactinomycin, and methotrexate, 12 had an objective response to such therapy, and seven (30%) had dramatic, essentially complete, clinical responses. Whereas four patients ultimately relapsed, three have remained free of recurrence for years (Table 3). Of the three drugs used in this treatment program, only chlorambucil had been adequately shown, by today's standards, to have significant antitumor activity clinically. The inclusion of methotrexate and dactinomyin was based on a small amount of data from clinical trials treating metastatic gestational choricarcinoma and on data from animal tumor studies. Because the most important principle in designing combination chemotherapy programs is to include only those drugs that have demonstrable antitumor activity, or that favorably alter another drug's antitumor effects, the design of this drug combination was both insightful and fortuitous.

Unlike the other urogenital neoplasms, testicular carcinomas are sensitive to a wide range of chemotherapeutic agents (Table 4); indeed, it appears that almost any chemotherapeutic agent with known antitumor activity in humans, if adequately tested, will probably have some level of activity against testicular neoplasms (63). Because therapeutic efficacy of these agents must be maximized and toxicities minimized, the most effective regimen(s) should be defined. During the next decade after the report of Li and associates (61), several other investigators reported similar results with treatment programs. All shared the following characteristics: [1] The combination chemotherapy program was based on the use of an alkylating agent such as chlorambucil, cyclophosphamide, or nitrogen mustard, an antibiotic such as dactinomycin or mithramycin, and an antimetabolite such as methotrexate or a combination thereof; [2] these regimens were easily administered producing only modest bone-marrow, gastrointestinal, epidermal, pulmonary, and renal toxicity; [3] all reports that summarized reasonably large numbers of patients reported complete response rates of 7% to 16% (61-65). The next important advance came with the introduction of the vinblastine-bleomycin regimen by Samuels, Table 4. Activity of Singjle Agents in Advanced Testicular Net>plasms* Drug

phenylalanine mustard cyclophosphamide ifosfamide chlorambucil dactinomycin mithramycin bleomycin doxorubicin vinblastine cis-dichlorodiammine platinum

Responses

Patients Complete Responses

Partial Responses

Total

no. (%)

no. (%)

no. (%)

42f 14 18 8 61 133 54 29 41

19 (45) 4(29) 2(11) 2(25) 11 (18) 12 (9) 6(11) 0 5(12)

19 (45) 7(50) 13 (72) 2(25) 9(15) 37 (28) 17 (32) 5(17) 10 (25)

38 (90) 11 (79) 13 (83) 4(50) 20 (33) 49 (37) 23 (43) 5(17) 15 (37)

58

30 (52)

11 (19)

41 (71)

* Modified from Muggia and Jacobs(62). t Seminomas only; all other drug results are from series with nonseminomatous germ-cell tumors. Anderson

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(cyclophospha-

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Table 5. Activity of Chemotherapy Responses Based on Vinblastine-Bleomycin

Drugs*

VLB + VLB + VLB + VLB +

Patients

BLEO BLEO BLEO BLEO + DaCT(VAB I)

no. 23 11 92 68

References

Responses Complete Responses

Partial Responses

Total

no. (%) 9(39) 5(45) 52 (57) 15(22)

no. (%) 8(32) 4(36)

no. (%) 17 (71) 9 (82)

17(25)

32 (47)

Samuels, Johnson, and Holoye (66) Spigel and Coltman (67) Samuels and associates (68) Wittes and associates (69)

* VLB = vinblastine, BLEO == bleomycin , DaCT = dactinomycin.

Johnson, and Holoye (66) in 1975. This new intensive program was based on the cyclic administration of large doses of both the vinca alkaloid vinblastine and the antibiotic bleomycin. Such programs [1] omitted alkylating agents and metabolites; [2] produced severe bone-marrow suppression, hemolytic anemia, hypertension, mucositis, and pulmonary fibrosis; and [3] consistently produced complete response rates of 2 2 % to 5 7 % (Table 5) (6669). The most recent advance has occurred with the development of new combination-chemotherapy regimens using the platinum coordination compound c/s-dichlorodiammine platinum (II), D D P . The remarkable clinically demonstrable antitumor properties of this agent include the ability of produce complete response rates of 2 0 % to 5 0 % in patients whose tumors were previously refractory to a variety of single agents or combination chemotherapy programs, or both (62). Although its emetic properties still remain a significant problem, its renal toxicity can be controlled with judicious dose-scheduling and with hydration and diuresis. Its bone-marrow suppressive effects are only moderate. Thus, with the inclusion of D D P into vinblastine-bleomycin regimens: [1] The logistics of drug administration are more complicated than the previous regimens; [2] the toxicity of such regimens is potentially more severe; and [3] for the first time, clinicians are consistently capable of producing greater than 5 0 % complete response rates in patients with advanced, metastatic testicular carcinoma,

with complete response rates ranging from 56% to 89% (Table 6) (70-73). Clearly, newer treatment regimens are dramatically more effective than those originally developed, but it is also important to examine the recurrence rates with the current chemotherapy regimens. In view of previous experience with surgery and radiotherapy, together with kinetic studies, 2- or 3-year disease-free survival may indicate potential cure. Most of the treatment regimens have not yet been used for long periods of time; therefore, most series include a preponderance of patients followed for relatively short periods, and only a small proportion of patients have been evaluated for potential disease-free survival 2 or more years after therapy. Nevertheless, early analysis of many regimens indicates that the relapse rate of the various programs looks reasonably low and, in the case of the large long-term study of Samuels and colleagues (68) and the sequential VAB I-VAB IV studies from Memorial Sloan-Kettering (69, 71, 72), it appears that not only are the initial complete remission rates higher using the modern regimens, but the relapse rates are probably lower than those observed previously. Despite these impressive achievements, subgroups of patients with relatively unfavorable prognoses exist. Prognostically, the distinction between testicular seminoma and carcinoma is important, as is determination of the histologic subtype of testicular carcinomas. Summarizing the data from the larger series reporting the results of modern chemotherapy (68, 70, 72, 73), clearly patients

Table 6. Activity of Chemotherapy Regimens with Addition of Cis-Dichlorodiammine Platinum

Drugs *

Patients

Responses

Relapses

References

Total Complete Responses Responses no. DDP + BLEO + VLB DDP + BLEO + VLB + DaCT + (VAB II) DDP + BLEO + VLB + DaCT + CTX(CLB) - (VAB III) DDP + BLEO + (VAB IV) DDP + BLEO + DDP + BLEO + DDP + BLEO +

47 50 90

no. (%) 47 (100)

no. (%) 35 (74)

45 (90)

30(60)

77 (86)

54(60)

42 (86) 22 (73) 40 (100)

29 (59) 17 (56) 32 (80) 39 (50)

no. (%) 3 (8.6) 13(43) 15 (28)

Einhorn and Donohue (70) Cheng and associates (71) Cvitkovic, Hayes, and Golbey (72)

VLB + DaCT + CTX(CLB) + DOX VLB + DaCT + CTX + DOX VLB + VCR + DaCT + PRED VLB + DaCT + CLB

49 30 40 78

2 (7) 4 (23.5) 7(21.9) 4 (10.3)

Golbey f Merrin (73) Merrin (73) Samson f

* DDP = c/s-dichlorodiammine platinum ( I I ) , BLEO = bleomycin, VLB = vinblastine , DaCT = dactinomycin, CTX = cyclophosphamide, CLB = chlorambucil, DOX = doxorubicin, PRED = prednisone. t Personal communication. 382

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with embryonal carcinoma with or without a seminomatous element respond to chemotherapy (complete response rate, 72.4% [65.8% to 84%]), better than do patients with "teratocarcinoma," (complete response rate, 44.9% [36.0% to 55.5%]), or choriocarcinoma, (complete response rate, 40% [0% to 60%]) (Table 7). Another poor prognostic factor is the presence of a nontesticular germ-cell tumor, that variant of testicular neoplasms arising from germ cell rests along the axial skeleton. The rare patients with this tumor have a complete response rate to chemotherapy of only 36.4% (16.7% to 60%) (Table 7). Finally, the pattern or amount of malignant tumor, or both, are also of prognostic significance. Although difficult to measure with precision (the use of alpha-fetoprotein and human chorionic gonadotropin levels may improve our ability to quantify this prognostic indicator), patients with massive retroperitoneal lymph-node involvement or multiple and large pulmonary metastases, or both, have lower complete remission rates (Table 7). Several potential therapeutic techniques are being investigated for such patients. At M. D. Anderson Hospital, Samuels and coworkers (68) are treating such patients with even larger doses of vinblastine, as high as 0.6 to 0.8 mg/kg body weight. Such therapy produces severe bonemarrow suppression and mucositis, frequently necessitating isolation in a laminar flow unit or total parenteral nutrition, or both. Results of this approach are not yet available. If patients could have a significant proportion of their initial tumor burden reduced before drug treatment, such therapy might be more effective. This is analogous to the current use of adjuvant chemotherapy for Wilms' tumor, gestational choriocarcinoma, and carcinoma of the breast. The report by Merrin (73) indicates this is technically feasible and potentially efficacious. Such a program, however, because of its inherent technical difficulties, cannot be considered advisable unless proved to improve drug efficacy and ultimate survival. In conjunction with the NCI Surgery Branch, a prospective clinical trial of such an approach to therapy is being investigated. National Cancer Institute Randomized Trial

Dr. Javadpour: To date, no prospective, randomized trial has been done to test whether the results of effective chemotherapy can be enhanced by cytoreductive (debulking) surgery in patients with tumors not curable by surgery. Although such an approach has a scientific rationale (74, 75), and results from treatment programs involving some patients support its possible role (70, 73, 76), the ethical and technical aspects of such a study have been difficult to overcome. Patients with testicular carcinoma who have multiple poor prognostic features are appropriate for such a study because, [1] compared with patients with minimal tumor burden, their prognosis is relatively poor; [2] ability to achieve a complete remission can be expected to significantly alter subsequent survival; [3] the patient is usually otherwise healthy, without other significant medical problems; [4] a major proportion of the metastatic disease

Table 7. Testicular Carcinoma: Prognostic Factors for Chemotherapy Response*

Prognostic Factor

no. Histology Embryonal (± seminoma) 92/127 ** Teratocarcinoma'' 40/89 Choriocarcinoma 8/20 Tumor burden Nonbulky Gynecomastia or elevated human chorionic gonadotropin 5/5 Supraclavicular nodes 3/3 Less than five pulmonary metastases (less than 2-cm diameter) 33/39 Above plus nonbulky nodes 24/32 Bulky Greater than five pulmonary nodes (greater than 2-cm diameter) 22/40 Large retroperitoneal nodes 21/39 Visceral involvement 2/20 Extragonadal primary tumor 4/11

%

(%)

= 72.4 (65.8 to 84.0) = 44.9 (36.0 to 55.5) = 40 (0 to 60)

= 100 = 100 = 84.6 (66.7 to 90) = 75.0 (57.2 to 88.9)

= = = =

55.0 (51.6 to 53.8 (52.2 to 10 ( 7.7 to 36.4 (16.7 to

66.7) 56.2) 14.3) 60)

* Data results from analysis of results from studies by Samuels and associates (68); Samson (personal communication); Cvitkovic, Hayes, and Golbey (72); Golbey (personal communication); Einhorn and Donohue (70); Menin (73).

can be surgically removed; [5] the known chemotherapeutic regimens have excellent antitumor activity in patients with small amounts of tumor; and [6] the levels of circulating tumor-associated proteins, that is alpha-fetoprotein and human chorionic gonadotropin, can be used to assist in quantitatively evaluating efficacy of cytoreductive surgery. With these considerations, the Surgical Oncology Branch and Medicine Branch, NCI, have begun a prospective, randomized trial of cytoreductive surgery in patients with stage III testicular carcinoma. Half the patients will undergo debulking surgery of large retroperitoneal tumor masses (and of large isolated lung metastases) before chemotherapy. All patients are treated with a fivedrug intensive chemotherapy regimen (basically a modification of the VAB III-VAB IV programs) (Figure 5). To date, 15 cases have been randomized in this study; five of eight patients treated with surgery and chemotherapy have achieved a complete response compared with zero of seven treated with chemotherapy alone. Although it is too early to show a significant difference in overall complete remission rates and subsequent ultimate survival, the following findings have emerged. Cytoreductive surgery is technically feasible, and major portions of clinically evident macroscopic disease can be removed. Moreover, because 90% of the patients had tumors that produced human chorionic gonadotropin, alpha-fetoprotein, or both, and the circulating levels of these markers correlated with initial tumor burden, they can be used to verify the magnitude of successful cytoreductive surgery. In some cases, all macroscopic disease was removed and the levels of human chorionic gonadotropin or alpha-fetoprotein, or both, decreased more than or equal to two logs, Anderson

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• Requests for reprints should be addressed to Tom Anderson, M.D.; Senior Investigator, Medicine Branch, Clinical Oncology Program, National Cancer Institute, National Institutes of Health; Building 10, Room 12N226, 9000 Rockville Pike; Bethesda, Md 20014. Received 20 November

1978; accepted 10 December 1978.

References

Figure 5. National Cancer Institute randomized clinical trial for bulky stage III nonseminomatous testicular tumor.

confirming a marked reduction in residual tumor to be treated with chemotherapy. Further follow-up will ascertain whether there is a relation between the magnitude of cytoreductive surgery and ultimate successful treatment. With the aid of newer diagnostic technology such as ultrasound, computerized axial tomography, and the tumor markers, the frequency of "evolution" from a histologically malignant carcinoma to a mature teratoma, previously described in other series (77-82), would appear to be quite high (perhaps as high as 25%) in this patient population who have not had surgery before chemotherapy. Three such patients were documented in the first 18 patients treated, and three more patients have residual cystic abdominal masses not yet rebiopsied. In our series none of the three documented cases had a prolonged disease-free survival, all relapsing with malignant elements. Other series have reported prolonged disease-free survival in such patients (77-82). It is unclear whether such "conversions" are chemotherapy-induced differentiation of previously malignant clones of cells or are selection of previously present benign clones of cells, and whether such "benign" tumor masses are indeed usually biologically benign. This situation poses a fascinating scientific question and a perplexing patient-management problem. Results of this and analogous studies can be expected to help answer these questions in the future. Those features of testicular carcinomas rendering them good models for advanced disease therapy studies also facilitate the introduction of adjuvant chemotherapy or radiotherapy trials, or both. Such features include clarification of histologic subtypes by immunocytochemical studies; early and sensitive detection of residual postoperative disease by use of alpha-fetoprotein and human chorionic gonadotropin assays; improvements in staging techniques using ultrasound, computerized axial tomography scans, and so forth; clarification of staging definitions with improved prediction of potential disease behavior; and effective therapy for advanced disease coupled with early evidence that patients with small tumor burden may be even more responsive. Because of all of these favorable features, an NCIsponsored extramural, nationwide intergroup adjuvant chemotherapy or radiotherapy study (or both) for these young patients will begin in the near future (Muggia FM, Jacobs EM, Cancer Treatment Evaluation Program, NCI, Bethesda, Maryland: personal communication). If successful, these studies may dramatically improve the prognosis for most patients with testicular neoplasms and can serve as a model for the integration of laboratorybased and clinically oriented research. 384

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nant tumors of the testis. Analysis of treatment results and sites of causes of failure. Cancer 39:1247-1253, 1977 55. DOORNBOS JF, HUSSEY DH, JOHNSON DE: Radiotherapy for pure seminoma of the testis. Radiology 116:401-404, 1975 56. WILLIAMS C: Current dilemmas in the management of nonseminomatous germ cell tumors of the testis. Cancer Treat Rev 4:275-298, 1977 57. P E C K H A M MJ, H E N R Y W, M C E L W A I N TJ, C A L M A N F M M : The multi-

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