Stage III Testicular Cancer
Clinical Trials of Chemotherapy for Disseminated Testis and Extragonadal Germ Cell Tumors
Special Considerations During Chemotherapy
Residual Masses After Chemotherapy in Men with Seminomas
Residual Masses After Chemotherapy in Men with Nonseminomas
Current Clinical Trials
Stage III seminoma and nonseminomas are usually curable but have different criteria for estimating prognosis.
Patients with disseminated seminomas can be divided into good-risk and intermediate-risk groups based on whether nonpulmonary visceral metastases are present. Good-risk patients (i.e., those with metastases only to lymph nodes and/or lungs) have a 5-year progression-free survival (PFS) and overall survival (OS) of 82% and 86%, respectively. Intermediate-risk seminoma patients have a 5-year PFS and OS rate of 67% and 72%, respectively.
Patients with disseminated nonseminomas can be divided into good-, intermediate-, and poor-risk groups based on whether nonpulmonary visceral metastases are present, the site of the primary tumor (i.e., mediastinal vs. either gonadal or retroperitoneal), and the level of serum tumor markers.
- Poor-risk: Men with mediastinal primary tumors, nonpulmonary visceral metastases, or very highly elevated serum tumor markers are considered to be at poor risk. (Refer to the Stage Information for Testicular Cancer section of this summary for more information.)
- Intermediate-risk: Men with intermediate tumor markers levels are considered to be at intermediate risk.
- Good-risk: Men with good-risk disease have a testis or retroperitoneal primary, metastases limited to lymph nodes and/or lungs, and tumor markers that are in the good-risk range.
In the 1997 analysis that established these risk groups, 5-year OS was 92%, 80% and 48% in good-, intermediate-, and poor-risk groups while the figures for PFS were 89%, 75% and 41%. However, a 2006 pooled analysis of chemotherapy trials reported improved outcomes compared with the 1997 paper: survival in the good-, intermediate-, and poor-risk groups was 94%, 83%, and 71%, respectively.Clinical Trials of Chemotherapy for Disseminated Testis and Extragonadal Germ Cell Tumors
Four cycles of bleomycin plus etoposide plus cisplatin (BEP) chemotherapy as a standard-of-care treatment option for patients with metastatic testicular germ cell tumors was established by a randomized trial showing that it produced similar outcomes with fewer toxic effects in comparison with cisplatin, vinblastine, and bleomycin (PVB). Two randomized trials comparing four courses of BEP with four courses of etoposide plus ifosfamide plus cisplatin (VIP) showed similar OS and time-to-treatment failure for the two regimens in patients with intermediate- and poor-risk advanced disseminated germ cell tumors who had not received prior chemotherapy.[4-6][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen. For good-risk patients, two randomized trials compared three versus four cycles of BEP and reported no significant benefit from longer treatment in that population.[7-9]
Numerous attempts have been made to develop a regimen superior to BEP for poor-prognosis germ cell tumors but none have been successful. Most recently, four cycles of BEP was compared with two cycles of BEP followed by two cycles of high-dose cyclophosphamide, etoposide, and carboplatin, but there was no difference in survival between the two arms. Earlier trials of higher dose cisplatin or long-term maintenance chemotherapy were similarly disappointing.
For good-risk patients, the goal of clinical trials has been to minimize the toxic effects of treatment without sacrificing the therapeutic effectiveness. As noted above, no difference in outcome was seen when comparing three versus four cycles of BEP chemotherapy. However, attempts to eliminate bleomycin produced more ambiguous and usually disappointing results. A randomized, controlled trial comparing three cycles of BEP with three cycles of EP reported lower OS (95% vs. 86%, P = .01) in the EP arm. Similarly, when three cycles of BEP was compared with four cycles of EP in a randomized trial in more than 260 patients, there were 6 relapses and 5 deaths in the bleomycin arm compared with 14 relapses and 12 deaths in the EP arm, but these differences were not statistically significant. Several other studies have compared bleomycin-containing regimens to etoposide and cisplatin and in every trial, the trend in survival has favored the bleomycin arm, but the differences have not usually been statistically significant.[13-15] These results have led to some controversy as to whether three cycles of BEP is superior to four cycles of EP.Special Considerations During Chemotherapy
In most patients, an orchiectomy is performed before starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site (or on the basis of highly elevated serum tumor markers and radiological imaging consistent with an advanced-stage germ cell tumor) and chemotherapy has been initiated, subsequent orchiectomy is generally performed because chemotherapy may not eradicate the primary tumor. Case reports illustrate that viable tumor has been found on postchemotherapy orchiectomy despite complete response of metastatic lesions.
Some retrospective data suggest that the experience of the treating institution may impact the outcome of patients with stage III nonseminoma. Data from 380 patients treated from 1990 to 1994 on the same study protocol at 49 institutions in the European Organization for Research and Treatment of Cancer and the Medical Research Council were analyzed. Overall, the 2-year survival rate for the 55 patients treated at institutions that entered fewer than five patients onto the protocol was 62% (95% confidence interval [CI], 48%–75%) versus 77% (95% CI, 72%–81%) in the institutions that entered five or more patients onto the protocol.
Similarly, a population-based study of testis cancer in Japan in the 1990s reported a significant association between survival and the number of testis cancer patients treated. The relative 5-year survival rate was 98.8% at high-volume hospitals compared with 79.7% at low-volume hospitals. After adjusting for stage and age, the hazard ratio for death in a high-volume hospital was 0.11 (95% CI, 0.025–0.495). Several other studies have reported similar findings.[19-21] As in any nonrandomized study design, patient selection factors and factors leading patients to choose treatment at one center versus another can make interpretation of these results difficult.
Many patients with poor-risk, nonseminomatous testicular germ cell tumors who have a serum beta human chorionic gonadotropin (beta-hCG) level higher than 50,000 IU/mL at the initiation of cisplatin-based therapy (BEP or PVB) will still have an elevated beta-hCG level at the completion of therapy, showing an initial rapid decrease in beta-hCG followed by a plateau. In the absence of other signs of progressing disease, monthly evaluation with initiation of salvage therapy, if and when there is serologic progression, may be appropriate. Many patients, however, will remain disease free without further therapy.[Level of evidence: 3iiDiv]Residual Masses After Chemotherapy in Men with Seminomas
Residual radiologic abnormalities are common at the completion of chemotherapy. Such masses are not treated unless they grow or are histopathologically shown to contain viable cancer. In a combined retrospective consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma that require additional therapy. Larger masses are more likely to harbor viable cancer, but there is no size criteria with high sensitivity and specificity. 18 fluorodeoxyglucose-positron emission tomography (FDG-PET) scans have been shown to be helpful in identifying patients who harbor viable cancers, but the false-positive rate is substantial in some series.[25-27] The strength of positron emission tomograph (PET) scans in residual seminoma masses is that they have a very high sensitivity and a low false-negative rate. Thus, for men with residual masses for whom resection is being planned, a negative PET scan provides evidence that surgery is not necessary.
Although larger residual masses are more likely to harbor viable seminoma, the size of the residual mass is of limited prognostic value.[24-26] Most residual masses do not grow, and regular marker and computed tomographic (CT) scan evaluation is a viable management option for large or small masses. An alternative approach is to operate on larger masses, to resect them when possible, and to perform biopsies of unresectable masses. Postchemotherapy masses are often difficult or impossible to resect because of a dense desmoplastic reaction. Historically, such surgery has been characterized by a high rate of complications or additional procedures such as nephrectomy or arterial or venous grafting.Residual Masses After Chemotherapy in Men with Nonseminomas
Residual masses following chemotherapy in men with nonseminomatous germ cell tumors often contain viable cancer or teratoma, and the standard of care is to resect all such masses when possible. However, there are no randomized, controlled trials evaluating this issue. Instead, the practice is based on the fact that viable neoplasm is often found at surgery in these patients, and the presumption is that such tumors would progress if not resected. If serum tumor markers are rising, salvage chemotherapy is usually given, but stable or slowly declining tumor markers are not a contraindication to resection of residual masses.
Case series of men undergoing postchemotherapy resections have reported that roughly 10% will have viable germ cell cancer, 45% will have teratoma, and 45% will have no viable tumor. Numerous attempts have been made to identify the patients who need surgery and the patients who can be safely observed. Variables predictive of finding only necrosis or fibrosis at surgery are:
- Absence of any teratoma in the primary tumor.
- Normal prechemotherapy serum alpha-fetoprotein, β-human chorionic gonadotropin, and lactase dehydrogenase.
- A small, residual mass.
- A large diminishment in mass size during chemotherapy.
However, only a very small proportion of men have favorable enough features to have less than a 10% chance of having viable neoplasm in their residual masses, and thus the utility of current models has been questioned.[24,32]
When multiple sites of residual disease are present, all residual masses are generally resected. If it is not surgically feasible, resection is generally not performed. Some patients may have discordant pathologic findings (e.g., fibrosis/necrosis, teratoma, or carcinoma) in residual masses in the abdomen versus the chest. Some medical centers perform simultaneous retroperitoneal and thoracic operations to remove residual masses,[28,33] but most do not. Although the agreement among the histologies of residual masses found after chemotherapy above the diaphragm versus those found below the diaphragm is only moderate (kappa statistic = 0.42), some evidence exists that if retroperitoneal resection is performed first, results can be used to guide decisions about whether to perform a thoracotomy.
In a multi-institutional case series of surgery to remove postchemotherapy residual masses in 159 patients, necrosis only was found at thoracotomy in about 90% of patients who had necrosis only in their retroperitoneal masses. The figure was about 95% if the original testicular primary tumor had contained no teratomatous elements. Conversely, the histology of residual masses at thoracotomy did not predict nearly as well the histology of retroperitoneal masses. Nonetheless, some centers continue to support resection of all residual masses, even if necrosis is found in the retroperitoneum.
The presence of persistent malignant elements in the resected specimen is considered by some clinicians to be an indication for additional chemotherapy. However, there are no prospective trials investigating the benefit of such treatment. In some cases, chemotherapy is initiated before the orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. A physiologic blood-testis barrier seems to appear, and there is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy. Some investigators have suggested that in children, 90% of whom have yolk sac tumors, radiation therapy should be given to residual masses after chemotherapy rather than surgery.
Standard treatment options for initial treatment for nonseminoma patients with good-risk disease:
- Radical inguinal orchiectomy followed by multidrug chemotherapy.
Chemotherapy combinations include:
- BEP: bleomycin plus etoposide plus cisplatin for three 21-day cycles.[7-9,11]
- EP: etoposide plus cisplatin for four 21-day cycles.[13,39,40] Four cycles of EP should be considered for men with good-risk metastatic seminoma who have a contraindication to receiving bleomycin.
Standard treatment options for initial treatment for nonseminoma patients with intermediate- and poor-risk disease:
- Radical inguinal orchiectomy followed by multidrug chemotherapy.
Chemotherapy combinations include:
- BEP: bleomycin plus etoposide plus cisplatin.[3,4,41,42]
- VIP: etoposide plus ifosfamide plus cisplatin.[5,41] Four cycles of VIP should be considered for patients with intermediate-risk metastatic seminoma who have a contraindication to receiving bleomycin.
Management of residual masses following chemotherapy for patients with seminoma
- In seminoma patients, the residual masses after chemotherapy are usually fibrotic but may contain residual seminoma that requires additional therapy.[43,44] There are three standard management strategies:
- Observation with no additional treatment or biopsies unless the residual mass(es) increase(s) in size.
- Observation of masses smaller than 3 cm and surgical resection of masses larger than 3 cm.
- FDG-PET scan 2 months after chemotherapy is completed with observation of PET-negative masses and resection of PET-positive masses.
Management of residual masses following chemotherapy for patients with nonseminoma
- In patients who have residual masses following chemotherapy, all such masses should be resected if technically feasible. If some, but not all, residual masses can be resected, surgery is not usually performed. The rationale for surgery in this setting is that about half of the masses will contain viable tumor, either teratoma or cancer.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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