The high cure rate of patients with advanced germ cell tumors is the result of effective cisplatin-based chemotherapy; both previously untreated and relapsing patients can be cured. Risk stratification is particularly important in previously untreated patients. While retrospective salvage therapy analyses suggest that a number of clinical factors are associated with outcome, the appropriate selection of patients for, and the sequencing of, conventional- and high-dose regimens are subjects of debate because of the introduction of paclitaxel and different approaches to the administration of high-dose chemotherapy. This therapeutic landscape has been molded in part by our current understanding of treatment-associated toxicity. In this paper, we review the use of serum tumor markers in risk assignment and response evaluation; the treatment of previously untreated and relapsing patients; the role of surgical resection of residual disease, including retroperitoneal node dissection; and the importance of clinical trials for addressing unanswered questions and testing new therapies. Management controversies and possible future treatment enhancements that incorporate serum tumor marker decline and tumor genomics will also be discussed.
Germ cell tumors are unique among solid neoplasms because cisplatin-based systemic therapy usually eradicates metastatic disease. This ability to cure patients with advanced disease led to evidence-based standards of care, well-defined risk-adjusted treatment algorithms, and the application of both the standards of care and the risk-adjusted algorithms in all disease stages. These achievements have resulted in an increase in the cure rate of metastatic disease from 10% in the 1960s to more than 80% today.
Ninety-five percent of germ cell tumors are testicular primary tumors, but germ cell tumors may also arise in the retroperitoneum, mediastinum, and pineal gland. Retroperitoneal primary germ cell tumors probably arise from an occult testicular germ cell tumor and should be managed as if they were of testicular origin. The incidence of testicular germ cell tumors has risen steadily over the last 20 years and is highest in white and Hispanic men and lowest in Asian and black men. Cryptorchidism predisposes both the affected and unaffected testis.[4,5] Treatment of the undescended testis before puberty decreases the risk of testicular cancer. A family history and certain genetic disorders, such as Klinefelter syndrome and testicular dysgenesis syndrome, also appear to be associated with an increased risk of germ cell tumor.[7,8] Seminoma and nonseminomatous germ cell tumor each comprise approximately 50% of germ cell tumor cases. All medical practitioners should be familiar with germ cell tumors because delays in diagnosis are associated with more extensive disease, more intensive treatment, and reduced cure rates. The management of early-stage (clinical stage IA–IIA, marker-negative) germ cell tumors is based on the histologic type and the American Joint Committee on Cancer stage. Surveillance, surgery, and chemotherapy all have putative roles in achieving cure rates that approach 99% in early-stage disease.
In this review, we discuss the management of patients with previously untreated and relapsing advanced germ cell tumors, the delayed and acute toxicities of systemic treatment, the implications of these toxicities for treatment decision making, surgical resection of residual disease, and potential future directions to improve outcomes. Of note, germ cell tumor trials use specific definitions of response that will be used throughout this paper (Box).
Serum Tumor Markers
Alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) levels are elevated in 80% of patients with advanced germ cell tumors. AFP production is restricted to nonseminomatous germ cell tumors. Causes of high levels of AFP other than a germ cell tumor include liver damage, hepatocellular carcinoma, other epithelial cancers, and, very rarely, hereditary persistence.[12-14] Increased levels of hCG may be observed in both patients with seminoma and those with nonseminomatous germ cell tumor. Causes of false-positive elevations of hCG include cross-reactivity of the antibody with luteinizing hormone, heterophile antibodies, and treatment-induced hypogonadism. Tumor lysis during the first cycle of chemotherapy may cause abrupt elevations of AFP and/or hCG (“marker surge”), but these do not represent tumor progression. Lactate dehydrogenase (LDH) is elevated in 40% to 60% of men with germ cell tumors. Although LDH elevations may be found in many benign and malignant conditions, LDH has independent prognostic value in patients with advanced germ cell tumors. Indeed, disease may be classified as intermediate or poor risk on the basis of the LDH level alone. Serum tumor markers should be measured before and after orchiectomy, with the “S” stage determined using the postorchiectomy marker values obtained closest to the start of chemotherapy.
Response Definitions Unique to Germ Cell Tumor Trials
- Complete response (CR): must last 4 weeks
– CR to chemotherapy: tumor marker and radiographic normalization or marker normalization plus full resection of tumor masses with necrosis and/or teratoma
– CR to chemotherapy plus surgery: marker normalization + full resection c/w viable germ cell tumor and negative margins
- Partial response with negative markers (PR−): must last 4 weeks; tumor marker normalization plus residual mass(es) on imaging but without progression of disease
- Incomplete response (IR): anything other than CR or PR−
- Favorable response (FR): CR or PR−
Knowledge of the LDH, AFP, and hCG levels immediately prior to chemotherapy is both diagnostic and prognostic and required for the allocation of patients to the proper International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratum (Table 1). Clinical stage I or IIA disease with elevated postorchiectomy levels of AFP and/or hCG is associated with a high likelihood of metastatic disease, and these patients should receive chemotherapy.[17-19] Similarly, increased levels of AFP and/or hCG at the conclusion of chemotherapy usually represent residual viable disease, although exceptions exist. Thus, serial monitoring of AFP and hCG levels is important in patient management. Mazumdar et al analyzed serum tumor marker half-life during the first 2 cycles of chemotherapy and showed that a satisfactory marker decline (< 7 days for AFP or < 3.5 days for hCG) was associated with a better likelihood of complete response (CR) and better event-free survival (EFS) and overall survival (OS) than a slow marker decline (P < .0001). Marker decline, particularly in the poor-risk group, remained a significant prognostic variable after adjustment for IGCCCG risk category (P < .01). Other studies have confirmed these observations, and prospective trials using marker decline as a response criterion are discussed below.
Initial Chemotherapy for Advanced Germ Cell Tumors
Good-risk advanced germ cell tumors
About 60% of patients with advanced disease have good-risk germ cell tumors. Clinical trials established the curability of metastatic disease with cisplatin-based combination chemotherapy. Subsequent investigations have focused on maintaining efficacy while decreasing toxicity (Table 2). Bleomycin was an early target for toxicity reduction due to its association with pulmonary toxicity, Raynaud phenomenon, and rare treatment-related death. A randomized trial comparing cisplatin, vinblastine, bleomycin, cyclophosphamide, and actinomycin-D (VAB-6) with 4 cycles of etoposide plus cisplatin (EP×4) revealed equivalent CR rates—and EP×4 had less toxicity. Based on these results, EP×4 became the standard treatment for good-risk disease at Memorial Sloan Kettering Cancer Center (MSKCC). Indiana University examined its standard regimen of 4 cycles of BEP (bleomycin, etoposide, cisplatin; BEP×4) in comparison with BEP×3 and showed that the two regimens had equivalent cure rates and minimal pulmonary toxicity. These results established BEP×3 as the standard regimen for good-risk germ cell tumors at Indiana University. Long-term follow-up studies of patients receiving BEP×3 and EP×4, with median follow-ups of 10.1 years and 7.7 years, respectively, showed that the favorable response rates approached 98%, with about 6% of patients relapsing, and 3% to 4% dying of the disease.[25,26] It is now accepted that these two regimens are equivalent in the management of good-risk disease.
Efforts to further reduce toxicity through dose reduction or drug substitution have been unsuccessful. Carboplatin is inferior to cisplatin in EFS, OS, and relapse-free survival.[27-29] A reduction in the cisplatin dose from 120 mg/m2/cycle to 75 mg/m2/cycle led to significantly worse response rates and survival. A reduction of the etoposide dose from 500 mg/m2/cycle to 360 mg/m2/cycle also led to worse OS.[31,32] Therefore, modifications of the recommended dose and schedule of the standard EP×4 and BEP×3 regimens are not routinely indicated. At MSKCC, if the white blood cell count is less than 2.5 × 103/μL, or the absolute neutrophil count is less than 700/μL on day 22 of the cycle, we delay the cycle for 1 week and have shown that this modification does not alter the cure rate. Delays beyond 1 week should be rare.
The only trial to directly compare EP×4 and BEP×3 was designed to determine a difference in the favorable response proportion. No difference between the two arms was observed (95% with BEP×3 and 97% with EP×4; P = .34). After retrospective assignment of patients by IGCCCG criteria and multiple interim data evaluations, the 4-year OS rates were 97% with BEP×3 and 93% with EP×4 (P = .08). However, the study was underpowered and used multiple post-hoc endpoint analyses, and dose delivery was compromised by protocol-directed dose modifications.
Intermediate- and poor-risk advanced germ cell tumors
BEP×4 is the standard of care for patients with an intermediate- or poor-risk advanced germ cell tumor; durable progression-free survival (PFS) rates are approximately 75% and 50%, respectively. Alternative regimens with equivalent efficacy and less toxicity have not been identified.[35-38] One trial randomized nearly 300 patients to receive either BEP×4 or 4 cycles of etoposide, ifosfamide, and cisplatin (VIP). After a median follow-up of 7.3 years and reclassification by IGCCCG criteria, no statistically significant difference in PFS or OS was observed in intermediate- and poor-risk patients, although VIP did cause greater myelotoxicity.[39,40] Therefore, VIP×4 is an acceptable alternative to BEP×4 if preexisting pulmonary compromise exists.
Recent trials in intermediate- and poor-risk patients have focused on dose intensification and paclitaxel-containing regimens (Table 3). de Wit and Daugaard reported randomized trials in which there were trends toward improved survival.[41,42] A phase III trial comparing BEP×4 vs BEP×2 followed by 2 cycles of high-dose carboplatin, etoposide, and cyclophosphamide with autologous stem cell transplant (ASCT) showed no improvement in CR, PFS, or OS from the addition of high-dose chemotherapy (HDCT). However, in patients with unsatisfactory tumor marker decline, the 1-year durable CR proportion was 61% for those who received HDCT vs 34% for those who received BEP alone (P = .03). These results and others[44-46] laid the groundwork for a phase III trial in which patients with an unsatisfactory tumor marker decline after BEP×1 were randomized to receive either BEP×3 or a dose-dense regimen incorporating paclitaxel, ifosfamide, and oxaliplatin. The 3-year PFS rate was 59% in the dose-dense group vs 48% in the BEP group (P = .05). No difference in grade 1/2 febrile neutropenia or toxic death was observed, more grade 3/4 neurologic and hematologic toxicity occurred in the dose-dense group, and salvage HDCT plus ASCT was required more often in the BEP group. The authors concluded that chemotherapy intensification in response to unsatisfactory tumor marker decline is a promising “personalized” strategy.
The efficacy of paclitaxel, ifosfamide, and cisplatin (TIP) as second-line treatment for patients with relapsed germ cell tumor led to a phase II trial of TIP×4 in 60 patients with intermediate-risk (n = 20) and poor-risk disease (n = 40). A favorable response was observed in 80% of patients, the 3-year PFS rate was 72%, and the estimated 3-year OS rate was 91%. The majority of grade 3 and 4 toxicities were hematologic or electrolyte abnormalities; 18% of all patients experienced neutropenic fever. Levofloxacin prophylaxis reduced the risk of neutropenic fever. A randomized phase II trial of TIP×4 vs BEP×4 in intermediate- and poor-risk patients is now open at MSKCC and several other institutions (ClinicalTrials.gov identifier: NCT01873326). A single-arm study of an accelerated BEP regimen was conducted, and a CR was observed in 17/28 (61%) of intermediate- and poor-risk patients; a randomized trial is ongoing in Australia (ANZCTR12613000496718; ClinicalTrials.gov identifier: NCT02582697).
Pulmonary toxicity, nephrotoxicity, auditory toxicity, peripheral neuropathy, anemia, and febrile neutropenia are well-known potential acute effects of chemotherapy for germ cell tumors. Since BEP×3 and EP×4 are both standards of care, toxicity should be considered in the choice of one regimen over the other in patients with good-risk germ cell tumors. Febrile neutropenia occurs in 5% to 7% of good-risk patients receiving EP×4 or BEP×3, and in 10% to 20% of intermediate- and poor-risk patients receiving BEP×4.[42,51] Compared with other tissues, the skin and lung have a reduced concentration of bleomycin hydrolase, which inactivates bleomycin. Up to 20% of patients who receive bleomycin develop cutaneous flagellate hyperpigmentation.[53,54] The incidence of bleomycin-induced pulmonary toxicity is associated with the cumulative drug dose. After 270 units (the amount given with BEP×3), high-grade lung toxicity is seen in 0% to 2% of patients, while rates range from 6% to 18% after 360 units (the amount given with BEP×4), with death occurring as a result in 1% to 3%.[40,51,55-59] These differences underscore the importance of correct initial assignment to the appropriate IGCCCG risk stratum to minimize the risk of acute toxicity. Life-threatening lung injury results from interstitial pulmonary fibrosis.[59-61] Bleomycin should be avoided in patients with preexisting pulmonary disease, elite athletes, avid scuba divers, and pilots, in whom even a minor decrease in pulmonary function may have a life-altering impact.
Bleomycin also causes Raynaud phenomenon, characterized by sudden vasoconstriction of the digital arteries in response to cold temperature or stress. Pallor and cyanosis occur at the onset of digital ischemia, followed by redness and pain upon reperfusion (hyperemia). Raynaud phenomenon occurs in 6% to 8% of patients, based on randomized trials.[55,63] In a trial comparing EP×4 vs BEP×4, 8% of patients receiving BEP and no patient receiving EP experienced Raynaud phenomenon. Raynaud phenomenon occurs most commonly between 4 and 12 months after completion of chemotherapy,[64,65] and symptoms may persist for 10 to 20 years after treatment.[64,66] Although Raynaud phenomenon has been classified as a dermatologic toxicity in some trials, its manifestations are thought to result from direct endothelial cell damage.
Less well known are the arterial and venous thromboembolic events that occur as acute side effects of cisplatin-based chemotherapy across a variety of solid tumors.[67,68] The thromboembolic event rate in patients with germ cell tumors who receive cisplatin-based chemotherapy has ranged from 8% to 18%.[67,69,70] A recent study demonstrated that retroperitoneal lymph nodes greater than 5 cm increased the risk of venous thromboembolism, possibly due to disruption of normal venous drainage of the lower extremities. Most venous events are pulmonary emboli. However, arterial events, including angina pectoris, myocardial infarction, and ischemic stroke, have been reported either during or shortly after cisplatin treatment.[67,69,71-76] In the series by Moore et al, arterial events accounted for 11% of all thromboembolic events. Most events occur in the first 2 cycles of therapy, but occasionally later. Therefore, all physicians who care for patients with germ cell tumors must be aware of the acute thromboembolic toxicity linked to cisplatin-based chemotherapy.
Toxicity from germ cell tumor chemotherapy is not only acute but may also be late, permanent, and fatal. Nephrotoxicity, ototoxicity, and neuropathy can persist in 20% to 40% of patients.[77-83] In addition, 20% of patients fail to regain normal spermatogenesis by 5 years after chemotherapy.[84,85] Data have also emerged showing both cardiovascular disease (CVD) and secondary malignancies in long-term survivors.
The evidence for late CVD toxicity after germ cell tumor chemotherapy was recently reviewed, summarizing possible direct effects on the vascular endothelium and indirect effects via the induction of CVD risk factors. The incidence and relative risk of coronary artery disease in patients with germ cell tumors who received chemotherapy, compared with germ cell tumor patients managed with surgery and surveillance alone, ranged from 5.7% to 6.7%, and from 1.35 to 7.1, respectively.[66,87-89] One study showed an increased risk of CVD mortality during the first year after treatment, but had insufficient follow-up to draw conclusions regarding long-term risk. In addition, multiple studies report an association between cisplatin-based chemotherapy and the development of CVD risk factors, including a higher risk of metabolic syndrome.[66,79,87,89,91-94] Patients should be informed of the increased risk for late cardiovascular toxicity and should be encouraged to incorporate lifestyle modifications such as smoking cessation, regular exercise, weight loss, and a heart-healthy diet.
Secondary non–germ cell tumor malignancy has been reported after radiation therapy and/or chemotherapy.[95-98] The overall relative risk of secondary non–germ cell solid tumors in germ cell tumor patients compared with the risk in the general population ranges from 1.4 to 1.9, with the risk increasing 5 years after therapy.[96,99,100] A study of almost 13,000 men treated for nonseminomatous germ cell tumors reported a 40% excess of solid tumors (standardized incidence ratio, 1.43 [95% CI, 1.18–1.73]) after cisplatin-based chemotherapy, whereas no increased incidence of secondary solid tumors followed surgery alone. Secondary myelodysplastic syndrome and leukemia have also been linked to cisplatin and etoposide.[95,101-103] Although the leukemia risk after etoposide seems to be dose-related, there is no apparent safe lower limit, suggesting that patients receiving adjuvant chemotherapy for clinical stage I or II disease need to be informed as well.[101,104]
The risk of both CVD and secondary malignancy is significantly higher when both radiation and chemotherapy are administered than when either modality is used alone.[95,100] Compared with the general population, the risk of developing a solid tumor is twofold higher with chemotherapy or radiation alone and threefold higher with the use of both modalities. These risks may figure prominently in the shared decision making in early-stage (I–IIA) disease. Patients with early-stage germ cell tumors should be informed of the high likelihood of being cured with surgery alone (orchiectomy alone followed by surveillance, or retroperitoneal lymph node dissection [RPLND] after orchiectomy when indicated in nonseminomatous germ cell tumor for clinical stage IB disease), especially since curative systemic chemotherapy is available if recurrent disease is detected during surveillance. If radiation is used, the risks of secondary malignant neoplasms and CVD, and the even greater risk if systemic chemotherapy is required for the treatment of relapse, should be discussed.
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