The treatment of testicular disease has made significant achievements today. Fifty years ago, a diagnosis of metastatic testicular cancer meant a 90 percent chance of death within one year. Today, the cure rate for testicular cancer is expected to be 95 percent, and the cure rate for metastatic testicular cancer is 80 percent.
Drs. Hanna and Einhorn from the Indiana University School of Medicine co-authored a review of new developments in testicular cancer, highlighting recent discoveries, new advances in clinical care, and some of the existing controversies about treatment, published in the November 20, 2014 issue of The NEW ENGLAND JOURNAL of MEDICINE. of MEDICINE).
The incidence of testicular cancer in the United States has increased progressively over the past 20 years, with the highest incidence among whites and the lowest incidence among blacks. The incidence has doubled in some areas of Northern Europe, and 1% of men in Denmark and Norway will be screened for testicular cancer over their lifetime.
Genetic and environmental factors play a role in the increase in incidence. The risk of testicular cancer increases 8-10 times in people whose brothers have testicular cancer, and 4-6 times in sons whose fathers have testicular cancer. Genetic disorders are also associated with an increased risk of testicular cancer, such as Down syndrome and testicular hypoplasia syndrome.
Cryptorchidism, which occurs in 2% to 5% of boys at birth, is the most characteristic risk factor for testicular cancer. The timing of testicular fixation also has an impact on the risk of developing testicular cancer in the future. In a study of 16,983 men with cryptorchidism, the relative risk of the disease increased after age 13, suggesting that changes in hormone levels during puberty in boys are a risk factor. Despite this, 90% of testicular cancer cases did not have a history of cryptorchidism.
Recent studies have elucidated the evolutionary mechanism of malignant transformation of normal germ cells into germ cell tumors. Germ cell tumors result in precursor lesions classified as endotubular germ cell tumor formation. Approximately 90% of germ cell tumors are associated with adjacent endoductal germ cell tumors and have a 50% risk of developing testicular cancer lesions within 5 years.
Endoductal germ cell tumors originate from germ cells that maintain the ability to develop into germ cells and body tissues; although such germ cells may be considered pluripotent stem cells, they fail to differentiate into spermatogonia. It is the changes in hormone levels after puberty that make intraductal germ cell tumors invasive.
Spermatogonial tumors consist of transformed germ cells that resemble germ cells, but the differentiation process is blocked. Embryonal carcinoma cells are similar to undifferentiated stem cells in that they have gene expression patterns similar to stem cells and endoductal germ cell tumors; choriocarcinoma and yolk sac tumors are extra-embryonic differentiated, whereas teratomas are somatic differentiated.
Multiple loci predisposing to testicular cancer have been identified through studies. The highest effect variant was detected at 12q21, encoding a protein locus involved in KITLG-KIT signaling. The generation of endotubular germ cell tumors may involve aberrant activation of KITLG-KIT in utero, overexpression of embryonic transcription factors that inhibit apoptosis, enhance cell proliferation, and accumulate germ cell mutations.
Different histological subtypes can develop through epigenetic regulation of different gene expression, including DNA methylation. Germoblasts carry almost completely demethylated DNA, contributing to the accumulation of mutations during cell replication and promoting the growth of intraductal germ cell tumors. The hypermethylation pattern in germ cell tumors is consistent with that seen in proto-germ cell-derived seminomatous and non-seminomatous germ cell tumors.
Most patients are in stage I at the time of testicular cancer diagnosis, and testicular masses are the main symptomatic presentation. It is often uncommon for patients to report back pain (enlarged retroperitoneal lymph nodes) or symptoms of metastatic disease such as cough, coughing up blood, pain and headache. A hypoechoic mass on scrotal ultrasonography can diagnose testicular cancer. Testicular biopsy should not be performed because of the possibility of contaminating the scrotum or altering the lymphatic drainage of the tumor. A complete inguinal orchiectomy is both diagnostic and therapeutic.
Pathologists use immunohistochemical analysis to determine the histologic composition of the tumor (including the percentage of various histomorphologies of the tumor) and to obtain key information such as tumor size and the presence of lymphatic infiltration. Accurate staging of the disease is critical and should be determined by CT scans of the thorax, abdomen and pelvis and by measuring human chorionic gonadotropin beta subgroup (beta-hCG), alpha-fetoprotein (AFP) and lactate dehydrogenase, the latter of which is not testicular cancer specific but is an indicator of multiple diseases.
Stage I seminoma
Most patients with stage I seminoma are clinically resolved with orchiectomy. Until the advent of effective chemotherapy, adjuvant radiotherapy was the standard of care for many years and was thought to help cure the disease. Over the past 20 years, the dose and field of radiotherapy have been significantly reduced, and in many instances radiation therapy has been eliminated altogether.
Most patients today are treated with active surveillance, but some are still treated with 20 Gy of retroperitoneal lymph node irradiation (sometimes including inguinal lymph nodes, depending on whether the patient has had previous surgery involving the inguinal, pelvic or scrotal areas) or supplemented with carboplatin. More relapsed cases were monitored than treated with radiotherapy (20% vs. 4%), with long-term survival rates approaching 100%, regardless of the initial regimen chosen.
A recent study showed that involvement of the testicular network or primary tumor diameter greater than 4 cm was a risk factor for disease recurrence. In a study of 1822 patients with stage I seminoma, the median active surveillance time was 15.4 years, with a 19.5% disease recurrence rate and a median time to recurrence of 13.7 months. The 10-year survival rate was 99.6 percent.
According to the NCCN guidelines, active surveillance includes physical examination, measurement of tumor marker levels (AFP and β-hCG), abdominal and pelvic CT, and intervals of surveillance: every 34 months for the first 2 years, every 612 months for the 34th year, and annually thereafter.
Stage II seminomatous cell tumors
For patients with small stage II seminomatous cell tumors (lesions confined to retroperitoneal lymph nodes and lymph nodes ≤3 cm in diameter), the standard of care remains 3036 Gy irradiation of the para-aortic and ipsilateral iliac lymph nodes. In other patients, the treatment of choice is chemotherapy with three cycles of bleomycin + etoposide + cisplatin (i.e., BEP) or four cycles of etoposide + cisplatin.
Chemotherapy is preferred for patients with large tumors because of the high rate of disease recurrence with radiotherapy alone. 98% of patients are cured. Residual masses are evaluated on imaging, and adhesion formation is common after chemotherapy. Because of the challenge of surgical resection and the low incidence of residual spermatocytoma, the mass is usually not removed but observed if it does not exceed 3 cm in diameter.
Masses larger than 3 cm in diameter are at high risk for seminoma and PET imaging may be performed 6 weeks after completion of treatment to determine the disposition of the mass for resection or observation.
Stage I non-seminomatous germ cell tumors
Most non-seminomatous germ cell tumors (all types of pathology except seminoma) are stage I. Treatment options after orchiectomy include active surveillance, nerve-preserving retroperitoneal lymph node dissection, and one or two cycles of BEP adjuvant therapy; several options are available with a long-term cure rate of 99%.
Patients are classified as high risk (50% recurrence rate after surveillance) or low risk (15% recurrence rate after surveillance) based on the presence of lymphovascular infiltration.
In a recent study by Kollmannsberger, active surveillance in 1034 patients with stage I non-seminomatous germ cell tumors resulted in a 99% long-term cure rate regardless of initial risk category. Monitoring was performed in almost all patients who complied with treatment.
The NCCN guidelines recommend a follow-up schedule of every 12 months in year 1, every 2 months in year 2, every 3 months in year 3, every 4 months in year 4, every 6 months in year 5, and once a year thereafter.
Follow-up examinations included chest X-ray, physical examination and tumor marker levels. Abdominal CT is recommended every 34 months in year 1, every 46 months in year 2, every 612 months in year 34, once in year 5, and once every 12 years thereafter.
Some clinical centers prefer monitoring for low-risk patients and adjunctive therapy for high-risk patients. Results from a trial of 745 subjects suggest that adjuvant BEP therapy is recommended when lymphovascular infiltration is present, but it is not required; if lymphovascular infiltration is not seen, adjuvant BEP therapy or active surveillance is recommended, but not required.
Approximately 41% of patients with lymphovascular infiltration relapsed during active surveillance, and 13.2% of patients without lymphovascular infiltration relapsed. After one cycle of BEP treatment, only 3.2% of patients with lymphovascular infiltration relapsed, while only 1.3% of patients without lymphovascular infiltration had disease recurrence.
The authors concluded that one cycle of BEP in patients with lymphovascular infiltration would reduce the chance of recurrence, but these patients were asked to have three cycles of BEP. Concerns have also been raised about this strategy, arguing that pathologic staging and interpretation of results are not universally accurate and that the long-term risk of one cycle of BEP therapy is not known.
An alternative approach is retroperitoneal lymph node dissection, which reduces the likelihood of chemotherapy and eliminates the need for abdominal CT if no lesions are detected after the dissection.
Stage II non-seminomatous germ cell tumors
For stage II non-seminomatous germ cell tumors with small tumor size (lesions confined to retroperitoneal lymph nodes and lymph node diameter <3 cm) and normal post-orchiectomy blood levels of β-hCG and AFP
In patients with normal levels of β-hCG and AFP in blood after orchiectomy, treatment with retroperitoneal lymph node dissection is generally indicated, but must be individualized.
Chemotherapy (three cycles of BEP or four cycles of etoposide + cisplatin) should be administered to large stage II non-seminomatous germ cell tumors and those with elevated cancer marker levels, with a cure rate of 9599%.
For stage II or III patients in complete serologic remission but with persistent retroperitoneal lymph node enlargement, retroperitoneal lymph node dissection is the standard of care after chemotherapy. However, there is controversy in the industry regarding the role of retroperitoneal lymph node dissection in patients in serologic and imaging evidence of remission after chemotherapy.
The authors do not advocate retroperitoneal lymph node dissection if the retroperitoneal lymph nodes are normal on CT. The 15-year cancer-related survival rate with this approach is 97%. Other investigators have recommended post-chemotherapy retroperitoneal lymph node dissection because in some cases the CT
germ cell tumors and teratomas have been found in patients with normal sized retroperitoneal lymph nodes on CT. A meta-analysis investigating retroperitoneal lymph node dissection after chemotherapy showed that 70% of patients had necrosis, 25% had teratomas, and 5% had active tumors. The combined recurrence rate was estimated to be 5% in patients monitored and 3% in patients with retroperitoneal lymph node recurrence.
In this analysis, only 2 of 15 male patients with retroperitoneal lymph node recurrence died of the disease. Post-chemotherapy retroperitoneal lymph node dissection can be avoided in approximately 95% of patients if serology and imaging demonstrate complete remission and active surveillance.
Stage III testicular cancer
The discovery of cisplatin in 1965 was a historic landmark in oncology, revolutionizing the treatment of testicular cancer. the addition of cisplatin to vincristine + bleomycin in 1974 achieved a 64% 5-year survival outcome; an unprecedented improvement over contemporaneous chemotherapy.
Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) established 4 cycles of etoposide + cisplatin chemotherapy as the standard regimen for low-risk patients, replacing cisplatin + vincristine + bleomycin with BEP, based on the excellent results of a phase III clinical trial. The study found that three cycles of BEP in low-risk patients was equivalent to four cycles of treatment.
Low-risk patients with metastatic cancer continue to be treated with three cycles of BEP or four cycles of etoposide + cisplatin as the standard regimen. A direct comparison of the efficacy of these two regimens in low-risk patients found that BEP three cycles was more effective (91% event-free survival at year four for BEP three cycles versus 86% for etoposide + cisplatin four cycles), although the difference was not significant.
Disposition of residual tumors with abnormal imaging after chemotherapy requires specialized surgery and personalized care involving urologists, thoracic surgeons, general surgeons, and otolaryngologists. Such patients should be referred to a medical institution experienced in the management of testicular cancer.
In 1997, the International Germ Cell Carcinoma Collaborative Group introduced a risk stratification system. The system takes into account the primary tumor site (testicular versus mediastinal), metastatic site and fluctuations in serum tumor marker levels to estimate risk categories. Three risk categories were defined: low risk (cure rate
>90%), intermediate risk (75% cure rate), and high risk (50% cure rate).
Low-risk patients were treated with a three-cycle BEP or a four-cycle etoposide + cisplatin regimen, and intermediate- and high-risk patients received four cycles of triple drug therapy (usually BEP or etoposide + isocyclophosphamide + cisplatin [VIP]). Cure rates in intermediate- and high-risk patients do not outperform those who complete four cycles of BEP or VIP therapy.
Some investigators have advocated intensifying therapy after cycle 1 or 2 of BEP therapy depending on the rate of decline in tumor marker levels. Retrospective analyses have shown that this strategy has resulted in fewer recurrences requiring salvage therapy and improved overall survival. Recent studies have shown that the paclitaxel + isocyclophosphamide +
cisplatin regimen (TIP) achieved a 74% complete remission rate and 97% overall survival at 3 years in a high-risk population. A randomized trial comparing BEP with TIP
A randomized trial comparing BEP to TIP is still ongoing. (ClinicalTrials.gov registry number: NCT01873326).
Recurrent disease
The question of which approach is most effective in treating recurrent germ cell tumors is controversial. Patients who relapse after initial treatment with chemotherapy should be referred preferentially to a provider experienced in the treatment of testicular cancer and may still be cured with second- or even third-line therapy. vip, vincristine
+ isocyclophosphamide + cisplatin, TIP, etc. are all commonly used treatment options.
In 1986, researchers at Indiana University found that high-dose chemotherapy was still effective in recurrent germ cell tumors, and that even third-line therapy could cure patients. in 1996, Indiana University also performed peripheral blood stem cell transplantation instead of bone marrow transplantation for recurrent germ cell tumors. The first 184 patients with disease progression after first-line chemotherapy with cisplatin, treated with high-dose chemotherapy and peripheral blood stem cell transplantation, achieved cure rates of 70% and 45% with second-line and third-line and follow-up therapy, respectively.
Some patients had elevated tumor marker levels during the first cycle of high-dose chemotherapy versus the second week. Almost all patients showed a decrease in tumor marker levels after the second cycle of high-dose chemotherapy. Twenty-eight percent of the patients in this subgroup were in the disease-free phase. The cumulative dose of etoposide was associated with an increased risk of leukemia, with 3 of the 184 patients developing acute leukemia.
MSKCC researchers have also evaluated the effects of high-dose chemotherapy, using paclitaxel + isocyclophosphamide as induction chemotherapy combined with stem cell mobilization, followed by three cycles of carboplatin + etoposide high-dose chemotherapy and peripheral blood stem cell transplantation, achieving a 5-year survival rate of 52%.
The effect of high-dose chemotherapy in reducing tumor marker levels in patients was satisfactory. Progression-free and overall survival results were excellent, and a curative outcome was achieved even when tumor markers were not reduced to the extent desired.
Two prospective phase III clinical trials designed to differentiate the role of high-dose chemotherapy from standard chemotherapy in salvage therapy showed mixed results. Randomized to four cycles or three cycles of VIP followed by one cycle of high-dose carboplatin + etoposide + cyclophosphamide, no significant difference in survival was seen between the two groups.
The second trial compared the effect of one cycle of VIP followed by three cycles of high-dose carboplatin + etoposide (group A) with three cycles of VIP followed by one cycle of high-dose chemotherapy (group B). The trial was terminated after 216 subjects were enrolled due to high mortality in Group B.
The 1-year overall survival rates were 80% and 61% for Groups A and B, respectively, and the treatment-related mortality rates were 4% and 16%, respectively, with longer cycles of high-dose chemotherapy appearing more beneficial. The latest 5-year overall survival rates were 49% and 39% in Groups A and B, respectively, and continue to support a multi-cycle chemotherapy regimen.
The issue of patient selection is a current clinical challenge to determine which patients should receive standard salvage chemotherapy and which should receive high-dose chemotherapy and peripheral blood stem cell transplantation. Relapsed patients are classified into different risk categories.
In a study that included 1500 subjects, high-dose chemotherapy appeared to be more effective in high-risk groups, including the group of patients with the poorest prognosis, in which treatment with high-dose chemotherapy had a 27% cure rate compared with only 3% with standard-dose salvage therapy.
Other studies have shown that high-risk groups, including primary mediastinal nonseminomatous germ cell tumors, can be cured with high-dose chemotherapy, while such results are rarely achieved with standard-dose regimens.
Some physicians advocate high-dose chemotherapy as second-line treatment for most patients, while others recommend high-dose chemotherapy only for high-risk patients, defined as those who have relapsed after receiving isocyclophosphamide chemotherapy or after two lines of standard salvage chemotherapy.
The TIGER trial, a randomized phase III trial of initial salvage chemotherapy for germ cell tumors, is currently underway.
The TIGER trial, a randomized phase III clinical trial of initial salvage chemotherapy for germ cell tumors, is designed to compare the efficacy of standard chemotherapy with high-dose chemotherapy in patients who have relapsed. In the trial, patients are randomized to receive four cycles of TIP or two cycles of isocyclophosphamide + paclitaxel, followed by three cycles of high-dose chemotherapy with carboplatin + etoposide.
Patient survival
Although most patients survive after being diagnosed with testicular cancer, clinicians must take care to reduce the long-term risk of treatment and limit unnecessary morbidity and early mortality.Walraven et al. explored the issue of the association of diagnostic imaging with secondary cancers in 2500 cases, and their report concluded that the risk of secondary cancers was not elevated as a result.
However, the study’s median follow-up time of 11 years was not sufficient to observe new secondary tumors. Radiation therapy has been suggested as a risk factor for secondary cancers. Chemotherapy has also been studied as a risk factor for kidney, thyroid, bladder, stomach, and pancreatic tumors, as well as lymphoma and leukemia.
Testicular cancer survivors also face the risk of distant disease recurrence (i.e., recurrence 2 years after healing), metabolic syndrome, cardiovascular disease, infertility, neurotoxicity, nephrotoxicity and pulmonary toxicity, Raynaud’s phenomenon, psychological disorders, hypogonadism, fatigue, depression, and osteoporosis. Retrograde ejaculation may occur in male patients after retroperitoneal lymph node dissection.
To date, this is the most comprehensive study to understand the long-term toxicity and genetic susceptibility to platinum-based chemotherapy in testicular cancer survivors.
Conclusion
Although most testicular cancers are curable with an expected survival time of more than 10 years, yet thousands of men around the world still die from testicular cancer each year and many clinical challenges remain. The mainstay of treatment for advanced testicular cancer remains cytotoxic drug chemotherapy. Early attempts at molecularly targeted therapy have yielded disappointing results.
Meanwhile, researchers worldwide continue to collaborate across regions on clinical trials, sharing research findings and exploring outstanding questions. It is this spirit of collaboration that has led to impressive advances in curing testicular cancer in men.