Treatment of Non-Seminoma
Non-Seminoma Stage I - III
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/1/2018)
Patients with stage I testicular cancer of non-seminoma type have a primary cancer that is limited to the testes and is curable in more than 95% of cases.
Standard Approach: Retroperitoneal Lymph Node Dissection and Surveillance
Currently, surgical orchiectomy and retroperitoneal lymph node dissection is considered to be the standard approach to treatment of stage I and II non-seminoma in adults, but not in children. The major advantage of retroperitoneal node dissection is accuracy of staging. Following surgery, patients undergo surveillance, which consists of monthly checking of cancer markers and chest x-rays for the first year and slightly less frequent evaluations in the second year. Patients that experience a cancer recurrence are treated with chemotherapy.
In clinical studies, 15% of patients with a negative lymph node dissection (no evidence of spread) experienced cancer recurrence, usually in the lungs. Recurrences usually occur within 18 months of surgery and most patients are subsequently cured with combination chemotherapy. In patients with stage I cancer confirmed by retroperitoneal lymph node dissection, the presence of lymphatic or venous invasion in the primary cancer appears to predict for a greater chance of cancer relapse.
Alternative Approach: No Retroperitoneal Lymph Node Dissection, Surveillance, and Chemotherapy for Those Who Relapse
Since virtually all patients with stage I-II non-seminoma that relapse after orchiectomy can be cured with combination chemotherapy, some doctors believe it is not necessary to perform a retroperitoneal lymph node dissection. Patients who elect this approach are treated with orchiectomy, but do not undergo retroperitoneal lymph node dissection. Instead, they have frequent follow-up visits with their doctor (surveillance) including chest x-rays, evaluations of cancer markers and, during the first year, abdominal CT scan every 2 months. Since approximately 25% of patients initially diagnosed with stage I cancer who are treated with orchiectomy and careful observation will in fact have a stage II cancer with spread to the retroperitoneal lymph nodes, careful follow-up and prompt administration of chemotherapy for relapse is important.
In a large clinical study involving 105 patients with clinical stage I disease (no retroperitoneal lymph node dissection), not including patients with choriocarcinoma, the relapse rate following treatment with orchiectomy alone was 26%. All cancer recurrences occurred within 2 years of diagnosis and 24 of the 27 patients with recurrent cancer were cured with chemotherapy. Relapses have, however, been reported more than 5 years after the orchiectomy in patients who did not undergo a retroperitoneal lymph node dissection. The option of no lymph node dissection is considered only if a CT scan and cancer markers are negative.
Alternative Approach: No Lymph Node Dissection and Adjuvant Chemotherapy
Patients with clinical stage I non-seminoma may also elect to receive treatment with chemotherapy following orchiectomy and avoid a retroperitoneal lymph node dissection. Two courses of bleomycin, etoposide and Platinol® (BEP) have been given to patients with clinical stage I disease who were considered at high risk of relapse based on the presence of vascular invasion and aggressive histology. In these studies, 95-98% of patients were cured. These results may be better than results achieved in patients treated with orchiectomy followed by surveillance, with chemotherapy reserved only for patients who relapse.
The number of patients treated with adjuvant chemotherapy is too small to draw conclusions about the risk of chemotherapy-induced secondary malignancies, impact on fertility or risk of late relapse. It is unclear if the 3 approaches to treatment are equivalent or one is superior to another. It is clear, however, that the differences will be small and hard to detect without an extremely large clinical trial performing a direct comparison of the 3 approaches.
Factors Which Affect Decision Making
Physicians have been surveyed to determine which therapy they would select. Half chose surgery and half chose chemotherapy. However, 82% of medical oncologists chose chemotherapy and 83% of urologists chose surgery. Medical oncologists are experts in the delivery of chemotherapy and urologists perform surgery. This survey demonstrated that physicians often make decisions based on their experience and comfort level with the procedure they perform. Thus, the treatment offered for early stage testicular cancer patient may depend on the type of physician the patient sees. This survey demonstrates the importance of having all treatment information presented in an objective fashion and for the need to seek the opinion of more than one physician, preferably in a different subspecialty.
Questions to Ask Your Physician
- What are the advantages, disadvantages and side effects of a retroperitoneal lymph node dissection?
- What are the chances of my disease coming back without lymph node dissection or chemotherapy?
- How frequently do I need to have CT scans if I do not receive adjuvant chemotherapy treatment?
- What are the long-term side effects of adjuvant chemotherapy?
Non-Seminoma: Stage II
Patients with stage II non-seminoma have cancer that involves the testicle and the retroperitoneal lymph nodes and is curable in over 90% of cases
There are several treatment options for patients with stage II non-seminoma based on the extent of the disease at diagnosis. All include surgical removal of the cancer with orchiectomy and pelvic lymph node dissection or adjuvant therapy.
Lymph Node Dissection and Surveillance
Because surgical removal of the cancer cures the majority of patients and chemotherapy can cure most patients whose cancer returns following surgery, a surgical orchiectomy and retroperitoneal lymph node dissection followed by close surveillance is the standard treatment. Surveillance consists of monthly checkups, physical examination, chest x-ray, and cancer marker tests (AFP, BHCG and LDH) with CT scans every 2 months. This option of surgery and careful surveillance, reserving chemotherapy to only treat cancer recurrences, is usually advised for patients who have fewer than 6 lymph nodes involved with cancer at retroperitoneal lymph node dissection, none of which are greater than 2 centimeters (about one inch) in diameter and cancer that is without evidence of venous or lymphatic invasion. Such patients have a cancer recurrence rate of approximately 20-30% if treated with surgery alone and most are curable with standard combination chemotherapy containing Platinol® when recurrence occurs. By utilizing this approach, the majority of patients are cured and 70-80% of patients will not require chemotherapy.
Lymph Node Dissection and Adjuvant Chemotherapy
It is important to understand that some patients with non-seminoma already have small amounts of cancer that have spread beyond what was removed surgically and cannot be detected with any of the currently available tests. Undetectable areas of cancer are referred to as micrometastases. The presence of micrometastases causes cancer recurrence following treatment with surgery alone. An effective treatment is needed to cleanse the body of micrometastases in order to improve a patient’s potential for cure. The delivery of cancer treatment following local treatment with surgery is referred to as adjuvant therapy and may include chemotherapy or radiation therapy.
Following orchiectomy and lymph node dissection, some patients will experience cancer recurrence if they are not treated with adjuvant therapy. By routinely administering adjuvant chemotherapy after surgery, the chance of cancer recurrence can almost be completely eliminated. The choice of receiving adjuvant chemotherapy is influenced by the risk of cancer recurrence and the preferences of the patient concerning surveillance.
Tumors larger than 2 centimeters, involvement of more than 6 lymph nodes with cancer and evidence of vascular invasion of the primary tumor are all associated with an increased risk of cancer recurrence. The relapse rate after retroperitoneal lymph node dissection has been reported to be approximately 60% in patients who had microscopic evidence of vascular invasion in the primary tumor. Patients whose tumor markers do not return to normal following the removal of retroperitoneal lymph nodes are also at a high risk for cancer recurrence. These patients may elect to be treated with adjuvant chemotherapy to reduce their risk of recurrence.
The results of a large clinical trial comparing adjuvant chemotherapy to surveillance demonstrated that 2 courses of Platinol®-based chemotherapy (either Platinol®, Velban®, bleomycin (PVB) or Velban®, bleomycin, cyclophosphamide, Platinol® (VAB VI)) prevented cancer recurrences in more than 95% of patients with stage II non-seminoma. There was a 49% recurrence rate in patients assigned to surveillance; however, almost all of these patients could be effectively treated with chemotherapy at the time of relapse. This study suggests that although adjuvant therapy will almost always prevent recurrences, the alternative approach of surveillance with chemotherapy only for patients who relapse results in an equivalent overall cure rate.
Neoadjuvant Chemotherapy with Delayed Surgery for Large Volume Disease
Neoadjuvant therapy consists of chemotherapy or radiation therapy that is administered prior to surgery with the intent of shrinking the cancer so that it is easier to remove. Some patients have large cancers and it may be difficult to remove the entire cancer with surgery. Treatment with neoadjuvant chemotherapy may decrease the size of the cancer, thereby allowing for easier and more complete removal with surgery. Standard chemotherapy regimens include bleomycin, etoposide and Platinol® (BEP) for 3 courses or a regimen of etoposide and Platinol® for 4 courses.
If patients do not achieve a complete response from neoadjuvant chemotherapy, surgical removal of residual cancer is performed. The timing of such surgery requires clinical judgment, but typically occurs after 3 or 4 cycles of combination chemotherapy and normalization of tumor markers. The chance of finding residual cancer after chemotherapy is dependent on the histology of the primary tumor. Patients whose primary tumor contained teratomatous elements have a higher probability of having residual teratoma or carcinoma in the lymph nodes than do patients whose primary tumor contains only embryonal cancer. However, one study has reported that regardless of initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Therefore, some physicians think that neither the size of the initial cancer nor the degree of shrinkage accurately identifies patients likely to have residual teratoma or carcinoma. This has led some physicians to recommend surgery with resection of all residual masses apparent on CT scans in patients who have normal cancer markers after responding to chemotherapy. If patients have persistent non-seminomatous germ cell malignant cancer in the surgically removed mass, additional chemotherapy is required.
Chemotherapy Before Orchiectomy for Life-Threatening Disease
In some cases, cancer has spread to other areas of the body and has become life threatening. In these instances, chemotherapy is initiated prior to orchiectomy. When this is done, orchiectomy after chemotherapy is advisable in order to remove the primary cancer. This is because there is a blood-testes barrier to chemotherapy. There are two places in the body where chemotherapy cannot penetrate, the brain and the testes. The blood-testes barrier prevents chemotherapy from reaching the testicle, thereby resulting in a high incidence of residual cancer in the testicle after completion of a full course of chemotherapy. In other words, all cancer outside the testes can be eliminated with a full course of chemotherapy, but there could still be cancer in the testes.
The standard chemotherapy regimens based on controlled studies consist of 3 cycles of bleomycin, etoposide and Platinol® (BEP) or 4 cycles of etoposide and Platinol® using a 5-day etoposide schedule.
Adjuvant Therapy and No Lymph Node Dissection for Low Volume Disease
In some clinical trials, primary chemotherapy has been administered to patients with small volume cancers in an effort to avoid lymph node dissection. Although clinical trials directly comparing lymph node dissection to chemotherapy have not been performed, it appears that primary chemotherapy, when compared to primary retroperitoneal node dissection, produces similar cure rates in patients with clinical stage II non-seminoma.
Questions to Ask Your Physician
- Based on my situation, what is the best treatment option?
- What are the risks of delaying treatment compared to getting adjuvant chemotherapy?
Non-Seminoma Stage III
Patients with stage III non-seminoma have cancer that has spread outside the retroperitoneal lymph nodes. The majority of patients are cured with standard multi-agent chemotherapy.
Since patients with stage III non-seminoma have widespread cancer, the treatment of choice is systemic chemotherapy. However, patients with cancer involving the brain are typically treated with both chemotherapy and simultaneous whole-brain radiation. Chemotherapy is a treatment modality that utilizes anti-cancer drugs. When chemotherapy is delivered systemically, it can kill cancer cells throughout the body, including cancer cells that reside in areas outside of the original location of the cancer. The most frequently utilized chemotherapy combinations include bleomycin, etoposide and Platinol® (BEP) for 3 courses or etoposide and Platinol® (EP) for 4 courses in good-prognosis patients. Other chemotherapy regimens may produce similar results, but are not as commonly used.
The expected outcome following Platinol®-based combination chemotherapy can be predicted based on the extent of the cancer. This is an important consideration because patients likely to have a poor outcome may want to consider participation in clinical trials evaluating new treatment approaches in an attempt to improve their chance of cure.
*Disease-free survival (DFS) refers to the number of patients surviving without a cancer recurrence following treatment.
The table above outlines the risk levels for patients with different levels of tumor markers in their blood following treatment with standard chemotherapy. Only 10% of “good-risk” patients experienced a cancer recurrence following treatment with standard chemotherapy. However, 25% of “intermediate-risk” patients and 60% of “high-risk” patients experienced a cancer recurrence after treatment with standard chemotherapy. Patients who fall in the intermediate and high-risk categories may wish to consider other treatment options to help reduce their risk of a cancer recurrence.
One such treatment option involves high-dose chemotherapy (HDC) with stem cell transplant. High-dose chemotherapy with autologous blood stem cell support has been successful in producing long-term complete remissions in patients with refractory cancer. High-dose chemotherapy (HDC) kills more cancer cells than lower-dose conventional chemotherapy. Unfortunately, HDC also kills more normal cells, especially the blood-producing stem cells in the bone marrow. Stem cells are immature cells produced in the bone marrow that eventually develop into red blood cells, which provide oxygen to tissues; white blood cells, which fight infection; or platelets, which aid in blood clotting. The treatment strategy utilizing stem cell transplant is an attempt to restore the blood-producing stem cells after HDC has reduced them to dangerously low levels. When stem cells reach critically low levels from HDC, complications such as anemia, infection and bleeding can occur. Thus, it is imperative to restore stem cell levels as quickly as possible. Autologous stem cell transplants involve the collection of a patient’s own stem cells prior to chemotherapy treatment. These stem cells are frozen and then infused back into the patients after treatment to “rescue” the bone marrow.
Physicians in Germany further evaluated HDC with stem cell transplant as initial therapy for high-risk patients. The study involved 146 patients who received HDC and stem cell transplant. These patients were then directly compared to similar patients who received conventional-dose therapy. The results of this study indicated that 72% of patients who were treated with HDC and stem cell transplant experienced a 3-year cancer-free survival, compared to 59% of patients who were treated with conventional chemotherapy.
Role of Surgery
In selected cases, surgery should be used after chemotherapy to remove residual masses to determine if viable cancer cells remain, since such a finding is an indication for further chemotherapy. Surgical removal of residual masses is also necessary to prevent regrowth of teratomas and growth of non-germ cell elements present in some of these masses. Results from one study have indicated that regardless of the initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Neither the size of the initial tumor nor the degree of cancer shrinkage while on therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some physicians to recommend surgery with resection of all residual masses apparent on scans, even in patients who have normal markers after responding to chemotherapy.
Chemotherapy Before Orchiectomy for Life-Threatening Disease
In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening spread of cancer. When this is done, orchiectomy after chemotherapy is advisable in order to remove the primary cancer. This is because there is a blood-testes barrier to chemotherapy. There are two places in the body where chemotherapy cannot penetrate, the brain and the testes. The blood-testes barrier prevents chemotherapy from reaching the testicle, thereby resulting in a high incidence of residual cancer in the testicle after completion of a full course of chemotherapy. In other words, all cancer outside the testes can be eliminated with a full course of chemotherapy, but there could still be cancer in the testes.
Strategies to Improve Treatment
The progress that has been made in the treatment of testicular cancer has resulted from improved development of chemotherapy and radiation treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of testicular cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of stage III non-seminoma testicular cancer.
Patients can experience a recurrence of cancer after initial therapy and/or become refractory to chemotherapy following treatment. Outcomes for patients with recurrent cancer depend on the extent of disease, prior therapy and the interval from primary treatment to relapse. Many patients with recurrent disease remain curable.
Patients with Cancer Recurrence after Surgery or Radiation Therapy
Patients who experience a cancer recurrence after treatment with orchiectomy and/or radiation therapy can typically be treated with chemotherapy. The most frequently administered chemotherapy combinations include bleomycin, etoposide and Platinol® (BEP) for 3 courses or etoposide and Platinol® (EP) for 4 courses in good-prognosis patients. Over 90% of patients who relapse after surgery and/or radiation therapy appear cured with Platinol® based chemotherapy.
Treatment of Patients who Fail Initial Chemotherapy
Patients whose cancer progresses following Platinol®-based chemotherapy require treatment with different chemotherapy regimens. Currently available chemotherapy regimens can induce long-term complete remissions in approximately 25% of patients with cancer that persisted or recurred following initial Platinol®-based treatment. Patients who experience a complete response to initial chemotherapy and those without extensive disease at the time of recurrence have the most favorable outcomes.
Patients who are refractory to Platinol®-based chemotherapy have a markedly poor prognosis. Several chemotherapeutic agents have been evaluated in intensively treated or Platinol®-refractory patients. Doxorubin, Ellence®, Navelbine®, Hycamtin®, or biologic agents such as a suramin and retinoic acid have not demonstrated significant activity in Platinol®-refractory patients. However, paclitaxel has shown a response rate of approximately 21%, with a few patients having a complete response. Current clinical trials are evaluating paclitaxel combined with other agents. Gemzar® has also shown anti-cancer activity in intensively pretreated and refractory patients with germ-cell cancer and is a reasonable palliative option.
High-dose chemotherapy with autologous blood stem cell support has been successful in producing long-term complete remissions in patients with refractory cancer. High-dose chemotherapy (HDC) kills more cancer cells than lower-dose conventional chemotherapy. Unfortunately, HDC also kills more normal cells, especially the blood-producing stem cells in the bone marrow. Stem cells are immature cells produced in the bone marrow that eventually develop into red blood cells, which provide oxygen to tissues; white blood cells, which fight infection; or platelets, which aid in blood clotting. The treatment strategy utilizing stem cell transplant is an attempt to restore the blood-producing stem cells after HDC has reduced them to dangerously low levels. When stem cells reach critically low levels from HDC, complications such as anemia, infection and bleeding can occur. Thus, it is imperative to restore stem cell levels as quickly as possible. Autologous stem cell transplants involve the collection of a patient’s own stem cells prior to chemotherapy treatment. These stem cells are frozen and then infused back into the patients after treatment to “rescue” the bone marrow.
In a recent clinical trial, researchers evaluated the novel treatment strategy involving two sequential doses of HDC and autologous stem cell transplants in patients with recurrent testicular cancer. All of these patients received HDC and autologous stem cell transplant as initial therapy following their recurrence. Three years following this treatment, almost 60% of these patients were cancer free.
Another large clinical study involving 150 patients evaluated high-dose Platinol®, etoposide and Ifex®. The chance of surviving without cancer recurrence was 29%, which may be greater than expected with non-stem cell supported conventional-dose therapy.
Strategies to Improve Treatment
The progress that has been made in the treatment of testicular cancer has resulted from improved development of chemotherapy and radiation treatments in patients with more advanced stages of cancer and participation in clinical trials.
Clinical trials for patients with stage I non-seminoma testicular cancer are limited to determining the initial extent of treatment necessary for optimal results and what the factors are that favor one approach over another. It will be important to determine which treatment approach produces the fewest long-term side effects in patients with stage I non-seminoma.
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research carried out in phase II clinical trials.
High-Dose Chemotherapy with Stem Cell Support: Different high-dose chemotherapy regimens are being evaluated in patients with refractory disease. There are also trials of sequential administration of more than one high-dose regimen.
Phase I Trials: New chemotherapeutic agents continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.™ Testicular Cancer. V.2.2008. © National Comprehensive Cancer Network, Inc. 2008. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.