We are honored to present the following interview with Dr. Craig Nichols, one of the leading Testis Cancer oncologists in the world. His candid and knowledgeable answers make this a "must read" document for anyone interested in testicular cancer...Editor's Note: This interview is getting rather old. When it was first conducted, Dr Nichols was still at Indiana University and Lance Armstrong had not won the Tour de France even once. Nevertheless, the treatment of testicular cancer has not really changed all that much since the early 1990's, and the information presented here is basically accurate. I will endeavor to get the Q & A updated in 2013.
Craig Nichols: The history and development of the cure of testis cancer began before IU became prominent in this area; however, it was the integration of cisplatin into the regimen that made the major leap forward and the cure of this disease. At Indiana University in the early '70's Dr. Lawrence Einhorn was beginning his career in medical oncology and conceived of the idea of incorporating cisplatin into the commonly used regimen of velban and bleomycin.
By good fortune there also happened to be a rapidly developing urologic expertise in germ cell tumors at that time at Indiana University with Dr. John Donohue. These two individuals formed the framework of the modern combined approach to advanced germ cell tumors with effective chemotherapy and aggressive integration of surgery.
Landmark papers on the management of germ cell tumors subsequently emerged from Indiana University and attracted young medical scholars and surgeons from around the country to train at Indiana University. Over the years the urologic group added strength and breadth with Dr. Richard Foster, Dr. Richard Bihrle, Dr. Randall Rowland, and Dr. Gregory Wahle. The medical oncology group also added expertise first with Dr. Stephen Williams, and then Dr. Patrick Loehrer, subsequently myself, Dr. Bruce Roth, and more recently Dr. Scott Saxman.
Additional interest and expertise developed in the areas of pathology, radiology, and thoracic surgery due to the large number of patients seen at Indiana University. In some regards this became a self feeding program in that as expertise grew, patient volume grew, scientific interest grew and this generated additional interest at the institution.
2) What are the most current theories regarding the cause(s) of TC?
CN: For the most part, this is unknown. There has been a large bit of speculation supported by some genetic data that would suggest that the risk for development for testicular cancer is an event that occurs very early on in embryonic development. The disease is commonly associated with other urologic abnormalities such as undescended testicles, horseshoe kidneys, duplication of ureters, and other inborn developmental abnormalities.
It is clear that there is almost certainly an association between the development of testicular cancer and HIV disease. With this exception it is not clear that there are any exogenous (outside) factors that meaningfully contribute to the development of testicular cancer. Unlike other diseases, such as lung cancer, where the risk is largely attributable to patterns of behavior, there are no clear cut patterns existing for testicular cancer.
Likewise I think there is little evidence that lifestyle, diet, or habits that the patient engages in during or after the treatment of testicular cancer meaningfully effect the outcome. That said, it is always easier for patients who are generally healthy to deal with rigors of chemotherapy and surgery.
3) What are the main symptoms and tests that lead to a diagnosis of testicular cancer versus that of something else?
CN: In the vast majority of cases the patient presents with a mass within the body of the testicle. While this is usually painless, the mass can be associated with pain and the presence of pain does not provide any consistent reassurance that the mass is not cancerous. More rarely, patients present with symptoms of metastatic disease, the most common being severe, unrelenting back pain related to retroperitoneal metastases or shortness of breath, and hemoptysis (coughing up blood) related to lung metastases.
The signs doctors commonly rely on to make diagnosis are:
4) What is the best way to locate competent TC medical help in a given area?
CN: This is a somewhat complex question as Testicular Cancer is a rare disease. While it is the most common cancer in young males, overall only about 7,500 cases are diagnosed in the United States each year. The rarity of the disease and the enormous consequences of either misdiagnosis or mismanagement suggests that such patients should be managed at centers with a large amount of experience in these diseases. Most large cities have experienced urologic and oncology groups that see sufficient numbers of patients with testicular cancer to have the experience to manage most cases of this disease. Many universities and medical schools have significant experience in the integrated management of these diseases as well.
For very complex or advanced cases it is often suggested that those patients be seen at centers with particular expertise and excellence in testicular cancer. There are a variety of centers around the country; most prominent among these centers are (in no particular order):
Dana Farber Cancer Institute in Boston, Memorial Sloan-Kettering Cancer Institute in New York City, University of Pennsylvania in Philadelphia, University of Chicago, Indiana University in Indianapolis, Providence Cancer Center in Portland, USC, UCLA, and Stanford University in Palo Alto.
To find more Testicular Cancer experts, please see the TCRC's Experts Page.
5) What specific path(s) does TC use to spread throughout the body?
CN: The two dominant pathways are: 1) Through the lymph node system. This is a primary modality of spread from the testis primary to the retroperitoneum and in some cases to other lymph nodes along the mid-line of the body. 2) Thereafter, spread is usually via the blood stream (hematogenous). This is most common in patients with advanced germ cell tumors or those patients with choriocarcinoma or embryonal carcinoma elements. The most common sites for blood borne metastases are the lungs, followed by the liver, bone, and brain.
6) Why do an inguinal orchiectomy vs. a biopsy? Could you explain an inguinal orchiectomy?
CN: Inguinal orchiectomy is the diagnostic procedure of choice for several reasons: If a biopsy is performed through the scrotum, the scrotum is contaminated and then serves as a potential site for development of metastatic disease. Also in biopsying through the scrotum, the pattern of nodal metastases is disturbed and makes subsequent surgery difficult to predict. Modern day ultrasound, serum markers, and experienced physical exam enable diagnostic accuracy prior to any surgery to be quite high. If a simple biopsy was done as the initial procedure, a high percentage of patients would have to undergo a second procedure for full removal of the primary tumor.
Additionally, it is insufficient to rely on chemotherapy to manage the primary as the testis serves as a chemotherapy sanctuary with relatively poor penetration of chemotherapy into the testis. Under virtually all circumstances we recommend that the primary be removed at some point during the course of the treatment plan.
The inguinal orchiectomy is done through an incision made above the inguinal ligament. This is the ligament that runs diagonally from the crease in the top of the leg to the scrotum. The testicle is brought up through the inguinal canal and examined visually. Again in most circumstances the pre-operative suspicion is confirmed by visual inspection and the whole testis and its associated structures are removed. Since testis cancer can involve many of the adjacent structures including the spermatic cord, this must be removed at some distance from the testis primary site. This is examined pathologically to make sure that the margins of the surgery are clean.
7) Are there any situations in which the other testicle should be biopsied to identify pre-cancerous cells?
CN: In certain situations there appears to be a relatively high risk of what is called "carcinoma in situ" in the opposite testis. Some studies have suggested that an atrophic testis, an undescended testis, or low sperm count may be associated with a higher incidence of carcinoma in situ. It is common practice in Scandinavia for patients with a testis primary to have a biopsy of the remaining testicle. If carcinoma in situ is identified, radiation is administered. The incidence of carcinoma in situ in Scandinavia studies is higher than studies in other countries. In practical terms only about 1-2% of patients will develop a second primary testis cancer.
This incidence seems diminished in those patients who receive systemic chemotherapy. It is US policy (where the incidence of carcinoma in situ appears to be less) that the biopsy of the contralateral testis not be undertaken and the patient simply be counseled regarding careful testicular and physician exam.
8) What kind of information do you need from the pathology report in order to determine the proper treatment? Is TC something most pathologists are familiar with?
CN: The primary information that is useful for treatment determinations is whether the tumor is of the non-seminomatous variety or pure seminoma. Even in patients who have a pathological appearance of pure seminoma, the elevation of alpha-fetoprotein in the serum mandates management as a non-seminoma.
Secondary information that contributes to the management of the patient are the presence or absence of teratomatous elements, the presence of and percentage of embryonal cell carcinoma elements and the presence of vascular invasion (the venous or lymphatic channels within the testis). On occasion there are non-germ cell tumors of the testis for which very different management is required. These are quite rare tumors and any suspicion of a non-germ cell testicular tumor probably should suggest a pathology second opinion be obtained.
Pathology in testis cancer can be complex. When coupled with tumor markers and clinical findings most experienced pathologists in larger centers are able to render correct diagnoses. Situations that suggest the need for pathology review are unusual clinical circumstances, unanticipated lack of response to therapy, or unusual sites of disease.
9) What are the overall percentages of various types of tumors diagnosed?
CN: Seminoma is far and away the most common subtype of testicular cancer and accounts for about 40% of all cases. Non-seminoma subtypes in various percentages account for the rest. Most common subtypes are teratocarcinoma and embryonal cell carcinoma. Pure choriocarcinoma and pure yolk sac tumors of the testis are rare.
10) Are you seeing an increase in testicular cancer in immunocompromised patients (i.e. AIDS)? Is the treatment any different for these patients?
CN: From several very large data bases it does appear that there is an increase in incidence of germ cell cancer in patients who are HIV positive. The exact mechanisms of these associations are not well delineated. Our approach to patients with HIV disease and germ cell cancer is similar in that we have approached every patient with optimism and intent to cure them of the germ cell cancer. Patients who are HIV positive seems to have more difficulty tolerating full dose chemotherapy and accordingly frequently require support with hemopoietic growth factors. With this exception, we approach such patients with the same vigor that we approach patients who are not HIV positive.
11) What is the overall time table for testicular cancer recurrence?
CN: Our general time table is that 80-90% of cases will recur within the first year of diagnosis. The vast majority of the remaining 10-20% of patients will recur in the second year after initial management. Recurrence beyond two years seems to be a less than 5% proposition and may be in the 2-3% range. Late relapses of germ cell cancers have a unique biology and clinical management. Such patients probably should be seen at a center of excellence.
12)What is the percentage of left side/right side TC cases?
CN: It appears that testicular cancer is equally distributed between left and right sided diseases. If there is a slight percentage variation between the two sides there are no clinical outcome differences in the different sides. However, right-sided vs. left-sided does required a different surgical template.
13) How common are false negative tests in testicular cancer?
CN: Radiographic tests are good but imperfect. Even at very experienced centers, such as Indiana University, a negative CT scan can be associated with up to a 10-20% incidence of grossly positive tumor at the time of retroperitoneal lymphadenectomy -- the incidence is probably higher in centers with less experience. Likewise, blood markers are imperfect and there are frequent false positives and sometimes false negatives in all centers. All the vagaries of testing suggest that the decisions regarding management should be made in the context of a number of tests and in some situations repetitive testing . It is rare that a treatment decision is based on a single value or a single equivocal radiographic finding.
14) What level of trust should the doctors have in testicular cancer markers? Are there any new tests on the horizon?
CN: Again, as mentioned in the previous question there is no perfect test and there are frequent false positives and occasional false negatives, particularly with respect to beta HCG. Beta HCG determinations in the assay test is sometimes falsely elevated related to marijuana use, low testosterone states, and other situations. Likewise alpha-fetoprotein can be elevated in patients with severe liver disease. Again, it is rare that major deviations in management are made on the basis of a single marker value. It is important to see the pattern of marker behavior prior to making fundamental treatment changes.
Several investigators, including those here at IU, are looking at molecular markers of germ cell cancer. These are still in the investigational stage and currently not applicable to general practice.
15) If the patient's blood markers are elevated, does that always mean they have active cancer?
CN: We know there are false positives for both beta HCG (more commonly) and alpha-fetoprotein (less commonly) -- this is particularly true at very low levels of elevation. Again, it is most important that the markers be determined and repeated and a pattern of change be established prior to making management determinations.
16) If a man is not concerned about fertility and cannot live with the risk of developing a contralateral primary tumor, should he receive preventive radiation?
CN: In my view this is an over reaction to a rare situation. Radiation does diminish the incidence of progression of carcinoma in situ to testicular cancer; however this is probably not a 100% solution to the problem.
Secondly, radiation is not without both short and long term side effects. There certainly short term effects on skin. There may be long term effects with respect to second malignancies. Again, the development of a second testicular cancer is certainly less than 5% proposition and this seems an inconvenient, expensive, imperfect and potentially dangerous approach to a very low statistical likelihood event.
17) Considering that testicular cancer has such a high cure rate, what are researchers concentrating on now? What are the research plans for the future?
CN: This is certainly a delightful dilemma to ponder in patients with malignancies! In germ cell tumors we have made astounding progress, but this is far from complete.
On the clinical side the most important investigational issues, I believe, remain management of patients with poor risk disease. These include those with mediastinal non-seminomatous germ cell tumors, patients who present with wide spread disease and high markers, and those with recurrent germ cell tumors after chemotherapy. In this arena investigations regarding the incorporation of new agents, new drug schedules, and dose intensity are underway both in the United States and in Europe.
In good risk disease the challenge has been to maintain the excellent cure rates with lesser degrees of toxicity. We and others are looking at ways to refine surveillance in management of clinical stage A disease as well as ways to diminish chemotherapy toxicity. With the currently available regimens it is generally recognized that we are beginning to reach the lower limits of length of treatment and further reductions will likely result in lesser cure rates.
Currently and in the future I believe the focus will be on enhancing the biological understanding of these fascinating tumors. These are models of differentiation and growth. They are also unique in their chemotherapy sensitivity and it is hoped that through study of the biology of these tumors that this unique sensitivity can be understood and perhaps induced in other less chemotherapy sensitive tumor types. There has been a great deal of progress in understanding the genetic abnormalities in germ cell tumors. It is likely that in some near time period the genes controlling growth and development of germ cell tumors will be clearly identified. These than may serve as a therapeutic target for new drug development.
18) Why aren't MRIs used instead of abdominal CT scans?
CN: MRI has not be shown to be superior in evaluating the abdomen relative to abdominal CT. We have done a head-on-head comparison here at Indiana University and abdominal CT, particularly with the newer scanners, was superior.
19) Would an MRI or PET scan show more details about a residual mass in the abdomen than CT scan in patients with seminoma?
CN: This is not yet known. We are currently investigating the use of PET scan in seminoma at Indiana University in order to try to discern viable tissue from fibrosis (scar tissue). This is the the primary difficulty with residual masses in patients with seminoma.
20) What exactly is a PET scan, and what is it's role in testis cancer?
CN: PET stands for Positive Emission Tomography and is used for biological imaging of tumors and other conditions. The patients is given a glucose like substance that is taken up by biologically active tissues. The hope of PET scan is to be able to distinguish scar tissue from active viable tumor and in the case of germ cell cancer, teratoma. As yet this is still experimental. We found that the PET scan was potentially useful in discriminating scar tissue from active germ cell cancer in patients who had residual radiographic abnormalities after chemotherapy. However, it was unable distinguish patients with teratoma. Others have looked at this in early stage disease to help define patients appropriate for surveillance. As of yet the use of PET scanning in most cases of germ cell tumor is still investigational.
21) What is the normal time for microscopic cancer in the abdomen to grow into something recognizable (such as via CT)?
CN: This is mostly speculation, but, for instance in surveillance programs, the majority of patients who recur (80%+) do so in the first year, most of the rest do so in the second year and relapse after two years is uncommon (a few percent) We continue to follow patients fairly aggressively until year five, and then once a year thereafter.
22) If a man has passed through puberty and has an undescended testicle that has not been brought down, how should it be managed?
CN: In most situations the "protective" effect of bringing down the testis has been missed in those patients who have had a retained testis for that period of time. It is not clear that removal substantially reduces the risk of developing germ cell cancer in such patients. We currently do not remove the testis routinely.
23) Do patients with undescended testis have a higher risk of recurrence and is the risk of recurrence affected by whether or not the testis is "brought down"?
CN: By this question, I assume that the patient has had a primary testis cancer in the normally descended testis and has an abnormally descended testis on the other side...the patient does not have a higher risk of developing a recurrence of the first tumor but does have a small chance of developing a second primary in the abnormally descended testis. How much higher this is than the standard risk (less than 5%) is unknown. We would not routinely do orchiopexy (bringing down the testis) in this situation.
24) How common are non-germ cell tumors of the testis, and do they require the attention of a specialist?
CN: These are quite rare, particularly in young men. As men get older there are a variety of non-germ cell tumors of the testis with the most common being lymphoma. All of these are rare entities and I believe would benefit from consultation with a urologic group with experience in all aspects of testicular tumors.
25) Extragonadal germ cell tumors and choriocarcinomas are considered rare and deadly-could you talk a little bit about these entities?
CN: First, extragonadal germ cell tumors are certainly rare and account for about 5% of germ cell tumors in adults. The most common sites are the retroperitoneum, the mediastinum, and the pineal gland (a gland within the brain). The prognosis for extragonadal germ cell tumors varies markedly with the subtype of tumor at those sites.
Seminoma at any extragonadal site carries a similar prognosis to testicular seminoma and most of these patients do quite well. Retroperitoneal non-seminoma is of intermediate prognosis and the majority of these patients are cured. Patients with mediastinal non-seminoma have a variety of clinical and biological problems associated with these tumors. This clearly is among the poor prognosis germ cell tumor entities. However, a substantial portion of these patients still are cured and everyone, even with these mediastinal non-seminomas, should be approached initially with the prospect of curing them of their illness.
In the past choriocarcinoma and choriocarcinoma syndrome seemed to be particularly virulent. With increasing experience it is now felt that choriocarcinoma in and of itself does not portend a particularly poor prognosis, and it is much more dependent on the level of the HCG or degree of spread of the tumor to determine the prognosis.
26) What is the difference between germ cell tumors in men and women?
CN: The primary difference is the frequency with which they occur. Germ cell tumors of the ovary are quite rare and hence the number of clinical trials and state of clinical knowledge are certainly not as complete as those for male germ cell tumors. The main histologic subtypes are represented as in male germ cell tumors, management includes primary surgery (usually a one sided removal of the ovary and associated tube) frequently followed by similar cisplatin based chemotherapy. These are highly curable tumors and similar treatments have resulted in similar success in women as men.
27) What are your thoughts on universal screening for testicular cancer?
CN: This is a very difficult subject concept that is counter intuitive to many patients and physicians. In all cancer screening programs the value is largely related to the incidence of the disease and the impact of finding the disease early.
For instance, screening for lung cancer (which is 20 times more common than testicular cancer) has never been found to be useful partly because the screening methods are imprecise and there is common early dissemination of the disease even at the time of identification by screening. The value of mammography is certainly well established, but even in this setting there is a great deal of debate of when and how women should be screened for breast cancer.
The problem in testis cancer is that the incidence is so low and the initial screening methodology (physician examination of the testis) is so imprecise that you develop a problem of a high false positive rate. I would imagine that for every 100 young men who think they feel a mass in their testis only 1 or 2 will have testicular cancer. The difficulty is that this results in a great deal of medical evaluation and probably occasional surgeries that are not warranted. It is also difficult to see where this would impact on the cure rate for this disease since most patients are curable even when they present with disease beyond the testis.
I would prefer to concentrate on testicular cancer awareness rather than massive promotions of screening. It would be I think more prudent to emphasize to young men that the testis is a site of potential cancer development and a common cancer in young men and make them aware that if there is a definite consistent and changing mass within the body of testis that they should be seen by an urologist.
28) Should a man taking replacement testosterone be concerned about long term carcinogenic effects?
CN: If the testosterone levels remain within the physiologic range, there is little concern regarding long term carcinogenic effects. Most of the concerns are related to doses above the physiologic level.
29) Are patients who have had testicular cancer are more likely to develop cancers elsewhere than someone who has never had any form of cancer?
CN: If you remove treatment as a factor, the primary risk of developing a second cancer in someone with testis cancer is that of developing a second primary testis cancer. There have been inconsistent suggestions that there may be a higher incidence of other urologic tumors such as renal and bladder cancer, but this is not been found generally.
There is a higher risk of second tumors in patients who have received chemotherapy and radiation therapy. There is a very low but definite incidence of chemotherapy-induced malignancies and a definite incidence of radiation therapy induced malignancies (particularly with older radiation therapy equipment). This is one reason why continued long term follow-up of testicular cancer patients is important by someone who is cognizant of these risks factors.
30) Are there any ideas why teratoma is benign in children and malignant in adults?
CN: Teratoma is benign by definition. Benign teratoma occurs in both adults and children and, after chemotherapy, we frequently find benign teratoma that must be removed surgically. The incidence of benign teratoma as a presenting syndrome is certainly higher in children, but not exclusively a pediatric disease. Teratoma is a biologic process that can grow locally and become adherent to local structures. If at all possible, it should be removed at some course during the treatment of the disease. If benign teratoma is the only pathologic feature of the tumor, chemotherapy or radiation therapy is not required.
31) When is surveillance appropriate in someone with early stage testicular cancer?
CN: This is an extremely complex question and there certainly are no totally right or wrong answers. In non-seminoma, the factors that drive my recommendations and decision making are the availability of excellent surgeons who can perform nerve sparing procedures, the patient's desire for a family, and their access to good medical care.
In patients in whom fertility is an issue, I commonly consider the recommendation for retroperitoneal lymphadenectomy (also known as RPLND surgery) as this diminishes significantly the chances of the patient ever requiring chemotherapy -- chemotherapy is clearly a larger threat to a person's fertility than nerve sparing retroperitoneal lymphadenectomy.
Likewise, if there is reason to suspect that the patient will have difficulty accessing or complying with the rigorous follow-up, we encourage initial management with retroperitoneal lymphadenectomy as this established a prognosis and provides management of disease in the abdomen early on in the course of the disease. Unfortunately there is no set answer and it is an individual decision of the patient and doctor jointly.
In seminoma I think there certainly are situations in which is surveillance is appropriate, again in those patients who have access to an experienced and committed physician.
32) Can radiation cause permanent infertility? What are the prime negative effects concerning radiation therapy and testicular cancer?
CN: Radiation certainly can cause permanent impairment of sperm production, but there are techniques for testicular shielding that minimize these chances. Other concerns about radiation therapy primarily are the long term concerns about inducing second malignancies. In seminoma this is a relatively uncommon problem, however, these second malignancies do not appear often times for 10 to 20 years. Fortunately the dose given in modern times for seminoma is low and hopefully not as associated with the development of secondary malignancies as doses in years past. There are a variety of minor and more rare side effects, such as, skin changes, ulcer disease, etc. with radiation therapy but these are uncommon and usually easily managed.
33) If a patient has had stage I seminoma and received adjuvant radiation therapy and subsequently develops a second early stage seminoma on the other side, could he receive additional radiation therapy?
CN: In theory, yes, but this would be at a significant risk of increased toxicity. It is usually my preference in that situation to manage the patient with aggressive surveillance and consider chemotherapy for the small percentage of patients who relapse.
34) What are the chances of recurrence after surveillance vs. adjuvant radiation therapy in stage I seminoma? If they are close, why isn't surveillance used more commonly?
CN: A very high percentage of patients (in excess of 95%) who receive adjuvant radiation therapy for stage I seminoma will not have recurrence. The recurrence rate for patients with surveillance in stage I seminoma is about 15-20%. Those patients who relapse are frequently successfully salvaged by radiation therapy or chemotherapy.
Again this is more a personal decision than a medical one. I think these are both acceptable management strategies that should result in a 100% cure rate, and again the issues regarding access to good surveillance is critical in choosing a non-treatment approach.
In all these issues of surveillance, it is important to recognize that there is an unacceptably high drop out rate from surveillance programs. This has recently been looked at by the group in Vancouver and both doctors and patients dropped out of the recommended surveillance program. It is important to be absolutely vigilant about the surveillance programs because it is in this group of patients that drop out of active surveillance who occasionally present later with advanced poorly treatable disease. The patient must be willing to accept the rigors of surveillance in order to make it an effective ultimate strategy.
35) Are there any situations where chemotherapy is appropriate for primary management of early stage non-seminoma? (For example, a patient with 100% embryonal cell on the orchiectomy specimen, normal blood markers and a negative CT scan).
CN: This is an area of some controversy...in Europe, many testis cancer centers would give such patients two courses of standard chemotherapy in this setting, and this clearly is associated with a high percentage cure rate, but the cure rate is not 100%. In addition, the ability to predict occult spread from the testis based on factors associated with the orchiectomy specimen (vascular invasion, percent embryonal cell, etc.) is imperfect and at best we can predict only half of those patients who will develop recurrent disease.
Accordingly at least 50% of patients probably are receiving chemotherapy that they don't need and a smaller percentage of patients are receiving inadequate amounts of chemotherapy. As mentioned in a previous question, there are false negative CT scans and a small percentage of patients will have grossly positive disease were they to undergo retroperitoneal lymphadenectomy. Two cycles of chemotherapy is probably inadequate for some of these patients.
In the United States most investigators would not apply primary chemotherapy in this setting. Chemotherapy is unpleasant and it has some potential for serious short term and long term side effects. We would prefer in most setting to reserve it for those patients who need it.
The only exception to this are those patients in whom they are otherwise early stage disease but have persistent elevation of alpha-fetoprotein. These patients almost always develop distant metastases if they are managed by surgery alone and we have been treating these as good risk metastatic disease with three cycles of therapy.
36) Do different approaches to early stage non-seminoma (surveillance, retroperitoneal lymphadenectomy, adjuvant chemotherapy) have similar long term cure rates?
CN: We anticipate the cure rates in these with surveillance and lymphadenectomy (RPLND) to be very similar providing that either modality is done with the appropriate expertise and vigilance. My personal opinion is that we have insufficient data on the long term follow-up of chemotherapy patients in this setting to be absolutely assured that they patients fair as well as non-chemotherapy strategies. I believe these likely will result in similar outcomes but this is not entirely clear at this juncture.
37) What are the chemotherapy treatments for patients with disseminated germ cell tumors, why are they used in combination, and why do some doctors prefer to delete bleomycin?
CN: The standard agents for chemotherapy treatment for germ cell tumors are cisplatin, etoposide, and bleomycin. Ifosfamide, vinblastine, and carboplatin are additional drugs that are occasionally used. The most common and well studied regimen is the three drug combination of bleomycin, etoposide, and cisplatin (BEP).
The reason that chemotherapy drugs are used in combination is that this seems to prevent the develop of chemotherapy resistance among sub populations of cancer cells. As well the agents appear to be synergistic not just additive in their effects.
The use of bleomycin is of some minor controversy. In the past, when more extended courses of chemotherapy were given, bleomycin did have some significant long term morbidity and occasionally mortality associated by the development of lung damage. The "down side" of not using bleomycin is that in every head-on-head comparison of bleomycin containing regimens vs. the regimen not utilizing bleomycin there has been inferior outcome with respect to curing the germ cell cancer. The current standard for good risk germ cell tumor in the United States is three cycles of bleomycin, etoposide, and cisplatin. At the low cumulative doses of bleomycin in this regimen significant difficulties with bleomycin are rare.
We believe the only safe alternative in good risk disease is four cycles of etoposide and platinum without bleomycin. While these regimens have never been compared head-on-head to insure equal efficacy, three cycles of etoposide and cisplatin have been compared to three cycles of etoposide, cisplatin, and bleomycin and the two drug combination was definitely inferior. Despite many clinical trials addressing the issue of deletion of bleomycin it remains an important component of combination chemotherapy in germ cell cancer.
38) Are there any chemotherapy combinations that are better than others? Are there any regimens that fallen out of favor over the years?
CN: The world standard for chemotherapy is three cycles of bleomycin, etoposide, and cisplatin (BEP) for good risk disease and four cycles for poor risk disease. There is no clearly defined regimen that is better than the three drug combination but there are certainly ones that are more toxic and ones that are less effective. A competitive regimen to BEP is the regimen of etoposide, ifosfamide, and cisplatin (VIP). This has a bit more toxicity but has the advantage of eliminated bleomycin from the regimen. In certain patients with pre-existing lung disease this is an acceptable substitution. Over the last 20 years certain regimens have lost favor. The older regimens containing the drugs vinblastine, cyclophosphamide, and actinomycin D have, for the most part, been replaced.
39) Could you talk a little bit about the discovery of cisplatin and its place in the history of treating TC?
CN: The drug cisplatin was discovery almost purely by accident. A biologist in Michigan was doing experiments with bacterial cultures and electrical fields. There was a platinum anode and the scientist noted that there was no bacterial growth around the platinum anode. He speculated that the platinum served as an inhibitor of bacterial synthesis and this proved to be correct. Ultimately this was translated into consideration of using platinum as anti-neoplastic agent. This became formulated for human administration and the first human tests of cisplatin were begun in the early 1970's. (At that time the drug had intolerable side effects with extraordinary nausea and vomiting plus adverse effects on the kidneys.) By good fortune, some of the early patients tested using cisplatin happened to have testicular cancer. Some of these patients manifested a response to the treatment.
At that time, the standard management of metastatic testicular cancer included the two drugs, vinblastine and bleomycin. It was marginally effective, but some patients did have a complete and occasionally durable responses. Dr. Einhorn recognized the activity of cisplatin in patients with testicular cancer from the early trials and also recognized the side effects of cisplatin did not overlap with the combination of vinblastine and bleomycin. Efforts were made to mitigate side effects of cisplatin with anti-emetics and aggressive hydration. These partially ameliorated the side effects of cisplatin and made it tolerable for human usage. The combination of cisplatin, vinblastine, and bleomycin (PVB or the "Einhorn regimen") forever changed the face of chemotherapy for testicular cancer -- with the introduction of cisplatin the cure rate jumped markedly. The incorporation of cisplatin laid the ground work for modern therapy and subsequently every chemotherapy combination for testicular cancer has contained a platinum based compound.
40) What is the difference between cisplatin and carboplatin?
CN: Carboplatin is similar to cisplatin, and was developed as a non-nephrotoxic (does not damage the kidneys), non-emetogenic (does not cause vomiting) alternative to cisplatin, but there are two problems: First, the profile of side effects (primarily low platelets and white count) makes it difficult to combine with other agents such as etoposide. Second, in almost every study in every disease, carboplatin is a little bit inferior to cisplatin as far as the outcome is concerned. For disease such as lung cancer where treatment is simply palliative this small difference probably doesn't mean much. In diseases such as testis cancer where cure is the goal, this is very important!!
41) What determines whether a patient should receive 2, 3, or 4 cycles of chemotherapy?
CN: This is entirely based on the predicted prognosis. In patients who have had fully resected (totally removed) abdominal disease at the time of a retroperitoneal lymph node dissection, it is common to consider the use of 2 cycles of adjuvant (preventive) chemotherapy. In this setting, this virtually 100% guarantees that the patient will not experience a recurrence of their disease. Three cycles of chemotherapy are given to those patients who have more disseminated germ cell tumor, but still have what are felt to be good risk features. Three cycles of chemotherapy will cure approximately 90+% of these patients.
Four cycles of therapy is reserved for those patients with poor prognostic features, including those with mediastinal non-seminomatous germ cell tumor or widespread disease involving liver, bone, or brain or those with very, very high serum markers.
42) If the testis is a sanctuary site for chemo, how come all the germ cells are killed and the patient becomes infertile?
CN: It is a relative sanctuary site and we clearly see patients in whom cancer everywhere else is eradicated by surgery and, at post-chemo orchiectomy there is still viable germ cell tumor in the testis. The issues of fertility are a bit different and there is probably a differential sensitivity between malignant germ cell tumors and differentiated normal germ cells. There is little question that differentiated germ cells are wiped out by chemo, but the cells from which these cells are derived probably aren't killed in most patients and many recover spermatogenesis even after months or years pass.
43) Is there any difference between the chemo regimens used for seminoma and nonseminoma? Is there any difference based on Staging?
CN: There should be no difference between doses according to tumor type or stage. Only the number of cycles and occasionally the intervals between cycles changes. Not every one's dose is the same because it is calculated by the body surface area which is a nomogram based on height and weight the answer comes out in square meters M2.
44) Do cancer cells become resistant to chemotherapy?
CN: Absolutely. Most tumors are made up of subpopulations of cells with variable sensitivity to chemotherapy agents. Some subpopulations are resistant prior to ever seeing chemotherapy, some acquire resistance through ongoing mutations, some remain sensitive throughout their life. The reason we use combinations of drugs is in the hope that if a subpopulation is resistant to one chemotherapy agent it will be sensitive to others in the combination; this also why we try to switch treatments in patients who have recurrent disease after primary chemotherapy. How cells become resistant, if this resistance can be reversed or modulated, and why TC is so uniformly sensitive are all Nobel prize winning questions. We have a LONG way to go in this area...
45) Is there any difference between outpatient and inpatient chemo for testicular cancer? Is this a hospital or insurance decision, or is it just the wave of the future?
CN: It is all of the above. We believe it can be done in healthy good risk patients receiving primary chemotherapy. Others and those receiving ifosfamide should have it as an inpatient.
46) Is high dose chemotherapy still a viable option for patients with advanced disease or recurrent disease?
CN: There certainly patients who have been cured with high dose chemotherapy where first, second, and occasionally even third line chemotherapy has failed. High dose chemotherapy works best earlier in the course of recurrent disease and in patients who are not refractory to cisplatin. It is not a cure for all patients and should be done only at select centers with experience in making the determinations who should or who can potentially benefit from such aggressive treatments. In the situation of untreated disease, the role of high dose chemotherapy is undefined. Currently there is an international protocol assessing this question that compares standard therapy with BEP to abbreviated BEP followed by high dose chemotherapy.
47) When and why is surgery needed after chemotherapy?
CN: At Indiana University, the decision to add surgery to the treatment plan is considered in those patients with non seminoma and with residual abnormalities on X-ray after completing chemotherapy. The rationale for surgery is two fold:
a) It is removed at surgery and this serves as a therapeutic maneuver
in many patients.
b) It identifies the need for further chemotherapy in these patients.
The timing of surgery is somewhat variable but ordinarily this is felt to be a semi-elective procedure. We like the patient to recover nutritionally and from the rigors of chemotherapy and, accordingly, we generally schedule the surgery 4-6 weeks after the last chemotherapy.
48) How does chemotherapy effect fertility and is there an increased risk of birth defects in patients who have received chemotherapy?
CN: The issues regarding the effect of chemotherapy on fertility is complex. Many patients with testis cancer are sub-fertile to begin with even prior to the diagnosis of testicular cancer. The risk of chemotherapy-induced azo or oligospermia (none or few sperm) depends to some degree on the starting point. Those patients with a low sperm count prior to the initiation of chemotherapy have a higher chance of not recovering their sperm counts after chemotherapy. Ordinarily we would estimate that in patients with normal sperm counts before hand (the minority of patients) that normal sperm counts would be obtained after chemotherapy in at least 50% of patients. Patients who have low sperm counts to begin with have a poor chance of ultimately developing normal sperm counts.
These issues aside, there have been marked advances in fertilization technology and in some situations a single sperm is sufficient for impregnation using in vitro techniques.
There is no clear evidence in patients who have received chemotherapy, recover their sperm counts, and subsequently father children, that their children have a higher chance of birth defects than anyone else.
49) What treatment should be recommended for a patient with otherwise stage I non-seminoma but elevated tumor markers?
CN: I have mentioned previously that it is important to get a sense of what is happening with the tumor markers after orchiectomy. If the elevated tumor markers fall to normal or are falling at rate consistent with half lives of alpha-fetoprotein or beta HCG, the patient is considered clinical stage I and the usual discussion of surveillance vs. retroperitoneal lymphadenectomy should ensue. In patients who, after orchiectomy, have persistently elevated markers that are not falling at the appropriate rate, this is prima facie evidence of occult disease somewhere. It has been our experience that in those with elevated beta HCG that retroperitoneal lymphadenectomy is a viable consideration in this setting. In those patients with persistently elevated alpha-fetoprotein, we generally give these patients 3 cycles of BEP.
50) What is the latest word on testicular implants?
CN: These are not available in the United States as far as I am aware unless by some consideration under an orphan devise act. I think most urologists and patients are fairly dissatisfied with the results of testicular implantation. With the scare regarding breast implants, the manufacturers have understandably become concerned about litigation and class action suits and hence have suspended development and production of these devises. I still believe they are available in certain centers in Europe.
51) Some people have claimed that RPLND surgery is "barbaric" surgery and overly invasive in the era of modern medicine. Why is this procedure still used?
CN: It is odd to be in the position of a medical oncologist defending surgery, but I believe most people having gone through both procedures would rather have retroperitoneal lymphadenectomy than several cycles of chemotherapy.
There is no question that there are some short term discomforts with lymphadenectomy. At Indiana University the average length of stay is 4 to 5 days in patients who are receiving a primary lymphadenectomy. Most people are able to return to desk work in several weeks and their interruption of life is minimal compared to chemotherapy.
Retroperitoneal lymphadenectomy accomplishes a variety of benefits in this disease. Obviously, in the post chemotherapy setting, there is no substitution for this surgery particularly with reference to teratoma. There are also clear cut cases of patients who are out-and-out resistant to chemotherapy who have been cured with aggressive surgery. The "barbaric surgery" concept may be a reference to a bygone era. In the past, primary retroperitoneal lymphadenectomy in an era when there was not effective chemotherapy was a very aggressive and extensive surgery. However, much like minimizing surgery in breast cancer, surgeons have been able to develop more tightly constructed surgical templates that minimize morbidity while retaining efficacy.
Currently with primary lymphadenectomy, an experienced surgeon can, in virtually all cases, spare fertility. This used to be the biggest concern with retroperitoneal lymphadenectomy; however, nowadays chemotherapy is much more a threat to long term fertility than primary lymphadenectomy.
52) Could you describe the RPLND in layman's terms, and how "templates" are used?
CN: A retroperitoneal lymphadenectomy is done as primary management of early stage disease and is designed to remove the "landing zone" for testicular cancer metastases to the retroperitoneal lymph nodes. By careful mapping studies done in the 1960's and 70's, the pattern of spread of testis cancer from a right or left sided primary is quite predictable. Accordingly over the years, the surgeons have been able to do dissections that incorporate the predicted landing zones of these tumors with extraordinary accuracy.
Using these templates, the extension of the dissections have been limited again and with newer technologies (including dissecting microscopes), nerves that control ejaculation have been able to be spared in most situations. The spread of TC goes from the testis to the lymph nodes in the region of the kidneys on both sides. The surgeon dissects out these packages of lymph nodes after identifying the nerves and removes the package of lymph nodes in total.
53) How difficult is it to perform the RPLND, and are many urologists experienced with such procedures? How realistic is it to expect a curative yet nerve sparing procedure?
CN: It is a difficult operation that depends a great deal on experience. The judgment as to whether the surgeon has sufficient experience is difficult -- this is one reason why I believe that surgery should be done at centers with large volumes of patients. Like anything else, experience breeds confidence and judgment. Whereas delivering chemotherapy after therapeutic decisions are made is relatively straight forward, surgical technique cannot be imparted over the phone...
In most primary lymph node dissections, nerves can be spared in close to 100% of cases while having the same quality cancer operation. In the post chemotherapy setting, this is much more difficult to predict, but , in general, the larger the residual tumor the less likely nerves can be spared.
The experience of the surgeon is particularly important in the situation where post chemotherapy dissections are required. Nerve sparing techniques are less able to be performed in these settings but with experience some templates are successful in this post chemotherapy situation. In particular patients with massive residual abnormalities or mass of teratoma almost certainly would benefit from surgical expertise available at just a few centers around the country.
54) What are the dangers and concerns regarding RPLND?
CN: The complexity and dangers of the procedure depends largely on the whether it is a primary retroperitoneal lymphadenectomy e.g. normal abdominal CT or small volume abdominal disease or a post chemotherapy lymph node dissection.
In the case of a primary RPLND, the risk of serious complications is low. I would imagine the biggest concern in most situations are the general risks of surgery, and in the case of RPLND, retrograde (backwards) ejaculation related to a non-nerve sparing technique.
In the situation where there is significant residual disease after chemotherapy, a much bigger template of surgery is required. Frequently in this setting there is a need for removal of a kidney, vascular repair and dissection of teratoma or tumor off the spine. As you might imagine, this is more hazardous surgery and there is a risk for variety of complications. Despite this the experiences at good centers is remarkably favorable and the procedure is considered "safe".
55) How soon after orchiectomy should RPLND be performed to be considered useful?
CN: Generally we would like to have RPLND done within six or so weeks of the orchiectomy.
Dr Richard Foster, a urologist at IU, adds: The reason we say that RPLND for low stage disease should be performed within 6 weeks is that the biology of most testis cancer is rapid compared to many other cancers. Hence, if a patient waits, his stage may change (for instance, he may develop pulmonary metastases) and a different therapy (chemotherapy) may become the appropriate treatment. Also, if a patient has already waited 3-4 months, he has already passed through a fair portion of the high risk period for recurrence on surveillance and effectively has opted for surveillance.
56) If a patient is unable to have normal ejaculation after the RPLND, does it ever come back or can the function be improved by treatments?
CN: The likelihood of the ejaculatory function coming back would be quite small if it does not return in a reasonable time after surgery. There are some medications that can be given to improve the chances forward ejaculation. Additionally there are some mechanisms to "harvest" sperm even in those patients who have persistent retrograde ejaculation.
57) Is it ever possible for the lymph nodes to grow back being surgically removed?
CN: Lymph nodes that are removed cannot grow back. However, all abdominal lymph nodes are not removed in even the most complete retroperitoneal lymphadenectomy. There are certain situations where abdominal recurrences happen even after the best retroperitoneal lymphadenectomy. In general those patients who have a good primary retroperitoneal lymphadenectomy by an experienced surgeon have virtually no chance of an abdominal relapse.
58) Is it ever necessary to have abdominal CTs after an RPLND, and are chest or pelvic CTs ever useful in surveillance strategies?
CN: We do not use abdominal CTs as part of surveillance after primary retroperitoneal lymphadenectomy. Patients who have post chemotherapy lymphadenectomies are managed differently however. The follow up is determined to a large degree by the findings at surgery. Patients with massive amounts of teratoma in their post chemotherapy specimens do have a risk of developing recurrent teratoma. Accordingly we do do regular CTs and follow up of these patients.
Ordinarily we do not do chest CT scans in surveillance. Pelvic CT scans are usually part of most abdominal CT scans but we do not order these separately in patients with germ cell tumor unless there is some unusual anatomical variance that would suggest a risk of pelvic relapse.
59) Do you foresee laparoscopic retroperitoneal lymphadenectomy in the future?
CN: This has been advocated by some surgeons. It is my view that retroperitoneal lymphadenectomy is a cancer operation. The great value is not in sampling the lymph nodes, but in removing the abdomen as a source of relapse as well as identifying prognosis. My understanding of these techniques are that these do not represent full cancer operations in most settings, so I am somewhat dubious as to whether this will replace lymphadenectomy.
I think the likely advances in imaging technology and biological predictors of relapse may reduce the incidences of lymphadenectomy, particularly as primary management, but I do not see the technique itself changing markedly.
60) What is/are the primary determining factors between doing an RPLND (with or without chemo) vs. just doing chemo?
CN: When you ask the question of RPLND + chemo versus just chemo, this applies most commonly to the situation of having a slightly abnormal CT in the work-up after orchiectomy for non-seminomatous GCT. (Clinical stage II). If the abnormalities on CT are greater than 2-3 cm, we almost always recommend chemotherapy as primary treatment because it offers the best chance to cure the disease with one modality rather than two. If surgery is done in that setting, about 75-80% of the time disease is found and removed (which means that up to 20% of the time there are false positive CT scans). If the operation is performed by an experienced surgeon, the patient is cured 50-70% of the time with surgery alone. We do not feel in this situation that adjuvant "preventive" chemotherapy is ever a mandate and, in patients willing to comply with close follow-up (CXR + markers), we believe surgery alone is a very acceptable (?preferred) option with 3 cycles of BEP for the 30% or so that relapse (nearly 100% overall cure rate). If the person elects to receive preventive chemotherapy we give two cycles of BEP post operatively with nearly a 100% cure rate.
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