EDITORIAL

Doctor ... Will I Still Be Able To Have Children?

Scott Saxman

Correspondence to: Scott Saxman, MD, FACP, Cancer Therapy Evaluation Program, National Cancer Institute, 6130 Executive Blvd., Rm. 7025, Bethesda, MD 20892 (e-mail: saxmans{at}ctep.nci.nih.gov).

Few experiences in the professional life of a practicing oncologist are as satisfying as treating a patient with testicular cancer. By and large these are young, healthy males, able to easily tolerate the associated acute side effects of aggressive therapy. Thanks to the vision of the pioneers in this field and their commitment to evidence-based medicine, we are routinely guided by high-quality phase III data in making treatment decisions. Unlike the situation for most solid tumors, even when patients present with metastases the cure rates are extraordinary, and for early-stage disease the cure rate approaches 100%. This success is evidenced by the fact that although only approximately 8000 men will be diagnosed with testicular cancer in the United States in 2005, there are roughly 185 000 men alive in the United States who have a history of testicular cancer (1). Long-term complications of the disease and/or its treatment are therefore an important public and personal health issue that will continue to increase in magnitude over the next several decades.

Testicular cancer commonly occurs before or during the peak reproductive period of life, and patients who are cured of their disease have a long life expectancy and often desire families and children. However, the paucity of high-quality data concerning the effects of a testicular cancer diagnosis and its associated therapy on fertility makes it difficult to educate and advise patients on their likelihood of fathering biologic children. Both the disease and the treatment can affect fertility, but our understanding of the basic biologic processes that cause or predict for posttreatment infertility is woefully limited. This problem is compounded by the fact that clinical studies addressing the issue of fertility in testicular cancer patients often use surrogate endpoints such as sperm count, sperm quality, or hormone levels, which may not accurately reflect the ability to father children. Moreover, analyses frequently combine relatively small subsets of patients receiving a wide variety of treatments, making the results difficult to extrapolate to a population of patients receiving a specific therapy. Also, young patients are highly mobile and can be difficult to locate or track, which poses challenges to carrying out studies of this type. Current medical delivery systems and privacy regulations make such studies particularly difficult to carry out in the United States, and most of these reports therefore come from investigators in countries with national cancer registries.

Perhaps most important, because of the long follow-up period that is necessary to determine success rates for fathering children, the therapeutic interventions that were used during the study period frequently become obsolete and are no longer relevant to modern treatments by the time results are available. The report by Brydøy et al. in this issue of the Journal (2) illustrates this problem. In this study, the investigators identified, through their national cancer registry and regional university hospitals, all surviving unilateral germ-cell testicular cancer patients treated in Norway from 1980 through 1994. A total of 1814 men were invited to participate and were asked to complete a mailed questionnaire and submit to an outpatient clinical examination. The questionnaire consisted of 14 questions pertaining to the men's marital status as well as to whether they had attempted to father a child before and/or after their testicular cancer diagnosis and treatment and whether they had been successful. Overall, 79% of the men initially identified returned the questionnaire and constituted the study population. For the subset of men who reported that they had attempted to father children, successful paternity unassisted by reproductive technologies was evaluated along with primary data from the medical records that included the stage of disease at time of diagnosis, histology of the tumor, and treatment received (surgery, radiation, and/or chemotherapy).

With a median follow-up of 11.1 years, 65% of the men in the Brydøy study who reported that they had attempted to conceive following therapy for their testicular cancer successfully fathered children without medical assistance. Although the paternity rates are broken down by treatment received, some of this information may no longer be applicable, given that treatment modalities and options have improved or changed substantially since the early 1990s. The conventional retroperitoneal lymph node dissection (RPLND) procedures, which caused retrograde ejaculation and infertility in the majority of patients, have been replaced with a nerve-sparing technique that preserves antegrade ejaculation in more than 95% of clinical stage I patients (3). The report by Brydøy does not describe in detail the surgical approaches that were used for the patients in their study. For patients with clinical stage I seminoma being treated with radiotherapy, a randomized study published in 1999 (4) confirmed that using a simple para-aortic portal that excludes the ipsilateral iliac and pelvic nodes does not have a negative impact on survival. Another recently reported randomized study (5) demonstrated that doses of radiotherapy can be reduced to as low as 20 Gy without compromising efficacy. By comparison, in the Brydøy study, only 7% (44/610) of the patients who received radiotherapy had ports limited to the para-aortic area, and the dose of radiotherapy was 36–40 Gy in the early 1980s and was gradually reduced to 25.2–27 Gy by the end of the study period.

The Brydøy study also included a group of men described as receiving "high-dose" chemotherapy (total cisplatin dose >850 mg), which roughly equates to patients who received more than four cycles of cisplatin-based chemotherapy; they determined that this cohort of patients had a substantial reduction in the ability to father children compared with that of patients in the "low-dose" group. However, present primary treatment for metastatic testicular cancer consists of no more than two to four cycles of combination chemotherapy, again limiting the practical applicability of their finding (6). A more clinically relevant question would have been whether the rates of infertility were different among patients who received two, three, or four cycles of combination chemotherapy.

One of the most important advances in the treatment of testicular cancer has been the demonstration that patients with clinical stage I disease (both seminoma and nonseminoma) can be closely observed with no additional immediate therapy after orchiectomy without compromising the overall cure rate (7). Here the data from the Brydøy study more closely reflect a current practice standard, showing that 81% (42/52) of the surveillance patients who attempted posttreatment conception without medical assistance were successful. These results are similar to those of a study conducted in the United Kingdom in which 85% (56/66) of patients with testicular cancer who tried to conceive while being followed on a surveillance program were able to do so (8). This finding is important information that can be given to patients who are considering their treatment options and for whom maximizing the potential for preservation of fertility is a concern.

Another key finding in the Brydøy study comes from their comparison of paternity rates for patients treated during the first 10 years of the sample period with those for patients treated in the last 5 years, when more contemporary therapies described previously were being implemented. This analysis showed that the 10-year actuarial paternity rate increased statistically significantly from 55% to 76%, and that these rates were essentially unchanged even when the patients followed by surveillance were removed from the calculation. These data provide the first clear evidence that therapeutic changes designed to reduce morbidity have indeed had a salutary effect on reducing the rate of infertility and will serve as a benchmark against which future studies can be compared.

So, when the data published by Brydøy et al. in this issue are added to the cumulative body of evidence, what can we tell patients with testicular cancer when they ask, "Doctor ... will I still be able to have children?"

Most patients with stage I disease will retain or recover fertility, with patients followed by surveillance [and most likely those undergoing nerve-sparing RPLND (9)] having a success rate approaching 80%–85%. Patients with seminoma treated with modern radiotherapy techniques may or may not have a slightly lower success rate, but data to precisely quantify the risk of infertility for these patients are not currently available.

The majority of patients treated with modern doses and schedules of platinum-based chemotherapy will also be able to father children, with an overall success rate that may be as high as 60% or 70%. Insufficient data are available to accurately quantify the success rates after four cycles of chemotherapy compared with either two or three cycles.

Although highly selected postchemotherapy patients with small-volume retroperitoneal disease may be candidates for nerve-sparing RPLND (10), the rate of retrograde ejaculation in men undergoing RPLND for residual masses after chemotherapy is high overall. The unassisted paternity rate is very low for this patient group.

All patients with testicular cancer who wish to maintain fertility (and who do not require emergent treatment) should be counseled and offered the option of sperm banking. Sperm banking is an option even for patients who are oligospermic because current fertility technologies can prove successful even for men with nominal sperm counts. Sperm banking should be considered even for men who choose to be followed up with surveillance because overall 20%–30% of such patients will recur and require aggressive chemotherapy (11,12).

Clearly the impact of therapy on fertility, as well as other long-term complications, for men with testicular cancer needs to be better categorized and understood. However, this will be a moving target as treatment approaches continue to change and improve. Seriously addressing these public health issues for patients in the United States will require a national collaborative effort that identifies and collects, on an ongoing basis, longitudinal information on the health status of these men—similar to what the Childhood Cancer Survivor Study has done for childhood cancers. Several initiatives are currently under way whose goals are to identify research gaps and generate ideas for future research pertaining to young adults with cancer—including testicular cancer. These activities include the President's Cancer Panel (co-chaired by Lance Armstrong), which has formulated recommendations to address the challenge of understanding and improving the health status of young adult cancer survivors. In addition, the National Cancer Institute, in collaboration with the Lance Armstrong Foundation, will be sponsoring an Adolescent and Young Adult Oncology Progress Review Group that will bring experts in the field together to assess the state of the science and develop recommendations for research opportunities. As we move toward a day when all patients with testicular cancer will be survivors, long-term quality-of-life issues will become paramount. We owe it to our patients to begin now to more fully address them.

REFERENCES

(1) SEER Cancer Statistics: Estimated New Cancer Cases and Deaths for 2005. Available at: http://seer.cancer.gov/statfacts/html/testis.html?statfacts_page=testis.html&x=12&y=12.

(2) Brydøy M, Fosså SD, Klepp O, Bremnes RM, Wist EA, Wentzel-Larsen T, Dahl O. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005;97:1580–8.[Abstract/Free Full Text]

(3) Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R. Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): modifications of technique and impact on ejaculation. J Urol 1993;149:237–43.[ISI][Medline]

(4) Fossa SD, Horwich A, Russell JM, Roberts JT, Cullen MH, Hodson NJ. Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 1999;17:1146–54.[Abstract/Free Full Text]

(5) Jones WG, Fossa SD, Mead GM, Roberts JT, Sokal M, Horwich A, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 2005;23:1200–8.[Abstract/Free Full Text]

(6) Jones RH, Vasey PA. Part II: testicular cancer—management of advanced disease. Lancet Oncol 2003;4:738–47.[CrossRef][ISI][Medline]

(7) Jones RH, Vasey PA. Part I: testicular cancer—management of early disease. Lancet Oncol 2003;4:730–7.[CrossRef][ISI][Medline]

(8) Huddart RA, Norman A, Moynihan C, Horwich A, Parker C, Nicholls E, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer 2005;93:200–7.[CrossRef][ISI][Medline]

(9) Foster RS, McNulty A, Rubin LR, Bennett R, Rowland RG, Sledge GW, et al. The fertility of patients with clinical stage I testis cancer managed by nerve sparing retroperitoneal lymph node dissection. J Urol 1994;152:1139–42.[ISI][Medline]

(10) Coogan CL, Hejase MJ, Wahle GR, Foster RS, Rowland RG, Bihrle R, et al. Nerve sparing post-chemotherapy retroperitoneal lymph node dissection for advanced testicular cancer. J Urol 1996;156:1656–8.[CrossRef][ISI][Medline]

(11) Warde P, Specht L, Horwich A, Oliver T, Panzarella T, Gospodarowicz M, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002;20:4448–52.[Abstract/Free Full Text]

(12) Read G, Stenning SP, Cullen MH, Parkinson MC, Horwich A, Kaye SB, et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol 1992;10:1762–8.[Abstract/Free Full Text]



             
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