DIAGNOSTIC TESTS AND RISK OF TESTICULAR CANCER

Over the last 40 years, there has been a doubling in the incidence of testicular cancer. Over the same period, there has been a 20-fold increase in the use of diagnostic radiation, and the doses of radiation used have increased sevenfold. Perhaps the two are related?

The suggestion comes from researchers reporting a new case-control study in which they show that repeated diagnostic radiation below the waist was associated with an increase the risk of testicular germ cell tumor (TGCT).

The study involved 315 men with TGCT and 931 controls from hospital and population-based settings, and analyzed medical records and individuals'  recall of diagnostic radiation such as CT scans, x-rays, and barium enema.

Compared with men who did not undergo any diagnostic radiation, the risk of testicular cancer was nearly twofold higher among men who had undergone three or more diagnostic X-rays and CT scans, and more than fourfold higher among men who had undergone three or more lower gastrointestinal (GI) series or barium enema.

The study was published online November 11 in PLoS ONE.

Testicular cancer, the most common cancer in white men aged 15-44, has steadily increased in incidence in the United States over the past three or four decades: the rate has jumped from 3 out 100,000 men in 1975 to 6 out of 100,000 men today, say senior author Katherine Nathanson, MD, of the University of Pennsylvania in Philadelphia, and colleagues.

"Our data suggests that the increased use of diagnostic radiation below the waist in men over that same time may contribute to the increase in incidence," Nathanson said in a press statement.

Reducing diagnostic radiation doses to the testes "should be prioritized," say the investigators, if these results are validated by additional research.

It's "undoubtedly prudent" to reduce those doses "as much as possible," said David Brenner, PhD, director, Center for Radiological Research, Columbia University Medical Center, New York City, who was asked for comment.

I do find the results quite surprising. Dr David Brenner

However, Brenner also had reservations about the new study. "I do find the results quite surprising," given what is known historically about testicular cancer and radiation exposure, he said.

Higher radiation doses (than in the current study) in two other settings (among post-atomic bomb survivors and in the treatment of ankylosing spondylitis) are not associated with an increased risk of testicular cancer, he told Medscape Medical News in an email.

"Underlying conditions for which the individual received radiation imaging," may be one potential explanation for the increased testicular cancer risk seen in this study, he added.

Nathanson responded to Brenner's critique by focusing on atomic bomb survivors and pointing out that the baseline rate of testicular cancer in Asia, including Japan, is "very, very low" and therefore that population, including bomb survivors, is not a highly applicable comparison.

Take-Home Message: Testicular Shielding

Nathanson noted that diagnostic imaging below the waist is most commonly administered as a result of GI tract complaints such as constipation and abdominal pain.

For clinicians, the study's take-home message supports testicular shielding, she told Medscape Medical News.

Testicular shielding during diagnostic imaging can be protective, but audits show that correct use and positioning occurs in just 25% of pediatric diagnostic scans, the authors comment.

Recent epidemiologic studies support a tie between diagnostic radiation and other cancers, the authors also point out.

For example, women undergoing frequent x-rays for scoliosis may have an increased risk of breast cancer, and likewise for individuals undergoing repeat routine dental x-rays and thyroid cancer. Additionally, a National Health Service study among 175,000 children revealed an excess risk of subsequent brain tumors and leukemia tied to CT scans, say Nathanson and coauthors.

Total-dose and number of exposures were associated with an increasing cancer risk in each of the aforementioned studies.

Nathanson pointed out that Penn researchers have collected testicular cancer data since 2001 for the sake of research on related, inherited risk. The new study is an outgrowth of those efforts and is a rare effort in this subject area, in part, because testicular cancer is a very treatable rare cancer, with a 95% survival rate at 5 years.

A larger prospective study of the association between diagnostic radiation and testicular cancer would be better for determining causality, but is impractical given the needed time and associated costs. "A case-control design is a methodology that is ideally suited for studies investigating rare disease outcomes such as TGCT," the authors comment.

The study was supported with grants from the National Cancer Institute and the National Institutes of Health. The study authors and Brenner have disclosed no relevant financial relationships.

PLoS One. Published online November 11, 2020. Full text

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay, MedPageToday and has had bylines on WashingtonPost.com, MSNBC, and Yahoo. Email: nmulcahy@medscape.net and on Twitter: @MulcahyNick

 

RISK OF METACHRONOUS TESTICULAR CANCER

In a Dutch study reported in the Journal of Clinical Oncology, Blok et al found a significant association between an increased number of cycles of platinum-based chemotherapy and a reduced risk of metachronous contralateral testicular cancer. As noted by the investigators, patients with testicular germ cell tumor are at increased risk of developing a contralateral testicular germ cell tumor.

Study Details

The study involved data from a nationwide cohort of 4,755 patients aged < 50 years who were diagnosed with and treated for primary testicular germ cell tumor in the Netherlands between 1989 and 2007. Metachronous contralateral testicular germ cell tumor was defined as any testicular germ cell tumor identified in the contralateral testicle ≥ 2 months after diagnosis of the first testicular germ cell tumor. The cohort included 2,612 patients with seminomatous germ cell tumor and 2,143 with nonseminomatous germ cell tumor.

Standardized incidence ratios were used to compare the incidence of contralateral testicular germ cell tumor incidence with expected incidence of testicular germ cell tumor in the general population. The effect of treatment with platinum-based chemotherapy on contralateral testicular germ cell tumor risk was assessed via multivariable Cox proportional hazards regression models.

“Approximately 1 in every 30 survivors of testicular germ cell tumor will develop a contralateral testicular germ cell tumor, with contralateral incidence increasing up to 20 years after a primary testicular germ cell tumor. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with contralateral testicular germ cell tumor risk.”

— Blok et al

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Key Findings

Metachronous contralateral testicular germ cell tumor was diagnosed in 136 patients (standardized incidence ratio = 14.6, 95% confidence interval [CI] =12.2–17.2). The cumulative incidence increased to 3.4% at 20 years of follow-up, including cumulative incidence of 4.0% after seminomatous germ cell tumor and 2.6% after nonseminomatous germ cell tumor.

The median interval between primary testicular germ cell tumor and metachronous contralateral testicular germ cell tumor was 6.1 years, with no difference between patents with seminomatous germ cell tumor vs nonseminomatous germ cell tumor (P = .090).

The 20-year cumulative incidence was 1.7% in patients who had been treated with platinum-based chemotherapy and 4.4% in patients without platinum exposure (median intervals of 4.9 vs 7.5 years, P = .23).

On multivariate analysis, risk of a contralateral testicular germ cell tumor decreased with every additional cycle of platinum-based chemotherapy (hazard ratio [HR] per cycle = 0.74, 95% CI = 0.64–0.85). The hazard ratio for patients receiving four cycles of platinum-based chemotherapy vs those not receiving platinum-based chemotherapy was 0.18 (95% CI = 0.08–0.43).

Additional significant factors on meta-analysis consisted of reduced risk with increasing age (HR = 0.93, 95% CI = 0.90–0.96) and reduced risk after primary nonseminomatous germ cell tumor vs seminomatous germ cell tumor (HR = 0.58, 95% CI = 0.35–0.96).  

The investigators concluded, “Approximately 1 in every 30 survivors of testicular germ cell tumor will develop a contralateral testicular germ cell tumor, with contralateral incidence increasing up to 20 years after a primary testicular germ cell tumor. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with contralateral testicular germ cell tumor risk.”

Michael Schaapveld, PhD, of the Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by KWF Kankerbestrijding and Dutch Uro-Oncology Studygroup. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

RELAPSE AFTER ADJUVANT BEP IN STAGE I NON-SEMINOMA

In a study reported in the Journal of Clinical Oncology, Fischer et al found different patterns of relapse and associated outcomes among men with relapse after treatment with adjuvant bleomycin/etoposide/cisplatin for clinical stage I nonseminoma.

The study included data on 51 patients from 18 centers in 11 countries who relapsed after orchiectomy and adjuvant bleomycin/etoposide/cisplatin for clinical stage I nonseminoma. Patients had a median age of 30.5 years at orchiectomy, and adjuvant chemotherapy was started at a median of 40 days after surgery. Overall and progression-free survival were calculated from day 1 of treatment at first relapse.

Key Findings  

Median follow-up was 96 months. Among all patients, 5-year progression-free survival was 67% and 5-year overall survival was 81%.

Median time to relapse was 13 months, with the earliest relapse occurring at 2 months after start of bleomycin/etoposide/cisplatin treatment and the latest after 25 years. Overall, 63% of relapses occurred during the first 2 years after adjuvant treatment; 8% occurred between year 2 and 3, and 29% occurred at ≥ 3 years.

Median time to relapse among patients relapsing with teratoma only was shorter than that among patients experiencing relapse with nonteratoma (9 vs 20 months, P < .001). A total of 10 patients (20%) had relapse more than 5 years after adjuvant treatment, and these relapses were associated with increased risk for subsequent progression or death (hazard ratio [HR] = 1.13 per year, P = .002) and increased risk for death (HR = 1.10 per year, P = .01).

After treatment for relapse, 15 patients (29%) experienced subsequent relapse; median time from first to subsequent relapse was 9 months. Death occurred in nine of these patients and was due to nonseminoma progression in eight.

Overall, relapses could be categorized as: pure teratoma relapses treated with surgery alone; early nonseminoma relapses less than 2 years after adjuvant treatment; and late nonseminoma relapses more than 2 years after adjuvant treatment. The nonseminoma-specific death rates in these three groups were 0%, 13%, and 28%, respectively.

The investigators concluded, “We report the first, to our knowledge, retrospective analysis focusing exclusively on patients with [clinical stage I nonseminoma] who were treated with adjuvant bleomycin/etoposide/cisplatin and who had an unequivocal relapse. The median time to relapse in this analysis was long, at 13 months, and approximately one-third of patients experienced relapse more than 3 years after adjuvant treatment…. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable [nonseminoma] relapse (< 2 years), and late viable [nonseminoma] relapse (> 2 years).”

MARIJUANA USE AND TESTICULAR CANCER RISK

More than 10 years of marijuana use is associated with the development of testicular germ cell tumor (TGCT), but the quality of the evidence is "low strength" and there is insufficient evidence to support an association between ever having used marijuana and other types of cancer.

These are the conclusions from a new systematic review and meta-analysis published online today in JAMA Open Network.

Lead author Mehrnaz Ghasemiesfe, MD, Northern California Institute of Research and Education, San Francisco, and colleagues explain that they wondered if marijuana smoke might cause cancer, because tobacco smoke does. Once burned, the two substances share carcinogens, including toxic gases, reactive oxygen species, and polycyclic aromatic hydrocarbons like benzo[α]pyrene and phenols.

So the investigators looked at studies from 1973 to 2018 comparing nonusers to marijuana ever-users, who were defined as using one joint per day for 1 year.

The team found 25 English-language studies (19 case-control, 5 cohort, and 1 cross-sectional). But only two studies were "low risk of bias."

In pooled analysis of case-control studies, ever-use of marijuana was not associated with two obvious cancer types: either head and neck squamous cell carcinoma or oral cancer.

But in pooled analysis of three case-control studies, more than 10 years of marijuana use was associated with TGCT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.03 - 1.81; P = .03) and nonseminoma TGCT (OR, 1.85; 95% CI, 1.10 - 3.11; P = .04).

The quality of the evidence was not high in any study.

For example, evaluations of ever-use generally found no association with cancers, but exposure levels were "low and poorly defined," said the authors. Also, findings for lung cancer studies were mixed, "confounded by few marijuana-only smokers, poor exposure assessment, and inadequate adjustment."

The authors believe that long-term studies in marijuana-only smokers "would improve understanding of marijuana's association with lung, oral, and other cancers."

Previous systematic reviews in this area have looked at multiple cancers, but examined them individually.

For example, there are two systematic reviews looking at the association between smoking marijuana and lung cancer. One looked at biological plausibility (ie, molecular, cytomorphologic, and histopathologic changes); the second study examined pulmonary toxic effects and found mixed evidence of an association with lung cancer (but did not pool data to estimate an overall association).

"Our findings are notable in a time of increasing marijuana use in the United States, with novel drug delivery methods, including vaping and edibles, becoming more popular, particularly in states that have legalized recreational use and among adolescents," the authors comment.

However, most of the studies included in their review are not recent, an important fact because, in the past, marijuana "smoking was the near-universal form of exposure," the authors note. Vaped marijuana is believed to have fewer long-term toxic effects than smoked marijuana.

Until more is known about any carcinogenicity of marijuana, "clinicians should discuss marijuana use with patients to raise awareness of the lack of clarity on potential clinically important harms and to debunk beliefs in unproven benefits," say the authors.

RPLND-I FOR STAGE I SEMINOMA? DEFINITION OF BEEE

Retroperitoneal lymph node dissection (RPLND) could potentially be a first-line option for men with stage II A/B testicular seminoma in order to reduce long-term toxicity and secondary malignancies, suggest data from two new studies.

Although RPLND is currently rarely used as first-line therapy in testicular seminoma, overall survival rates appear to be excellent, presenters said here at the Genitourinary Cancers Symposium (GUCS) 2019.

Discussing both studies, Sia Daneshmand, MD, associate professor of urology at the University of Southern California's Keck School of Medicine in Los Angeles, commented that RPLND as a primary treatment for stage ll seminoma is a fairly new approach. "Although it's an old concept that's basically been resurfaced and brought back to us, and it's a logical treatment," he added.

He pointed out that this approach has been a highly efficacious strategy in germ cell tumor management for years. The new data presented at the meeting suggest it can also be beneficial in testicular seminoma, and this approach is being investigated in an ongoing US study — the Surgery in Early Metastatic Seminoma (SEMS) trial — that has so far accrued 48 patients at 15 sites, with a planned accrual of 55 patients over 4 years.

"The goal, really, in this day and age is to maintain the high survival rates and reduce the long-term related toxicities," explained Daneshmand, who is also the principal investigator of the SEMS trial.

I think we can reduce long-term, treatment-related toxicities and lead to cure. Dr Sia Danesmand

RPLND as a primary treatment for treatment of metastatic seminoma is a paradigm shift, he said. "I think we can reduce long-term, treatment-related toxicities and lead to cure," he said. "And importantly, it's important to note that all the patients who do relapse are cured with chemotherapy."

Standard Therapy Has Toxicity 

Standard management is radiotherapy for stage IIA or chemotherapy for stage IIB seminoma, but "both of those options are toxic and lead to secondary malignancies, so we are looking for less-toxic treatment options," said Peter Albers, MD, professor of urology at Heinrich-Heine-University Düsseldorf, Germany, who presented one of the new studies.

"Toxicity and secondary malignancies definitely influence overall survival of testis cancer patients," he noted. For example, data on long term survival in testicular cancer from a Norwegian study show that — as compared with melanoma patients of the same age — there was a considerable drop in survival 35 to 40 years after testes cancer, and treatment-related toxicity took away about 6 to 7 years of life.

The new study that Albers presented at the meeting is part of an ongoing phase 2 trial, which is assessing the role of RPLND for men with low volume Stage II A/B seminoma without planned adjuvant therapy

This was a two-part study, which began with a 9-patient feasibility pilot phase. To date, an additional 14 patients were accrued, bringing the total to 23 patients enrolled in both studies.

All patients had clinical stage II A/B seminoma, <5 a="" cm="" diameter="" disease="" during="" experienced="" following="" had="" href="https://reference.medscape.com/drug/paraplatin-carboplatin-342107" ii="" in="" nbsp="" nodal="" or="" presented="" recurrence="" stage="" style="color: #416ed2; max-width: 100%; text-decoration: none;" surveillance="" transverse="" with="">carboplatin

 adjuvant therapy. RPLND was carried out by either open or robotic surgery, but was a unilateral template procedure, Albers explained.

The primary endpoint of the study was recurrence-free survival after 3 years, but if recurrence rates exceeded 30% in the first year after surgery, then the trial would be halted. This was the reason that the data was being presented now, Albers explained. "We had a planned interim analysis because of this stopping rule after one-and-a-half years."

Albers focused his presentation on the 14 patients in the phase II study. The median age was 36.5 years (range 28-49), and of this cohort, 6 patients were stage IIA and 8 were stage IIB. Ten patients had experienced disease recurrence while on surveillance, while 4 presented with metastatic disease and 2 had recurrences following treatment with adjuvant carboplatin.

The median tumor size was 1.8 cm, and 7 patients had open surgery, 7 had robotic RPLND, and 8 patients underwent an ipsilateral nerve sparing procedure.

At the interim analysis, 10 patients remain free of recurrence while 4 (29%) experienced disease recurrence. The mean time to recurrence was 6.8 months, and 3 of the recurrences occurred in patients with IIA disease. "This was a little bit astonishing for us, as well, that 3 of the 4 occurrences happened in stage IIA patients, with a considerable load of lymph node metastases taken out," said Albers.

All relapses were outside of the operative field, and all were cured with salvage chemotherapy. The surgical approach was not associated with recurrence rates, he said.

The recurrence rate of 29% matched the 30% rate observed in the pilot phase. "But in the first nine patients, we got the impression that recurrence is volume dependent, because only stage IIB and IIC patients relapsed," he said. "But this didn't hold true for the phase II trial."

Based on these interim results, the study will continue to completion. Albers and his colleagues now plan now to extend this trial to a multicenter setting in Germany in order to enhance accrual. "We would like to combine the data, at least for the IIA patients, with the ongoing US trial (SEMS)," he added. "And most importantly, we think that this is an ideal setting of testing the microRNA 371 measurement before and after surgery in search for a new biomarker that potentially could help [in] selecting patients for this approach."

US Data Show Good Survival Rates

The second study presented at the GUCS meeting was a retrospective analysis of US data.

Thomas L. Jang, MD, a urologic oncologist and assistant professor of surgery at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, and colleagues, used data from the 2004 to 2014 National Cancer Database to evaluate the use of RPLND in the primary and post-chemotherapy settings, as well as its impact on survival.

The final cohort included 412 men with testicular seminoma who were further stratified according to whether they had primary RPLND vs post-chemotherapy-RPLND; primary RPLND for stage IA-IIB without prior chemotherapy; and RPLND for stage IIA-IIIC disease after chemotherapy.

Of this group, 89% underwent RPLND in the first-line setting and the other 11% did so after being treated with chemotherapy, and no major differences were observed between these two groups. Most patients who underwent post- chemotherapy-RPLND did so at an academic center (63.8%) or comprehensive community cancer program (21.3%).

At a median follow-up of 4.1 years, the 5-year overall survival was 94.2% for primary RPLND, and 89% for those who had chemotherapy.

Among men with stage l or llA/B testicular seminoma, 10-year survival for those who underwent primary RPLND was 97.4% and 92.1% (P = .035), respectively.

"Although RPLND is rarely used as primary therapy in these men, overall survival rates appear to be favorable," said Jang in a statement. "Our findings are directional and, ultimately, ongoing prospective trials such as the SEMS trial will clarify the role of surgery in this setting."

No outside funding was disclosed for either study. Albers, Jang, and Daneshmand have disclosed no relevant financial relationships.

Genitourinary Cancers Symposium (GUCS) 2019: Abstracts 507 and 534. Presented February 15, 2019.

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SCREENING TESTICULAR CANCER SURVIVORS FOR ANDROGEN DEFICIENCY

Many neoplastic diseases that are common in childhood, adolescence and early adulthood were previously uniformly and swiftly fatal. These neoplastic diseases and their therapies are associated with an increased incidence of multiple endocrinopathies. For example, intracranial neoplasias invade the hypothalamus and/or pituitary and cause deficiencies of growth hormone, gonadotrophins, thyrotrophin or adrenocorticotrophin. Cranial radiation used to treat intracranial neoplasia is often associated with progressive hypopituitarism that may take years to develop into a clinically significant endocrinopathy.^[1] Neoplasias that destroy normal endocrine tissue outside of the brain may cause primary endocrinopathies. Testicular cancer, the most common solid malignancy in 18–35 years old men, may cause abnormalities in testicular function by damaging normal testicular histology. Alkylating chemotherapies used in the treatment of testicular cancer commonly cause primary testicular dysfunction.

With the advent of increasingly effective therapies for many of these diseases, many young patients are surviving for decades without recurrent disease.^[1,2] Recognition and management of the endocrine sequelae of cancers of childhood and early adulthood are now major considerations in the long-term care of these survivors. In boys and young men, disturbance of normal reproductive function is one of the common, late sequelae of neoplasia or its treatment.^[3] The most common long-term manifestation of reproductive dysfunction in male survivors of childhood and early adult neoplastic disease is reduced fertility as an adult. Although most clinicians equate hypogonadism with hypoandrogenaemia, normal gonadal function in men consists of spermatogenesis and production of sex steroid hormones. Hypogonadism may be defined as androgen deficiency, dysspermatogenesis or both.

In conjunction with very high intratesticular testosterone concentrations (100-fold higher than circulating concentrations in men) produced by Leydig cells, Sertoli cells nurture spermatogenesis.^[4,5] For normal sperm production, both high intratesticular testosterone concentrations and normal Sertoli cell function are required. It is rare to have significant testosterone deficiency without having some degree of impairment in sperm maturation.

Sertoli cells are more vulnerable to the effects of chemotherapy and testicular and pelvic radiation, and thus, reduced sperm production and fertility are much more common than androgen deficiency in men who are long-term survivors of early-onset cancer.^[3] In the Childhood Cancer Survivors Study, the hazard ratio for ever siring a child was 0.56 (95% CI 0.49–0.63) compared with the brothers of the cancer survivors.^[6] Sertoli and germ cells for spermatogenesis are more vulnerable after puberty; adolescents and young adults treated for cancer are more likely to be infertile than children treated before puberty.^[6]

The prevalence of androgen deficiency in adult survivors of childhood and young adult cancer is unclear. In one study of men who had survived an average of 20 years after the diagnosis and treatment of cancers before age 18, 23% of the survivors had a low serum total testosterone concentration (<10 an="" concentration="" elevated="" lh="" nmol="" or="" serum="">10/IU/L) compared to 4% of controls.^[7] However, serum testosterone concentrations were not uniformly measured in the early morning hours. The normal range is based on peak testosterone concentrations that occur in the early morning; serum testosterone concentrations decline significantly after the early morning.^[8] In another study of young adult survivors, the prevalence of low early morning serum total testosterone concentrations (<10 14="" 2.5="" cancer.="" compared="" controls="" in="" less="" nmol="" style="font-size: 0.75em; line-height: 1; max-width: 100%;" sup="" than="" to="" was="" without="">[9]

Most recently, Isaksson and colleagues studied the prevalence of hypogonadism in adult survivors >18 years old) of childhood cancer (diagnosed before age 18) and another cohort of men who had survived testicular cancer diagnosed in early adulthood.^[10] These investigators showed a higher prevalence of hypogonadism compared to their control population, all of whom (patients and controls) resided in southern Sweden. They defined a gonadal function outcome based on the following:

• Primary hypogonadism: total testosterone < 10 nmol/L; LH and FSH > 10 IU/L with FSH > LH concentration; total testosterone < 10 nmol/L, LH ≤ 10 IU/L and FSH > 10 IU/L
• Secondary hypogonadism: total testosterone <10 10="" and="" fsh="" iu="" lh="" nmol="" p="">
• Compensated hypogonadism: total testosterone ≥ 10 nmol/L but LH > 10 IU/L
• Current testosterone therapy

For those in the cancer survivor cohort, they found an overall prevalence of hypogonadism of approximately 26% and an odds ratio of 2.1 compared to the control group. They observed that 6% of the cancer survivors had primary hypogonadism, 7% had secondary hypogonadism, 22% had compensated hypogonadism, and another 11% were being treated with testosterone. For the cohort of men who had survived testicular cancer, the prevalence of hypogonadism was 36% with an odds ratio of 6.9 compared to controls. For each subgroup, 14% had primary hypogonadism, 7% had secondary hypogonadism, 7% had compensated hypogonadism, and 10% were being treated with testosterone.

According to the Isaksson study,^[10] the prevalence of androgen deficiency is high enough to justify screening in long-term survivors of childhood cancer or testicular cancer in early adulthood. However, the study has several limitations. First, similar to other studies,^[7,9] the investigators do not have data on symptoms and signs of androgen deficiency. The diagnosis of androgen deficiency requires symptoms or signs of androgen deficiency.^[8] Second, the data in the Isaksson study are based on a single blood sample, and there is enough day-to-day variation of serum testosterone concentrations that it is required that androgen deficiency be confirmed with at least two low serum testosterone concentrations.^[8] Third, not all blood samples were obtained in the early morning, and it is unknown whether the men were acutely ill at the time of venipuncture for testosterone measurement. It is well known that measurement of testosterone on a sample after 10 AM or during acute illness may be associated with lower concentrations of testosterone.^[8] Fourth, the investigator uses total testosterone concentrations to define androgen deficiency. Many of these men may have had low serum sex hormone-binding globulin concentrations and had normal (calculated) free testosterone concentrations. Men with low total testosterone concentrations and normal calculated free testosterone concentrations are likely eugonadal.^[11] Fifth, compensated hypogonadism–a normal serum testosterone concentration, but raised LH concentration–might not be a clinically significant phenomenon. In addition, because LH is secreted in a pulsatile fashion, some men who were categorized as having compensated hypogonadism might have had serum LH concentrations measured during a pulse of LH secretion.^[12]Measurement on a second sample may have yielded a normal LH concentration in these men. Finally, the investigators conducted a number of subgroup analyses without evidence of preplanned comparisons. This approach increases the risk of type I and type II statistical errors.

Nonetheless, the study has a number of strengths including relatively large numbers of cancer survivors and a long follow-up period. The data are likely to be complete because the study was based on a Swedish national registry (in a single national healthcare system). The investigators correctly conclude that further studies must be carried out. A prospective, longitudinal cohort study with data on symptoms and signs of androgen deficiency and data on early morning testosterone, FSH and LH concentrations as well as seminal fluid analyses would be invaluable.

In the meantime, it is incumbent on the clinician to enquire about symptoms of testosterone deficiency in men who have survived childhood or testicular cancer and then conduct an appropriate evaluation to determine whether hypogonadism is present.

BLEOMYCIN USE AND SURGICAL MORBIDITYN

In a retrospective single-institution analysis reported in the Journal of Clinical Oncology, Calaway et al found that the addition of bleomycin to etoposide/cisplatin did not appear to increase risk of pulmonary or postoperative morbidity after postchemotherapy retroperitoneal lymph node dissection in men with International Germ Cell Cancer Collaborative Group (IGCCCG) good-risk germ cell tumors. 

Three cycles of bleomycin, etoposide, and cisplatin (BEP × 3) or four cycles of etoposide and cisplatin (EP × 4) are considered first-line regimens for men with good-risk germ cell tumors. Analysis of the prospectively maintained Indiana University Testis Database identified 234 good-risk patients treated between 2006 and 2016 who received BEP × 3 (n = 191) or EP × 4 (n = 43) as induction chemotherapy, had residual retroperitoneal mass > 1 cm, and had normal preoperative serum tumor markers.

The primary outcomes of interest were pulmonary morbidity (prolonged intubation, reintubation, supplemental oxygen use, intensive care unit [ICU] stay) and operative morbidity (operative time, length of stay, concomitant procedures, estimated blood loss).

Treatment Outcomes

All patients were extubated immediately after surgery, with none requiring reintubation or discharge on oxygen. Two patients in each group required ICU stay for nonpulmonary reasons. No significant differences between groups were found for preoperative mass size (P = .42) or concomitant surgeries (P = .58).

Patients receiving BEP had shorter use of supplemental oxygen (0.99 vs 1.63 days, P= .005), shorter operative time (131 vs 170 minutes, P < .01), and reduced estimated blood loss (194 vs 226 mL, P < .01). The length of hospital stay was reduced in patients receiving BEP (3.3 vs 3.9 days, P < .01).

The investigators concluded, “In a modern surgical cohort, the inclusion of bleomycin does not seem to influence pulmonary morbidity, operative difficulty, or nonpulmonary postoperative complications after [postchemotherapy retroperitoneal lymph node dissection] in men with IGCCCG good-risk [germ cell tumors].”

Adam C. Calaway, MD, of the Department of Urology, Indiana University School of Medicine, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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RISK OF SECOND CANCER AFTER TREATMENT OF TESTICULAR CANCER

In a Dutch study reported in the Journal of Clinical Oncology, Groot et al found that the risk of subsequent malignant neoplasms was increased in the long-term follow up of patients receiving cisplatin or radiotherapy for testicular germ cell cancer.

Risk vs General Population

The study involved 5,848 testicular cancer 1-year survivors treated before the age of 50 years between 1976 and 2007 in 13 Dutch hospitals. After a median follow-up of 14.1 years, 350 solid subsequent malignant neoplasms were observed, representing a 1.8-fold increased risk of solid cancers compared with the general population. Solid subsequent malignant neoplasm risk was increased in patients with seminoma (standardized incidence ratio = 1.52) and in those with nonseminoma (standardized incidence ratio = 2.21). Patients with nonseminoma had an increased risk of thyroid, lung, stomach, pancreatic, colon, and bladder cancers, as well as melanoma and soft-tissue sarcoma. Patients with seminoma had an increased risk of small intestine, pancreatic, and urinary bladder cancers. Overall, the 25-year cumulative incidence of solid subsequent malignant neoplasms was 10.3%.

Risk Factors 

In a multivariable analysis, receipt of platinum-based chemotherapy was associated with an increased risk of any solid subsequent malignant neoplasm (hazard ratio [HR] = 2.40, 95% confidence interval [CI] = 1.58–3.62), colorectal subsequent malignant neoplasm (HR = 3.85, 95% CI = 1.67–8.92), and noncolorectal gastrointestinal (GI) subsequent malignant neoplasm (HR = 5.00, 95% CI = 2.28–10.95). Receipt of a platinum chemotherapy dose of 400 to 499 mg/m² (HR = 2.43, 95% CI = 1.40–4.23) or ≥ 500 mg/m² (HR = 2.42, 95% CI = 1.50–3.90) was associated with an increased risk of solid subsequent malignant neoplasm vs receipt of surgery alone; no increased risk of subsequent malignant neoplasm was associated with the use of lower platinum doses (HR = 1.75, 95% CI = 0.90–3.43). The hazard ratio for GI subsequent malignant neoplasms increased by 53% per 100 mg/m² increase in platinum dose (P < .001 for trend). The hazard ratio for an infradiaphragmatic subsequent malignant neoplasms increased by 8% per Gy of infradiaphragmatic radiation dose vs no para-aortic radiation therapy (P < .001) for trend.

The investigators concluded, “Radiotherapy and platinum-containing chemotherapy are associated with increased solid [subsequent malignant neoplasm] risk, specifically with GI [subsequent malignant neoplasms].”

The study was supported by a grant from the Dutch Cancer Society.

Michael Schaapveld, PhD, of the Department of Epidemiology, Netherlands Cancer Institute, is the corresponding author of the Journal of Clinical Oncologyarticle.

MORBIDITY OF TESTICULAR CANCER SURRVIVORS

In a study reported in the Journal of Clinical Oncology, Kerns et al found that approximately 20% of testicular cancer survivors treated with cisplatin-based regimens had high cumulative burden of morbidity (CBM) scores and identified factors associated with risk for increased morbidity.

Study Details

The study population consisted of 1,214 patients from the testicular cancer cohort of the international multicenter Platinum Study. Participants were aged ≤ 55 years at diagnosis and had completed first-line cisplatin-based chemotherapy ≥ 1 year prior to enrolment. CBM scores were generated that reflected number and severity of adverse health outcomes. Patients had a median age of 37 years at evaluation, and median time since chemotherapy was 4.2 years.

CBM Scores and Risk Factors

Among all patients, CBM scores were very high/severe in 4%, high in 15%, medium in 30%, and low/very low in 47%. Risk factors for higher scores included treatment with 4 cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.04–3.71) or bleomycin, etoposide, and cisplatin (OR = 1.44, 95% CI = 1.04–1.98); older attained age (OR = 1.18, 95% CI = 1.10–1.26); current disability leave (OR = 3.53, 95% CI = 1.57–7.95); less than college education (OR = 1.44, 95% CI = 1.11–1.87); and current or former smoking status (OR = 1.28, 95% CI = 1.02–1.63); CBM scores did not differ between the 2 chemotherapy regimens (P = .36). Lower scores were associated with Asian race (OR = 0.41, 95% CI = 0.23–0.72) and vigorous exercise (OR = 0.68, 95% CI = 0.52–0.89).

Variable clustering analyses identified 6 significant adverse health outcome clusters (χ²  P < .001): hearing loss/damage, tinnitus (OR = 16.3); hyperlipidemia, hypertension, diabetes (OR = 9.8); neuropathy, pain, Raynaud phenomenon (OR = 5.5); cardiovascular and related conditions (OR = 5.0); thyroid disease, erectile dysfunction (OR = 4.2); and depression/anxiety, hypogonadism (OR = 2.8).

The investigators concluded, “Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified [adverse health outcome] clusters could guide the development of survivorship care strategies.”

The study was supported by grants from the National Cancer Institute.

Lawrence H. Einhorn, MD, of the Indiana University Melvin and Bren Simon Cancer Center, is the corresponding author for the Journal of Clinical Oncologyarticle. 

LONG TERM FOLLOW UP OF TESTICULAR CANCER SURVIVORS

Testicular cancer is the most common cancer in young men. The majority of patients are cured of their disease, but a newly published study shows many remain at risk for later complications from chemotherapy or other treatments. The study, published by Zaid et al in JNCCN –Journal of the National Comprehensive Cancer Network, confirms that testicular cancer survivors are more likely to develop hypertension, hypercholesterolemia, and obesity, which can significantly increase their risk of heart disease.

The Platinum Study, which was funded by the National Cancer Institute, is the largest study to examine the rates of metabolic abnormalities among testicular cancer survivors who received prior platinum-based chemotherapy and the only study of this sort using North American patients, rather than Europeans.

“The North American population is generally more ethnically and genetically diverse compared to Europeans, making it interesting to examine the similarities and differences in potential genetic risk factors for metabolic syndrome,” said Mohammad Abu Zaid, MD, Assistant Professor of Medicine at Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center.

Study Findings

For the study, metabolic syndrome was defined by the standard medical criteria of three or more of the following conditions: hypertension, abdominal obesity, hypertriglyceridemia (elevated triglyceride levels), decreased levels of high-density lipoprotein (HDL), and diabetes.

“We found that 1 in 10 testicular cancer survivors under age 30 had metabolic syndrome, and that increased to more than one-third of patients over age 50. However, some of the genetic changes that reportedly play a large role in increasing the risk of metabolic syndrome among Europeans were not factors for our patients.”

The researchers evaluated 486 testicular cancer survivors, with a median age of 38.1 years, and found they were more likely to have hypertension than their cancer-free peers, (43.2% vs 30.7%, P < .001) but were less likely to have lower levels of HDL (23.7% vs 34.8%, P < .001), or abdominal obesity (28.2% vs 40.1%, P < .001). As for other potential heart disease risk factors, testicular cancer survivors were significantly more likely to have higher amounts of low-density lipoprotein (17.7% vs 9.3%, P < .001), higher overall cholesterol levels (26.3% vs 11.1%, P < .001), and be classified as overweight based on their body mass index (75.1% vs 69.1%, P = .04).

“For testicular cancer survivors, as with most cancer survivors, the medical concerns don’t end with remission,” explained Timothy Gilligan, MD, MS, Vice Chair for Education and Associate Professor of Medicine, Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Dr. Gilligan chairs the National Comprehensive Cancer Network^®(NCCN^®) Guidelines Panel on Testicular Cancer.

“Testicular cancer survivors whose treatment included chemotherapy, radiation therapy, or both have an increased risk of dying from cardiovascular disease. This study provides valuable information as we try to understand why. It also serves as an important reminder for appropriate long-term health care after completing cancer treatment, as detailed in the NCCN Guidelines for Survivorship,” said Dr. Gilligan.

“The overarching goal of our study is to implement early interventions in order to reduce the risk of heart disease,” said Dr. Abu Zaid. “At this time, there are no criteria for determining what exactly causes metabolic syndrome in cancer survivors. Developing those criteria requires long-term follow-up of cancer survivors, which is something we’ll be doing as part of this ongoing Platinum Study. This will help us understand which risk factors are more likely to lead to heart disease for this particular population.”

Recommendations

The researchers encourage providers to screen and adequately treat testicular cancer survivors for hypertension, dyslipidemia, and hypogonadism and to advocate for the adoption of healthy lifestyle practices like regular exercise and tobacco avoidance. They also recommend that young testicular cancer survivors discuss the risks and benefits of testosterone replacement therapy with their physicians.

Testicular cancer survivors with abnormally low testosterone levels may experience fatigue, low energy, and decreased sexual desire. In addition, they can be at risk for metabolic syndrome, decreased muscle mass, osteoporosis, and potentially heart disease.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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EXPERIENCE IMPORTANT IN TREATING GERM CELL TUMORS

Institutional experience, hospital and physician volume have been associated with improved outcomes. However, there are little reports in term of impact of multidisciplinary cancer care. Investigation of the role of multidisciplinary clinic in improving the outcomes of patients with metastatic germ-cell tumours (GCTs) at high volume cancer center led to observed better survival compared with the historical International Germ Cell Cancer Collaborative Group (IGCCCG) and the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) distant cohort. The results are published in the Annals of Oncology. 

The optimal management of GCTs is complex, with options including chemotherapy and surgery. The Indiana University Cancer Center established a multidisciplinary clinic to evaluate newly diagnosed GCT patients and those who need additional consultation. The goals of this multidisciplinary clinic are to provide state-of-the-art cancer care and to educate patients, their families, medical students, residents, and fellows in training. This multidisciplinary clinic integrates dedicated team including medical oncologists, pathologists, urologic and thoracic surgical oncologists, full-time coordinator (responsible for data acquisition, scheduling, and following-up with patients and referring physicians) and oncology nurses. The team meets on a weekly basis in a multidisciplinary tumour board. Through this clinic, it is possible to establish the accurate pathologic diagnosis, offer combination chemotherapy, surgical resection of residual tumour and enroll patients on clinical trials all in one visit. 

The study authors commented that recent outcome data from large datasets are missing, and the difference in results of patients treated in large volume centers and community centers is unknown. They report survival outcomes in patients with metastatic GCT treated at their multidisciplinary clinic since the publication of IGCCCG and compare the outcome to those of SEER programme. It is the largest single-institution study evaluating survival outcomes of patients with metastatic GCT. 

In particular, they conducted a retrospective analysis and identified 1611 patients, of whom 704 patients received an initial evaluation in their multidisciplinary clinic and started first-line chemotherapy. These 704 patients were eligible for analysis. All patients in this cohort were treated with  cisplatin– etoposide-based combination chemotherapy. The study team compared the progression-free survival (PFS) and overall survival (OS) of patients treated at their centre with that of the published IGCCCG cohort. The OS of the testis cancer primary cohort in their institution (622 patients) was further compared with the SEER data of 1283 patients labelled with ‘distant’ disease. 

With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at their institution had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in their cohort was 79%. The 5-year OS for their cohort was 90%. Their cohort had 5-year OS 94% vs 75% for the SEER ‘distant’ cohort between 2000 and 2014 (p < 0.0001). 

Several factors may account for excellent survival outcomes seen in this study compared with the IGCCCG and SEER database. This could be attributed to the uniform utilisation of cisplatin–etoposide-based combination chemotherapy, improvement in supportive care avoiding delays between cycles, expertise in post-chemotherapy surgical resection of residual disease and the experience resulting from a large volume of patients. Their multidisciplinary team has specific academic interest in GCT supported by strong research and clinical trials. 

The analysis has also limitations. It is a retrospective single institution study. The study team did not have access to matched patient’s characteristics between the contemporary cohort in their centre and the historical IGCCCG cohort, and the community patients reported in SEER. Referral bias might have affected the results of this study. However, this study has a large sample size of consecutive patients with metastatic GCT treated at a tertiary care center with long follow-up. A large portion of patients enrolled in the study had poor risk disease 25.7% compared with 14% of patients from the IGCCCG. Besides, a limitation of this study is that NCI SEER uses a staging system including local, regional, and distant metastases which are not typically used in GCT. The IGCCCG classification of good, intermediate, and poor risk is not included in the SEER database which makes further analysis not possible. It is why the study team compared all patients with metastatic disease as one group. 

In this modern cohort of newly diagnosed patients with metastatic GCT, there was an improvement in PFS and OS for good, intermediate, and poor-risk disease compared with IGCCCG. Furthermore, the study team demonstrated that a multidisciplinary team care approach is associated with improved survival outcomes. 

HYPOGONADISM IS COMMON IN TESTICULAR CANCER PATIENTS

A substantial percentage of testicular cancer survivors have low testosterone levels, which in turn puts them at risk for a plethora of chronic health conditions, including hypertension, diabetes, erectile dysfunction, anxiety, and depression, according to findings from a large multicenter study.

For example, compared to survivors with normal testosterone levels, those with hypogonadism were about three times more likely to be taking medication for dyslipidemia (20% vs 6%; P < .001) and twice as likely to be treated for diabetes (6% vs 3%; P = .07).

They were also more likely to be undergoing treatment for hypertension (19% vs 11%; P = .01), anxiety or depression (15% vs 10%), and erectile dysfunction (20% vs 12%; P = .02).

"Testicular cancer occurs at a young age and is highly curable, and patients can expect to live for 40 years after their diagnosis, but there is a long-term risk for late complications from treatment," said lead study author Mohammad Issam Abu Zaid, MBBS, an assistant professor of medicine at the Indiana University School of Medicine in Indianapolis. He was presenting the findings here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.

"Clinical and genetic factors can increase the risk for hypogonadism, and providers should screen testicular cancer survivors for hypogonadism and treat those with symptoms," he said.

Late Events in Testicular Cancer Survivors

As previously reported by Medscape Medical News, survivors of testicular cancer face a worrisome risk of developing certain metabolic effects, such as hypertension, that are tied to platinum-based chemotherapy. Several European studies have shown that survivors have up to a sevenfold increased risk of developing cardiovascular disease.

Although it's been known for some time that low testosterone levels occur in a significant proportion of survivors of testicular cancer, the current study is one of the first to examine its relationship with long-term health complications in North American patients.

Research has also been limited, Dr Zaid noted, as far as taking into account genetic variations when evaluating the relationship between hypogonadism and adverse health outcomes. One European study, for example, reported that the prevalence of metabolic syndrome was higher among survivors of testicular cancer who were homozygous for a single-nucleotide polymorphism (SNP), rs523349 (V89L), in 5-α-reductase gene (SRD5A2). That study also found the prevalence of metabolic syndrome to be 67% in survivors with low testosterone levels who carried the variant genotype.

Clinical and Genetic Factors

In the current study, Dr Zaid and his colleagues evaluated the first 491 patients who are participants in the Platinum Study, which aims to be the largest study of survivors of testicular cancer worldwide. To date, more than 1600 survivors have been enrolled, and the study is still actively recruiting.

The focus of the findings that were presented was on the incidence of hypogonadism in this population, as well as predisposing factors.

All patients received chemotherapy and were younger than 55 years when they were diagnosed with cancer. The median age at clinical evaluation was 38 years.

The authors found that there were two SNPs in the sex-hormone-binding globulin (SHBG) locus, and survivors with two or more risk alleles for these 2 SNPs had a twofold increased risk for hypogonadism (odds ratio [OR] = 2.2; P = .12).

"This finding needs to be confirmed in larger studies, and we will do so in the next phase of the Platinum Study," said Dr Zaid.

Survivors with hypogonadism were also more likely to report adverse health outcomes. Roughly one third (35%) of those with hypogonadism reported having none or one adverse health outcome, compared to 49% with normal levels (P = .003).

Aside from the genetic profile, the authors identified other risk factors for developing hypogonadism. These included older age (OR = 1.4 per 10-year increase; P = .007) and a body mass index ≥25 kg/m² (OR = 2.2; P = .003).

In contrast, vigorous physical activity appeared protective (OR = 0.6; P = .06). They type of chemotherapy regimen and socioeconomic factors did not appear to have any impact.

SHBG polymorphisms appear important in survivors of testicular cancer, but the study was underpowered to confirm an association, Dr Zaid commented.

"Our findings underscore the need for clinicians to assess testicular cancer for physical signs or symptoms of hypogonadism and to measure testosterone in those who do," he concluded.

Caution in Testosterone Testing

"This is an important study and sends a loud message to those us who take care of these patients," commented ASCO Expert Timothy D. Gilligan, MD. "We need to watch for it and ask our patients about symptoms."

He added that these are young men with many years of life ahead of them, and thus not treating hypogonadism could leave them with long-term associated health problems. "We hope this study will get the message out there more broadly, as I don't think many doctors are as aware of it as they might be."

However, Dr Gilligan cautioned that the fact that hypogonadism affects a significant number of patients does not mean that testing should be universal. Testosterone levels can vary widely in men, a fact that underscores the importance of recognizing symptoms.

"We should not be testing testosterone levels in all patients, but instead, looking for symptoms is the key," he said.

The study was funded by the National Institutes of Health. Dr Zaid has disclosed no relevant financial relationships. Several coauthors have relationships with industry, as noted in the abstract. Dr Gilligan has a relationship with Wellpoint.

2017 American Society of Clinical Oncology (ASCO) Annual Meeting. Abstract LBA10012, presented June 3, 2017.

GENE FOUND IMPLICATED IN HEARING LOSS BY CISPLATIN

Cisplatin-induced ototoxic effects in patients with testicular cancer are associated with a protein-coding variation in the transporter gene SLC16A5, according to an international group of researchers.

As Dr. Bruce C. Carleton told Reuters Health by email, "Hearing loss is a debilitating side effect from cisplatin that occurs in 20 to 40% of testicular-cancer patients treated with this drug. In this study, we identified a variant in the SLC16A5 gene that decreases the chance of experiencing hearing loss caused by cisplatin more than tenfold."

Dr. Carleton, of BC Children’s Hospital Research Institute in Vancouver, Canada, and colleagues studied data on 188 patients with a median age of 31 years. All had been treated with cisplatin-based chemotherapy. The discovery cohort consisted of 23 cases and 73 controls and the replication cohort of 14 cases and 78 controls.

Cisplatin-associated ototoxic effects were diagnosed by two audiologists and the patients were screened for more than 7,900 variants within the absorption, distribution, metabolism and excretion gene regions.

Association and fine-mapping analyses revealed a protein-coding variant of SLC16A5 that had a protective effect against cisplatin-induced ototoxic effects in both independent cohorts. The association remained significant after Bonferroni correction in the combined cohort (odds ratio, 0.06), the researchers report in JAMA Oncology, online April 27.

In vitro studies showed that SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting its role in the development of cisplatin-induced ototoxic effects.

The researchers further note that SLC16A5 is inhibited by cimetidine. Its addition to cisplatin treatments in rat cochlear cultures and in mice prevented such ototoxic events without compromising cisplatin’s antitumor activity.

Given these results, continued Dr. Carleton, "Testing for this variant would aid in predicting which patients are more likely to experience hearing loss from cisplatin such that proper hearing screening can accompany cancer treatment."

"The findings from this study," he concluded, "also have important implications for the investigation of drugs that inhibit the SLC16A5 gene to potentially use as protective agents against the development of cisplatin-induced hearing loss."

ADVERSE EVENTS OF TESTICULAR CANCER TREATMENT

In a study reported in the Journal of Clinical Oncology, Fung et al found that although adverse health outcomes were common among testicular cancer survivors, there did not appear to be differences in such outcomes according to chemotherapy regimens commonly used to treat favorable-risk disease. Historically, standard chemotherapy has consisted of three cycles of bleomycin, etoposide, and cisplatin (BEPX3) or four cycles of etoposide and cisplatin (EPX4) for favorable-risk disease and four cycles of BEP (BEPX4) for intermediate- or poor-risk disease.

Study Details

The study involved 952 survivors treated at sites in the United States and Canada. Patients had a median age at evaluation of 37 years and a median time since chemotherapy of 4.3 years. Chemotherapy consisted of BEPX3 in 38.2%, EPX4 in 30.9%, and BEPX4 in 17.9%. None, 1 to 2, 3 to 4, and ≥ 5 adverse health outcomes were reported by 20.4%, 42.0%, 25.1%, and 12.5% of survivors, respectively.

The median number of adverse health outcomes was 2 after EPX4 (range = 0–9) or BEPX3 (0–11) and 2 (0–10) after BEPX4. EPX4 was associated with a higher rate of peripheral neuropathy (29.2% vs 21.4%, P = .02), and BEPX3 was associated with a higher rate of Raynaud’s phenomenon (21.4% vs 11.6%, P < .01) and obesity (33.0% vs 25.5%, P = .04).

A higher cumulative bleomycin dose was associated with risk of ≥ 5 adverse health outcomes (odds ratio [OR] = 1.44/90,000 IU). Increasing age was associated with risk of increasing number of adverse health outcomes (ORs = 1.22 for 1–2, 1.50 for 3–4, and 1.87 for ≥ 5 per 5 years of age; P < .01), whereas vigorous physical activity was protective against the occurrence of multiple adverse health outcomes (ORs = 0.62 for 1–2, 0.51 for 3–4, and 0.41 for ≥ 5; P < .05).

Significant risk factors for 3 to 4 and for ≥ 5 adverse health outcomes included current smoking (ORs = 3.05 and 3.73) or former smoking (ORs = 1.61 and 1.76; P < .05). Self-reported health was excellent/very good in 59.9% of survivors but decreased in quality with an increasing number of adverse health outcomes (P < .001).

The investigators concluded: “Numbers of [adverse health outcomes] after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of [adverse health outcomes].”

The study was supported by National Cancer Institute grants.