Treatment of Prostate Cancer in Obese Patients

Obesity is a complex, chronic disease that has reached epidemic proportions in the United States. Obesity is now linked with numerous health conditions, including many oncologic diagnoses. Its association with prostate cancer, the most prevalent cancer in men, has also been investigated, with studies suggesting a direct relationship between increasing obesity and prostate cancer mortality. Outcomes data for specific interventions in obese patients with prostate cancer have only recently begun to emerge. Surgery, while feasible even in the very obese, may result in less than optimal cancer control rates. Brachytherapy data are emerging, and are promising. No outcomes data are available for the use of external-beam radiation in obese patients. Long-term data for external-beam radiation, as well as for surgery and brachytherapy, are required to determine the most appropriate treatment for obese patients with prostate cancer. These data, coupled with a more thorough understanding of the biochemical relationship between obesity and prostate cancer, will be necessary to make optimal management decisions for obese patients with prostate cancer in the future.

Obesity has increased to epidemic proportions in the United States. The percentage of obese adults has swelled from 13.3% of the adult population in the early 1960s to 31.1% in 1999 through 2002.[1] The potential causes for this increase have been debated, as obesity is a complex, multifaceted, chronic disease mediated by genetics, the psychosocial environment, and physiologic variables.[2] The causes notwithstanding, the detrimental health effects of this demographic shift are becoming clear.

Obesity is a known risk factor for numerous health conditions, including cataracts, coronary heart disease, diabetes, erectile dysfunction, gastro-esophageal reflux disease (GERD), hypercholesterolemia, hypertension, osteoarthritis, and respiratory compromise, among others.[2] Moreover, while some analyses suggest that there is no such association,[3] many studies have linked obesity status with numerous oncologic diagnoses such as uterine, breast, gallbladder, and colon cancer.[4,5] In addition, several studies have investigated the relationship between obesity and prostate cancer with respect to epidemiology and outcome, often with seemingly conflicting results.

Body Mass Index

In such studies, the most frequently utilized method of assessing obesity is the calculation of body mass index (BMI), in which a person's weight in kilograms is divided by the person's height in square meters.[6] A BMI < 25 kg/m² is considered normal, 25 to 29.9 kg/m² is considered overweight, while BMI ≥ 30 kg/m² is considered obese. This latter group is further divided into grade 1 (30-34.9 kg/m²), grade 2 (35-39.9 kg/m²), and grade 3 (≥ 40 kg/m²).

In the Health Professionals Follow-up Study, which is a prospective cohort study of over 51,000 US male health professionals started in 1986, the risk of developing prostate cancer was found to be decreased in men with a BMI ≥ 30 kg/m² for men younger than 60 years of age or with a family history of prostate cancer. Among men with no family history of prostate cancer, BMI was not statistically associated with prostate cancer development.[7] Some other epidemiologic studies have supported this inverse relationship of obesity and the development of prostate cancer,[8,9] while some have not.[8]

The association between obesity and the risk of developing prostate cancer may be equivocal; studies are fairly consistent, however, in showing a relationship between increasing BMI levels and prostate cancer mortality. An American Cancer Society (ACS) study of over 400,000 US adults showed that the mortality risk associated with prostate cancer increased with higher BMI levels. Patients with grade 1 obesity had a 20% increase in mortality relative to men with a normal BMI between 18.5 and 24.9 kg/m². Furthermore, men with grade 2 obesity had a 34% increase in mortality relative to men with a normal BMI.[11] An earlier study by the ACS that followed over 450,000 men also suggested an increase in prostate cancer mortality with higher BMI levels.[12] Surgical series have generally demonstrated higher tumor grades and more advanced disease in obese patients, with higher biochemical failure rates even when surgical margins are clear.[13]

Explaining the Relationship

Several hypotheses have been proposed to explain the complex association between obesity and aggressive prostate cancer. Perhaps the most prevalent explanation, given that prostate cancer is a hormonally dependent malignancy, is that obesity affects the hormonal milieu, which in turn affects the biologic progression of prostate cancer. Decreased serum androgen levels have been shown to occur with obesity[14,15]; prostate cancer that proliferates in low-testosterone environments may be inherently partially androgen-independent, and therefore, a more aggressive form of the disease.[16,17] Other hormones, including estradiol, insulin, leptin, and adiponectin, may also exacerbate prostate cancer in obese patients.

Obese patients have increased levels of estradiol, which, in combination with testosterone, may enhance tumorigenesis relative to testosterone alone.[18,19] Obesity is also related to insulin resistance and elevated levels of insulin and insulin-like growth factor (IGF), the latter of which imparts a stimulatory, proliferative effect on cells.[20] Moreover, elevated IGF-1 levels have been shown to specifically increase the risk of prostate cancer, and have been correlated with advanced-stage disease.[21,22] Leptin, a polypeptide hormone produced by adipocytes, has been demonstrated to promote angiogenesis, as well as the growth of androgen-independent cell lines in-vitro. Leptin serum levels are directly associated with the degree of obesity and have been correlated with larger, higher-grade, and more advanced tumors.[23,24] Adiponectin, another adipocyte-produced polypeptide hormone, has been shown to inhibit angiogenesis, and is indirectly related to obesity. Lower adiponectin levels have been associated with higher-grade and more advanced cancer.[25,26]

In addition to these hormonal alterations, difficulties with prostate cancer detection may partly explain the more aggressive nature of prostate cancer at presentation in obese patients. Obesity may result in lower serum prostate-specific antigen (PSA) levels, resulting in delayed biopsies and, consequently, more advanced disease at diagnosis.[14,15] Alternatively, simply having an elevated BMI may impede cancer detection with prostate biopsy. Presti and colleagues reported that overweight and obese men had a lower cancer detection rate by biopsy compared to men with a normal BMI, even when controlling for PSA levels.[27]

Treatment

Clearly, the mechanisms by which obesity may affect both the development and diagnosis of prostate cancer remain unclear. Treatment outcomes for obese patients are only slightly better understood. Despite the prevalence of obesity, remarkably little has been published regarding outcome after treatment in these patients. There has been a recent increase in such information in the surgical literature, with limited outcomes data. Outcomes data regarding radiation are even more scarce.

Surgery

Operating on obese patients has been associated with an increased likelihood of typical surgical complications, including wound infections, worsening of underlying ventilation/perfusion disturbances, deep venous thrombosis (DVT), and increased risk of aspiration pneumonitis.[28,29] These data notwithstanding, several surgical series have been published regarding the feasibility of radical prostatectomy specifically in obese patients.

One early, retrospective series summarized short-term outcomes for seven obese patients (BMI > 30 kg/m²) following radical perineal prostatectomy. The average operative time and blood loss were 142 minutes and 542 mL, respectively, with no perioperative or postoperative complications reported. Two of seven patients were found to have a positive margin, and two of six patients were found to be incontinent 1 year following surgery (Figure 1).[30]

In a larger, more recent series, the outcomes for 18 morbidly obese patients who had undergone radical perineal prostatectomy were reported. Median BMI was 42 kg/m², with five patients having a BMI > 45 kg/m². The authors noted that mean operative time and estimated blood loss were significantly related to the experience of the operating surgeon. Experienced surgeons completed their cases in 174 minutes with 485 mL of blood loss, compared to 235 minutes and 838 mL for less experienced operators. Of the 18 patients, 5 (28%) had positive margins, and 4 (22%) experienced perioperative complications. Of 10 patients with longer follow-up, 3 reported usage of incontinence pads (Figure 1).[31]

• Laparascopic Surgery-Data regarding the use of laparoscopic radical prostatectomy in obese patients have been published as well. In a retrospective review of 54 obese patients (BMI ≥ 30 kg/m²) who had undergone laparoscopic radical prostatectomy, mean operative time was statistically higher for obese patients relative to patients with a normal BMI, at 208 minutes vs 192 minutes, respectively. Moreover, mean operative times directly correlated with increasing BMI: Patients with a BMI of 30 to 34.9 kg/m² (grade 1) had a mean operative time of 198 minutes; patients with a BMI of 35 to 39.9 kg/m² (grade 2) had a mean operative time of 220 minutes; patients with a BMI of 40 kg/m² or greater (grade 3) had a mean operative time of 249 minutes (Figure 2). No difference was reported between nonobese and obese patients with respect to positive margin status and pathologic stage. The rate of complications, minor or major, did not differ between the two groups.[32]

In a prospective review of 100 men undergoing robotic laparoscopic radical prostatectomy, Ahlering and colleagues summarized the outcome for 19 men with a BMI ≥ 30 kg/m².[33] Obese men were found to have a 1-hour longer operative time, as well as greater blood loss and complication rate (26% vs 5%, P = .01), with the latter including one deep-venous thrombosis, one pulmonary embolus, one prolonged compression nerve injury, and two bladder neck disruptions. Notably, 53% of obese patients at 6-month follow-up required the use of incontinence pads vs only 9% of men with a BMI < 30 kg/m² (Figure 1).

Laparoscopic surgery has been advocated to decrease general surgical morbidity. Nevertheless, Bhayani and colleagues, in a multi-institutional review, found that 15% (2/13) of patients who underwent conversion from laparoscopic radical prostatectomy to an open radical retropubic prostatectomy required the more extensive approach secondary to obesity.[34] While the total number of obese patients who underwent surgery was not stated, the authors did emphasize that obese patients, especially in a surgeon's initial experience, can be challenging laparoscopically due to excess subcutaneous fat complicating trocar insertion and manipulation, limitations with standard-length instrumentation, potential respiratory compromise, and increased periprostatic fat.

• Cancer-Control Outcomes-Despite these concerns, prostatectomy appears feasible even in very obese patients. The cancer-control outcomes for obese patients, however, appear to be inferior to the outcomes seen in nonobese patients. In the largest study published to date, Amling and colleagues conducted a retrospective, multi-institutional analysis of 3,162 men who had undergone radical prostatectomy at nine US military medical centers between 1987 and 2002.[35] Of these patients, 600 (19%) were obese (BMI ≥ 30 kg/m²), 1,534 (49%) were characterized as overweight (25 kg/m² ≤ BMI < 30 kg/m²), and the remaining 1,028 (32%) were categorized as normal (BMI < 25 kg/m²). Obese patients had higher-grade cancers, as well as a higher incidence of positive surgical margins. At a median follow-up of 4 years, obese patients had a higher rate of PSA recurrence, with BMI significantly associated with PSA recurrence on univariate analysis.

In another radical prostatectomy series, published by Freedland and colleagues, 1,106 men who had undergone radical prostatectomy between 1988 and 2002 at four institutions were retrospectively reviewed.[36] In this study, 248 men (22%) had a BMI ≥ 30 kg/m², while 528 men (48%) were characterized as overweight (25 kg/m² ≤ BMI < 30 kg/m²), and 330 men (30%) were characterized as normal (BMI < 25 kg/m²). Having a higher BMI was found to be a predictor of both a higher biopsy and pathologic Gleason score. Contrary to the Amling data, however, this series did not find an association between obesity and positive surgical margins, nor did it find an association between obesity and the risk for extracapsular extension or seminal vesicle invasion, although a trend toward increased risk of positive margins was seen in patients with a BMI ≥ 35 kg/m².

At a median follow-up of 33 months, obese men had a higher PSA failure rate than either overweight men or men with normal weight (Figure 3).[36] On multivariate analysis, elevated BMI was a predictor of PSA failure. To further elucidate the effect of BMI on biochemical failure, Freedland and colleagues analyzed 731 patients in their series who had pathologically organ-confined disease and negative surgical margins. At a median follow-up of 40 months, men with a BMI ≥ 35 kg/m² had a nearly fourfold higher PSA failure rate relative to normal-weight men when all other pathologic and preclinical factors were controlled.[13]

Mallah and colleagues retrospectively reviewed 2,210 men treated with radical retropubic prostatectomy between 1986 and 2003.[37] Similar to previous studies, higher BMI was associated with an increased likelihood of disease progression (Figure 3). The relationship was not as strong as in other studies, possibly due to the short median follow-up of only 26 months.

In the most recently published series, Bassett and colleagues reviewed prostatectomy data collected between 1989 and 2002 on 2,131 men from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a longitudinal, observational database of men with biopsy-proven prostate adenocarcinoma recruited from 31 US academic and community-based urology practices.[38] A total of 548 men (26%) had a BMI < 25 kg/m², while 1,126 men (52%) were overweight (25 kg/m² ≤ BMI < 30 kg/m²), 365 men (17%) were obese (30 kg/m² ≤ BMI < 35 kg/m²), and 113 men (5%) were found to be very obese (BMI ≥ 35 kg/m²). Clinical stage, PSA level, and biopsy Gleason score did not differ among the groups.

At a median follow-up of 23 months, BMI was found to be associated with disease recurrence.[38] Relative to men with a BMI < 30 kg/m², patients with a BMI ≥ 30 kg/m² had a 1.3-fold increased risk of biochemical recurrence, while patients with a BMI ≥ 35 kg/m² had a 1.7-fold increased risk of biochemical recurrence.

 • Need for Secondary Modalities-These surgical series have demonstrated that although surgical intervention is an option for obese patients with prostate cancer, increased operative times and blood loss are likely to occur in this setting. Furthermore, to the extent that obese patients may have a higher likelihood of positive surgical margins and biochemical recurrence, the use of secondary modalities will be necessary. Increasing evidence supports the use of postoperative radiation in patients with positive margins following radical prostatectomy.

Bolla and colleagues, in the European Organization for Research and Treatment of Cancer (EORTC) 22911 trial, randomly assigned 1,005 postprostatectomy patients with one or more pathologic risk factors (capsule perforation, positive surgical margins, or invasion of seminal vesicles) to observation vs 60 Gy of conventional radiation.[39] At a median follow-up of 60 months, biochemical progression-free survival was significantly improved in the irradiated group vs the observation group (74% vs 53%, P < .0001).

Similarly, Swanson and colleagues, in Southwest Oncology Group (SWOG) protocol 8794, randomized 473 postprostatectomy patients with extracapsular extension, positive margins, and/or seminal vesicle involvement, to observation vs 60-64 Gy of radiation.[40] At a median follow-up of 10 years, 10-year biochemical disease-free survival was improved with radiation (47% vs 23% at 10 years). Moreover, only 39% of patients receiving radiotherapy ultimately required androgen ablation vs 50% of patients in the observation arm.

While these results support the use of postoperative radiation in prostate cancer patients with advanced pathologic features, the use of such adjuvant therapy may also result in increased morbidity. To minimize the necessity for adjuvant therapies such as radiation or hormonal treatment following surgery, obese patients should be made aware of all available definitive modalities of therapy up front, and careful discussions should be conducted among the patient's providers regarding the optimal treatment modality.

External-Beam Radiation

Long-term data regarding the use of radiation therapy has established this strategy to be as efficacious as surgical intervention for prostate cancer.[41] Published data regarding the use of external-beam radiation therapy specifically in the treatment of obese patients with prostate cancer are limited, however. Difficulties such as increased mobility of skin tattoos relative to internal structures and targets, as well as practical hurdles such as treatment and computed tomography (CT) table weight limitations, are not uncommonly seen with obese prostate cancer patients. Additionally, significant skin-to-prostate distance, which can exceed 25 cm (Figure 4), may be encountered, making accurate, daily targeting of the prostate more difficult. As such, the treatment of obese prostate cancer patients with external-beam radiation can be challenging.

Luchka described the use of portal imaging for a 150-kg cervical cancer patient who exceeded the CT scanner weight maximum, and as such, could not receive meaningful permanent skin marks prior to treatment.[42] A megavoltage image was acquired at the initial treatment session for all four fields that were utilized during radiotherapy (anteroposterior, posteroanterior, and lateral fields). Subsequently, localization portal fields were taken daily and compared to the initial megavoltage images to ensure accuracy. The corrections that were made based on bony landmarks resulted in accurate positioning to within 5.7 mm without the use of online image enhancement or on-screen measurement tools. This use of daily images appeared to ensure accurate daily positioning but was somewhat cumbersome and did not control for intrafraction movement, which could be substantial in a very large patient.

Significant advancements have been made in electronic portal imaging, however, and coupled with the use of intraprostatic gold markers, improved targeting of the intact prostate has been demonstrated.[43] This technique has also been utilized with obese patients. Millender and colleagues reported on three morbidly obese (BMI > 40 kg/m²) patients who underwent external-beam radiation therapy with placement of gold seeds in the prostate.[44] Daily anteroposterior and left lateral electronic portal images were taken, and daily adjustments were made based on bony anatomy and seed location. The use of daily, electronic portal imaging with the use of gold seeds resulted in a mean improvement in accuracy of 7.2 mm, 11.4 mm, and 2.6 mm in the superior-inferior, left-to-right, and anteroposterior directions, respectively.

While very compelling, whether these techniques become broadly adopted for obese patients and prove clinically successful against the inherent challenges of daily setup, as well as against potential pelvic organ motion secondary to excessive intra-abdominal adipose tissue, will depend on additional studies.

Unlike the recent publications regarding surgical outcomes, no outcomes have been reported regarding the use of external-beam irradiation for prostate cancer specifically in obese men. Although advances in imaging and external-beam delivery technology should improve prostate targeting, the lack of published outcomes data for a common condition is troubling, especially in light of the historical difficulties with daily setup and organ motion in obese patients. Centers with extensive external-beam experience should publish their results regarding obese patients to compare outcomes with other treatment modalities.

Brachytherapy

Two centers have specifically addressed outcomes of brachytherapy in obese patients with prostate cancer. Rockhill and colleagues published a detailed analysis of three patients with a BMI ≥ 30 kg/m² who underwent prostate seed brachytherapy (Figure 5).[45,46] Transrectal ultrasound (TRUS) imaging was unaffected by patient body habitus, and no difficulties with increased skin-to-prostate distance at the perineum were noted, which allowed for the use of standard applicator needles. The two patients who had postimplant CT imaging showed good dosimetric coverage of the prostate, with V100s (the percentage of prostate volume receiving 100% of the prescription dose) of 88% and 95%.

Merrick and colleagues published a series of 32 obese patients who underwent brachytherapy between 1997 and 2001.[47] Twenty-three patients had a BMI between 35 and 40 kg/m², and nine patients had a BMI ≥ 40.0 kg/m². A total of 12 patients were treated with implant monotherapy, whereas 20 patients received implants with supplemental external-beam radiation therapy. Day 0 dosimetry for these patients was consistent with dosimetry for nonobese patients, with a median V100 value of 97%. At last follow-up, no patient had developed urinary incontinence (Figure 1).

In a more recent publication, Merrick and colleagues reported on 686 patients who had undergone brachytherapy between 1995 and 2001 and were stratified by BMI.[48] A total of 135 patients (20%) had grade 1 obesity (30 kg/m² ≤ BMI < 35 kg/m²), and 36 (5%) had grade 2 or 3 obesity (BMI ≥ 35 kg/m²). At 8 years, 94% and 100% of patients with grade 1 and 2/3 obesity, respectively, remained free from biochemical progression (Figure 3), with a median posttreatment PSA level of less than 0.1 ng/mL. Moreover, a reduction in cause-specific survival has not been seen with permanent prostate brachytherapy (unpublished data).

Of note, while the previously mentioned morbidities such as DVT were evaluated specifically in obese patients undergoing surgery, it is important to keep in mind that to the extent patients receiving prostate seed implants undergo general anesthesia and experience an invasive procedure, brachytherapy patients are also exposed to some of the morbidities previously outlined. Having recognized this risk, however, no intraoperative or anesthesia-related complications have been reported with brachytherapy in obese patients in the series that have been published. Whether this is a reflection of shorter operative times, the relatively less invasive nature of brachytherapy, or simply insufficient patient numbers that have been reported is unclear.

Conclusions

Obesity is a growing health problem that is increasingly affecting numerous aspects of medical care. Data regarding the effect of obesity on prostate cancer outcomes with the various treatment modalities are emerging. The optimal treatment choice for obese patients with prostate cancer will likely vary depending on the particular patient. The reported surgical outcomes suggest that obese patients have a poorer prognosis with respect to both morbidity and biochemical progression. Whether this can be addressed with improved surgical techniques, or whether this is simply a reflection of the aggressive nature of prostate cancer in obese patients, is unclear.

In contrast to the surgical series, the use of brachytherapy in experienced hands appears promising, with less short-term morbidity and a higher likelihood of cancer eradication. Experts in highly focused external-beam radiation should come forth with studies analyzing the effect of obesity on treatment outcomes, as obese patients represent an increasing segment of the prostate cancer population. Investigators and clinicians will ultimately require more long-term outcomes data, as well as a better understanding of the potential biochemical mechanisms regarding the association of obesity and prostate cancer, to optimally tailor treatment modalities for obese patients.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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