Eric M. Horwitz, M.D
 

I was asked to write this editorial as a radiation oncologist who specializes in the treatment of prostate cancer and to focus on why external beam radiotherapy (EBRT) is the treatment of choice for most men with early-stage nonmetastatic prostate cancer, instead of permanent seed implantation alone. Although seed implants alone are very effective for some men with early-stage, low-risk prostate cancer, they are not for everyone. In this editorial, when I am discussing the pluses of EBRT, I am referring to patients treated with intensity-modulated radiotherapy (IMRT) and for brachytherapy (BT) patients, I am referring to patients treated with permanent seed implantation alone. I am not referring to conventional RT or three-dimensional conformal RT (3D-CRT), both older techniques with increased morbidity. Although 3D-CRT was an improvement in regard to dose delivery and toxicity reduction, IMRT has been an exponential leap forward compared with 3D-CRT and should be the standard of care in the radiation oncology community in 2008.

The focus on why I believe that IMRT is better for more men revolves around 2 issues. The first question is which patients can be treated with either modality. The group of men who can be effectively treated with IMRT is far larger than those men who can appropriately be treated with seed implantation. Almost all men with early-stage prostate cancer are candidates for EBRT, regardless of age, health status, or prostate size. Simply, fewer contraindications exist to the use of IMRT. The most common contraindication for IMRT is the presence of inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis). Other than this contraindication, there are just very few other indications that would prevent a man from undergoing IMRT (active inflammatory bowel disease is also a contraindication for BT patients, although in some instances a seed implant can be done).

The technical requirements for patients to receive seed implants include the ability to tolerate spinal and/or general anesthesia and medical comorbidities that would not safely preclude anesthesia, a prostate size of 20-60 cm3, no previous transurethral resection of the prostate or other procedure that creates an internal defect in the prostate anatomy, no pubic arch interference, and an American Urological Association voiding function score typically <15, although it can be higher for certain men. Thus, although exceptions exist, the criteria are more selective for men who wish to be successfully treated with an implant with minimal morbidity. For men treated with IMRT, the limitations are fewer. The most common issue that patients and advocates of BT frequently discuss as a negative for IMRT is the length of time required for treatment. Patients undergoing modern RT receive doses of 7600-8000 cGy and treatment can typically last 7.5-8.5 weeks. Some men, because of travel distance, work hours, or time commitment, simply refuse IMRT. Another point is the role of the physician in determining the outcome for either treatment. Outcomes (both oncologic and quality of life) after seed implants are much more operator dependent. Once the techniques have been established, IMRT can be delivered in a more consistent and uniform pattern between individual and facility. The range of dose delivered for patients treated with an implantation is wider. An inadequate dose can result in the greater likelihood of biochemical and clinical failure and toxicity.[3]

The second, and I believe more important, reason to consider IMRT instead of permanent prostate implantation is related to the toxicity. Some studies have shown increased side effects with implantation and some with EBRT; however, few direct comparisons between the 2 modalities have been done.  In an effort to directly compare these 2 treatments, Eade  reported the Fox Chase experience comparing the outcomes and morbidity for patients with low-risk prostate cancer treated with prostate implantation or IMRT.

From 1998 to 2004, 374 patients with low-risk prostate cancer (PSA level <10 ng/dL, Stage T1c-T2b, Gleason score ≤6, and no neoadjuvant hormonal therapy) were treated at the Fox Chase Cancer Center and were included in the analysis. Of the 374 patients, 216 underwent IMRT and 158 underwent 125I prostate implantation. The median follow-up for both groups was similar, 43 months for the IMRT patients and 48 months for the 125I patients. The IMRT prescription dose range was 74-78 Gy and the 125I prescription dose was 145 Gy for all men. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was recorded using a modified Radiation Therapy Oncology Group scale. Freedom from biochemical failure was determined using the Phoenix definition.

In our experience, patients treated with IMRT were more likely to be older, have a greater baseline American Urological Association symptom index score, have a history of previous transurethral resection of the prostate, and have a larger prostate volume. On multivariate analysis, IMRT was an independent predictor of lower acute and late grade 2 or greater GU toxicity and late grade 2 or greater GI toxicity. The 3-year actuarial estimate of late grade 2 or greater toxicity was 2.4% for GI and 3.5% for GU toxicity using IMRT compared with 7.7% for GI and 19.2% for GU toxicity for 125I. The 4-year actuarial estimate of freedom from biochemical failure was 99.5% for IMRT and 93.5% for 125I. No statistically significant difference was found between the 2 groups in the freedom from biochemical failure on multivariate analysis. We concluded that IMRT and 125I produced similar biochemical and clinical outcomes, although IMRT appeared to result in less acute and chronic toxicity.

Other investigators have reported the toxicity results for both treatment modalities, although direct comparisons have not been done. Reports of treatment-related toxicity fall into 2 categories, physician-reported and, more recently, patient-reported outcomes. The addition of health-related quality-of-life tools has added to our knowledge of RT morbidity. Acute and chronic GU toxicity for patients receiving either RT technique include irritative and obstructive symptoms. The side effects for IMRT typically begin within 2-3 weeks after treatment begins and resolve within 4-6 weeks after it is completed.

Both acute and late toxicity in our IMRT patients remains very low, with only a 2.4% and 3.5% actuarial risk at 3 years of grade 2 GI and GU toxicity, respectively. Similar low toxicity was reported by Zelefsky  at the Memorial Sloan-Kettering Cancer Center for 561 IMRT patients treated to similar doses. The reduction in late rectal toxicity with IMRT should be highlighted, because the 125I patients in our series had a greater incidence of grade 2 rectal side effects than those treated with IMRT (7.8% vs 2.4% at 3 years). The 8-year actuarial likelihood of grade 2 rectal bleeding was 1.6%. Three patients (0.1%) experienced grade 3 rectal toxicity requiring either ≥1 transfusions or a laser cauterization procedure. No grade 4 rectal complications were observed. The 8-year likelihood of late grade 2 and 3 (urethral stricture) urinary toxicities was 9% and 3%, respectively. Of the patients who were potent before IMRT, erectile dysfunction developed in 49%. In contrast, late grade 2 or greater GI toxicity of >20% has been reported when doses to the isocenter of 78 Gy were used with a 3D conformal technique.

For implant patients, the acute toxicity profile develops in a bimodal pattern. The first symptoms are related to the procedure itself and the placement of 15-20 needles directly into the prostate. The radiation symptoms begin approximately 2-3 weeks after implantation, and the worst of the acute effects can last for 2-6 months, depending on the isotope used. For the 2 most common isotopes, the half life of 103Pd is 17 days and the half life of 125I is 60 days. In addition to the irritative and obstructive symptoms, additional side effects include the peri- and postoperative complications of bleeding, infection, and urinary retention requiring a catheter. One of the more detailed BT toxicity reports by Merrick  used the multifactorial Rectal Function Assessment Score quality-of-life questionnaire. A comparison between the Rectal Function Assessment Scores and a modified Radiation Therapy Oncology Group scale for the same patient showed the more detailed quality-of-life questionnaire was required to identify rectal toxicities related to dose-volume constraints.How bothersome late Radiation Therapy Oncology Group grade 2 or even some grade 3 toxicities are to a patient is unclear. More detailed quality-of-life studies have attempted to quantify bother. The Fox Chase data have illustrated that with follow-up approaching 4 years, significant late toxicities such as strictures are observed, with an expected effect on urinary quality of life.

Litwin  reported the results of their quality-of-life study involving 475 men. In their study, they sought to compare the health-related quality of life outcomes after the most commonly used treatments. A total of 475 men completed the Medical Outcomes Study short form-36, the University of California, Los Angeles, Prostate Cancer Index, and the American Urological Association symptom index before and through 24 months after treatment with radical prostatectomy, external beam radiotherapy (3D-CRT and IMRT in their series), or BT. The investigators showed that the general health-related quality of life did not appear to be affected by treatment. Obstructive and irritative urinary symptoms were more common after prostate implantation (P < .001). Urinary control and sexual function were better after EBRT than after BT (P < .001 and P = .02, respectively) and better after BT than after radical prostatectomy (P < .001 and P = .01, respectively). Among potent men, the recovery of sexual function was best after EBRT and was equivalent after bilateral nerve-sparing surgery or BT. Sexual bother was more common than urinary or bowel bother after all 3 treatments. Litwin concluded that urinary control and sexual function were better after EBRT (although bilateral nerve-sparing surgery diminished these differences among potent men undergoing radical prostatectomy), BT caused more obstructive and irritative GU symptoms, and both forms of RT caused more GI dysfunction.

Although treatment with a permanent seed implant alone is an excellent option for some men, it is not for all. IMRT remains an excellent option for most eligible men. The long-term clinical results have been excellent and acute, subacute, and chronic morbidity have been low. The tradeoff between the 2 treatment techniques is fewer side effects vs a greater time commitment, and I believe that is why EBRT is the treatment of choice for most men with early-stage nonmetastatic prostate cancer.