Faculty Bibliography

PURPOSE/OBJECTIVE:Based on contemporary epidemiological and pathological characteristics of prostate cancer we explain the rationale for and concerns about focal therapy for low risk prostate cancer, review potential methods of delivery and propose study design parameters. MATERIALS AND METHODS/METHODS:Articles regarding the epidemiology, diagnosis, imaging, treatment and pathology of localized prostate cancer were reviewed with a particular emphasis on technologies applicable for focal therapy, defined as targeted ablation of a limited area of the prostate expected to contain the dominant or only focus of cancer. A consensus summary was constructed by a multidisciplinary international task force of prostate cancer experts, forming the basis of the current review. RESULTS:In regions with a high prevalence of prostate specific antigen screening the over detection and subsequent overtreatment of prostate cancer is common. The incidence of unifocal cancers in radical prostatectomy specimens is 13% to 38%. In many others there is an index lesion with secondary foci containing pathological features similar to those found incidentally at autopsy. Because biopsy strategies and imaging techniques can provide more precise tumor localization and characterization, there is growing interest in focal therapy targeting unifocal or biologically unifocal tumors. The major arguments against focal therapy are multifocality, limited accuracy of staging, the unpredictable aggressiveness of secondary foci and the lack of established technology for focal ablation. Emerging technologies with the potential for focal therapy include high intensity focused ultrasound, cryotherapy, radio frequency ablation and photodynamic therapy. CONCLUSIONS:Early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. We encourage the investigation of focal therapy in select men with low risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.

PURPOSE/OBJECTIVE:To determine whether prostate cancer local recurrence after radiation therapy (RT) occurs at the site of primary tumor by retrospectively comparing the tumor location on pre-RT and post-RT magnetic resonance imaging (MRI) and using step-section pathology after salvage radical prostatectomy (SRP) as the reference standard. METHODS AND MATERIALS/METHODS:Nine patients with localized prostate cancer were treated with intensity modulated RT (69-86.4 Gy), and had pre-RT and post-RT prostate MRI, biopsy-proven local recurrence, and SRP. The location and volume of lesions on pre-RT and post-RT MRI were correlated with step-section pathology findings. Tumor foci >0.2 cm(3) and/or resulting in extraprostatic disease on pathology were considered clinically significant. RESULTS:All nine significant tumor foci (one in each patient; volume range, 0.22-8.63 cm(3)) were detected both on pre-RT and post-RT MRI and displayed strikingly similar appearances on pre-RT and post-RT MRI and step-section pathology. Two clinically insignificant tumor foci (</=0.06 cm(3)) were not detected on imaging. The ratios between tumor volumes on pathology and on post-RT MRI ranged from 0.52 to 2.80. CONCLUSIONS:Our study provides a direct visual confirmation that clinically significant post-RT local recurrence occurs at the site of primary tumor. Our results are in agreement with reported clinical and pathologic results and support the current practice of boosting the radiation dose within the primary tumor using imaging guidance. They also suggest that monitoring of primary tumor with pre-RT and post-RT MRI could lead to early detection of local recurrence amenable to salvage treatment.

PURPOSE/OBJECTIVE:To evaluate the cosmetic outcome of patients treated with wide local excision and intraoperative radiotherapy for early-stage breast cancer. METHODS AND MATERIALS/METHODS:A total of 50 women were treated on a pilot study to evaluate the feasibility of intraoperative radiotherapy at wide local excision. The eligibility criteria included age >60, tumor size </=2.0 cm, clinically negative lymph nodes, and biopsy-established diagnosis. After wide local excision, a custom breast applicator was placed in the excision cavity, and a dose of 20 Gy was prescribed to a depth of 1 cm. After 18 patients were treated, the dose was constrained laterally to 18 Gy. The cosmetic outcome was evaluated by photographs at baseline and at 6 and 12 months postoperatively. Four examiners graded the photographs for symmetry, edema, discoloration, contour, and scarring. The grades were evaluated in relationship to the volume of irradiated tissue, tumor location, and dose at the lateral aspects of the cavity. RESULTS:The median volume of tissue receiving 100% of the prescription dose was 47 cm(3) (range, 20-97 cm(3)). Patients with </=47 cm(3) of treated tissue had better cosmetic outcomes than did the women who had >47 cm(3) of treated tissue. Women who had received 18 Gy at the lateral aspects of their cavities had better cosmetic outcomes than did women who had received 20 Gy at the lateral aspects. When comparing the 6- and 12-month results, the scores remained stable for 63%, improved for 17%, and worsened for 20%. CONCLUSION/CONCLUSIONS:Intraoperative radiotherapy appears feasible for selected patients. A favorable cosmetic outcome appears to be related to a smaller treatment volume. The cosmetic outcome is acceptable, although additional follow-up is necessary.

PURPOSE/OBJECTIVE:To determine the rate and magnitude of late genitourinary (GU) and gastrointestinal (GI) toxicities after salvage or adjuvant radiotherapy (RT) for prostate cancer, and to determine predictive factors for these toxicities. METHODS AND MATERIALS/METHODS:A large multi-institutional database that included 959 men who received postoperative RT after radical prostatectomy (RP) was analyzed: 19% received adjuvant RT, 81% received salvage RT, 78% were treated to the prostate bed only, and 22% received radiation to the pelvis. RESULTS:The median follow-up time was 55 months. At 5 years, 10% of patients had Grade 2 late GU toxicity and 1% had Grade 3 late GU toxicity, while 4% of patients had Grade 2 late GI toxicity and 0.4% had Grade 3 late GI toxicity. Multivariate analysis demonstrated that adjuvant RT (p = 0.03), androgen deprivation (p < 0.0001), and prostate bed-only RT (p = 0.007) predicted for Grade 2 or higher late GU toxicity. For GI toxicity, although adjuvant RT was significant in the univariate analysis, no significant factors were found in the multivariate analysis. CONCLUSIONS:Overall, the number of high-grade toxicities for postoperative RT was low. Therefore, adjuvant and salvage RT can safely be used in the appropriate settings.

OBJECTIVES/OBJECTIVE:To update our previously published nomogram predicting for biochemical outcome with 10-year data from a larger cohort of patients treated with three-dimensional conformal radiotherapy (RT) or intensity-modulated RT for localized prostate cancer. METHODS:From 1988 to 2004, 2253 patients were treated with three-dimensional conformal RT or intensity-modulated RT for clinical Stage T1-T3 prostate cancer. Prescription doses ranged from 64.8 to 86.4 Gy. The median follow-up time was 7 years. The nomogram was developed using a proportional hazards regression model predicting for the probability of biochemical relapse after RT according to the nadir plus 2 ng/mL definition of prostate-specific antigen (PSA) relapse. RESULTS:The 10-year PSA relapse-free survival rate was 62%. The nomogram incorporated the following variables to predict likelihood of PSA failure after RT: pretreatment PSA level, Gleason score, radiation dose, use of neoadjuvant androgen deprivation, and clinical stage. The concordance index of this long-term nomogram was 0.72. CONCLUSIONS:A nomogram predicting the 10-year probability of biochemical control after three-dimensional conformal RT or intensity-modulated RT for prostate cancer was reasonably accurate and discriminating. The nomogram also provided evidence that long-term biochemical control can be achieved after conformal RT for the treatment of localized prostate cancer.

PURPOSE/OBJECTIVE:To report the dosimetric outcome of patients with clinically localized prostate cancer treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique. METHODS AND MATERIALS/METHODS:Five hundred and sixty-two patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real-time intraoperative treatment planning software that incorporates inverse planning optimization was used. Dose-volume constraints for this inverse-planning system included: prostate V100 >or=95%, maximal urethral dose <or=120%, and average rectal dose <80% of the prescription dose. Day zero computed tomography scans were acquired for post-implantation dosimetric evaluation. RESULTS:The median V100 and D90 to the prostate target were 96% and 166 Gy, respectively. In 91% of cases a D90 of >or=140 Gy was achieved. In these patients, the V100 and D90 values did not have a significant influence on PSA relapse-free survival outcomes. The median maximum rectal dose and urethral doses were 104 Gy (72% of the prescription dose) and 187 Gy (130% of the prescription dose). The average and maximum rectal doses exceeding 100% of the prescription dose were less than 1% and 10% of patients, respectively. Average and maximum urethral doses exceeding 150% of the prescription dose were noted in 3% and 24% of patients, respectively. Average and maximum urethral doses exceeded 120% of the prescription dose in 21% and 58% of patients, respectively. Among patients where >or=2.5 cm(3) of the rectum was exposed to the prescription dose, the incidence of late grade 2 toxicity rectal toxicity was 9% compared to 4% for smaller volumes of the rectum exposed to similar doses (p=0.003). No dosimetric parameter in these patients with tight dose confines for the urethra influenced acute or late urinary toxicity. CONCLUSION/CONCLUSIONS:Real-time intraoperative planning was associated with a 90% consistency of achieving the planned intraoperative dose constraints for target coverage and maintaining planned urethral and rectal constraints in a high percentage of implants. Rectal volumes of >or=2.5 cm(3) exposed to the prescription doses were associated with an increased incidence of grade 2 rectal bleeding. Further enhancements in imaging guidance for optimal seed deposition are needed to guarantee optimal dose distribution for all patients. Whether such improvements lead to further reduction in acute and late morbidities associated with therapy requires further study.

PURPOSE/OBJECTIVE:To identify factors significantly influencing accrual to clinical protocols by analyzing radiation Patterns of Care Study (PCS) surveys of 3,047 randomly selected radiotherapy (RT) patients. METHODS AND MATERIALS/METHODS:Patterns of Care Study surveys from disease sites studied for the periods 1992-1994 and 1996-1999 (breast cancer, n = 1,080; prostate cancer, n = 1,149; esophageal cancer, n = 818) were analyzed. The PCS is a National Cancer Institute-funded national survey of randomly selected RT institutions in the United States. Patients with nonmetastatic disease who received RT as definitive or adjuvant therapy were randomly selected from eligible patients at each institution. To determine national estimates, individual patient records were weighted by the relative contribution of each institution and patients within each institution. Data regarding participation in clinical trials were recorded. The factors age, gender, race, type of insurance, and practice type of treating institution (academic or not) were studied by univariate and multivariate analyses. RESULTS:Overall, only 2.7% of all patients were accrued to clinical protocols. Of these, 57% were enrolled on institutional review board-approved institutional trials, and 43% on National Cancer Institute collaborative group studies. On multivariate analysis, patients treated at academic facilities (p = 0.0001) and white patients (vs. African Americans, p = 0.0002) were significantly more likely to participate in clinical oncology trials. Age, gender, type of cancer, and type of insurance were not predictive. CONCLUSIONS:Practice type and race significantly influence enrollment onto clinical oncology trials. This suggests that increased communication and education regarding protocols, particularly focusing on physicians in nonacademic settings and minority patients, will be essential to enhance accrual.

PURPOSE: To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. METHODS AND MATERIALS: From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). RESULTS: With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. CONCLUSIONS: Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted

PURPOSE/OBJECTIVE:An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. PATIENTS AND METHODS/METHODS:Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients. RESULTS:The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69. CONCLUSION/CONCLUSIONS:Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

PURPOSE: Although high-dose-rate brachytherapy (HDRBT) offers significant advantages over low dose rate brachytherapy, there are scant data on improved local control (LC) and treatment-related complications in patients with recurrent head and neck (H&N) cancers. We report our preliminary results in patients with recurrent H&N cancers treated with interstitial HDRBT. METHODS AND MATERIALS: Thirty patients with recurrent H&N cancers were treated with HDRBT between September 2003 and October 2005. Seventy-seven percent (23/30) of the patients had either local or regional recurrence in the area of previous external beam radiation therapy. The treatment sites were oral cavity/oropharynx (11/30), neck (10/30), face/nasal cavity (6/30), and parotid bed (3/30). Whereas 18 patients underwent surgical resection followed by HDRBT, 3 patients were treated with combined external beam radiation and HDRBT, and the remaining 9 were treated with HDRBT alone. The dose and fractionation schedules used were 3.4Gy twice per day (b.i.d.) to 34Gy for postoperative cases, 4Gy b.i.d. to 20Gy when combined with 40-50Gy external beam, and 4Gy b.i.d. to 40Gy for definitive treatment. HDRBT was initiated 5 days after catheter placement to allow for tissue healing. RESULTS: With a median followup of 12 months, 6 local recurrences were observed 1-10 months after the procedure. The 2-year LC and overall survival outcomes for the entire group were 71% and 63%, respectively. Patients treated with surgical resection and HDRBT had an improved 2-year LC compared to the patients treated with HDRBT+/-external beam radiation alone (88% vs. 40%, p=0.05). Six Grade II and four Grade III complications were noted in five patients, all observed in the postoperative HDRBT group. CONCLUSION: The preliminary results of HDRBT indicate an acceptable LC and morbidity in recurrent H&N cancers. A planned surgical resection followed by HDRBT is associated with improved tumor control in these high-risk patients. Based on these encouraging results, prospective clinical trials are warranted using HDRBT in recurrent H&N cancers to decrease late toxicity