R. Charles Nichols

Early Outcomes From Three Prospective Trials of Image-Guided Proton Therapy for Prostate Cancer

PURPOSE To report early outcomes with image-guided proton therapy for prostate cancer. METHODS AND MATERIALS We accrued 211 prostate cancer patients on prospective Institutional Review Board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low-risk disease, dose escalation from 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel followed by androgen deprivation for high-risk disease. Minimum follow-up was 2 years. RESULTS One intermediate-risk patient and 2 high-risk patients had disease progression. Pretreatment genitourinary (GU) symptom management was required in 38% of patients. A cumulative 88 (42%) patients required posttreatment GU symptom management. Four transient Grade 3 GU toxicities occurred, all among patients requiring pretreatment GU symptom management. Multivariate analysis showed correlation between posttreatment GU 2+ symptoms and pretreatment GU symptom management (p < 0.0001) and age (p = 0.0048). Only 1 Grade 3+ gastrointestinal (GI) symptom occurred. The prevalence of Grade 2+ GI symptoms was 0 (0%), 10 (5%), 12 (6%), and 8 (4%) at 6, 12, 18, and 24 months, with a cumulative incidence of 20 (10%) patients at 2 years after proton therapy. Univariate and multivariate analyses showed significant correlation between Grade 2+ rectal bleeding and proctitis and the percentage of rectal wall (rectum) receiving doses ranging from 40 CGE (10 CGE) to 80 CGE. CONCLUSIONS Early outcomes with image-guided proton therapy suggest high efficacy and minimal toxicity with only 1.9% Grade 3 GU symptoms and <0.5% Grade 3 GI toxicities.

Proton Radiation Therapy Offers Reduced Normal Lung and Bone Marrow Exposure for Patients Receiving Dose-Escalated Radiation Therapy for Unresectable Stage III Non-Small-Cell Lung Cancer: A Dosimetric Study

INTRODUCTION The purpose of this study was to determine the potential benefit of proton radiation therapy over photon radiation therapy in patients with unresectable stage III non-small-cell lung cancer. MATERIALS AND METHODS Optimized 3-dimensional conformal photon (3DCRT), intensity-modulated radiation therapy (IMRT) and proton therapy (PT) plans were generated for 8 consecutive patients with unresectable stage III non-small-cell lung cancer using the same target goals and normal tissue constraints. The radiation exposure to non-targeted normal structures, including lung, bone marrow, esophagus, heart, and spinal cord, were compared. Photon doses are expressed in gray (Gy). Proton doses are expressed in cobalt gray equivalents (CGE). RESULTS In all patients, 3DCRT, IMRT, and PT plans, achieved the dose goals for the target volumes. Compared with the 3DCRT plans, proton plans offered a median 29% reduction in normal lung V(20) Gy (CGE), a median 33% reduction in mean lung dose (MLD), and a median 30% reduction in the volume of bone marrow receiving a dose of 10 Gy (CGE). Compared with the IMRT plans, the proton plans offered a median 26% reduction in normal lung V(20) Gy (CGE), a median 31% reduction in MLD, and a median 27% reduction in the volume of bone marrow receiving a dose of 10 Gy (CGE). CONCLUSION By reducing the volumes of normal structures irradiated, protons can potentially improve the therapeutic index for patients with unresectable stage III non-small-cell lung cancer receiving combined radiation therapy and chemotherapy.

Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity

Abstract Background. To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution. Material and methods. From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE. Results. Median follow-up for all patients was 11 (range 5–36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure. Discussion. Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.

Is radical prostatectomy the "gold standard" for localized prostate cancer?

The purpose of this article is to review the pertinent literature and compare the outcomes after radical prostatectomy (RP) and radiotherapy (RT). The probability of cure is similar after either RP or RT. The likelihood of significant treatment complications is probably higher after RP compared with RT. Preservation of erectile function is at least as good or better with RT compared with RP. Urinary continence is more likely to be preserved after RT compared with RP. Each treatment results in distinct patterns of adverse changes in quality of life that are worsened by factors including obesity, large prostate size, high prostate-specific antigen (PSA), and older age.

Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life After Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer

PURPOSE To report clinical outcomes in patients treated with image guided proton therapy (PT) for localized prostate cancer. METHODS AND MATERIALS The medical records of 1327 men were reviewed. Each man was enrolled on an outcomes tracking study. Dual enrollment on a prospective clinical trial was allowed. Each patient was treated for localized prostate cancer with PT at our institution between 2006 and 2010. Ninety-eight percent of patients received 78 Gy (radiobiological equivalent [RBE]) or higher; 18% received androgen deprivation therapy (ADT). The 5-year freedom from biochemical progression (FFBP), distant metastasis-free survival, and cause-specific survival rates are reported for each risk group. Data on patient-reported quality of life and high-grade toxicities were prospectively collected and reported. A multivariate analysis was performed to identify clinical predictors of biochemical failure and urologic toxicity. RESULTS The median follow-up time was 5.5 years. The 5-year FFBP rates were 99%, 94%, and 74% in low-risk, intermediate-risk, and high-risk patients, respectively. The actuarial 5-year rates of late grade 3+ Common Terminology Criteria for Adverse Events, version 4.0, gastrointestinal (GI) and genitourinary (GU) toxicity were 0.6% and 2.9%, respectively. Multivariate analysis showed a significant correlation between grade 3+ GU toxicity and pretreatment prostate reductive procedures (P<.0001), prostate volume (P=.0085), pretreatment α-blockers (P=.0067), diabetes (P=.0195), and dose-volume histogram parameters (P=.0208). The median International Prostate Symptom Scores pretreatment scores and scores at 5 years after treatment were 7 and 7, respectively. The mean Expanded Prostate Cancer Index Composite (EPIC) scores significantly declined for sexual summary for patients not receiving ADT (from 67 to 53) between baseline and 5 years. CONCLUSIONS Image guided PT provided excellent biochemical control rates for patients with localized prostate cancer. The actuarial rates of high-grade toxicity were low after PT. From pretreatment to 5 years of follow-up, a significant decline was found only in mean EPIC sexual summary scores. Prospective clinical studies are needed to determine the comparative effectiveness of PT and other radiation treatment strategies.

Dosimetric comparison study between intensity modulated radiation therapy and three-dimensional conformal proton therapy for pelvic bone marrow sparing in the treatment of cervical cancer

The objective was to compare intensity‐modulated radiation therapy (IMRT) with 3D conformal proton therapy (3DCPT) in the treatment of cervical cancer. In particular, each techniques ability to spare pelvic bone marrow (PBM) was of primary interest in this study. A total of six cervical cancer patients (3 postoperative and 3 intact) were planned and analyzed. All plans had uniform 1.0 cm CTV‐PTV margin and satisfied the 95% PTV with 100% isodose (prescription dose=45Gy) coverage. Dose‐volume histograms (DVH) were analyzed for comparison. The overall PTV and PBM volumes were 1035.9±192.2 cc and 1151.4±198.3 cc, respectively. In terms of PTV dose conformity index (DCI) and dose homogeneity index (DHI), 3DCPT was slightly superior to IMRT with 1.00±0.001,1.01±0.02, and 1.10±0.02,1.13±0.01, respectively. In addition, 3DCPT demonstrated superiority in reducing lower doses (i.e., V30 or less) to PBM, small bowel and bladder. Particularly in PBM, average V10 and V20 reductions of 10.8% and 7.4%(p=0.001 and 0.04), respectively, were observed. However, in the higher dose range, IMRT provided better sparing (>V30). For example, in small bowel and PBM, average reductions in V45 of 4.9% and 10.0%(p=0.048 and 0.008), respectively, were observed. Due to its physical characteristics such as low entrance dose, spread‐out Bragg peak and finite particle range of protons, 3DCPT illustrated superior target coverage uniformity and sparing of the lower doses in PBM and other organs. Further studies are, however, needed to fully exploit the benefits of protons for general use in cervical cancer. PACS number: 87.55.D‐, 87.55.dk

Proton Therapy With Concurrent Chemotherapy for Non–Small-Cell Lung Cancer: Technique and Early Results

BACKGROUND Proton therapy can deliver a more conformal dose distribution than photon radiation and may allow safe dose escalation in stage III lung cancer. Early outcomes are presented here for patients who received proton therapy with concurrent chemotherapy for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Nineteen patients with regionally advanced NSCLC were treated with concurrent chemotherapy (carboplatin and paclitaxel [n = 18]) and proton therapy from August 2008 to April 2010 either with (n = 7) or without (n = 12) induction chemotherapy. Eighteen patients had stage III NSCLC, and 1 patient had stage IIB disease. The median proton therapy dose was 74 cobalt gray equivalent (CGE) in 2 CGE fractions with 18 patients who received ≥70 CGE. Twelve patients also received selective nodal proton therapy to the adjacent uninvolved nodal regions, with a median dose of 40 CGE (range, 40-46 CGE). The patients were routinely evaluated for treatment-related toxicity and disease progression every 3 months, with a history, physical, and computed tomography or positron emission tomography-computed tomography. RESULTS The median follow-ups for living patients were 15 and 16 months (range, 7-26 months), respectively. Nonhematologic and hematologic acute grade 3+ toxicity (<90 days) developed in 1 and 4 patients, respectively. Two of 16 patients assessable for late toxicity (≥90 days) developed a significant grade 3+ nonhematologic late toxicity, whereas 1 patient developed a grade 3+ hematologic late toxicity. Local progression was the site of first relapse in one patient. CONCLUSION Mediastinal proton therapy with concomitant chemotherapy was associated with acceptable toxicity. Although encouraging, longer follow-up with more patients is needed to confirm the long-term efficacy of this treatment.

Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials.

Abstract Background. To assess genitourinary (GU) function and toxicity in patients treated with image-guided proton therapy (PT) for early- and intermediate-risk prostate cancer and to analyze the impact of pretreatment urinary obstructive symptoms on urinary function after PT. Material and methods. Two prospective trials accrued 171 prostate cancer patients from August 2006 to September 2007. Low-risk patients received 78 cobalt gray equivalent (CGE) in 39 fractions and intermediate-risk patients received 78–82 CGE. Median follow-up was five years. The International Prostate Symptom Score (IPSS) and GU toxicities (per CTCAE v3.0 and v4.0) were documented prospectively. Results. Five transient GU events were scored Gr 3 per CTCAE v4.0, for a cumulative late GU toxicity rate of 2.9% at five years. There were no Gr 4 or 5 events. On multivariate analysis (MVA), the only factor predictive of Gr 2 + GU toxicity was pretreatment GU symptom management (p = 0.0058). Patients with pretreatment IPSS of 15–25 had a decline (clinical improvement) in median IPSS from 18 before treatment to 10 at their 60-month follow-up. At last follow-up, 18 (54.5%) patients had a > 5-point decline, 14 (42.5%) remained stable, and two patients (3%) had a > 5-point rise (deterioration) in IPSS. Patients with IPSS < 15 had a stable median IPSS of 6 before treatment and at 60 months. Conclusion. Urologic toxicity at five years with image-guided PT has been uncommon and transient. Patients with pretreatment IPSS of < 15 had stable urinary function five years after PT, but patients with 15–25 showed substantial improvement (decline) in median IPSS, a finding not explained by initiation or dose adjustment of alpha blockers. This suggests that PT provides a minimally toxic and effective treatment for low and intermediate prostate cancer patients, including those with significant pretreatment GU dysfunction (IPSS 15–25).

Proton Therapy and Concomitant Capecitabine for Non-Metastatic Unresectable Pancreatic Adenocarcinoma

Abstract Purpose: To review early outcomes for patients enrolled on our institutions protocol (PC01) for patients with unresectable pancreatic cancer, and to test whether the serious adverse event rate could be reduced from 15% (expected) to <5%. Patients and Methods: Twelve patients were enrolled, but only 11 patients are reported in this analysis. Pathology on all patients was reviewed at University of Florida Health Medical Center in Jacksonville to confirm the diagnosis of pancreatic adenocarcinoma. Unresectability was defined by radiographic evidence of encasement of the celiac axis and/or superior mesenteric artery or by occlusion of the superior mesenteric vein, portal vein, or both confluences. Patients received proton therapy to a planning target volume dose of 59.4 Gy (relative biological effective) at 1.8 Gy (relative biological effective) per fraction over 7 weeks with concomitant oral capecitabine (1000 mg orally twice-daily, 5 days/week on radiation treatment days only). Only gross disease ...

Postprostatectomy radiotherapy for prostate cancer.

The roles of adjuvant postoperative radiotherapy (RT) after radical prostatectomy, and salvage RT for apparent local-regional recurrence, are reviewed.Postprostatectomy patients with pT3N0 disease have improved biochemical progression-free survival, clinical progression-free survival, and local-regional control after postoperative RT. Although a benefit in overall survival has not been demonstrated, patients who have a life expectancy of ≥10 years likely will have improved long-term cause-specific survival if postoperative RT is administered. The optimal postoperative RT dose is probably about 70 Gy at 2 Gy per once-daily fraction. Salvage RT should be considered for patients with local regionally recurrent cancer without distant metastasis and those with a biochemical relapse. The optimal dose probably exceeds 70 Gy, but is likely not feasible because of the risk of late toxicity. Thus, the preferred dose-fractionation schedule is approximately 70 Gy in 35 once-daily fractions.The role of androgen deprivation therapy in combination with RT is ill defined, but it should be considered for high-risk patients. Similarly, the role for whole-pelvis RT is unclear, but it may be considered for those with a ≥20% risk of positive pelvic nodes.