Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy.

BACKGROUND: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy. PATIENTS AND METHODS: Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy. The primary end point of this study was distant MBM control. Secondary end points were local MBM control defined as a >20% volume increase on follow-up MRI, systemic progression-free survival, overall survival (OS) from both SRS and cranial metastases diagnosis, and neurotoxicity. Images were reviewed alongside two neuro-radiologists at our institution. RESULTS: Ninety-six patients were treated to 314 MBMs over 119 SRS treatment sessions between January 2007 and August 2015. No significant differences were noted in age (P = 0.27), gender (P = 0.85), treated gross tumor volume (P = 0.26), or the diagnosis-specific graded prognostic assessment (P = 0.51) between the treatment cohorts. Twelve-month Kaplan-Meier (KM) distant MBM control rates were 38%, 21%, 20%, 8%, and 5% (P = 0.008) for SRS with anti-PD-1 therapies, anti-CTLA-4 therapy, BRAF/MEKi, BRAFi, and conventional chemotherapy, respectively. No significant differences were noted in the KM local MBM control rates among treatment groups (P = 0.25). Treatment with anti-PD-1 therapy, anti-CTLA-4 therapy, or BRAF/MEKi significantly improved OS on both univariate and multivariate analyses when compared with conventional chemotherapy. CONCLUSION: In our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.

Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy.

BACKGROUND: The anti-programmed death-1 (anti-PD-1) therapy nivolumab has significant clinical activity in patients with metastatic melanoma. However, little is known about the safety and outcomes in patients receiving anti-PD-1 therapy and stereotactic radiation for the treatment of brain metastases (BMs). PATIENTS AND METHODS: Data were analyzed retrospectively from two prospective nivolumab protocols enrolling 160 patients with advanced resected and unresectable melanoma at a single institution. Patients were included if BMs were diagnosed and treated with stereotactic radiation within 6 months of receiving nivolumab. The primary end point of this study was neurotoxicity; secondary end points included BM control and survival. RESULTS: Twenty-six patients with a total of 73 BMs treated over 30 sessions were identified. Radiation was administered before, during and after nivolumab in 33 lesions (45%), 5 lesions (7%), and 35 lesions (48%), respectively. All BMs were treated with stereotactic radiosurgery (SRS) in a single session except 12 BMs treated with fractionated stereotactic radiation therapy, nine of which were in the postoperative setting. One patient experienced grade 2 headaches following SRS with symptomatic relief with steroid treatment. No other treatment-related neurologic toxicities or scalp reactions were reported. Eight (11%) local BM failures with a ≥20% increase in volume were noted. Of these lesions, hemorrhage was noted in 4, and edema was noted in 7. Kaplan-Meier estimates for local BM control following radiation at 6 and 12 months were 91% and 85%, respectively. Median overall survival (OS) from the date of stereotactic radiation and nivolumab initiation was 11.8 and 12.0 months, respectively, in patients receiving nivolumab for unresected disease (median OS was not reached in patients treated in the resected setting). CONCLUSIONS: In our series, stereotactic radiation to melanoma BMs is well tolerated in patients who received nivolumab. BM control and OS appear prolonged compared with standard current treatment. Prospective evaluation is warranted.

Prolonged survival after episiotomy recurrence of cervical cancer complicating pregnancy.

BACKGROUND: We report a case of recurrent cervical cancer in an episiotomy scar and the late treatment-related sequelae. CASE: Cervical cancer was diagnosed following a vaginal delivery, and was treated with surgery and radiotherapy. The patient developed a recurrence in her episiotomy scar, and was treated with chemoradiation. She remains without evidence of disease ten years later. CONCLUSION: Successful treatment of recurrent cervical cancer with chemoradiation is possible, but may be associated with significant normal tissue toxicity.

Grade migration in prostate cancer: an analysis using the Surveillance, Epidemiology, and End Results registry.

To utilize the Surveillance, Epidemiology, and End Results (SEER) registry to examine trends in grade assignment. Data from 411 325 patients from 1984 to 2003 were analyzed for grade migration and for cause-specific survival (CSS) as a function of grade. There has been a significant grade migration during the study period (P<0.001), principally from well-differentiated (WD) to moderately differentiated (MD) disease. Five-year CSS of MD and WD patients have converged, suggesting a decreasing role of grade as a prognostic factor. A grade migration from WD to MD assignment has occurred, suggesting that prognostic categorizations based on grade across eras may be difficult to interpret.

'Insignificant' prostate cancer on biopsy: pathologic results from subsequent radical prostatectomy.

'Insignificant' prostate cancer is defined as disease of virulence insufficient to threaten survival. In this review, which describes nine articles and two abstracts discussing almost 800 cases, we discuss the correlation of such 'insignificant' biopsy findings in the context of subsequent radical prostatectomy data. From our review, minimal disease on biopsy does not reliably predict minimal disease in the subsequent prostatectomy specimen, in terms of the size and grade of tumor, extracapsular extension or positive margins. Thus, reasoned accounting should be made of other data before undertaking a course of radiation therapy as monotherapy, particularly prostate-specific antigen kinetics and potential molecular markers.

Lack of survival benefit of post-operative radiation therapy in prostate cancer patients with positive lymph nodes.

Randomized data from SWOG 8794 and EORTC 22911 confirm the benefit of post-operative radiation therapy (RT) for selected patients with pT3 prostate cancer (CaP) after radical prostatectomy (RP). However, data regarding the potential benefit of RT for patients post-RP with positive lymph node (+LN) involvement are limited. We analyzed the Surveillance Epidemiology End Results (SEER) registry for population-based data on efficacy of post-operative RT for +LN patients after RP. As LN data have only been captured by SEER since 1988, we analyzed data for 1988-1992, with specific attention to 10-year relative survival (defined as observed survival divided by the survival of a gender-, age- and race-matched population cohort without disease). Specifically analyzed were data for 1921 patients with nonmetastatic prostate cancer who underwent surgery alone, or surgery followed by RT, and who had +LNs documented. SEER does not code the interval between surgery and RT, so the ratio of patients receiving salvage versus adjuvant therapy is unknown. Using follow-up data through 2002, post-diagnosis survival was examined by number of +LNs. There was no significant relative survival benefit for +LN patients receiving post-operative RT (chi(2)P=0.270). These data do not support routine use of post-operative RT for patients with +LNs in the surgical specimen.

The 100-day PSA: usefulness as surrogate end point for biochemical disease-free survival after definitive radiotherapy of prostate cancer.

Overall and biochemical disease-free (bNED) survival data after definitive radiotherapy (RT) for prostate cancer (CaP) requires decades of patient follow-up. Surrogates involving dynamics of prostate-specific antigen (PSA) decline, PSA nadir and time thereto have been unrewarding. This study investigated the metric of the PSA value 100 days after RT (PSA(100)), analyzed with respect to 8-y bNED survival. A total of 214 patients with T1-3 CaP were treated with definitive RT (defined as dose >66 Gy) in our institution between 1/1/1988 and 12/31/2000. All were subject to continuous follow-up with routine PSA levels. Biochemical failure (77 patients) was defined by the ASTRO criteria (n=67) or by the date of first hormonal therapy for a rising PSA, which did not meet the ASTRO criteria (n=10). No patients were included if they received postoperative radiation, or if hormones were administered prior to bNED recurrence, if any. Patients were stratified by PSA(100) values 4.0 ng/ml, and 4.0 ng/ml had 20% 8-y bNED survival (P<0.001). Use of a PSA(100) cutoff of 2.5 ng/ml yielded no significant difference in 8-y bNED survival (P=0.229). Cox proportional analysis revealed that initial PSA (P=0.006), stage (P=0.001) and PSA(100)

Treatment modalities of bladder/prostate rhabdomyosarcoma: a review.

Treatment outcomes of bladder/prostate rhabdomyosarcoma (RMS) in multi- and single-institutional trials are reviewed. Remarkable strides have occurred in the treatment of this disease. Decreasing duration of chemotherapy, less cumulative doses of radiation therapy, and improving survival have been documented. A focus on bladder preservation has not adversely affected survival in most studies. Even if organ preservation is not possible, improvements in urinary diversion surgical technique still offer improved quality of life. The IRS III was a pivotal study in improving survival and quality of life. We recommend protocol enrollment whenever available. We also emphasize the use of magnetic resonance imaging and second look surgery.

Initiation of salvage therapy for prostate cancer.

Physicians and patients have variable and individual levels of comfort regarding when to begin salvage therapy for rising prostate specific antigen (PSA) after definitive treatment of prostate cancer. The decision to start salvage therapy is a multifactorial process for which few rigorous data or guidelines exist. A questionnaire survey of urologists of the Department of Defense (DoD) Center for Prostate Disease Research (CPDR) was undertaken to obtain current perspectives on when to begin salvage therapy for biochemical failure after definitive therapy. Variables of age, grade, T-stage, nodal status, performance status, latency since prior therapy, PSA velocity, and ploidy were prioritized in four clinical situations; subsequent questions assessed consensus PSA cut-offs for beginning adjuvant therapy in 84 clinical scenarios. Consensus on PSA cut-off points was limited to postoperative radiotherapy (RT), where values of 1.0-1.5 were the mean cut-off points. CPDR urologists consider salvage prostatectomy post-RT only for patients <70-y-old with node negative, grade 2-7 disease and excellent performance status. Ploidy was not generally considered useful in any scenario. Many variables in addition to PSA level are involved in the decision of when to commence adjuvant therapy for initial biochemical failure. These are strikingly interdependent, and few clear absolutes are evident from this questionnaire. This is a point of necessary further research and continued discussion among physicians caring for these patients.

Management of recurrent colorectal carcinoma.

BACKGROUND/OBJECTIVE: The records of patients treated for adenocarcinoma of the colon and rectum between 1 January 1988 and 31 December 1995 at Naval Medical Center San Diego were reviewed. Analysis was made of patients who developed recurrences after potentially definitive primary therapy. METHODS: A retrospective review of 410 patients diagnosed with colorectal cancer at our institution was conducted. The focus of this review was to identify patients with recurrent disease after curative initial procedures, and to determine how recurrences were detected and treated. Survival data for 48 patients undergoing various curative and palliative procedures, or no therapy, were generated. RESULTS: The decision to re-operate with curative intent was made after a multidisciplinary review of restaging studies. Laparoscopy was not used in this determination. Curative resection of recurrence confers increased survival over non-curative surgery and no surgery (P < 0.001). This is misleading because of patient selection; several patients undergo potentially curative surgery but are determined intraoperatively to best be palliated, or to have further surgery aborted. Analysis of results in patients undergoing potentially curative surgery vs. those undergoing planned palliation vs. those not operated reveals that these also provide significantly different outcomes (P < 0.003). CONCLUSIONS: Proper delineation of resectable lesions in patients with recurrent colorectal cancer contributes to better outcomes for them. That determination is difficult, and efforts are underway in our institution and elsewhere to better delineate which patients are optimal preoperatively. We consider multidisciplinary Tumor Board evaluation to be central to this process.

Efficacy of digital rectal examination after radiotherapy for prostate cancer.

PURPOSE: Digital rectal examination is widely performed for following patients with localized prostate cancer after definitive therapy. This examination has marginal efficacy for detecting initial prostate cancer and postoperative recurrence. To determine the efficacy of digital rectal examination in terms of new information provided after radiotherapy we analyzed the results of digital rectal examination in the followup of patients with prostate cancer after radiotherapy. MATERIALS AND METHODS: We performed a nonrandomized study in 235 consecutive patients with prostate cancer followed at a large tertiary care military hospital between January 1, 1995 and December 31, 1999. All patients had been treated with prostate radiotherapy and had no evidence of metastatic disease at the first visit within that interval. Digital rectal examination was done at followup and the main outcome measure was new information provided by that examination. RESULTS: A total of 1,544 digital rectal examinations were performed in 1,627 visits. New information was provided by digital rectal examination in only 30% of 286 abnormal examinations, of which more than three-quarters were related to bleeding and would otherwise have been noted on routine examination by the primary care provider. All 8 persistent recurrent prostate nodules were noted in the context of increasing prostate specific antigen. CONCLUSIONS: Routine digital rectal examination in patients with prostate cancer after radiotherapy may be omitted from followup protocols.

Radiation therapy for Bowen's disease: lessons for lesions of the lower extremity.

OBJECTIVE: A retrospective outcomes review of radiotherapy for Bowen's disease was performed to analyze all patients treated with radiation therapy between 1993 and 1997 at the Naval Medical Center, San Diego. METHODS: Eleven patients with 16 lesions were treated with a median time-dose-fractionation value of 105 (range, 93-108). RESULTS: All 11 patients were without evidence of disease within 1 to 2 months of completing treatment. Four of the 16 lesions (25%) were unhealed at time of last follow-up; the remainder healed with good cosmetic result. All unhealed lesions were on the lower extremity. Median follow-up was 27.5 months (range, 9-57 months). CONCLUSION: Radiation remains a good therapeutic option in selected patients with Bowen's disease, but caution should be exercised before selection of patients with lesions in potentially poor healing areas, such as the lower extremity.

20-year outcome of patients with T1-3N0 surgically staged prostate cancer treated with external beam radiation therapy.

PURPOSE: Patients with surgically staged localized prostate cancer treated with external beam radiation therapy were retrospectively analyzed for 15 and 20-year overall and cause specific survival. The need for additional therapy was also evaluated. MATERIALS AND METHODS: We analyzed 145 patients who received external beam radiotherapy after negative staging pelvic lymphadenectomy. Followup data were available for 129 patients. Overall and cause specific survival was calculated with the Kaplan-Meier method. RESULTS: Median followup was 14.9 years. Actuarial overall survival at 15 and 20 years was 45.9% and 24.6%, respectively. Cause specific survival at 15 and 20 years was 64.5% and 37.7% for having all patients dying of unknown causes censored, and 54.4% and 30.1% for those dying of unknown causes categorized as having prostate cancer, respectively. Of the patients who survived 47% were on hormonal therapy. CONCLUSIONS: Longer followup after external beam radiation therapy continues to demonstrate a decrease in cause specific survival. Many patients ultimately require hormonal therapy.

Survival patterns of cancer patients.

BACKGROUND: Optimal means of modeling death rates of large populations with a specific disease have not been described in the literature. METHODS: Statistical modeling was used on archival data. RESULTS: In the authors' prior publications describing the survival of untreated cancer patients, data that were adequately fitted by an exponential curve were found to be much better fitted by an inverse Gompertz curve (R(2) = 99.7% for untreated breast carcinoma, 99.9% for untreated cervical carcinoma). However, when data from treated patients are examined, fits show that successive stages begin at successive positions on the inverse Gompertz curve. Breast carcinoma data showed that treatment begun at an early stage raised survival to a linear decline; at an intermediate stage led to a modified inverse Gompertz, the earlier the stage at which therapy was begun, the greater the survival rate; and at a late stage exhibited an exponential decline showing a negligible effect of late treatment. Confidence in this approach was enhanced by its applicability using published data from the National Cancer Database for breast, pancreatic, bone, and skin cancers. CONCLUSIONS: The use of data modeling allowed us to assess realistically the value of intervention in cancer populations and to optimize staging schemas. It strongly reinforced the concept that early detection provides a far greater impact on a population's subsequent survival than therapy of advanced disease.

Acupuncture for pilocarpine-resistant xerostomia following radiotherapy for head and neck malignancies.

OBJECTIVE: Xerostomia is a frequent and potentially debilitating toxicity of radiotherapy (XRT) for cancers of the head and neck. This report describes the use of acupuncture as palliation for such patients. METHODS AND MATERIALS: Eighteen patients with xerostomia refractory to pilocarpine therapy after XRT for head and neck malignancy were offered acupuncture as palliation. All patients are without evidence of cancer recurrence at the primary site. Acupuncture was provided to three auricular points and one digital point bilaterally, with electrostimulation used variably. The Xerostomia Inventory (XI) was administered retrospectively to provide an objective measure of efficacy. RESULTS: Acupuncture contributed to relief from xerostomia to varying degrees. Palliative effect as measured by the XI varied from nil to robust (pre- minus post- therapy values of over 20 points). Nine patients had benefit of over 10 points on the XI. CONCLUSIONS: Acupuncture reduces xerostomia in some patients who are otherwise refractory to best current management.

Merkel cell carcinoma arising in the head and neck: optimizing therapy.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine dermal neoplasm. Because of the limited number of cases described in the literature (approximately 600 to date), statistically significant data regarding treatment are difficult to obtain. The majority of MCC cases affect the head and neck and are thought to be caused by the actinic damage associated with sun exposure. This study evaluates cases of head and neck MCC at Naval Medical Center San Diego (NMCSD) and compares the treatment regimens and outcomes from multiple institutions. This study is a retrospective outcomes analysis of all cases of head and neck MCC seen at NMCSD, between January 1, 1988 and June 30, 1998. The records of the NMCSD Tumor Registry were searched for patients with that diagnosis, and supplemental information was retrieved from the Radiation Oncology and Head & Neck Surgery Clinic charts. Eight of nine patients in this study were treated with either wide-local excision or Mohs microsurgery. The surgical margins were free of disease in all eight patients. One patient presented with distant metastatic disease, and two others were subsequently found to have nodal involvement. Subsequent therapy varied among the patients. Survey of the available literature revealed inconsistency in terms of which treatment regimens are optimal. Tumor resections are recommended by most groups to include a 2-cm to 3-cm tumor-free margin around the primary lesion when possible, but this is often difficult to achieve in the head and neck. Data, which do not reach statistical significance, suggest improved outcomes with tumor-free margins. Treatment of the regional draining lymph nodes is also recommended in most series. Prophylactic lymph node dissection or radiation therapy to the nodal chain may decrease local recurrence but does not consistently affect overall survival. Adjuvant chemotherapy is advocated by most groups in the treatment of metastatic disease because MCC is pathologically similar to small-cell lung carcinoma. However, no chemotherapy protocol has been shown to improve survival. Head and neck MCC is a rare and aggressive dermal tumor of neuroendocrine origin that requires multimodality therapy, including surgery, radiation therapy, and possibly adjuvant chemotherapy. Multiinstitutional studies are crucial to obtain sufficiently large populations to investigate and optimize therapy in this disease.

Yield of mammography in selected patients age < or = 30 years.

BACKGROUND: An outcomes analysis study was performed to quantify the benefit of directed diagnostic imaging of selected very young women (defined as < or = 30 years of age) in our population. Summary results are presented. PATIENTS AND METHODS: Women's Imaging Services were queried for studies performed between April 1, 1997 and December 31, 1998 on women < or = 30 years of age. The authors' referral pathway mandates breast examination by a general surgeon or by the head of Women's Imaging before mammography in all such patients. Studies were excluded if there were reviews of scans performed at other sites. The resulting 142 mammograms were evaluated. RESULTS: Ninety percent of the 142 studies were within normal limits. Only 11 mammograms indicated any required action (7.8%), and only 5 of these merited biopsy. All biopsies revealed benign disease. No carcinomas were detected by biopsy or on clinical follow-up in this cohort of women. These values are congruent with the scarce literature on mammography in this population. CONCLUSIONS: The yield of mammography in the age < or = 30 years population is low.

Risk management in a community Gamma Knife unit.

OBJECTIVE: The records of the San Diego Gamma Knife Center were retrospectively reviewed for unprogrammed events as part of a risk management assessment. MATERIALS AND METHODS: Review was made of the physicist notes of the first 1,000 patients successfully treated at the center. This encompassed 1,020 stereotactic frame placement procedures, accompanied by Gamma Knife radiosurgery in 98.0% of intended cases. A total of 7,145 Gamma Knife shots were delivered to 1,509 lesions. RESULTS: Of the 43 unprogrammed events documented, 8 were patient related and 14 were related to lesion growth or location; these were considered unavoidable. Further, one event was related to dose administration, 5 to diagnosis, 15 to technique; these were considered potentially avoidable. This yielded an avoidable error rate of 2.1% per patient, 1.4% per lesion treated, and 0.29% per shot. It was clear that more avoidable errors occurred early in the center's operation, consistent with a learning curve. Review of individual physician's cases revealed none appeared more likely to have an avoidable event. CONCLUSIONS: Consistently high quality may be achieved at a community-based Gamma Knife center if sufficient multidisciplinary involvement is achieved.

Rectal bleeding after radiation therapy for prostate cancer: endoscopic evaluation.

PURPOSE: To analyze the frequency and clinical importance of proctitis and hematochezia after radiation therapy for prostate cancer. MATERIALS AND METHODS: Of 63 patients with prostate cancer treated with curative intent by a single radiation oncologist between July 1, 1993, and December 31, 1997, 30 were asymptomatic, but 33 had heme-positive digital rectal examination (DRE) results or hematochezia at routine follow-up. Twenty-six of these patients underwent endoscopy of the sigmoid colon or colon for evaluation of these symptoms. Median doses of 60.0 Gy at postoperative radiation therapy and 68.4 Gy at definitive radiation therapy were delivered to four fields daily by using blocking customized on the basis of computed tomographically documented evidence of disease. The Fisher exact test and the Kaplan-Meier method were used to analyze the results. RESULTS: The frequency of rectal bleeding approached 80% at 3 years after radiation therapy in definitively treated patients. Only 14 patients had proctitis: eight as the only sign, and six in association with other disease. Six patients had other disease without proctitis, and four patients had normal examination findings. The frequency of rectal bleeding in the presence of proctitis was similar to that in the presence of other disease (Fisher exact test, P =.68). CONCLUSION: Hematochezia or positive DRE findings are frequent sequelae of definitive radiation therapy for prostate cancer; however, causes other than proctitis are often documented at endoscopy. Symptomatic individuals warrant rigorous evaluation to rule out serious coexistent disease.