Primary breast lymphoma (PBL) comprises < 1% of breast malignancies, leading to a paucity of data to guide management. We evaluated PBL recurrence patterns across two academic hospitals in the era of modern systemic-therapy and radiotherapy.

Vitiligo is an acquired mucocutaneous depigmentation disorder characterized by white macules and patches secondary to destruction of melanocytes. Several case reports describe isolated incidents of in-field depigmentation after radiation therapy (RT) in patients with vitiligo ( 1 Levine E.L. Ribeiro G.G. Vitiligo and radiotherapy: The Koebner phenomenon demonstrated in patients with vitiligo undergoing radiotherapy for carcinoma of the breast. Clin Oncol (R Coll Radiol). 1994; 6: 133-134 Abstract Full Text PDF PubMed Scopus (34) Google Scholar , 2 Pajonk F. Weissenberger C. Witucki G. et al. Vitiligo at the sites of irradiation in a patient with Hodgkin's disease. Strahlenther Onkol. 2002; 178: 159-162 Crossref Scopus (23) Google Scholar , 3 Koo S.W. Suh C.O. Hann S.K. Vitiligo following radiotherapy for carcinoma of the breast. Br J Dermatol. 1996; 135: 852-853 Crossref PubMed Scopus (18) Google Scholar , 4 Weitzen R. Pfeffer R. Mandel M. Benign lesions in cancer patients: Case 3. Vitiligo after radiotherapy for breast cancer in a woman with depigmentation disorder. J Clin Oncol. 2005; 23: 644 Crossref PubMed Scopus (16) Google Scholar , 5 Kim D.H. Kim C.W. Kim T.Y. Vitiligo at the site of radiotherapy for malignant thymoma. Acta Derm Venereol. 1999; 79: 497 Crossref Scopus (11) Google Scholar , 6 Munshi A. Jain S. Budrukkar A. et al. Radiotherapy-induced depigmentation in a patient with breast cancer. Indian J Cancer. 2007; 44: 157-158 Crossref PubMed Scopus (9) Google Scholar , 7 Polat M. Yalcin B. Alli N. Vitiligo at the site of radiotherapy for nasopharyngeal carcinoma. Am J Clin Dermatol. 2007; 8: 247-249 Crossref PubMed Scopus (13) Google Scholar , 8 Sanghavi S.A. Dongre A.M. Khopkar U.S. Koebnerization and generalized spread of vitiligo following radiotherapy. Indian Dermatol Online J. 2013; 4: 147-148 Crossref Google Scholar , 9 Vajrala G. Jain P.K. Surana S. et al. Generalized vitiligo post radiotherapy in a breast cancer patient. J Cancer Res Ther. 2014; 10: 365-367 Crossref Scopus (3) Google Scholar , 10 Biswas A. Chaudhari P.B. Julka P.K. et al. Radiation induced depigmentation disorder in two patients with breast cancer: Exploring a rare accompaniment. J Egypt Natl Cancer Inst. 2015; 27: 101-104 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ). Depigmentation localized to an area of injury or irritation in predisposed individuals is known as the Koebner phenomenon ( 1 Levine E.L. Ribeiro G.G. Vitiligo and radiotherapy: The Koebner phenomenon demonstrated in patients with vitiligo undergoing radiotherapy for carcinoma of the breast. Clin Oncol (R Coll Radiol). 1994; 6: 133-134 Abstract Full Text PDF PubMed Scopus (34) Google Scholar ).

Purpose: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes.Methods and Materials: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS.Results: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty- four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow- up of 3 years, the 3- year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p<0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients.Conclusions: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients. (C) 2012 Elsevier Inc.

We report a case history of a patient with Parkinson's disease (PD) treated with androgen deprivation therapy (ADT) and external beam radiation for prostate cancer, who developed severe deterioration of his PD during ADT.

PURPOSE:We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer.PATIENTS AND METHODS:Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation.RESULTS:Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months.CONCLUSION:Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

PURPOSE:To determine whether intratherapy prostate-specific antigen (itPSA) changes during radiotherapy (RT) predict prostate cancer outcomes. METHODS AND MATERIALS:We retrospectively identified patients treated with definitive external beam RT without hormonal therapy who had at least two itPSA measurements. We calculated the adjusted ratio of rise (ARR) in itPSA relative to the pretreatment baseline PSA for each patient. This was defined as ln(maximal itPSA + 1)/ln(baseline PSA + 1). We stratified patients according to an ARR of <1 vs. >1.1. This corresponded to an approximately <30% vs. >30% increase in PSA during RT. Univariate and multivariate analyses were performed examining for biochemical failure-free survival (BFFS) and overall survival (OS). RESULTS:At a median follow-up of 74 months, we identified 307 patients who met our criteria. Univariate analysis revealed that patients with an ARR of <1.1 (n = 182) had statistically significant inferior BFFS and OS compared with those with an ARR of >1.1 (n = 125). The median BFFS and OS for these two groups was 51 vs. 101 months (p = 0.001) and 96 vs. 128 months (p = 0.01), respectively. On multivariate analysis, the effect of ARR on the risk of biochemical failure for patients with an ARR of <1.1 was significant (p = 0.03) only during the first year after RT. In contrast, the effect of the ARR on OS remained significant for a full 5 years (p = 0.05). CONCLUSION:The results of our study have shown that an ARR of <1.1 predicts for inferior BFFS and OS in patients treated with RT alone. PSA measurement during RT is a novel clinical tool that could be used to identify patients who might warrant more aggressive therapeutic intervention.

OBJECTIVES The Radiation Therapy Oncology Group 9413 trial has shown an improvement in progression- free survival (PFS) with external beam radiotherapy that included the pelvic nodes. In clinical practice, two pelvic field size designs are in use. We examined the effect of differences in the level of pelvic nodal coverage using three-dimensional conformal radiotherapy on biochemical failure-free survival (BFFS) and PFS in early-stage prostate cancer.METHODS The patients were identified retrospectively who had undergone whole pelvis (WP) or minipelvis (MP) three-dimensional conformal radiotherapy. Biochemical failure was defined as the nadir prostate-specific antigen (PSA) level plus 2 ng/mL.RESULTS Of the 669 patients identified, 384 had undergone NIP (57%) and 285 WP (42%) treatment, with a median PSA follow-up of 56 months. Of the 669 patients, 11%, 35%, and 54% were at low, intermediate, and high risk, respectively. The median dose was 75 Gy for the NIP and 71 Gy for the WP groups. Of the MP and WP groups, 52% and 36% underwent hormonal therapy. The median BFFS and 5-year BFFS rate was 128 months and 73% for the MP group and 96 months and 58% for the WP group. The median PFS and 5-year PFS rate was 128 months and 72% for the NIP group and 83 months and 56% for the WP group. Multivariate analysis revealed no difference between MP and WP treatment. However T stage, pretreatment PSA level, and Gleason score were significant predictors of BFFS and PFS.CONCLUSIONS We observed no difference in outcomes between patients undergoing WP versus MP using three-dimensional conformal radiotherapy. Therefore, the exclusion of the common iliac lymph nodes in the treatment of patients with high-risk prostate cancer might be acceptable.

PURPOSE:To characterize the demographics and survival outcomes of localized prostate cancer patients who developed biochemical failure (BF) according to a prostate-specific antigen (PSA) nadir plus 2 ng/mL. METHODS AND MATERIALS:We identified 375 prostate cancer patients who had undergone external beam radiotherapy without androgen deprivation therapy but with sufficient PSA data to study PSA kinetics. Of these patients, we identified 82 with BF. The pretreatment PSA velocity was calculated for each patient. RESULTS:For the BF cohort, 26% were low-risk and 74% were intermediate- or high-risk patients. Of the 82 BF patients, 16 (20%) were noted to have both low-risk disease and a pretreatment low PSA velocity of < or =2 ng/mL/y (termed "low-risk low-velocity" [LRLV]). The remaining BF patients had either intermediate- or high-risk features or a high PSA velocity >2 ng/mL/y (termed "higher risk" [HR]). For patients who had BF, the LRLV group had a delayed median time to BF of 55 months compared with 33 months for the HR patients (p = 0.04). With a median clinical follow-up of 112 months, the 5-year overall survival rate was 100% for the LRLV BF patients vs. 84% for the HR patients (p = 0.02). CONCLUSIONS:We observed that LRLV BF patients represent a sizeable proportion of all patients with treatment failure. However, when comparing LRLV BF with HR BF patients, the former had significantly better overall survival and a longer interval to BF. This suggests that not all BF events are equivalent and emphasizes the challenges associated with using BF alone as a surrogate for a survival endpoint.

OBJECTIVES To examine the effect: of concurrent statin use during definitive radiotherapy (RT) on the biochemical Outcomes for localized prostate cancer.METHODS A total of 968 patients treated with RT had information about medication use available. Of these, 23% had been taking using statins during RT. Progress ion-free survival (PFS) was determined by a biochemical failure definition of prostate-specific antigen nadir plus 2 ng/mL, clinical failure, start of androgen deprivation therapy, or death.RESULTS The mean patient age was 68 years. The median radiation dose was 76 Gy. Of the patients, 29% underwent androgen deprivation therapy. The 5-year overall survival rate was 83%. The median PFS time was 7.8 years versus 6.4 years, and the 5-year PFS rate was 70% versus 59% in favor of the statin users (P = 0.03). The analysis by risk group demonstrated no significant statin effect in any of the three risk strata. Stratification by hydrophilic versus hydrophobic statin agents revealed similar results. Multivariate analysis revealed that T stage (P <0.0001), pretreatment prostate-specific antigen level (P <0.0001), and Gleason score (P = 0.0026) were significant predictors of PFS; however, statin use (P = 0.48), androgen deprivation therapy (P = 0,95), pelvic RT (P = 0.96), radiation dose (P = 0.13), age (P = 0.19), and year of treatment (P 0.07) were not.CONCLUSIONS Statin use did not affect PFS after adjusting for differences in treatment year and multiple prognostic factors. However, T stage, baseline prostate-specific antigen level, and Gleason score were critical determinants of prostate-specific antigen failure. These results did not differ when hydrophilic pravastatin was excluded. UROLOGY 73: 158-162, 2009 (C) 2009 Elsevier Inc.

Introduction To determine if pretreatment PSA doubling time (PSA-DT) can predict post-radiation therapy (RT) PSA trajectories for localized prostate cancer. Materials and methods Three hundred and seventy-five prostate cancer patients treated with external beam RT without androgen deprivation therapy (ADT) were identified with an adequate number of PSA values. We utilized a linear mixed model (LMM) analysis to model longitudinal PSA data sets after definitive treatment. Post-treatment PSA trajectories were allowed to depend on the pre-RT PSA-DT, pre-RT PSA (iPSA), Gleason score (GS), and T-stage. Results Pre-RT PSA-DT had a borderline impact on predicting the rate of PSA rise after nadir (p = 0.08). For a typical low risk patient (T1, GS ⩽ 6, iPSA 10), the predicted PSA-DT post-nadir was 21% shorter for pre-RT PSA-DT < 24 month compared to pre-RT PSA-DT > 24 month (19 month vs. 24 month). Additional significant predictors of post-RT PSA rate of rise included GS (p < 0.0001), iPSA (p < 0.0001), and T-stage (p = 0.02). Conclusions We observed a trend between rapidly rising pre-RT PSA and the post-RT post-nadir PSA rise. This effect appeared to be independent of iPSA, GS, or T-stage. The results presented suggest that pretreatment PSA-DT may help predict post-RT PSA trajectories.

A number of series have been published examining the utility of combining low-dose rate permanent interstitial implants with external-beam radiation (CMT). However, the data show conflicting results. Comparisons of these studies are confounded by the lack of similar biochemical failure definitions, inequities in risk groups between compared arms, variable implant quality, and differences in implant margins and techniques. Despite these limitations, the literature does suggest that CMT may help spare patients the need for androgen deprivation, overcome adverse pathologic factors, and correct for poor implant quality. We present the recent innovation and potential benefits of using implant dose-adjusted intensity-modulated radiation therapy.

HMG-CoA reductase inhibitors or statins have demonstrated in vitro anti-cancer activity as well synergistic effects with radiation. Several retrospective studies of radiation (RT) treated non-prostate cancer patients have suggested improvements in endpoints such as pathologic response rate and local control. However, conflicting results have been published for prostate cancer patients. In this study we examine the impact of concurrent statin use during definitive radiation therapy on biochemical outcomes for localized prostate cancer. Patients were identified retrospectively in an IRB-approved prostate cancer data base if they had T1-T3N0M0 prostate cancer treated with definitive 3-Dimensional Conformal RT between 1987 and 2005. There were a total of 999 patients of which 968 had information about medication usage available. Of the 968, 23% were found to be utilizing statins during treatment. Low risk patients were defined as T1, (Gleason Score) GS ≤6, or PSA <10, high risk were noted as having T ≥2, GS > 7, or PSA > 20 and the remaining patients were considered intermediate risk. Progression free survival (PFS) events were defined as a PSA rise of 2 ng/ml or more above current nadir, the start of androgen deprivation therapy (ADT), clinical local failure, distant failure, salvage surgery or death after completion of RT. A traditional Cox model was utilized two compare the impact of statin use. A multivariable analysis was carried out to determine which factors independently predicted progression. There were 28% low risk patients, 42% intermediate risk and 30% high risk patients. Median age was 69 years. Median radiation dose was 76 Gy. A total of 29% of patients received adjuvant ADT. With a median follow-up of 47 months the 5 yr OS was 82%. Median PFS was 83 months for statin users vs. 73 mo for control patients. The 5-yr PFS was 67% and 57% respectively (p = 0.03). Analysis by risk group demonstrated no significant statin effect in all three risk strata. Multivariable analysis revealed that T stage (p < 0.0001), pretreatment PSA (p < 0.0001), and GS (p = 0.0029) were significant predictors of biochemical failure; however statin use (p = 0.48), ADT (p = 0.74), pelvic RT (p = 0.45), dose (p = 0.2), age (p = 0.83) and year of treatment (p = 0.54) were not. This single institution retrospective study redemonstrated that T-stage, pretreatment PSA and GS were critical determinants of PSA failure. After adjusting for differences in follow-up and multiple prognostic factors, statin use in our population did not impact PFS. However, given the conflicting clinical retrospective data, large pooled studies, longer follow-up, or prospectively collected data may help to determine whether a statin effect exists.

Background: The purpose of this study was to determine the clinical outcomes and patterns of failure of limited-stage extrapulmonary small cell carcinoma (EPSCC) treated with modern chemotherapy and radiation (RT). Methods: We retrospectively identified 18 patients with limited-stage EPSCC treated definitively with three-dimensional conformal RT or intensity modulated radiation therapy and chemotherapy. Patients were treated between November 1987 and May 2006. Primary sites of disease included head and neck (n = 7), genitourinary (n = 7), gynecologic (n = 3), and gastrointestinal (n = 1). Chemotherapy consisted of combined platinum and etoposide in 88% of patients. The median number of chemotherapy cycles was 4 (range 3–6), and the median RT dose was 62 Gy (range 32.4–85 Gy). No patient received prophylactic cranial radiation. Results: With a median follow-up for all patients of 14 months (range 4–42 months), the median overall survival was 17 months, and median disease-free survival was 6 months. Eleven percent (2 of 18) of patients had a locoregional failure, and 78% (14 of 18) had a distant failure. One of these patients had a brain failure. There were no significant differences between the overall survival for patients with gynecologic, head and neck, and genitourinary disease. Conclusions: Despite modern chemotherapy and RT, patients with limited-stage EPSCC do poorly. Consistent with previous findings the majority of the first failures are distant. Brain failures in this series were uncommon despite no prophylactic cranial radiation. These findings support the need for further studies in an attempt to improve systemic therapies for this disease.

Background and purpose: To assess whether the pretreatment FDG-PET-defined biologic target volume (PET-BTV) correlates with the anatomical sites of loco-regional failure (LRF) after RT for head and neck cancer (HNC).Materials and methods: We retrospectively identified 61 HNC patients treated definitively with either 3-D CRT or IMRT who had a pre-therapy PET/CT. The GTV and high-risk CTV1 definitions included composite data obtained from diagnostic CT, PET/CT, physical examination, and MRI when available. The median CTV1 dose was 70 Gy. 95% received chemotherapy. For patients with LRF, a recurrence volume (V-r) was identified and was mapped to the pretreatment planning CT and pretreatment PET scan.Results: At a median follow-up of 22 months, 15% (9/61) patients had LRF. For patients with a LRF, 100% (9/9) of failures were inside the GTV. One of nine [11% (95% Cl: 3-45%)] had V-r which mapped outside of the pretreatment PET-BTV, while 8/9 patients had Vr within the PET-BTV. Predictors of LRF in our series included GTV volume (p = 0.003), but not mean SUV (p = 0.13) or max SUV (p = 0.25).Conclusions: Following treatment in which the GTV was defined based on the composite of imaging and physical examination, the majority, but not all, LRF occurred within the PET-BTV. These results support an important, but not exclusive, role of FDG-PET in defining the GTV. (C) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 89 (2008) 13-18.

The 5-year survival rate for patients with stage III non-small cell lung cancer (NSCLC) is 10%. A number of genetic alterations are associated with this disease including mutations and amplifications of EGFR (70%) and Ras (20–30%), both of which are upstream of PI3K. Our previous data show that these regulate tumor radiation sensitivity. Here we ask whether the activation of this pathway has prognostic relevance in NSCLC. Two series of patients were retrospectively analyzed. The first series consisted of 23 Stage III NSCLC patients treated preoperatively with a chemo/radiation protocol. The second consisted of 12 Stage III NSCLC patients treated with chemo/radiation without surgery who had survived more than 2 years. Expression levels of EGFR and Her-2 were assessed by immunohistochemical staining. PI3K signaling was evaluated by staining for phosphorylated Akt (P-Akt), a downstream target of PI3K. The staining for EGFR, Her-2, and P-Akt were related to outcome in the two groups. Additionally, the importance of PI3K signaling was evaluated in 3 NSCLC cell lines using a pharmacological blockade of PI3K by LY294002. In the first series of patients, 43% were positive for EGFR, 5% for Her-2, and 82.6% for P-Akt. Of the survivors, 25% were positive for EGFR, 0% for Her-2, and 42% for P-Akt. For P-Akt, this difference had a probability calculation of 0.003. The three NSCLC cell lines that we tested were found to have high levels of P-Akt. Pharmacologically inhibiting PI3K led to decreased Akt phosphorylation and radio sensitization of all three cell lines. The finding that NSCLC survivors treated by radiation have lower levels of PI3K and Akt signaling is consistent with the idea that inhibition of Akt leads to radio sensitization. This further suggests that Akt might be a useful target for sensitization of NSCLC to radiation.

Transformation with ras oncogenes results in increased radiation sur vival in many but not all cells. In addition, prenyltransferase inhibitors which inhibit ras proteins by blocking posttranslational modification radiosensitize cells with oncogenic ras. These findings suggest that oncogenic ras contributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and because prenyltransferase inhibitors target molecules other than ras, these studies left the conclusion that ras increases the intrinsic radi ation resistance of tumor cells in doubt. Here we show that genetic inactivation of K- or N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) leads to increased radiosensitivity. Reintroduction of the activated N-ras gene into the HT1080 line, having lost its mutant allele, resulted in increased radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resistance in human tumor cells and extends this finding to the K- and N- members of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.

The toxicity of radiation to living tissues was discovered soon after the discovery of radioactivity itself and this toxicity is the basis for cancer therapy with radiation. Although this mode of therapy is often effective, its success is far from assured. One major difficulty in the implementation of radiotherapy is that normal tissues are also sensitive to killing by radiation so that treatment is often limited by the tolerance of normal tissues for radiation. Thus methods that sensitize tumor cells while sparing normal tissues could potentially lead to greater success with radiation as a therapy. Oncogenes are frequently altered in tumors, but are not in normal tissue making them potential targets for altering radiosensitivity and apoptosis in tumors.