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1.  Current therapy and recent advances in the management of retinoblastoma 
Retinoblastoma is the most common intraocular malignancy in children. The survival of retinoblastoma patients and visual outcome has improved dramatically in the developed world. This can be attributed to early tumor recognition and advances in the management of retinoblastoma. Chemoreduction followed by adjuvant consolidative treatment has replaced external beam radiotherapy as the primary modality of treatment for intraocular retinoblastoma. Further, histopathological high-risk factors have been identified in enucleated eyes, allowing use of prophylactic chemotherapy to take care of possible micrometastasis. The survival in case of extraocular retinoblastoma is still low, and the reported survival rate ranges between 50% and 70%. In developing countries, the overall survival of retinoblastoma patients remains low, primarily due to a delayed presentation, resulting in larger proportions of extraocular disease compared with the developed world, where majority of the disease is intraocular. Greater efforts need to be directed toward early tumor recognition in order to improve the survival of retinoblastoma patients in the developing world. In this article, we provide an overview of the current clinical management of retinoblastoma.
PMCID: PMC3439795  PMID: 22988349
Recent advances; retinoblastoma; treatment
2.  Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma 
Radiology and Oncology  2010;44(3):194-198.
External beam radiotherapy (EBRT) for retinoblastoma has traditionally been done with conventional radiotherapy techniques which resulted high doses to the surrounding normal tissues.
Case report
A 20 month-old girl with group D bilateral retinoblastoma underwent intensity modulated radiotherapy (IMRT) to both eyes after failing chemoreduction and focal therapies including cryotherapy and transpupillary thermotherapy. In this report, we discuss the use of IMRT as a method for reducing doses to adjacent normal tissues while delivering therapeutic doses to the tumour tissues compared with 3-dimensional conformal radiotherapy (3DCRT). At one year follow-up, the patient remained free of any obvious radiation complications.
Image guided IMRT provides better dose distribution than 3DCRT in retinoblastoma eyes, delivering the therapeutic dose to the tumours and minimizing adjacent tissue damage.
PMCID: PMC3423696  PMID: 22933915
retinoblastoma; radiotherapy; intensity modulated radiotherapy
3.  Efficacy of vincristine and carboplatin as chemo-reduction for advanced bilateral retinoblastoma, the Saudi experience 
Saudi Journal of Ophthalmology  2013;27(3):193-196.
To evaluate the efficacy of a 2-drug chemotherapy regimen without external-beam radiotherapy (EBRT) and/or without enucleation in bilateral retinoblastoma.
From 1996 to 2010, 79 patients were diagnosed with bilateral RB and were eligible for chemotherapy. Chemotherapy was administered prior to and/or following local therapy to the eye. All patients received 3 cycles of chemo-reduction with carboplatin and vincristine, additional cycles of the same or other chemotherapy, local therapy, EBRT and enucleation were determined according to re-evaluation by the ophthalmologist.
Advanced disease was seen in 115 (79%) eyes (group IV and V: 96, Group D and E: 19) out of 146 affected eyes. Tumor response after chemotherapy was observed in 78 patients (98.7%); complete response in 25 (32.1%), partial response in 49 (62.8%) Four (5.1%) had progressive disease. A total of 50 (63.3%) patients required EBRT; 38 for persistent disease, 4 for progressive disease, 2 for new lesions, 2 for re-activation and 4 for disease control. Enucleation was required in 15 (19%). Secondary malignancies occurred in two patients who underwent EBRT; one osteogenic sarcoma and one rhabdomyosarcoma then later osteogenic sarcoma. The 10 year overall survival was 96.3% with a median follow-up time of 3.124 ± 0.536 years (95%CI: 2.074–4.174).
The 2-drug chemotherapy regimen combined with local therapy appears to be adequate therapy for low stage disease but not in patients with advanced disease. The occurrence of secondary cancers in this group of patients is worrisome further highlighting the deleterious effects of EBRT.
PMCID: PMC3770227  PMID: 24227985
Retinoblastoma; Chemo-reduction; Enucleation; External beam radiation therapy; Secondary malignancy
4.  External beam radiotherapy for retinoblastoma: II. Lens sparing technique. 
A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.
PMCID: PMC505039  PMID: 7696228
5.  Ophthalmic Artery Chemosurgery for Less Advanced Intraocular Retinoblastoma: Five Year Review 
PLoS ONE  2012;7(4):e34120.
Ophthalmic artery chemosurgery (OAC) for retinoblastoma was introduced by us 5 years ago for advanced intraocular retinoblastoma. Because the success was higher than with existing alternatives and systemic side effects limited we have now treated less advanced intraocular retinoblastoma (Reese-Ellsworth (RE) I-III and International Classification Retinoblastoma (ICRB) B and C).
Methodology/Principal Findings
Retrospective review of 5 year experience in eyes with Reese Ellsworth (Table 1) I (7 eyes), II (6 eyes) or III (6 eyes) and/or International Classification (Table 2) B (19 eyes) and C (11 eyes) treated with OAC (melphalan with or without topotecan) introduced directly into the ophthalmic artery. Patient survival was 100%. Ocular event-free survival was 100% for Reese-Ellsworth Groups I, II and III (and 96% for ICRB B and C) at a median of 16 months follow-up. One ICRB Group C (Reese-Ellsworth Vb) eye could not be treated on the second attempt for technical reasons and was therefore enucleated. No patient required a port and only one patient required transfusion of blood products. The electroretinogram (ERG) was unchanged or improved in 14/19 eyes.
Ophthalmic artery chemosurgery for retinoblastoma that was Reese-Ellsworth I, II and III (or International Classification B or C) was associated with high success (100% of treatable eyes were retained) and limited toxicity with results that equal or exceed conventional therapy with less toxicity.
PMCID: PMC3335846  PMID: 22545080
6.  Long-Term Survival After Radical Prostatectomy Versus External Beam Radiotherapy for Patients with High-Risk Prostate Cancer 
Cancer  2011;117(13):2883-2891.
We compared the long-term survival of patients with high-risk prostate cancer following radical prostatectomy (RRP) and external beam radiation therapy (EBRT) with and without adjuvant androgen deprivation treatment (ADT).
We identified 1,238 patients who underwent RRP and 609 patients treated with EBRT (344 with EBRT + ADT and 265 with EBRT alone) between 1988–2004 who had a pretreatment prostate-specific antigen level (PSA) ≥ 20 ng/mL, biopsy Gleason score 8–10, or clinical stage ≥ T3. Median follow-up was 10.2, 6.0, and 7.2 years after RRP, EBRT + ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer-specific, and overall survival was evaluated using multivariable Cox proportional hazard regression analysis and a competing risk-regression model.
Ten-year cancer-specific survival was 92%, 92%, and 88% following RRP, EBRT + ADT, and EBRT alone (p=0.06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio, 0.78; 95% CI, 0.51 to 1.18; p=0.23) or prostate cancer death (hazard ratio 1.14; 95% CI, 0.68 to 1.91; p=0.61) were seen between patients treated with EBRT + ADT and patients who underwent RRP. The risk of all-cause mortality was, however, greater after EBRT + ADT than RRP (hazard ratio, 1.60; 95% CI, 1.25 to 2.05; p=0.0002).
RRP and EBRT + ADT provide similar long-term cancer control for patients with high-risk disease. Continued investigation into the differing impact of treatments on quality-of-life and non-cancer mortality are necessary to determine the optimal management approach for these patients.
PMCID: PMC3139725  PMID: 21692049
prostate cancer; radical prostatectomy; radiation therapy; androgen-deprivation therapy; prostate-specific antigen
7.  Isolated Limb Perfusion and External Beam Radiotherapy for Soft Tissue Sarcomas of the Extremity: Long-Term Effects on Normal Tissue According to the LENT-SOMA Scoring System 
Annals of Surgical Oncology  2008;15(5):1502-1510.
With the combined treatment procedure of isolated limb perfusion (ILP), delayed surgical resection and external beam radiotherapy (EBRT) for locally advanced soft tissue sarcomas (STS) of the extremities, limb salvage rates of more than 80% can be achieved. However, long-term damage to the healthy surrounding tissue cannot be prevented. We studied the late effects on the normal tissue using the LENT-SOMA scoring system.
Patients and Methods
A total of 32 patients—median age 47 (range 14–71) years—were treated for a locally advanced STS with ILP, surgical resection and often adjuvant 60–70 Gy EBRT. After a median follow-up of 88 (range 17–159) months, the patients were scored, using the LENT-SOMA scales, for the following late tissue damage: muscle/soft tissue, peripheral nerves, skin/subcutaneous tissue and vessels.
According to the individual SOM parameters of the LENT-SOMA scales, 20 patients (63%) scored grade-3 toxicity on one or more separate items, reflecting severe symptoms with a negative impact on daily activities. Of these patients, 3 (9%) even scored grade-4 toxicity on some of the parameters, denoting irreversible functional damage necessitating major therapeutic intervention.
In evaluating long-term morbidity after a combined treatment procedure for STS of the extremity, using modified LENT-SOMA scores, two-thirds of patients were found to have experienced serious late toxic effects.
PMCID: PMC2277454  PMID: 18330652
Sarcoma; Perfusion; Radiation; LENT-SOMA; Complications
8.  The Effect of Cancer Therapies on Pediatric Anophthalmic Sockets 
Ophthalmology  2011;118(12):2480-2486.
To determine the impact of chemotherapy or external beam radiotherapy (EBRT) on pediatric anophthalmic sockets.
A retrospective, nonrandomized, interventional cohort study.
A total of 135 sockets of 133 children undergoing enucleation from late 1999 to early 2009 at the St. Jude Children’s Research Hospital were included.
A retrospective chart review of outcomes after enucleation in patients treated with systemic chemotherapy or orbital EBRT either before or after removal of the eye compared with patients who received no other treatment.
Main Outcome Measures
Incidence of implant exposure, migration, extrusion, socket contracture, and pyogenic granuloma formation.
Retinoblastoma was the primary diagnosis in 128 eyes (95%). Median follow-up was 3.6 years (range, 0.1–9.3 years). Event-free course was observed in 94 sockets (69.6%). Complications included implant exposure (n = 28, 20.7%), socket contracture (n = 16, 11.9%), pyogenic granuloma (n = 9, 6.7%), implant extrusion (n = 3, 2.2%), and migration (n = 2, 1.5%). Exposure resolved in 21 sockets (77.8%) and improved in 2 sockets (11.1%); 1 patient with exposure died. Use of prior, adjuvant, or subsequent chemotherapy increased the long-term risk of exposure (odds ratio [OR] = 3.7; 95% confidence interval [CI], 1.4–9.4), and contracture (OR could not be calculated, P<0.0001). External beam radiotherapy greatly increased the risk of contracture (OR 24.0; 95% CI, 6.9–82.8) and exposure (OR 2.89; 95% CI, 1.1–7.9).
In this unique pediatric population with cancer, chemotherapy and EBRT had an additive effect, significantly increasing the incidence of exposure and socket contracture.
PMCID: PMC3539308  PMID: 21856015
9.  Histopathologic Findings of Eyes Enucleated After Treatment with Chemosurgery for Retinoblastoma 
Intra-arterial chemotherapy (chemosurgery) for the treatment of retinoblastoma has been performed more than 1600 times (more than 1400 times in Japan and 200 times in New York) over the past 20 years.Despite this treatment’s success some eyes cannot be saved and require enucleation. Here we report the histopathologic findings of the remaining intraocular tumor of eyes that were enucleated following treatment that included chemosurgery in New York City.
Materials and Methodology:
Independent histopathologic review of the enucleated eyes was correlated with the clinical findings that prompted enucleation.
Between May 1, 2006 and April 30, 2009, 56 eyes received chemosurgery at our institution, and 10 of these were enucleated subsequently. All were Reese Ellsworth Group 5 at enucleation. Of the 21 eyes that were treated with chemosurgery as the primary treatment, 1 (5%) was enucleated subsequently; its histopathology revealed residual non-necrotic, non-calcified tumor. Of the 34 eyes treated with chemosurgery after other treatments, 9 (24%) were enucleated, and 5 of these eyes contained non-calcified, non-necrotic tumor. None was enucleated for complications of chemosurgery. All patients were alive and free of metastatic disease as of September 2009.
A significant number of eyes with advanced intraocular retinoblastoma avoided enucleation as a result of chemosurgery. The rate of eyes that were enucleated was higher when chemosurgery was the secondary rather than the primary treatment. Of the eight eyes enucleated for progressive disease six had non-necrotic, non-calcified tumor cells.
PMCID: PMC3052645  PMID: 21399766
Retinoblastoma; histopathology; chemosurgery.
10.  Intraoperative Electron Radiation Therapy (IOERT) in the management of locally recurrent rectal cancer 
BMC Cancer  2012;12:592.
To evaluate disease control, overall survival and prognostic factors in patients with locally recurrent rectal cancer after IOERT-containing multimodal therapy.
Between 1991 and 2006, 97 patients with locally recurrent rectal cancer have been treated with surgery and IOERT. IOERT was preceded or followed by external beam radiation therapy (EBRT) in 54 previously untreated patients (median dose 41.4 Gy) usually combined with 5-Fluouracil-based chemotherapy (89%). IOERT was delivered via cylindric cones with doses of 10–20 Gy. Adjuvant CHT was given only in a minority of patients (34%). Median follow-up was 51 months.
Margin status was R0 in 37%, R1 in 33% and R2 in 30% of the patients. Neoadjuvant EBRT resulted in significantly increased rates of free margins (52% vs. 24%). Median overall survival was 39 months. Estimated 5-year rates for central control (inside the IOERT area), local control (inside the pelvis), distant control and overall survival were 54%, 41%, 40% and 30%. Resection margin was the strongest prognostic factor for overall survival (3-year OS of 80% (R0), 37% (R1), 35% (R2)) and LC (3-year LC 82% (R0), 41% (R1), 18% (R2)) in the multivariate model. OS was further significantly affected by clinical stage at first diagnosis and achievement of local control after treatment in the univariate model. Distant failures were found in 46 patients, predominantly in the lung. 90-day postoperative mortality was 3.1%.
Long term OS and LC can be achieved in a substantial proportion of patients with recurrent rectal cancer using a multimodality IOERT-containing approach, especially in case of clear margins. LC and OS remain limited in patients with incomplete resection. Preoperative re-irradiation and adjuvant chemotherapy may be considered to improve outcome.
PMCID: PMC3557137  PMID: 23231663
Recurrent; Rectal cancer; IOERT
11.  Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: A comparison of spatial dose distribution within a matched-pair analysis 
Radiotherapy and Oncology  2011;100(3):468-472.
It has been shown that a cumulative dose of ⩾87 Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/− concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR).
Material and methods
From 1998 to 2010, 265 patients were treated with definitive EBRT +/− concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy.
DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions.
For each matched patient in the control group the measurements were performed on the same quadrant and at the same level.
Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77 Gy and 61 Gy for patients with LR and 95 Gy and 71 Gy for patients in CCLR, respectively (p < 0.01). The MPD for HR CTV was 72 Gy for patients in the LR arm and 99 Gy for patients in the CCLR arm (p < 0.01). In the LR arm seven patients had a D90 for HR CTV ⩾87 Gy, however, in only three patients the MPD was ⩾87 Gy.
This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87 Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ⩾87 Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription.
PMCID: PMC3200439  PMID: 21924510
Cervical cancer; Image-guided adaptive brachytherapy; Local recurrences; DVH
12.  Conservative treatment modalities in retinoblastoma 
Indian Journal of Ophthalmology  2013;61(9):479-485.
Retinoblastoma is the most common primary intraocular malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. The purpose of this article is to review the literature on various conservative treatment modalities available for the treatment of retinoblastoma and their effectiveness, when used alone or in combination. Pubmed, Medline, Embase, and the Cochrane library were searched through 2012 for published peer reviewed data on conservative treatment modalities for retinoblastoma. Various studies show that while enucleation remains the standard of care for advanced intraocular tumors, conservative modalities that can result in globe salvage and preservation of useful vision are being increasingly employed. Such modalities include systemic chemotherapy, focal consolidation with transpupillary thermotherapy, laser photocoagulation and cryotherapy, plaque brachytherapy, and delivery of local chemotherapy using subconjunctival, sub-tenon, or intra-arterial routes. When used alone or in combination, these treatment modalities can help in avoidance of external beam radiotherapy or enucleation, thus reducing the potential for long-term side effects, while salvaging useful vision. Radioactive plaque brachytherapy has an established role in selected patients with intraocular retinoblastoma. Local injections of chemotherapeutic agents via the sub-tenon or sub-conjunctival route have been used with varying degrees of success, usually as an adjunct to systemic chemotherapy. Intra-arterial ophthalmic artery delivery of melphalan has shown promising results. It is important to recognize that today, several treatment options are available that can obviate the need for enucleation, and cure the cancer with preservation of functional vision. A thorough knowledge and understanding of these conservative treatment modalities is essential for appropriate management.
PMCID: PMC3831762  PMID: 24104705
Chemotherapy; focal treatment; retinoblastoma
13.  Metastasis After Radical Prostatectomy or External Beam Radiotherapy for Patients With Clinically Localized Prostate Cancer: A Comparison of Clinical Cohorts Adjusted for Case Mix 
Journal of Clinical Oncology  2010;28(9):1508-1513.
We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center.
Patients and Methods
Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (≥ 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment.
The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer–specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression).
Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer–specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.
PMCID: PMC3731893  PMID: 20159826
14.  Does External Beam Radiation Therapy Improve Survival Following Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma? 
Transcatheter arterial chemoembolization (TACE) improves survival in patients with unresectable hepatocellular carcinoma (HCC). Partial liver radiotherapy with modern techniques has been shown to be safe. The purpose of this study was to evaluate the survival value of external beam radiation therapy (EBRT) with concurrent chemotherapy combined with TACE.
A University of Virginia Interventional Radiology patient log was used to identify patients treated with TACE ± another modality from 1999 through 2005. During this time, 44 patients received TACE for unresectable HCC, and 7 of these received adjuvant EBRT. Univariate analysis and multivariable proportional hazards survival modeling were used to identify factors impacting survival.
We compared 37 patients receiving TACE alone to 7 receiving TACE and EBRT (5 with concurrent capecitabine). Unadjusted mean transplant-free survival times were TACE only = 376 days (standard error [SE] = 63 days), TACE + EBRT = 879 days (SE = 100 days). EBRT, TNM stage, and MELD score were important predictors for survival on univariate analysis (p < .10). The adjusted hazard ratio for transplant or death in the TACE + EBRT group was 0.15 (0.02–0.95, p = .026).
EBRT with concurrent chemotherapy following TACE is feasible and well tolerated with modern treatment techniques. Further research should be directed toward determining the potential overall survival benefit of adjuvant EBRT with chemotherapy following TACE for hepatocellular carcinoma.
PMCID: PMC3348711  PMID: 22574232
To evaluate individual tumor control following chemoreduction for retinoblastoma.
Prospective nonrandomized single-center case series of 457 retinoblastomas managed with six cycles of chemoreduction (vincristine, etoposide, and carboplatin). The tumors were then managed with chemoreduction alone (group A) or chemoreduction combined with thermotherapy (group B), cryotherapy (group C), or both thermotherapy and cryotherapy (group D). The main outcome measure was development of tumor recurrence.
Of 457 retinoblastomas, 63 (14%) were in group A, 256 (56%) in group B, 127 (28%) in group C, and 11 (2%) in group D. The tumor was located in the macula in 33 (52%) of group A, 109 (43%) of group B, 3 (2%) of group C, and 1 (9%) of group D. Using Kaplan-Meier analysis, recurrence of the individual retinoblastoma at 7 years was found in 45% of group A and in 18% of combined groups B, C, and D. Treatment of the 93 tumor recurrences included thermotherapy, cryotherapy, or plaque radiotherapy in 62 cases (67%) and external beam radiotherapy or enucleation in 31 cases (33%). Risk factors predictive of tumor recurrence by multivariate analysis included macular tumor location for all groups and, additionally, female sex for group A and increasing tumor thickness for groups B, C, and D.
Chemoreduction alone or combined with cryotherapy and/or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence is greatest for those located in the macula and those with greater thickness. Globe salvage is usually achieved despite tumor recurrence.
PMCID: PMC1280085  PMID: 15747743
16.  External beam radiotherapy for retinoblastoma: I. Whole eye technique. 
A retrospective analysis has been performed of the results of external beam radiotherapy for retinoblastoma using a whole eye technique. Local tumour control has been assessed in a consecutive series of 175 eyes in 142 children all of whom received external beam radiotherapy as the primary treatment for retinoblastoma. Follow up ranged from 2 to 17 years (median 9 years). Tumour control rates have been analysed with respect to the Reese Ellsworth classification and the series includes eyes in groups I to V. Focal salvage therapy was given for persistent, recurrent, or new tumours after radiotherapy. Following whole eye radiotherapy alone, the overall ocular cure rate was 57%, though with salvage therapy 80% of eyes could be preserved.
PMCID: PMC505038  PMID: 7696227
17.  The Role of Radiotherapy in Endometrial Cancer: Current Evidence and Trends 
Current Oncology Reports  2011;13(6):472-478.
Adjuvant treatment of patients with endometrial cancer is tailored to clinical-pathological prognostic factors. Pelvic radiation therapy for stage I endometrial cancer (EC) provides a highly significant improvement of local control, but without survival advantage. Low-risk EC patients have a very favorable prognosis, and should be observed after surgery. Use of adjuvant radiotherapy (RT) is limited to patients with high-intermediate or high-risk factors. For those with high-intermediate risk features, vaginal brachytherapy alone provides excellent vaginal control with less morbidity and better quality of life than pelvic external beam RT (EBRT). For patients with stage I–III EC with high-risk features, the use of adjuvant chemotherapy alone has not shown survival benefit as compared to pelvic EBRT. A first trial comparing pelvic EBRT with or without adjuvant chemotherapy has shown better progression-free survival with combined therapy. Current ongoing trials are exploring the role of combined RT and chemotherapy, compared to chemotherapy or RT alone.
PMCID: PMC3212694  PMID: 21845420
Endometrial cancer; Adjuvant therapy; Radiation therapy; Prognostic factors; Side effects; Quality of life
18.  Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma 
The purpose of this study is to report the complication profile and safety evaluation of supraselective intra-arterial melphalan chemotherapy in children undergoing treatment with advanced retinoblastoma.
Twelve eyes of 10 children with advanced retinoblastoma (Reese-Ellsworth Group Vb or International Classification Group D) were treated with supraselective intra-ophthalmic artery infusion of melphalan. Eleven eyes of nine children had previously failed traditional management with systemic chemotherapy and laser ablation and underwent intra-ophthalmic artery infusion of melphalan as an alternative to enucleation. Serial ophthalmic examinations, retinal photography, and ultrasonographic imaging were used to evaluate treatment regime.
Ophthalmic artery cannulation was successfully performed in 12 eyes of 10 patients (total 16 times). Striking regression of tumor, subretinal and vitreous seeds were seen early in each case. No severe systemic side effects occurred. Grade III neutropenia was seen in one patient. No transfusions were required. Three patients developed a vitreous hemorrhage obscuring tumor visualization. One patient developed periocular edema associated with inferior rectus muscle inflammation per orbital MRI. This same patient had scattered intraretinal hemorrhages and peripapillary cotton wool spots consistent with a Purtscher’s-like retinopathy that resolved spontaneously. At the 6-month follow-up examination, nine eyes had no evidence of tumor progression, whereas three eyes were enucleated for tumor progression. In each enucleated case, viable tumor was identified on histopathologic examination.
Ophthalmic intra-arterial infusion with melphalan is an excellent globe-conserving treatment option in advanced retinoblastoma cases with minimal systemic side effects. Local toxicities include microemboli to the retina and choroid (1/12, 8%), vitreous hemorrhage (3/12, 25%), and myositis (1/12, 8%). Enucleation remained a definitive treatment for tumor progression in 3 of 12 eyes in this small case series with limited follow-up. Further studies are necessary to establish the role of supraselective intra-arterial melphalan chemotherapy for children with retinoblastoma.
PMCID: PMC3045066  PMID: 21383945
retinoblastoma; intra-arterial chemotherapy; melphalan
19.  The effect of external beam radiotherapy volume on locoregional control in patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer 
We evaluated outcomes of patients treated with external beam radiotherapy (EBRT) for locoregionally advanced or recurrent nonanaplastic thyroid cancer and analyzed the effect of EBRT volume on locoregional control.
This study included 23 patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer who were treated with EBRT. Two different EBRT target volumes were executed as follows: 1) limited field (LF, n = 11) included the primary (involved lobe) or recurrent tumor bed and the positive nodal area; 2) elective field (EF, n = 12) included the primary (involved lobe) or recurrent tumor bed and the regional nodal areas in the cervical neck and upper mediastinum. Clinical parameters, such as gender, age, histologic type, recurrence, stage, thyroglobulin level, postoperative residuum, radioiodine treatment, and EBRT volume were analyzed to identify prognostic factors associated with locoregional control.
There were no significant differences in the clinical parameter distributions between the LF and EF groups. In the LF group, six (55%) patients developed locoregional recurrence and three (27%) developed distant metastasis. In the EF group, one (8%) patient developed locoregional recurrence and one (8%) developed a distant metastasis. There was a significant difference in locoregional control rate at 5 years in the LF and EF groups (40% vs. 89%, p = 0.041). There were no significant differences in incidences of acute and late toxicities between two groups (p >0.05).
EBRT with EF provided significantly better locoregional control than that of LF; however, further larger scaled studies are warranted.
PMCID: PMC2924345  PMID: 20687967
20.  The safety and usefulness of neutron brachytherapy and external beam radiation in the treatment of patients with gastroesophageal junction adenocarcinoma with or without chemotherapy 
To assess the safety and usefulness of neutron brachytherapy (NBT) as an adjuvant in the treatment of patients with gastroesophageal junction adenocarcinoma (GEJAC) with external beam radiation (EBRT), with or without chemotherapy.
Methods and Materials
In total, 197 patients with localized, advanced GEJAC received EBRT and NBT with or without chemotherapy. Radiotherapy consisted of external irradiation to a total dose of 40–54 Gy (median 50 Gy) and brachytherapy to 8–25 Gy (median 20 Gy) in two to five fractions. In total, 88 patients received chemotherapy that consisted of two cycles of a regimen with CDDP and 5FU from days l-4. The cycles were administered on days 1 and 29. MMC was given alone in bolus injection on day 1 each week. The cycles were administered on days 1, 8, 15 and 22.
The duration of follow-up ranged from six to 106 months (median 30.4 months). The median survival time for the 197 patients was 13.3 months, and the one, two, three- and five-year rates for overall survival were 57.1%, 35.1%, 23.0% and 9.2%, respectively. For acute toxicity, no incidences of fistula and massive bleeding were observed during this treatment period. In total, 159 (80.7%) patients developed Grade 2 hematologic toxicity and 146 (74.1%) patients developed Grade ≥ 2 esophagitis. The median times of incidence of fistula and bleeding were 9.5 (3–27.3) months and 12.7 (5–43.4) months, respectively. The incidence of severe, late complications was related to higher NBT dose/f (20–25 Gy/5 F) and higher total dose(≥70 Gy). In total, 75.2% of the patients resumed normal swallowing and 2.0% had some residual dysphagia (non-malignant) requiring intermittent dilatation.
A combination of EBRT and NBT with the balloon type applicator was feasible and well tolerated. Better local-regional control and overall survival cannot achieved by a higher dose, and in contrast, a higher dose caused more severe esophageal injury.
PMCID: PMC4016616  PMID: 24774780
Gastroesophageal junction adenocarcinoma (GEJAC); Neutron brachytherapy (NBT); External beam radiation (EBRT); Overall survival acute/late toxicity
21.  Tumour angiogenesis as a prognostic factor for disease dissemination in retinoblastoma 
The British Journal of Ophthalmology  2003;87(10):1224-1228.
Aim: To evaluate tumour angiogenesis as a predictor of prognosis in retinoblastoma.
Methods: This was a retrospective, non-randomised comparative clinicopathological study. The histopathology from 24 cases of Reese-Ellsworth (RE) group V unilateral retinoblastoma treated by enucleation alone was reviewed. Group I consisted of five patients (four RE group Vb and one group Va) who developed disseminated disease at a mean of 10.4 months after enucleation. The remaining 19 patients constitute group II (18 RE group Vb and 1 group Va), none of whom had developed metastatic disease with a mean follow up of 54 months. None of the 24 patients had evidence of extraocular disease at enucleation. The surgical specimens from patients with unilateral retinoblastoma treated by enucleation at Hospital do Cancer AC Camargo between January 1992 and December 1995 were identified, reviewed and the clinical data recorded. Two subsequent histological sections were prepared. One stained with haematoxylin and eosin for assessment of choroidal and optic nerve invasion, and the other for immunoreaction with an endothelium specific marker (antibody anti-CD 34). The main outcome measures were choroidal and/or optic nerve invasion and quantification of the tumour’s relative vascular area (TRVA) obtained by Chalkley counting.
Results: Choroidal invasion was present in three eyes of group I (all massive) and six eyes of group II (two focal and four massive). Optic nerve invasion was found in two eyes of group I (all post-laminar) and four eyes of group II (three prelaminar and one post-laminar). There was no statistical difference regarding choroidal or optic nerve between the two groups. The TRVA was the only independent variable found to predict disease dissemination (p = 0.008 by Cox analysis). A TRVA equal to or greater than 3.9% had 100% sensitivity and 79% specificity in predicting disease dissemination.
Conclusions: Quantification of angiogenesis, through measurement of the TRVA, can help to identify patients with retinoblastoma at high risk for disease dissemination after enucleation.
PMCID: PMC1920792  PMID: 14507753
angiogenesis; retinoblastoma
22.  Salvage radiotherapy after high-intensity focused ultrasound treatment for localized prostate cancer: feasibility, tolerance and efficacy 
The objective of this study is to evaluate the feasibility, tolerance and efficacy of salvage external beam radiotherapy (EBRT) in persistent or recurrent prostate cancer after failed high intensity focused ultrasound (HIFU) therapy.
We reviewed data on tolerance and oncologic outcomes for all patients with biopsy-proven locally recurrent or persistent prostate cancer who underwent salvage EBRT in our department between April 2004 and June 2008. Minimum follow-up for inclusion was 2 years. Failure with EBRT was defined as biochemical relapse (Phoenix definition) or introduction of androgen deprivation therapy (ADT). Gastrointestinal and urinary toxicity and urinary stress incontinence were scored at 12 and 24 months (Radiation Therapy Oncology Group and Ingelman Sundberg rating, respectively).
The mean age of the patients was 68.8 years (range: 60–79). Mean prostate-specific antigen (PSA) before EBRT was 5.57 ng/mL (range: 2.5–14.8). Median follow-up was 36.5 ± 10.9 months (range: 24–54). No patient received adjunctive ADT. The EBRT course was well-tolerated and completed by all patients. The mean PSA nadir was 0.62 ng/mL (range: 0.03–2.4) and occurred after a median of 22 months (range: 12–36). One patient experienced biochemical failure and was prescribed ADT 30 months after EBRT. The disease-free survival rate was 83.3% at 36.5 months. There was no major EBRT-related toxicity at 12 or 24 months.
Our early clinical results confirm the feasibility and good tolerance of salvage radiotherapy after HIFU failure. Oncological outcomes were promising. A prospective study with longer follow-up is needed to identify factors predictive of success for salvage EBRT therapy after HIFU failure.
PMCID: PMC3478387  PMID: 21539766
23.  Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2012;12:110.
Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.
This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 (125I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with 125I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during 125I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.
The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.
To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.
Trial registration
PMCID: PMC3350387  PMID: 22439742
Prostate cancer; Trimodality; Radiation therapy; Brachytherapy; External beam radiation therapy; Hormone therapy; Randomized controlled trial; Biochemical progression-free survival
24.  Pure Accelerated Radiation Versus Concomitant Chemoradiation in Selected Cases of Locally Advanced Carcinoma Cervix: A Prospective Study 
This non-randomized study was conducted to assess and compare the response and safety of true accelerated radiation alone to concomitant chemoradiation in locally advanced squamous cell carcinoma of the uterine cervix.
Sixty patients with locally advanced squamous cell carcinoma of the uterine cervix, FIGO Stages (2009) IB2–IIIB were non-randomized to receive six fractions per week of external beam radiation (EBRT) (will be henceforth referred to as Arm A or Study arm or pure accelerated radiation arm) and five fractions per week of EBRT and chemotherapy with inj cisplatin 40 mg/m2 i.v. every Monday during the course of EBRT (will be henceforth referred to as Arm B or Control arm or chemoradiation arm).
The median follow-up was 15 months in both the arms. The overall treatment time was 56.54 days for Arm A and 62.59 days for patients in Arm B (P value < 0.000**). The median EBRT time was 32.25 days in Arm A and 38.85 days in Arm B, a statistically significant delay for patients of chemoradiation Arm B (P value < 0.000**). The response assessment at the end of the study was not statistically different among the patients in both the treatment arms (P value 0.631).
The early responses to treatment with pure accelerated EBRT are non-inferior to concomitant chemoradiation and the acute toxicities are lesser.
PMCID: PMC3575906  PMID: 24293847
Carcinoma; Cervix; Accelerated; Radiation; Concurrent
25.  A Role for Radiotherapy in the Management of Advanced Medullary Thyroid Carcinoma: the Mayo Clinic Experience 
Rare Tumors  2013;5(3):e37.
Outcomes of external beam radiotherapy (EBRT) in advanced medullary thyroid carcinoma (MTC) are largely unknown. Retrospective review of data from patients with MTC, diagnosed from June 1, 1970, through December 31, 2007. Overall survival and locoregional tumor control rates were calculated. Seventeen patients had adjuvant or palliative EBRT delivered to 41 sites. Six patients initially had adjuvant EBRT (median, 60.80 Gy); none had relapse in the treated area. Five patients with locoregional recurrence after surgery were treated (median, 59.40 Gy), and durable disease control was achieved in 3. Twelve patients received palliative EBRT to 29 sites of metastatic disease (median, 30.00 Gy), which provided sustained symptom relief at 45% of sites. Five- and ten-year overall survival rates were 44% and 19%, respectively. Adjuvant EBRT may be most effective for prevention of locoregional recurrence. EBRT may provide sustained control of advanced, metastatic disease in select patients.
PMCID: PMC3804812  PMID: 24179649
medullary thyroid carcinoma; radiotherapy

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