Najeeb Mohideen

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline

Purpose To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. Methods and Materials Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. Results The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. Conclusions Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).

Assessment of different IMRT boost delivery methods on target coverage and normal-tissue sparing.

PURPOSE Because of biologic, medical, and sometimes logistic reasons, patients may be treated with 3D conformal therapy or intensity-modulated radiation therapy (IMRT) for the initial treatment volume (PTV(1)) followed by a sequential IMRT boost dose delivered to the boost volume (PTV(2)). In some patients, both PTV(1) and PTV(2) may be simultaneously treated by IMRT (simultaneous integrated boost technique). The purpose of this work was to assess the sequential and simultaneous integrated boost IMRT delivery techniques on target coverage and normal-tissue sparing. MATERIALS AND METHODS Fifteen patients with head-and-neck (H&N), lung, and prostate cancer were selected for this comparative study. Each site included 5 patients. In all patients, the target consisted of PTV(1) and PTV(2). The prescription doses to PTV(1) and PTV(2) were 46 Gy and 66 Gy (H&N cases), 45 Gy and 66.6 Gy (lung cases), 50 Gy and 78 Gy (prostate cases), respectively. The critical structures included the following: spinal cord, parotid glands, and brainstem (H&N structures); spinal cord, esophagus, lungs, and heart (lung structures); and bladder, rectum, femurs (prostate structures). For all cases, three IMRT plans were created: (1) 3D conformal therapy to PTV(1) followed by sequential IMRT boost to PTV(2) (sequential-IMRT(1)), (2) IMRT to PTV(1) followed by sequential IMRT boost to PTV(2) (sequential-IMRT(2)), and (3) Simultaneous integrated IMRT boost to both PTV(1) and PTV(2) (SIB-IMRT). The treatment plans were compared in terms of their dose-volume histograms, target volume covered by 100% of the prescription dose (D(100%)), and maximum and mean structure doses (D(max) and D(mean)). RESULTS H&N cases: SIB-IMRT produced better sparing of both parotids than sequential-IMRT(1), although sequential-IMRT(2) also provided adequate parotid sparing. On average, the mean cord dose for sequential-IMRT(1) was 29 Gy. The mean cord dose was reduced to approximately 20 Gy with both sequential-IMRT(2) and SIB-IMRT. Prostate cases: The volume of rectum receiving 70 Gy or more (V(>70 Gy)) was reduced to 18.6 Gy with SIB-IMRT from 22.2 Gy with sequential-IMRT(2). SIB-IMRT reduced the mean doses to both bladder and rectum by approximately 10% and approximately 7%, respectively, as compared to sequential-IMRT(2). The mean left and right femur doses with SIB-IMRT were approximately 32% lower than obtained with sequential-IMRT(1). Lung cases: The mean heart dose was reduced by approximately 33% with SIB-IMRT as compared to sequential-IMRT(1). The mean esophagus dose was also reduced by approximately 10% using SIB-IMRT as compared to sequential-IMRT(1). The percentage of the lung volume receiving 20 Gy (V(20 Gy)) was reduced to 26% by SIB-IMRT from 30.6% with sequential-IMRT(1). CONCLUSIONS For equal PTV coverage, both sequential-IMRT techniques demonstrated moderately improved sparing of the critical structures. SIB-IMRT, however, markedly reduced doses to the critical structures for most of the cases considered in this study. The conformality of the SIB-IMRT plans was also much superior to that obtained with both sequential-IMRT techniques. The improved conformality gained with SIB-IMRT may suggest that the dose to nontarget tissues will be lower.

Second primary cancers in patients with laryngeal cancer: A population-based study

BACKGROUND Literature regarding incidence of site-specific second cancers after laryngeal cancer is limited. Risk factors associated with second primaries are unknown. METHODS Second primaries after laryngeal cancer in the SEER database (1973-1996) were analyzed for incidence, relative risk compared with the general population, and potential risk factors, including radiotherapy. Information on chemotherapy and tobacco smoking was not available in the SEER database. RESULTS Of 20,074 laryngeal cancer patients surviving at least 3 months, 3533 (17.6%) developed second cancers. The cumulative risk of developing a second cancer was 26% at 10 years and 47% at 20 years. Compared with age-adjusted, gender, and tumor-specific rates in the general population, laryngeal cancer patients had higher risks of second cancers overall (observed-to-expected ratio [O/E] = 1.68, 95% confidence interval [CI] = 1.58-1.79), head-and-neck (4.81 [4.31-5.58]), esophageal (3.99 [3.29-4.83]), and lung (3.56 [3.34-3.79]) cancer. Advanced age at initial diagnosis was associated with increased risks of second cancers (p = 0.0001). Radiotherapy was associated with increased risk of second cancers overall (relative risk [RR] = 1.10 [1.02-1.18], p = 0.012), especially second cancers of the lung (RR = 1.18, [1.05-1.33], p = 0.006) and possibly second cancers of the head and neck (RR = 1.26, [0.99-1.60], p = 0.061). Radiotherapy was associated with a 68% excess risk (RR = 1.68, [1.16-2.43], p = 0.007) of developing a second head-and-neck cancer in patients who survived more than 5 years. Second primary was associated with a poor survival (p = 0.0001). CONCLUSIONS Second cancers after laryngeal cancer are common, especially for long-term survivors. Radiotherapy was associated with a small increased risk of developing second cancers overall and long-term risk of head-and-neck cancers. This data should be interpreted with caution in light of the lack of information on chemotherapy and tobacco smoking in the SEER database. Prevention and early detection are indicated.

Effect of tumor bulk on local control and survival of patients with T1 glottic cancer

PURPOSE To evaluate the effect of tumor bulk in relation to various tumor-related prognostic factors and treatment-related variables on local control and survival of patients with T1 N0 M0 squamous cell carcinoma of the glottis. MATERIALS AND METHODS In 114 patients with T1 squamous cell carcinoma of the glottic larynx who were irradiated with curative intent, we determined the effect of tumor bulk in relation to mucosal extent (stage and anterior commissure involvement), histologic differentiation and various radiation factors, especially overall treatment time on local control and survival. Tumors were classified retrospectively as small surface lesions or bulky tumors. Seventy-seven patients had small lesions and 37 had bulky tumors. The anterior commissure was involved with cancer in 43 patients. The overall duration of irradiation ranged from 39 to 64 days. The median follow-up time was 6 years (range 5-24 years). RESULTS The 5-year actuarial local control rate for all patients was 82% after radiotherapy and 92% after salvage laryngectomy. On univariate analysis, bulky tumors and tumors involving the anterior commissure showed an adverse effect on local control, whereas the overall duration of irradiation had a borderline significance. The actuarial local control rate was 91% for small tumors and 58% for bulky tumors (P = 0.0002), 88% when the anterior commissure was not involved and 67% when the anterior commissure was involved (P = 0.01) and 89% when radiation was given in less than 50 days and 73% when irradiation exceeded 50 days (P = 0.06). On multivariate analysis. tumor bulk was the only significant factor that affected local control (P = 0.02). The 5-year actuarial survival for all patients was 73% and the disease-free survival was 92%. CONCLUSION This study shows that tumor bulk has a highly significant effect on the radiation control of T1 glottic cancer. Patients who had bulky tumors had lower local control and disease-free survival rates than those patients who had small tumors.

Radiation exposure to the corporeal bodies during 3-dimensional conformal radiation therapy for prostate cancer.

PURPOSE Radiation therapy for prostate cancer is associated with the development of post-treatment erectile dysfunction. Use of 3-dimensional (D) conformal delivery techniques has reduced delivery of radiation to periprostatic tissues. However, the exact magnitude of radiation that the corporeal bodies are exposed to using this delivery technique is currently unknown. This study was undertaken to calculate the radiation dose delivered to the corporeal bodies during 3-D conformal radiotherapy. MATERIALS AND METHODS Ten patients with proven prostate adenocarcinoma who underwent pre-therapy computerized tomography simulation and radiation delivery planning had the proximal corporeal bodies outlined on axial computerized tomography. The dose to the proximal penile tissues was then calculated using computer modeling. RESULTS The total dose of radiation administered to the prostate and seminal vesicles was 73.8 Gy. Mean radiation delivered to the most proximal 2 cm. of the corporeal bodies was 31 +/- 12.8 Gy., equating to 43% of the total dose of radiation delivered to the prostate and seminal vesicles. CONCLUSIONS These data indicate that large doses of radiation are being delivered to erectile tissue in the proximal penis despite careful pretreatment planning for 3-D conformal radiation therapy for prostate cancer. These data should encourage the development of radiation delivery strategies that minimize corporeal tissue exposure.

Effect of prostatic edema on CT-based postimplant dosimetry

PURPOSE To investigate the magnitude of edema after prostate brachytherapy and its effect on the CT-based postimplant dosimetry based on the sequential CT scans using dose-volume histograms, dose conformity, and homogeneity indices in patients with prostate cancer. METHODS AND MATERIALS CT scans were obtained for 25 patients who underwent prostate brachytherapy with 125I or 103Pd before implant and postimplant Day 1, Day 7, and Day 28. The prostate, rectum, and bladder volumes on each scan were contoured by the same physician. Posttreatment dose distributions were generated using FOCUS (CMS Inc., St. Louis, MO) brachytherapy planning software. Dose calculations were based on TG43 formalism. Dose-volume histograms for target, rectum, and bladder were created for all patients, and the quality of the implants was analyzed using the dose conformity indices: CT-based target volumes ratios, TVR(1) and TVR(2); dose homogeneity indices, DHI(1), DHI(2), and DNR; dose coverage index, CI; the percentage of the prostate volume enclosed by 100%, 90%, and 80% of the prescription dose: V(100), V(90), and V(80); the volume of the rectum covered by 100%, 80%, and 70% of the prescription dose; and the dose covering 90% of the prostate volume (D(90)). RESULTS The prostate volume increased between the prescan and the implant Day 1 scans and then decreased between Day 1 and Day 28 scans. The average increase in prostate volume was 30% between the prescan and implant Day 1 scans for the 25 cases evaluated. The prostate volume decreased 20% between the Day 1 and Day 28 scans. The preplan dose coverage to the periphery of the prostate was 100% for all cases evaluated. V(100) increased from an average of 77% to 85% between the Day 1 and Day 28 scans, respectively. On average, D(90) increased from 84% for Day 1 to 93% for Day 28. The average TVR(1), TVR(2), and CI were 1.99, 2.28, and 0.87, respectively, based on the Day 28 scans. The average DHI(1), DHI(2), and DNR were 0.52, 0.46, and 0.48, respectively, based on the Day 28 scans. CONCLUSIONS The decrease in prostate volume from Day 1 to Day 28 after the implant markedly improved the prescription dose covering the prostate from 77% to 85%. Day 28 prostate volumes were still about 10% larger than the preimplant CT volumes for the 25 cases evaluated. Postimplant dosimetry using dose conformity and homogeneity indices is dependent on the timing of CT studies, as a result of changing prostate volumes from edema.

Role of IMRT in reducing penile doses in dose escalation for prostate cancer

PURPOSE In three-dimensional conformal radiotherapy (3D-CRT), penile tissues adjacent to the prostate are exposed to significant doses of radiation. This is likely to be a factor in development of posttreatment erectile dysfunction. In this study, we investigate whether intensity-modulated radiation therapy (IMRT) leads to lower radiation exposure to proximal penile tissues (PPT) when compared with 3D-CRT. MATERIALS AND METHODS Ten randomly selected patients with clinically localized prostate cancer constituted the study group. Using identical structure sets, 3D-CRT and IMRT plans were designed for each patient. For IMRT, both tomographic (TOMO) and step-and-shoot (SS) techniques were used. Treatment plans were developed using 18 MV photons for 3D-CRT, 6 MV photons for TOMO, and 6 MV and 18 MV photons for SS plans. The PPT up to the beginning of the penile shaft (usually measuring 2-3 cm) was outlined by a team composed of a board-certified urologist and a radiation oncologist. The outlined PPT was subdivided into three segments (P1, P2, P3), and the radiation dose to each segment and to the entire structure was calculated. In addition, PPT was subdivided into corporal cavernosa (CC) and corpus spongiosum (bulb). The prostate dose was escalated from 73.8 Gy to 81 Gy to 90 Gy. Target D(95) (dose to 95% volume), critical structure D(5) (dose to 5% volume), and D(mean) (mean dose) were used in the comparison among treatment plans. Because 3D-CRT uses larger field margins than does IMRT, target and critical structure doses were recalculated in 3D-CRT plans employing field margins obtained from IMRT plans. Planning target volumes in original and modified 3D-CRT plans were the same. RESULTS Compared with 3D-CRT plans, the mean PPT doses were reduced by 40.2%, 43.6%, and 46.2%, respectively, at the three prescription dose levels in TOMO plans. The average D(mean) for CC was lower by 46.4%, 48.4%, and 51.4%, whereas the average bulb D(mean) was reduced by 44.2%, 44.9%, and 47.9%, respectively. There was also considerable sparing of P1, with a reduction in average D(mean) of 41.9%, 45.5%, and 48.5% compared with 3D-CRT. All differences between 3D-CRT and IMRT doses were statistically significant (p < 0.001). Similar improvements were noticed in maximum doses (D(5)) for penile structures. The percent dose reduction with IMRT plans improved as prostate dose was escalated. When compared with 3D-CRT plans with reduced fields, IMRT plans showed slightly smaller but still significant improvements in critical structure doses (p < 0.001). Compared with SS plans, TOMO plans produced improved sparing of dose to critical structures. CONCLUSIONS IMRT allows for dose escalation in prostate cancer while keeping penile tissue doses significantly lower compared to conformal radiotherapy. This may result in improved potency rates over current results observed with 3D-CRT.

THE EXTENT OF BIOPSY INVOLVEMENT AS AN INDEPENDENT PREDICTOR OF EXTRAPROSTATIC EXTENSION AND SURGICAL MARGIN STATUS IN LOW RISK PROSTATE CANCER: : IMPLICATIONS FOR TREATMENT SELECTION

PURPOSE We identify predictors of extraprostatic extension and positive surgical margins in patients with low risk prostate cancer (prostate specific antigen [PSA] 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b). MATERIALS AND METHODS From August 1997 to January 1999, 143 previously untreated patients underwent radical retropubic prostatectomy for clinically localized prostate cancer. A total of 62 patients were low risk, with PSA 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b, and had sextant biopsy with separate pathological evaluation of each sextant cores. PSA, clinical stage, biopsy Gleason score, average percentage of cancer in the entire biopsy specimen, maximum percentage of cancer on the most involved core, number of cores involved and bilaterality were evaluated for association with extraprostatic extension, seminal vesicle involvement and positive surgical margins. RESULTS Of the 62 patients 13 (21%) had extraprostatic extension, 6 (10%) seminal vesicle involvement and 20 (32%) positive surgical margins. Average percentage greater than 10% and maximum percentage greater than 25% were associated with extraprostatic extension (p = 0.01 and 0.004, respectively). Average percentage greater than 10%, maximum percentage greater than 25%, more than 2 cores involved and bilaterality were associated with positive surgical margins (p = 0.007, 0.01, 0.002 and 0.03, respectively). On multivariate analysis maximum percentage remained the only independent predictor of extraprostatic extension (p = 0.03), and the number of cores involved remained an independent predictor of positive surgical margins (p = 0.01). Biopsy Gleason score, PSA and clinical stage did not correlate with extraprostatic extension or positive surgical margins in this patient population. CONCLUSIONS In low risk prostate cancer the extent of biopsy involvement significantly correlates with the risk of extraprostatic extension and positive surgical margins. Biopsy information should be considered when selecting and modifying treatment modalities.

Inhibition of radiation-induced apoptosis by dexamethasone in cervical carcinoma cell lines depends upon increased HPV E6/E7

Through a glucocorticoid-responsive promoter, glucocorticoids can regulate the transcription of the human papillomavirus (HPV) E6 and E7 viral genes which target the tumour suppressor proteins p53 and Rb respectively. In C4-1 cells, the glucocorticoid dexamethasone up-regulated HPV E6/E7 mRNA and decreased radiation-induced apoptosis. In contrast, dexamethasone had no effect on apoptosis of cells that either lack the HPV genome (C33-a) or in which HPV E6/E7 transcription is repressed by dexamethasone (SW756). Irradiated C4-1 cells showed increased p53 expression, while dexamethasone treatment prior to irradiation decreased p53 protein expression. In addition, p21 mRNA was regulated by irradiation and dexamethasone in accordance with the observed changes in p53. Overall, glucocorticoids decreased radiation-induced apoptosis in cervical carcinoma cells which exhibit increased HPV E6/E7 transcription and decreased p53 expression. Therefore, in HPV-infected cervical epithelial cells, p53-dependent apoptosis appears to depend upon the levels of HPV E6/E7 mRNA.

Androgen receptor levels are increased by interferons in human prostate stromal and epithelial cells

Proliferation of normal and malignant prostate epithelium is regulated by androgen stimulation via both the androgen receptor (AR)-positive stromal and epithelial cells. However, it is not known how AR expression is regulated in human prostate cells. We report that treatment of normal human prostate stromal cells (PrSCs) with type I IFN (alpha or beta), but not type II IFN (gamma), resulted in increased levels of AR protein. The maximal increase in AR protein levels was dependent on the dose and the duration of the IFN-alpha treatment. We found that the increase in AR protein levels was independent of de novo transcription and protein synthesis. Interestingly, the IFN-alpha treatment of PrSCs resulted in considerable nuclear accumulation of AR, stimulation of AR-mediated transcription of reporter genes, and retardation of cell proliferation. Furthermore, treatment of normal human prostate epithelial cells with IFNs (alpha, beta or gamma) also resulted in increased levels of AR protein. Together, our observations identify the androgen receptor as an IFN-regulated protein in normal human prostate stromal and epithelial cells and predict that IFN-induced levels of AR in prostate cells contribute to the regulation of androgen signaling.