Edgar Ben-Josef

RADIOTHERAPEUTIC MANAGEMENT OF OSSEOUS METASTASES: A SURVEY OF CURRENT PATTERNS OF CARE

PURPOSEnRadiotherapy plays a major role in the management of painful osseous metastases. This survey was conducted to study the current approaches to this clinical problem in the radiotherapy community.nnnMETHODS AND MATERIALSnA questionnaire was sent to 2500 members of the American Society for Therapeutic Radiology and Oncology. It consisted of 30 multiple-choice questions regarding four hypothetical clinical scenarios likely to be encountered in daily practice. Questions related to the technique of choice [local field (LF) vs. hemibody radiotherapy (HBI)], the use of systemic radionuclides (SR), fractionation schemes, dose, the integration of modalities, and the follow-up of these patients. The analysis is based on 817 (33%) responses received regarding 3268 cases.nnnRESULTSnLocal field is the most common form of therapy. Overall, LF was used, alone or in combination with other forms of therapy, in 54% and 74% of patients, respectively. LF was used more frequently in patients with breast cancer than in patients with prostate cancer (79% vs. 45%; p = 0.0001). Long fractionation schemes were used by 90% of physicians in 96% of cases. Short fractionation schemes were used by 7% of physicians in 4% of cases. This tendency was more pronounced in private practice than in the university or government/ multidisciplinary settings (p = 0.008) and in physicians starting their practice before 1982 (p = 0.05). The most common schedule was 30 Gy in 10 fractions, used by 77% of physicians in 64% of cases. HBI was used, alone or in combination with other forms of therapy, in 1% and 2% of patients, respectively. It was used more frequently in patients with prostate cancer than in patients with breast cancer (1.2% vs. 0.1%, respectively; p < 0.0001). SR were used alone or in combination with local-field irradiation in 21% and 40% of cases, respectively. SR were used more frequently in patients with prostate cancer than in those with breast cancer (28% vs. 0.2%, respectively;p < 0.00001). The most common radionuclide in use is Sr-89 (99%) at a dose of 4 mCi (73%) or 10.8 mCi (26%).nnnCONCLUSIONSnAlthough LF remains the mainstay of therapy, our results demonstrate the emergence of a new pattern of practice: LF to the painful site in combination with SR for clinically occult metastases. Despite an ongoing academic debate regarding fractionation schemes, the vast majority of American practitioners advocate long schedules.

Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: analysis of prognostic factors

PURPOSEnTo evaluate the long-term outcome of surgery and postoperative radiotherapy (RT) in retroperitoneal and deep-trunk soft-tissue sarcoma, and to identify the prognostic factors for local control, disease-free survival, and overall survival.nnnMETHODS AND MATERIALSnBetween January 1980 and December 1998, 60 patients with nonmetastatic retroperitoneal and deep-trunk soft-tissue sarcoma were treated at Wayne State University using combined surgery and RT. The location was retroperitoneal in 38 patients (63%) and deep trunk in 22 (27%). Forty-six patients (76%) were treated for primary disease and 14 (24%) for recurrent disease. The resection margins were negative in 24 patients (40%), close in 3 (5%), and positive in 33 (55%; 18 microscopic and 15 macroscopic). The median tumor size was 8.6 cm (range 2-55). External beam RT (EBRT; median dose 5220 cGy) was given to 44 patients (73%) and combined EBRT (median dose 4200 cGy) and brachytherapy (median dose 1600 cGy) to 16 patients (27%). Univariate and multivariate Cox regression analyses were conducted to identify the possible associations between patient age, race, gender, tumor site, histologic features, grade, size, stage, surgical margin, RT dose, modality (EBRT vs. EBRT plus brachytherapy), and presentation (primary vs. recurrent) and disease control.nnnRESULTSnThe actuarial 5- and 10-year disease-free survival rate was 53% and 44%, respectively. Disease-free survival was significantly associated with female gender on univariate analysis (67% for female patients and 37% for male patients at 5 years, p = 0.05). On multivariate analysis, both gender and surgical margin had borderline significance (p = 0.06). The actuarial local control rate was 71% and 54% at 5 and 10 years, respectively. The median time to local relapse was 10.2 months, with 75% of all failures occurring within 29 months. The surgical margin status was significantly associated with local control (78% for patients with negative or close margins vs. 52% for patients with positive margins at 5 years, p = 0.04). Gender was borderline significant (85% for female patients vs. 54% for male patients at 5 years, p = 0.06). On multivariate analysis, only surgical margin status remained significant (p = 0.032). The distant metastasis-free survival rate at 5 and 10 years was 58% and 54%, respectively. The median time to distant metastases was 15.6 months. The lungs were the most common site of metastases. The only significant factor associated with distant metastasis-free survival was local control (73% for patients with locally controlled tumors vs. 19% for patients with local recurrence at 5 years, p = 0.0013). The actuarial 5- and 10-year overall survival rate was 56% and 47%, respectively. Gender (74% for female patients vs. 37% for male patients at 5 years), surgical margin status (66% for patients with negative or close margins vs. 48% for patients with positive margins at 5 years), and local control (64% for patients with locally controlled tumors vs. 21% for patients with uncontrolled primary tumors at 5 years) were significant predictors on both univariate and multivariate analyses (p <0.05).nnnCONCLUSIONnThe results of this study demonstrate the paramount importance of local control and complete surgical resection in the management of soft-tissue sarcoma of the retroperitoneum and deep trunk.

Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters

Despite the exceedingly poor prognosis of pancreatic cancer, it is often histologically well to moderately differentiated. The apparent resistance to conventional therapeutic modalities is poorly understood and may be related to the molecules involved in its progression or its propensity for perineurial invasion. Cyclooxygenase-2 (COX-2) is an inducible enzyme homologous to COX-1 that is responsible for production of prostaglandins at sites of inflammation. It is activated by a variety of growth factors and tumor promoters, and it has been implicated in cancer progression. It may also have a role in the resistance to therapy. Anti-COX-2 agents have been documented to have antitumor activity, and some are now being tested in the therapy for various cancers, including those of the pancreas. Experience regarding the rate of COX-2 expression in pancreatic cancer and its relationship to the clinical and biologic parameters is very limited. In this study, immunohistochemical stains for COX-2 have been performed on 120 cases of pancreatic ductal adenocarcinoma. The stains were scored according to the percentage (0: no staining, 1: < 10%, 2: 10–50%, and 3: >50% of the cells staining) and intensity (0 for no staining, 1 for mild staining, and 2 for dark staining) of staining. Based on the combined score for each case, they were divided into low expressors (percentage and intensity ≤1) and high expressors (percentage or intensity >1). In addition to global scoring for each case, the glandular and solid (poorly differentiated) components, when present, were scored separately. The global scores were correlated with clinical and biologic parameters. Seventy-four percent of the cases exhibited expression of COX-2 and 53% were high expressors. No significant association was observed when comparing the global COX-2 expression to survival, tumor size, stage, and vascular invasion. Increased perineural invasion was found to be significantly associated with COX-2 expression (p < 0.05). Increased expression was also more common in the glandular component as compared with the solid component of the tumors (68% versus 35%, p < 0.05). Of the 34 patients who received radiotherapy, 9 were low expressor (median survival 19.5 months) and 25 were high expressors (median survival 14 months). The difference in survival was not statistically significant.

Prostate secretory protein (PSP94) suppresses the growth of androgen-independent prostate cancer cell line (PC3) and xenografts by inducing apoptosis†

PSP94 (prostate secretory protein of 94 aa; also called PIP), one of the predominant proteins secreted into the seminal fluid, was proposed as an independent diagnostic/prognostic marker for prostate cancers. It was also shown to inhibit rat prostate cancer growth. In this study, we investigated the effect of purified PSP94 on the growth of androgen‐independent human prostate cancer cells (PC3) and its potential mechanism of action.

A SINGLE-INSTITUTION EXPERIENCE WITH CONCURRENT CAPECITABINE AND RADIATION THERAPY IN GASTROINTESTINAL MALIGNANCIES

PURPOSEnWe report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine.nnnMETHODS AND MATERIALSnMedical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed.nnnRESULTSnThe population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response.nnnCONCLUSIONnConcurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury.

PURPOSEnClinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken.nnnMETHODS AND MATERIALSnTwenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status >or=70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up.nnnRESULTSnAll patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500-1000 mg than in patients receiving 1500-2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test).nnnCONCLUSIONnIntrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.

Radioisotopes in the Treatment of Bone Metastases

Systemic radionuclide therapy is gaining popularity in the radiotherapy community and changing the management of painful osseous metastases. This form of therapy has two major advantages: (i) it addresses all sites of involvement; and (ii) selective absorption limits normal tissue dose. As a result, toxicity is reduced and the therapeutic ratio increased. The biokinetics, dosimetry, and clinical experience with these compounds are reviewed. To date, the best studied and most commonly used radionuclide is strontium-89. Large, prospectively randomized clinical trials have demonstrated its efficacy as a first-line therapy or as an adjuvant to external-beam radiotherapy. It is particularly useful when external-beam therapy options have been exhausted, and normal tissue tolerance has been reached. In metastatic prostate cancer, our recent survey suggests the formation of a new paradigm: local field external-beam radiotherapy to the painful index site in combination with prophylactic administration of systemic radionuclides for clinically occult metastases.

Effect of MLC leaf width on the planning and delivery of SMLC IMRT using the CORVUS inverse treatment planning system

This study investigates the influence of multileaf collimator (MLC) leaf width on intensity modulated radiation therapy (IMRT) plans delivered via the segmented multileaf collimator (SMLC) technique. IMRT plans were calculated using the Corvus treatment planning system for three brain, three prostate, and three pancreas cases using leaf widths of 0.5 and 1 cm. Resulting differences in plan quality and complexity are presented here. Plans calculated using a 1 cm leaf width were chosen over the 0.5 cm leaf width plans in seven out of nine cases based on clinical judgment. Conversely, optimization results revealed a superior objective function result for the 0.5 cm leaf width plans in seven out of the nine comparisons. The 1 cm leaf width objective function result was superior only for very large target volumes, indicating that expanding the solution space for plan optimization by using narrower leaves may result in a decreased probability of finding the global minimum. In the remaining cases, we can conclude that we are often not utilizing the objective function as proficiently as possible to meet our clinical goals. There was often no apparent clinically significant difference between the two plans, and in such cases the issue becomes one of plan complexity. A comparison of plan complexity revealed that the average 1 cm leaf width plan required roughly 60% fewer segments and over 40% fewer monitor units than required by 0.5 cm leaf width plans. This allows a significant decrease in whole body dose and total treatment time. For very complex IMRT plans, the treatment delivery time may affect the biologically effective dose. A clinically significant improvement in plan quality from using narrower leaves was evident only in cases with very small target volumes or those with concavities that are small with respect to the MLC leaf width. For the remaining cases investigated in this study, there was no clinical advantage to reducing the MLC leaf width from 1 to 0.5 cm. In such cases, there is no justification for the increased treatment time and whole body dose associated with the narrower MLC leaf width.

External beam radiotherapy for painful osseous metastases: pooled data dose response analysis

PURPOSEnAlthough the effectiveness of external beam irradiation in palliation of pain from osseous metastases is well established, the optimal fractionation schedule has not been determined. Clinical studies to date have failed to demonstrate an advantage for higher doses. To further address this issue, we conducted a pooled dose response analysis using data from published Phase III clinical trials.nnnMETHODS AND MATERIALSnComplete response (CR) was used as an endpoint because it was felt to be least susceptible to inconsistencies in assessment.The biological effective dose (BED) was calculated for each schedule using the linear-quadratic model and an alpha/beta of 10. Using SAS version 6.12, the data were fitted using a weighted linear regression, a logistic model, and the spline technique. Finally, BED was categorized, and odds ratios for each level were calculated.nnnRESULTSnCR was assessed early and late in 383 and 1,007 patients, respectively. Linear regression on the early-response data yielded a poor fit and a nonsignificant dose coefficient. With the late-response data, there was an excellent fit (R-square = 0.842) and a highly significant dose coefficient (p = 0.0002). Fitting early CR to a logistic model, we could not establish a significant dose response relationship. However, with the late-response data there was an excellent fit and the dose coefficient was significantly different from zero (0.017 +/- 0.00524; p = 0.0012). Application of the spline technique or removal of an outlier resulted in an improved fit (p = 0.048 and p = 0.0001, respectively). Using BED of < 14.4 Gy as a reference level, the odds ratios for late CR were 2.29-3.32 (BED of 19.5-51.4 Gy, respectively).nnnCONCLUSIONnOur results demonstrate a clear dose-response for pain relief. Further testing of high intensity regiments is warranted.

Topical application of WR-2721 achieves high concentrations in the rectal wall.

Rectal wall injury is an important treatment-related morbidity in patients treated with radiation for prostate cancer. We have undertaken this study to investigate the merits of topical intrarectal application of the radioprotective compound WR-2721. Male Copenhagen rats were injected intrarectally with 2% WR-2721 gel. At 10, 20, 30 and 40 min after application, a laparotomy was performed, and the rectum and prostate were removed. Concentrations of total WR-1065 (the active metabolite of WR-2721) were determined in these samples by an HPLC assay. While the concentration in the rectal wall tended to increase with time, it did not change substantially in the prostate. The concentration in the rectal wall was found to be significantly higher at all times. We conclude that preferential accumulation of WR-2721 in the rectal wall can be achieved by topical application. This is a promising approach to modifying rectal wall tolerance that deserves more study.