Biomedical subjects

Jacob Rotmensch

Publications and source records attributed to Jacob Rotmensch.

10 recordsLinked to original sources

PubMed2004

Phase I trial of concomitant vinorelbine, cisplatin, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of vinorelbine in combination with weekly cisplatin and pelvic radiation therapy (RT). METHODS: Eligible patients included those with bulky or locally advanced cervical cancer. Women with other advanced gynecologic malignancies were also eligible. All patients received cisplatin 40 mg/m(-2)/week (maximum dose, 70 mg) during pelvic RT. Vinorelbine was administered on the same day as cisplatin at a starting dose of 10 mg/m(-2)/week and escalated in 5 mg/m(-2)/week increments. Dose-limiting toxicity (DLT) was defined as: grade 3-4 non-hematologic toxicity, grade 4 hematologic toxicity, or any toxicity which required > or =1 week delay in RT or an omission of >1 dose of chemotherapy. RESULTS: Between April 2001 and September 2002, 12 women with pelvic malignancies (11 cervical, 1 recurrent ovarian) were enrolled. Cohorts of 3, 6, and 3 patients were treated at 10, 15, and 20 mg/m(-2)/week dose levels of vinorelbine. At the 20 mg/m2 level, DLT was observed. Two of three patients missed >1 cycle of chemotherapy secondary to predominantly hematologic toxicity. One patient at the 20 mg level developed a creatinine clearance <50 ml/min and missed 1 dose of cisplatin. Another developed transient grade 3 diarrhea. No grade 4 toxicities were observed. CONCLUSIONS: The MTD of vinorelbine in combination with cisplatin and pelvic RT in patients with cervical cancer is 15 mg/m(-2)/week.

Adult↗

PubMed2003

Outcome and pattern of failure in pathologic stage I-II papillary serous carcinoma of the endometrium: implications for adjuvant radiation therapy.

PURPOSE: To evaluate the outcome and patterns of failure in women with pathologic Stage I-II papillary serous carcinoma of the uterus and to discuss the implications for adjuvant radiation therapy (RT). METHODS: Twenty-three pathologic Stage I-II uterine papillary serous carcinoma patients were treated at our institution between 1980 and 2001. All underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy and assessment of peritoneal cytology. Pelvic and para-aortic lymph node sampling was performed in 12 and 8 patients, respectively. FIGO stages were as follows: IA = 3, IB = 8, IC = 6, IIA = 5, and IIB = 1. Adjuvant therapies included the following: 9 none, 10 RT (6 pelvic, 1 vaginal brachytherapy, 3 both), 4 chemotherapy, and 1 hormonal therapy. No patient received whole abdominal radiation therapy or para-aortic RT. Disease-free survival, pelvic recurrence-free survival, and cause-specific survival were estimated using the method of Kaplan-Meier, and prognostic factors were analyzed by the log-rank test. Median follow-up was 38.7 months (range: 3-109 months). RESULTS: The 5-year actuarial disease-free survival and cause-specific survival for the entire group was 41% and 73.6%, respectively. Nine patients developed recurrent disease. Five failed in the pelvis, of which 4 relapsed in the vagina. No pelvic failures occurred in women treated with adjuvant RT. Patients treated with adjuvant RT had a better 5-year actuarial pelvic recurrence-free survival (100% vs. 57.5%, p = 0.06) than patients treated with surgery alone. Two patients failed in the abdomen. However, neither developed an isolated abdominal recurrence. Six patients failed in distant sites, primarily the lungs and bone. CONCLUSION: Although patients with pathologic Stage I-II uterine papillary serous carcinomas have organ-confined disease, recurrence is common, particularly in the pelvis and distant sites. Our results suggest that adjuvant RT reduces the risk of pelvic failure. Contrary to traditional assumptions, however, abdominal recurrence was uncommon in our patients, despite the lack of whole abdominal radiation therapy. Our results support the use of pelvic RT in these patients. Future studies should investigate the role of adjuvant chemotherapy.

Adult↗

PubMed2003

Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy.

PURPOSE: To evaluate intensity-modulated whole pelvis radiotherapy (IM-WPRT) (with bone marrow [BM] as a planning constraint) as a means to reduce the volume of pelvic BM irradiated. METHODS AND MATERIALS: Ten women with cervical or endometrial cancer previously treated using IM-WPRT were selected for this analysis. Using the treatment planning CT scan, the clinical target volume was defined to encompass the gross tumor, parametrial tissues, uterus (if present), and regional lymph nodes. The clinical target volume was expanded by a 1-cm margin to form the planning target volume (PTV). The bladder, rectum, small bowel, and pelvic BM were delineated in each patient. Three plans were created for each patient: a standard four-field WPRT plan, an IM-WPRT treatment plan designed to conform the dose to the PTV while minimizing dose to the normal tissues (excluding BM), and a BM-sparing (BMS) IM-WPRT plan that included the BM as an additional treatment planning constraint. Dose-volume histograms for the PTV, small bowel, and BM were compared for each patient. RESULTS: For each of the 10 patients, BMS IM-WPRT treatment plans demonstrated a significant reduction of the volume of BM receiving >40% (18 Gy) of the prescription dose (45 Gy) compared with both IM-WPRT and four-field treatment. On average, BMS IM-WPRT resulted in only 60% of the BM volume irradiated to >50% of the dose compared with 87.4% (p <0.001) of the BM volume in a four-field plan and 75.7% (p < 0.003) of the volume in an IM-WPRT plan. Furthermore, the BMS IM-WPRT plans resulted in significant sparing of all other normal tissues that was comparable to the original IM-WPRT. In all 10 cases, the BMS IM-WPRT treatment plan did not result in any significant differences in the PTV and small bowel dose-volume histograms compared with the IM-WPRT treatment plans. CONCLUSION: BMS IM-WPRT significantly reduces the volume of pelvic BM irradiated compared with conventional WPRT. In addition, BMS IM-WPRT did not compromise the improvements previously seen in IM-WPRT treatment plans that did not consider BM. Clinical studies are necessary to assess the significance of BMS IM-WPRT in reducing hematologic toxicity.

Bone Marrow Diseases↗

PubMed2003

Outcome and patterns of failure in pathologic stages I-IV clear-cell carcinoma of the endometrium: implications for adjuvant radiation therapy.

PURPOSE: To evaluate the outcome and patterns of failure in women with uterine clear-cell carcinoma and discuss implications for adjuvant radiation therapy (RT). METHODS: Between 1980 and 2000, 686 endometrial carcinoma patients underwent primary surgery at our institution. Thirty-eight women (5.5%) had clear-cell tumors (18 clear-cell only, 8 clear-cell + adenocarcinoma, and 12 clear-cell + other unfavorable histologies [10 papillary serous, 1 uterine sarcoma, 1 both]). All underwent surgery and assessment of peritoneal cytology. None received preoperative RT. Pelvic and para-aortic node samplings were performed in 26 and 17 patients, respectively. FIGO stages were as follows: 3 IA, 4 IB, 5 IC, 4 IIA, 6 IIB, 8 IIIA, 2 IIIB, 3 IIIC, and 6 IV. Adjuvant therapies included the following: 5 none, 22 RT (13 pelvic RT, 2 vaginal brachytherapy, 7 both), 11 chemotherapy (8 alone, 3 after pelvic RT), and 3 hormones. No patient received whole-abdominal RT or para-aortic RT. Median follow-up was 36.5 months. RESULTS: The 5-year actuarial disease-free survival of the entire group was 38.5%. No correlation was seen between relapse and stage, myometrial invasion, cytology, cervical extension, or involvement of extrauterine sites. Patients with clear +/- adenocarcinoma histology had a similar 5-year disease-free survival (38.8% vs. 38.7%, p = 0.95) compared with those with clear-cell + other unfavorable histologies. Sixteen patients relapsed (42%). Eight failed in the pelvis (5 vagina, 3 lateral pelvis). There were no pelvic failures in the group of 22 patients who received adjuvant RT, whereas in the group of 16 women who did not, 8 (50%) relapsed in the pelvis (p < 0.0001). Corresponding pelvic failure rates in the Stage IA-IIB patients with and without RT were 0/16 (0%) and 5/6 (83%) (p < 0.0001). Six patients (16%) failed in the para-aortic nodes and 2 (5%) in the abdomen. Only 1 (2%) patient developed an isolated abdominal failure (This patient had a mixed clear-cell/papillary serous tumor). Of the 26 women with clear-cell +/- adenocarcinoma histology, only 1 (3.8%) relapsed in the abdomen. Nine patients (24%) relapsed in distant sites, primarily the lungs and bone. CONCLUSION: Clear-cell carcinoma comprises a small percentage of endometrial cancers, frequently presents as a mixed histology, and has a poor overall outcome. Unlike papillary serous tumors, clear-cell carcinoma does not seem to have a high propensity for abdominal failure. Our results thus do not support the routine use of whole-abdominal RT in these patients. Future protocols should focus instead on combinations of locoregional RT and chemotherapy to reduce the risk of local and systemic recurrence.

Abdominal Neoplasms↗

PubMed2003

Image processing tools for alpha-particle track-etch dosimetry.

In cases where both the source and cell geometry are well known, track-etch dosimetry allows the potential for individual cell dosimetry. However, analysis of track-etch images is both tedious and time-consuming. We describe here several image processing tools that we are using in conjunction with a track-etch based irradiator. Briefly, cells grown on LR 115 (a track-etch material) are irradiated from below by a collimated, planar alpha-particle source. Prior to irradiation, images of the cells are obtained. A computer program reads each image and automatically determines the location of individual cells. Next, the algorithm automatically identifies the cellular and nuclear boundaries. Following irradiation, and after the cells have reached their biological endpoint (e.g., cell survival), the cell dish is etched and images are obtained of alpha-particle tracks. Using the characteristic background pattern in the LR 115, the etched images are spatially registered to the original images. These two sets of images are then superimposed to create a composite image of the cells and associated alpha-particle tracks. Incorporating this tool into our irradiation scheme will enable more efficient analysis of the large amounts of data that are essential in assessing biological endpoints.

Algorithms↗

PubMed2003

Characterization of an alpha-particle irradiator for individual cell dosimetry measurements.

A computer-controlled, alpha-particle irradiator is described that allows for the measurement of the number and location of alpha-particle hits to individual cell nuclei, and subsequent scoring of cell survival. Cells are grown on a track-etch material (LR 115) and images are obtained of the cells prior to irradiation. The cells are then irradiated from below by a planar, collimated Am-241 source. The exposure time is varied so that the average number of hits to cell nuclei ranges from 0 to 3. After cell survival has been scored, images of the etched material are obtained and spatially registered to the original cell images. The etched images and cellular images are superimposed allowing for the determination of the number and position of hits to individual cell nuclei. This paper characterizes the irradiator including the energy and fluence of the incident alpha particles. Additionally, we describe the sources of uncertainty associated with this experiment, including the cell dish repositioning and cell migration during scanning and irradiation.

Alpha Particles↗

PubMed2003

Binary methods for the microdosimetric analysis of cell survival data from alpha-particle irradiation.

A new type of alpha-particle irradiator allows survival of each cell to be observed individually along with the size and shape of its nucleus and the positions of the hits it receives. This paper discusses methods of data analysis that can utilize these additional data. Using idealizations of the cell nucleus geometry (i.e., spheres, ellipsoids), the path length (l), energy deposited (e), and specific energy (z) has been determined on a cell-by-cell basis for 772 cells all subjected to the same fluence. Each cell is regarded as a Bernoulli trial with a different probability for success (colony formation). For the survival expectation, A exp(-z/z(o)), the values of A and z(o) are chosen to maximize the likelihood for the observed outcome. Similar results are presented using the alternate functional forms A exp(-e/e(o)) and A exp(-l/l(o)). With these parameter values, the goodness of fit is also evaluated using a chi-square method with variances given by the binary (Bernoulli) methods. A further purpose of the paper is to assess the validity of the microdosimetric computations that would have had to be made if these individual cell-by-cell experimental measurements were not available or were incomplete.

Alpha Particles↗

PubMed2002

Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies.

PURPOSE: To evaluate the impact of intensity-modulated whole pelvic radiotherapy (IM-WPRT) on acute hematologic toxicity (HT) in gynecology patients. METHODS AND MATERIALS: Between February 2000 and June 2001, 36 patients (24 cervix, 12 uterus) received IM-WPRT. The target consisted of the upper vagina, parametria, uterus, and presacral and pelvic lymph nodes. Using commercially available software, seven or nine coplanar IM-WPRT plans were generated. The planning goals were to irradiate the target while minimizing the dose to the small bowel, bladder, and rectum. Pelvic bone marrow (BM) was not a constraint in the planning process. The variables analyzed included white blood count (WBC), absolute neutrophil count (ANC), platelets, and hemoglobin (Hgb) obtained before and weekly during RT. As a comparison, the HT in 88 patients (44 cervix, 44 uterus) treated to the same target volume and total dose (45 Gy) with conventional four-field WPRT was analyzed. In addition, the medullary spaces within the pelvic bones in 10 women were contoured and the average dose-volume histograms representing the pelvic BM were compared between the two groups. RESULTS: IM-WPRT patients had a lower median age (p = 0.008), higher percentage of squamous histologic features (p = 0.04), and were more likely to receive chemotherapy (CTX) (p = 0.02) than were the WPRT patients. No differences were seen in the baseline WBC, ANC, platelet, or Hgb levels between the two groups. Grade 2 or greater WBC, ANC, and Hgb toxicity was seen in 19.4%, 9.1%, and 8.6% of the IM-WPRT patients, respectively. Comparable rates were seen in the WPRT patients (WBC 21.6%, p = 0.79; ANC 8.3%, p = 0.91; Hgb 9.2%, p = 0.94). No Grade 2 or greater platelet toxicity was seen in either group. Significant HT was infrequent in women treated with RT alone and was comparable in the two groups. In contrast, WPRT + CTX patients experienced more Grade 2 or greater WBC toxicity (60% vs. 31.2%, p = 0.08) and developed lower median WBC (2.8 vs. 3.6 microg/dL, p = 0.05) and ANC (1874 vs. 2669, p = 0.04) nadirs than did IM-WPRT + CTX patients. Moreover, CTX was held more often in the WPRT group secondary to HT (40% vs. 12.5%, p = 0.06). Although Grade 2 or greater ANC (23.5% vs. 15.3%) and Hgb (35.2% vs. 15.2%) toxicity were lower in the IM-WPRT + CTX group, these differences did not reach statistical significance (p = 0.58 and p = 0.22, respectively). The comparison of pelvic BM dose-volume histograms revealed that IM-WPRT planning resulted in significantly less BM volume being irradiated compared with WPRT planning, particularly within the iliac crests. CONCLUSION: IM-WPRT has a favorable impact on the risk of acute HT in gynecology patients, particularly in those receiving CTX. Future work is needed to optimize BM sparing in these patients to reduce the risk of significant HT further.

Aged↗

PubMed2002

Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies.

PURPOSE: To describe our initial clinical experience with intensity-modulated whole pelvic radiotherapy (IM-WPRT) in women with gynecologic malignancies. METHODS AND MATERIALS: Between February 2000 and August 2001, 40 gynecology patients underwent IM-WPRT. After fabrication of customized immobilization, all patients underwent contrast-enhanced CT, and a clinical target volume was contoured consisting of the upper vagina, parametria, uterus (if present), and presacral and pelvic lymph node regions. The clinical target volume was expanded by 1 cm to create a planning target volume (PTV). Using commercially available software, 7- or 9-field, 6-MV, coplanar IM-WPRT plans were generated for all patients. The worst acute gastrointestinal and genitourinary toxicity during treatment was scored on a 4-point scale: 0, none; 1, mild, no medications required; 2, moderate, medications required; and 3, severe, treatment breaks or cessation, hospitalization. As a comparison, acute toxicities in 35 previously treated conventional WPRT patients were analyzed. No significant differences were noted in the clinicopathologic and treatment factors between the two groups. RESULTS: IM-WPRT plans provided excellent PTV coverage, with considerable sparing of the surrounding normal tissues. On average, 98.1% of the PTV received the prescription dose. The average percentage of the PTV receiving 110% and 115% of the prescription dose was 9.8% and 0.2%, respectively. IM-WPRT was well tolerated, with no patient developing Grade 3 toxicity. Grade 2 acute gastrointestinal toxicity was less common in the IM-WPRT group (60 vs. 91%, p = 0.002) than in the conventional WPRT group. Moreover, the percentage of IM-WPRT and WPRT patients requiring no or only infrequent antidiarrheal medications was 75% and 34%, respectively (p = 0.001). Although less Grade 2 genitourinary toxicity was seen in the IM-WPRT group (10% vs. 20%), this difference was not statistically significant (p = 0.22). CONCLUSION: IM-WPRT is a promising approach in gynecology patients. IMRT planning resulted in excellent PTV coverage, with considerable sparing of normal tissues. Treatment was well tolerated and associated with less acute gastrointestinal sequelae than conventional WPRT. Longer follow-up and more patients are needed, however, to evaluate the full merits of this novel approach.

Adult↗

PubMed2002

Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study.

OBJECTIVE: Because of preliminary observations favoring the use of mitomycin, doxorubicin, and cisplatin (MAP) chemotherapy in leiomyosarcomas, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of this combination regimen in patients with advanced disease. METHODS: Patients with histologically confirmed uterine leiomyosarcoma who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Mitomycin 8 mg/m(2) and doxorubicin 40 mg/m(2) were each given by iv injection followed immediately by cisplatin 60 mg/m(2) in 1 liter of 0.45% saline plus mannitol 25 g. Patients who remained free from tumor progression or intolerable toxicity received at least three, to a maximum of six, cycles of MAP. RESULTS: Forty-one patients were registered, of whom 4 were determined ineligible (wrong cell type, 2; wrong site of origin, 1; inadequate pathology material, 1). Thirty-five of the 37 were evaluable for response after receiving from one to six (median three) cycles of MAP. Three patients (9%) achieved a complete response and 5 (14%) exhibited a partial response. The most common adverse effects were leukopenia (33 patients) and thrombocytopenia (30 patients). Pulmonary toxicity was seen in 10 patients and was a factor in the clinical deterioration and death of 2. CONCLUSION: MAP is active against advanced uterine leiomyosarcomas, but not remarkably so. Despite its low therapeutic index, this novel, possibly interactive, combination may serve as a forerunner to regimens that more efficiently exploit the enhancement of sarcoma cell kill under hypoxic conditions.

Antineoplastic Combined Chemotherapy Protocols↗