Jacob Rotmensch

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.

Quality of life of patients with endometrial cancer undergoing laparoscopic International Federation of gynecology and obstetrics staging compared with laparotomy: A Gynecologic Oncology Group study

PURPOSE The studys objective was to compare the quality of life (QoL) of patients with endometrial cancer undergoing surgical staging via laparoscopy versus laparotomy. PATIENTS AND METHODS The first 802 eligible patients (laparoscopy, n = 535; laparotomy, n = 267) participated in the QoL study in a Gynecologic Oncology Group (GOG) randomized trial of laparoscopy versus laparotomy (GOG 2222). Patients completed QoL assessments at baseline; at 1, 3, and 6 weeks; and at 6 months postsurgery. RESULTS In an intent-to-treat analysis, laparoscopy patients reported significantly higher Functional Assessment of Cancer Therapy-General (FACT-G) scores (P = .001), better physical functioning (P = .006), better body image (BI; P < .001), less pain (P < .001) and its interference with QoL (P < .001), and an earlier resumption of normal activities (P = .003) and return to work (P = .04) over the 6-week postsurgery period, as compared with laparotomy patients. However, the differences in BI and return to work between groups were modest, and the adjusted FACT-G scores did not meet the minimally important difference (MID) between the two surgical arms over 6 weeks. By 6 months, except for better BI in laparoscopy patients (P < .001), the difference in QoL between the two surgical techniques was not statistically significant. CONCLUSION Although the FACT-G did not show a MID between the two surgical groups, and only modest differences in return to work and BI were found between the two groups, statistically significantly better QoL across many parameters in the laparoscopy arm at 6 weeks provides modest support for the QoL advantage of using laparoscopy to stage patients with early endometrial cancer.

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.

Phase II Trial of Bevacizumab in Recurrent or Persistent Endometrial Cancer: A Gynecologic Oncology Group Study

PURPOSE Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), has clinical activity in multiple tumor types. We conducted a phase II trial to assess the activity and tolerability of single-agent bevacizumab in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of ≤ 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or prohibitive toxicity. VEGF-A was assessed by immunohistochemistry in archival tumor and by enzyme-linked immunosorbent assay in pretreatment plasma. Primary end points were progression-free survival (PFS) at 6 months and overall response rate. RESULTS Fifty-six patients were enrolled. Fifty-two patients were eligible and evaluable. Median age was 62 years, and prior treatment consisted of one or two regimens in 33 (63.5%) and 19 (36.5%) patients, respectively. Twenty-nine patients (55.8%) received prior radiation. Adverse events were consistent with those expected with bevacizumab treatment. No GI perforations or fistulae were seen. Seven patients (13.5%) experienced clinical responses (one complete response and six partial responses; median response duration, 6.0 months), and 21 patients (40.4%) survived progression free for at least 6 months. Median PFS and overall survival times were 4.2 and 10.5 months, respectively. Suggested associations were observed between high VEGF-A and adjusted hazard of death or tumor response when evaluated in tumor/plasma or plasma, respectively. CONCLUSION Bevacizumab is well tolerated and active based on PFS at 6 months in recurrent or persistent EMC and warrants further investigation.

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.

Faster repair of DNA double-strand breaks in radioresistant human tumor cells

To investigate the molecular basis of radiation resistance in human tumor cells, the induction and repair of radiation-induced DNA single- and double-strand breaks was determined by DNA elution analysis in two normal human cell lines and 12 early-passage human tumor cell lines of varying radiosensitivities. The radiosensitivities (D0) of the cell lines ranged from 1 to 2.9 Gy. Inherent cellular radiosensitivity was found to directly correlate with the rate at which the DNA double-strand breaks were repaired. Radioresistant cell lines repaired approximately 90% of their radiation-induced DNA double-strand breaks within 1 hr of irradiation while more radiosensitive cell lines required 2-4 hr to repair the same fraction of damage. Radioresistant cell lines also had lower initial DNA double-strand break frequencies. DNA single-strand break induction and repair was not found to be an important factor in the radiation response of human tumor and normal cell lines. Therefore, the rate at which DNA double strand breaks are repaired is a critical factor underlying radioresistance in human tumor cell lines.

Histopathology of ovarian tumors in laying hens: a preclinical model of human ovarian cancer.

The high mortality rate due to ovarian cancer (OVCA) is attributed to the lack of an effective early detection method. Because of the nonspecificity of symptoms at early stage, most of the OVCA cases are detected at late stages. This makes the access to women with early-stage disease problematic and presents a barrier to development and validation of tests for detection of early stage of OVCA in humans. Animal models are used to elucidate disease etiologies and pathogenesis that are difficult to study in humans. Laying hen is the only available animal that develops OVCA spontaneously; however, detailed information on ovarian tumor histology is not available. The goal of this study was to determine the histological features of malignant ovarian tumors in laying hens. A total of 155 young and old (1-5 years of age) laying hens (Gallus domesticus) were selected randomly and evaluated grossly and microscopically for the presence of ovarian tumors. Histological classification of tumors with their stages and grades was determined with reference to those for humans. Similar to humans, all 4 types including serous, endometrioid, mucinous, and clear cell or mixed carcinomas were observed in hen ovarian tumors. Some early neoplastic as well as putative ovarian lesions were also observed. Similarities in histology, metastasis, and stages of hen OVCA to those of humans demonstrate the feasibility of the hen model for additional delineation of the mechanism underlying ovarian carcinogenesis, preclinical testing of new agents for the prevention, and therapy of this disease.

Significant pelvic recurrence in high-risk pathologic stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy.

OBJECTIVE To evaluate the risk of pelvic recurrence (PVR) in high-risk pathologic Stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone. METHODS Between 1992 and 1998, 43 high-risk endometrial cancer patients received adjuvant chemotherapy. All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patients received preoperative radiation therapy (RT). Regional lymph nodes and peritoneal cytology were sampled in 62.8% and 83.7% of cases, respectively. Most patients had Stage III--IV disease (83.7%) or unfavorable histology tumors (74.4%). None had evidence of extra-abdominal disease. All patients received 4-6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. Recurrent disease sites were divided into pelvic (vaginal, nonvaginal) and extrapelvic (para-aortic, upper abdomen, liver, and extra-abdominal). Median follow-up was 27 months (range, 2--96 months). RESULTS Twenty-nine women (67.4%) relapsed. Seventeen (39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. The 3-year actuarial PVR rate was 46.5%. The most significant factors correlated with PVR were cervical involvement (CI) (p = 0.01) and adnexal (p = 0.05) involvement. Of the 17 women who developed a PVR, 8 relapsed in the vagina, 3 in the nonvaginal pelvis, and 6 in both. The 3-year vaginal and nonvaginal PVR rates were 37.8% and 26%, respectively. The most significant factor correlated with vaginal PVR was CI (p = 0.0007). Deep myometrial invasion (p = 0.02) and lymph nodal involvement (p = 0.03) were both correlated with nonvaginal PVR. Nine of the 29 relapsed patients (31%) developed PVR as their only (6) or first site (3) of recurrence. Factors associated with a higher rate of PVR (as the first or only site) were CI and Stage I--II disease. CONCLUSIONS PVR is common in high-risk pathologic Stage I-IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy. Further studies are needed to test the addition of chemotherapy to locoregional RT.

Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: A dosimetric analysis☆

PURPOSE This study attempted to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients treated with radiation therapy (RT) for cervical carcinoma. METHODS AND MATERIALS A total of 183 patients with cervical carcinoma (67 Stage I, 93 Stage II, and 23 Stage III) treated with definitive RT with a minimum of 2 years follow-up were evaluated. Treatment consisted of external beam pelvic RT (EBRT) followed by intracavitary RT (ICRT) consisting of one or two insertions. Complications were scored and analyzed as a function of 25 patient and treatment factors. Conventional total rectal doses were obtained by adding together the EBRT and ICRT rectal doses. To account for differences in dose rate between the ICRT and EBRT, and variations in EBRT fractionation schemes, biologically equivalent rectal doses (BED) were calculated using a linear quadratic model. In addition, the influence of the varying proportions of EBRT and ICRT rectal doses were evaluated. RESULTS Twenty-eight patients (15.3%) developed late rectal sequelae (13 Grade 1, 3 Grade 2, and 12 Grade 3). Diabetes (p = 0.03), Point A dose (p = 0.04), and conventional EBRT dose (p = 0.03) were the most significant factors on multivariate analysis. Logistic regression analysis demonstrated a low risk (<10%) of late rectal sequelae below conventional and biological rectal doses of 75 Gy and 135 BED, respectively. The percentage of rectal dose delivered by the EBRT significantly influenced the dose-response relationship. A defined threshold percentage above which rectal sequelae were more common was identified over the range of doses evaluated. This threshold was 87% at a total rectal dose of 60 Gy and decreased to 60% at 80 Gy. CONCLUSION Diabetes, Point A, and EBRT doses are the most significant factors associated with the risk of late rectal sequelae in patients treated with RT for cervical carcinoma. The percentage of rectal dose delivered by the EBRT significantly affects the conventional and biological dose-response relationship. This suggests that the volume of rectum irradiated is an important and independent parameter in the development of late rectal sequelae.

Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). METHODS Eligible patients had persistent or recurrent EMC after receiving 1-2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2. Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. RESULTS Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months, respectively. CONCLUSION Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.