Pathologic stage I-II endometrial carcinoma in the elderly: radiotherapy indications and outcome

PURPOSE: To assess the indications for, and the outcome of, adjuvant radiotherapy (RT) in elderly patients with pathologic Stage I-II endometrial carcinoma. METHODS AND MATERIALS: Between 1980 and 2001, 79 elderly (age > or =75 years) patients with pathologic Stage I-II endometrial carcinoma were seen at our institution. All underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with assessment of peritoneal cytology. Pelvic and paraaortic lymph node sampling was performed in 39 and 29 women, respectively. Patients with Stage IA and IB Grade 1-2 were designated as low risk; those with Stage IB Grade 3 and IC-IIB were designated as high risk. Thirty-four received adjuvant RT consisting of whole pelvic (n = 23) or vaginal brachytherapy (n = 3), or both (n = 8). Actuarial disease-free survival, cause-specific survival, and pelvic recurrence-free survival analyses were performed by the Kaplan-Meier method. RESULTS: Adverse factors were common, including deep (>50%) myometrial invasion (47%), Grade 3 disease (28%), cervical involvement (15%), and unfavorable histologic features (15%). Overall, 46 patients (58%) had high-risk disease. Primarily because of concerns over toxicity, RT was administered in only 73%, 55%, and 67% of patients with deep myometrial invasion, Grade 3 disease, and cervical involvement, respectively. Thirty-one high-risk patients (67%) received adjuvant RT. At a median follow-up of 33.5 months, 19 patients had relapsed, for a 5-year actuarial disease-free survival rate of 67.7%. Ten patients (12%) had recurrence in the pelvis, 9 of whom had been patients treated with surgery alone. The 5-year pelvic recurrence-free survival rate of patients treated with and without RT was 97% and 73.1%, respectively (p = 0.02). The corresponding rates in the high-risk patients were 97% and 47% (p = 0.0001). High-risk patients treated with RT also had better 5-year actuarial disease-free survival (p = 0.0001) and cause-specific survival (p = 0.003) than those treated with surgery alone. RT was well tolerated, with all patients receiving their treatment as planned. Only 1 patient developed significant late toxicity. CONCLUSIONS: Adverse features are common in pathologic Stage I-II elderly endometrial carcinoma patients, and pelvic recurrence is high after surgery alone. Given the improvement in outcome and low incidence of toxicity, our results support the use of adjuvant RT in elderly pathologic Stage I-II patients with high-risk disease.     

Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer

PURPOSE: Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. METHODS AND MATERIALS: Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m(2)) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 x 20 Gy to the surface) or high-dose-rate applicator (3 x 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m(2)) and paclitaxel (175 mg/m(2)) were given at 4-week intervals after RT completion. RESULTS: Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. CONCLUSION: This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.     

Analysis of preoperative intracavitary cesium application versus postoperative external beam radiation in stage I endometrial carcinoma

Two groups of patients with surgical Stage I endometrial carcinoma treated at the LDS Hospital in Salt Lake City are analyzed. Group 1 comprises 112 patients treated from 1974 through 1976, during which time preoperative intracavitary cesium was routinely used in all patients. Group 2 comprises 117 patients treated 1981 through 1983 under the treatment policy of hysterectomy without preoperative cesium. High risk patients from each group (grade 3 and/or deep myometrial invasion) generally received similar postoperative external beam pelvic radiotherapy (4500-5000 cGy). While 5-year actuarial disease-free survival rates were similar in each group (94% Group 1 vs 91% Group 2), multivariate analysis by the Cox Regression Method revealed that inclusion within treatment Group 2 carried independent adverse prognostic significance (p = 0.018). Other independent predictors of adverse 5-year disease-free survival included deep myometrial invasion and increasing histologic grade. Group 1 patients with grade 3 lesions had a superior 5-year actuarial disease-free survival (76% vs 53%) compared to those from Group 2. Group 1 patients with deep myometrial invasion also had a superior 5-year disease-free survival (84% vs 69%). The remaining low risk patients (grade 1 or 2, less than 1/3 myometrial invasion) had an excellent 5-year disease-free survival with or without preoperative cesium. Immediate preoperative intracavitary cesium was well tolerated, did not obscure pathologic findings and in our experience, reduced the probability of recurrence in high risk Stage I endometrial carcinoma patients.     

A prospective trial of postoperative vaginal radium/cesium for grade 1-2 less than 50% myometrial invasion and pelvic radiation therapy for grade 3 or deep myometrial invasion in surgical stage I endometrial adenocarcinoma

A prospective trial was performed to evaluate the recurrence rate and 5-year disease-free survival rate in patients with surgical Stage I endometrial adenocarcinoma. Patients with Stage I, Grade 1 or 2 disease, less than 50% myometrial invasion, and no evidence of disease outside the corpus of the uterus were treated by hysterectomy and bilateral salpingo-oophorectomy and postoperative vaginal radium/cesium (Group 1). Patients with surgical Stage I, Grade 3 disease or deep myometrial invasion, and histologically negative paraaortic lymph nodes were treated with postoperative pelvic radiation therapy (5000-5040 cGY) (Group 2). Patients with malignant peritoneal cytologic findings also received progesterone therapy. Of the 92 Group 1 patients, there have been no recurrences and the 5-year estimated disease-free survival rate was 99%. Of the 41 Group 2 patients, there have been four (9.7%) recurrences but only one (2.4%) within the treated field (pelvis), and the 5-year estimated disease-free survival rate was 88%. Of the 133 patients, the 5-year estimated disease-free survival rate was 96%, and only one patient (0.7%) had a local pelvic recurrence. Of the 16 patients with malignant peritoneal cytologic findings who were treated with progesterone therapy, none has had a recurrence.     

Do conventional pathologic features lose their prognostic significance following postoperative radiation therapy in pathologic stage I-II endometrial adenocarcinoma?

Recent data have suggested that conventional pathologic features (myometrial invasion (MI), grade, stage) lose their prognostic significance following postoperative radiation therapy (RT) in Stage I-II endometrial carcinoma. Our goal was to test this finding in a large cohort of women treated at our institution. Between 1980 and 1997, 188 Stage I (140) and II (48) endometrial adenocarcinoma patients received postoperative RT. RT consisted of pelvic RT (112), vaginal brachytherapy (36), or both (40). Clinicopathologic factors were evaluated as prognostic factors on both univariate and multivariate analyses. Factors correlated with recurrence on univariate analysis included MI (P = 0.05), grade (P = 0.07), lymphovascular invasion (LVI) (P = 0.001) and stage (P = 0.03). Multivariate analysis confirmed the significance of grade (P = 0.02), LVI (P = 0.001), and stage (P = 0.02). Conventional pathologic features do not lose their prognostic significance in pathologic Stage I-II endometrial adenocarcinoma patients following postoperative RT. These factors should continue to be used to identify women at risk for recurrence despite adjuvant RT. New prognostic markers are needed to better identify high-risk patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 224-230 (2000).     

Adenocarcinoma of the endometrium treated with combined irradiation and surgery: study of 437 patients

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas. METHODS AND MATERIALS: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system (225 Stage IB, 107 Stage IC, 4 Stage IIA, 35 Stage IIB, 30 Stage IIIA, 6 Stage IIIB, and 30 Stage IIIC), underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of adjuvant RT was not randomized and depended on the usual practices of the surgical teams. Seventy-nine pts (Group I) received preoperative low-dose-rate uterovaginal brachytherapy (mean dose [MD]: 57 Gy). Three hundred fifty-eight pts (Group II) received postoperative RT. One hundred ninety-six pts received low-dose-rate vaginal brachytherapy alone (MD: 50 Gy). One hundred fifty-eight pts had external beam pelvic RT (MD: 46 Gy) followed by low-dose-rate vaginal brachytherapy (MD: 17 Gy). Four pts had external beam pelvic RT alone (MD: 47 Gy). The mean follow-up from the beginning of treatment was 128 months. RESULTS: The 10-year disease-free survival rate was 86%. From 57 recurrences, only 12 were isolated locoregional recurrences. The independent factors decreasing the probability of disease-free survival were as follows: histologic type (clear-cell carcinoma, p = 0.038), largest histologic tumor diameter >3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.005), and 1988 FIGO staging system (p = 9.10(-8)). In Group II, the addition of external beam pelvic RT did not seem to independently improve vaginal or pelvic control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were stage FIGO (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for Grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. External beam pelvic RT independently increased the rate for Grade 3 and 4 late complication (RR: 5.6, p = 0.0096). CONCLUSION: Postoperative external beam pelvic RT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in subgroup of "intermediate-risk" patients (Stage IA Grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with Stage III tumor are not satisfactory.     

High-dose-rate postoperative vaginal cuff irradiation alone for stage IB and IC endometrial cancer

PURPOSE: To evaluate the effectiveness of postoperative high-dose-rate (HDR) vaginal cuff irradiation alone (1500 cGy in 3 fractions) in patients with Stage Ib and Ic endometrial cancer. METHODS AND MATERIALS: This is a retrospective review of 102 patients with Stage Ib and Ic endometrial cancer treated with a hysterectomy and postoperative HDR intracavitary therapy alone during the period of 1/1/90-12/31/96. Each patient received 1500 cGy in 3 weekly treatments, dosed to a depth of 0.5 cm. Pathologic features such as depth of invasion, tumor grade, lower uterine segment (LUS) involvement, and lymphvascular invasion (LVI) were evaluated for their impact on recommended postoperative treatment. All survival curves were generated utilizing Kaplan-Meier methods and all statistical comparisons were via a Wilcoxon rank sum test. RESULTS: The 5-year actuarial overall survival (OS) is 84% and the 5-year disease-free survival (DFS) is 93%. Locoregional disease control (pelvic control) was excellent with 97% of the patients free of pelvic disease at 5 years. Of the three pelvic failures only one was in the vaginal cuff. LVI, LUS involvement, Grade 3 and/or outer third myometrial involvement were identified in 41 patients. Thirty-one of these patients underwent a lymphadenectomy and there were two regional failures within this increased-risk group. CONCLUSIONS: We obtained an excellent level of locoregional control with minimal morbidity and minimal time commitment for treatment with vaginal HDR brachytherapy alone. Our dose per fraction and total dose is lower than most reported series and there is no apparent loss in locoregional control. In addition, intermediate-risk patients and patients with an increased risk of recurrence (Grade 3, outer third myometrial involvement, LVI, LUS) may be treated with cuff irradiation alone, after surgical staging and a negative lymphadenectomy.     

Improved outcome in patients treated with postoperative radiation therapy for pathologic stage I/II endometrial cancer

: To evaluate prognostic factors and treatment outcome for high risk pathological Stage I and II endometrial cancer patients treated with consistent postoperative radiation therapy (RT) in a single institution and to compare these results to series where RT was variably applied.

: Between 1986 and 1993, 98 pathologic Stage I and II endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. Papillary serous and clear cell histologies were excluded. Fifty-five patients underwent lymph node evaluation. In 17 patients, RT consisted of intracavitary brachytherapy alone to a median dose of 21 Gy, and in 81 patients, RT consisted od external beam RT to a median dose of 45 Gy followed by intracavitary brachytherapy to a median dose of 12 Gy. Intracavitary brachytherapy generally consisted of three high dose rate implants with the dose prescribed to a depth of 0.5 cm. Median follow up was 47 months.

: The 5-year overall survival (OS), disease free survival (DFS), and freedon from pelvic recurrence (FPR) rates were 83, 85, and 89%, respectively. Pelvic recurrence either as the sole pattern of failure or combined with distant metastases was seen in 2 and 7% of patients, respectively. Distant metastases alone occurred in 4% of the patients. Univariate analysis of prognostic factors including age, grade, capillary lymphatic space invasion, depth of myometrial invasion, type of lymph node evaluation, pathologic stage, the use of brachytherapy and the number of risk factors was perfomed for OS, DFS, FPR, and FDM. Capillary kymphatic space invasion was the only statistically significant predictor for reduced DFS. Absence of lymph node dissection as well as a higher number of risk factors showed a trend toward poorer DFS (p = 0.06 for both). Multivariate analysis revealed older age to be the only factor significant for reduced DFS, with the presence of capillary lymphatic space invasion and the absence of a lymph node dissection showing a trend toward poorer outcome (p = 0.07).

: The results of this study suggest a continued role for the use of postoperative RT in the treatment of patients with high risk endometrial cancer and eill be compared tp other series with similar high-risk factors.     

Combined surgery and radiation in endometrial carcinoma: an analysis of prognostic factors

From 1969 to 1979, 300 patients with the diagnosis of endometrial cancer operated elsewhere were referred for treatment to the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center. All the patients were staged according to FIGO classification. One hundred and seventy-three patients were Stage IA, 105 patients were Stage IB, and 22 patients were Stage II. Within Stage IA, 141 patients had well differentiated tumor (G1), 20 had moderately well differentiated tumor (G2), and 12 patients had poorly differentiated (G3). One hundred and thirty-three patients had superficial myometrial invasion and 40 patients had deep myometrial invasion. Within Stage IB, 69 patients had G1 tumor, 23 had G2, and 13 had G3 tumors. Seventy-four patients in this group had superficial myometrial invasion and 31 patients had deep myometrial invasion. Two hundred and eighty-three patients had adenocarcinoma, 13 patients had adenoacanthoma, 4 patients had adenosquamous and other histological types. All of the patients received combined surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) and radiation. The radiation treatments consisted of external pelvic radiation and intravaginal vault radiation. External pelvic radiation was delivered with a megavoltage apparatus for a total dose of 4,000 cGy in 4 weeks preoperatively (47 patients) or postoperatively (105 patients) in patients presenting with high grade (G2,G3), more than 1/3 myometrial invasion, Stage II and extrauterine extension of disease at surgery. All patients received in addition, postoperative intravaginal vault irradiation consisting of 2100 cGy in 3 fractions over 4 weeks with a high dose rate remote afterloading technique. The follow-up in these patients ranged from 5-14 years. Survival data was calculated according to Kaplan-Meier Method and Cox regression multivariate analysis to identify the prognostic factors. The 10-year survival rate in Stage IA was 91%; in Stage IB 75%; and in Stage II it was 71%. Eleven patients (4%) developed recurrent disease with either local and/or distant metastasis. Nine-percent of the patients developed mild to moderate complications which resolved with conservative treatment. Patients with gross extra-uterine pelvic extension of disease had a poor survival compared with those presenting with microscopic involvement (40% vs. 80% at 5-years). No statistically significant difference in survival was observed between patients who received either preoperative or postoperative external pelvic irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Is there a role for a brachytherapy vaginal cuff boost in the adjuvant management of patients with uterine-confined endometrial cancer?

Purpose/Objective: Many patients who have uterine-confined endometrial cancer with prognostic factors predictive of recurrence are treated with adjuvant pelvic radiation. The addition of a brachytherapy vaginal cuff boost is controversial.Materials and Methods: Between 1983 and 1993, 270 patients received adjuvant postoperative pelvic irradiation following hysterectomy for Stage I or II endometrial cancer. Group A includes 173 patients who received external beam irradiation alone (EBRT), while group B includes 97 patients who received EBRT with a vaginal brachytherapy application. The median dose of EBRT was 45 Gy. Vaginal brachytherapy consisted of a low dose rate ovoid or cylinder in 41 patients, a high dose rate cylinder in 54 patients, and a radioactive gold seed implant in two patients. The median follow-up time was 64 months. The two groups were compared in terms of age, histologic grade, favorable versus unfavorable histology, capillary space invasion, depth of myometrial invasion, and pathologic stage.Results: Chi-square analysis revealed that the only difference between the two groups was the presence of more Stage II patients in group B (38% versus 14%). No difference was detected for 5 year pelvic control and disease-free survival rates between groups A and B.Conclusion: There is no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation is beneficial for pelvic control or disease-free survival for patients with Stage I or II endometrial cancer. Prospective randomized trials designed to study external irradiation alone versus external beam treatment plus vaginal brachytherapy are unlikely to show a positive result. Because EBRT provides excellent pelvic control, protocol development for uterine-confined corpus cancer should focus on identifying patients at risk for recurrence as well as other means of augmenting EBRT (e.g. addition of chemotherapy) in order to improve disease free survival in those subgroups.     

The role of adjunctive radiotherapy for stage I endometrial carcinoma: Preoperative vs postoperative irradiation

Eighty-five patients with clinical Stage I endometrial carcinoma were reviewed: 81% of patients had either pre-operative or post-operative radiotherapy (RT). The incidence of deep myometrial invasion (outer $\text{1}\text{3}$ of thickness) of pre-op RT vs. post-op RT group was 6% and 28% respectively; the pre-op irradiation seemed to alter the depth of myometrial invasion. Eleven patients (13%) developed recurrences: 9 of these patients (82%) had recurrences in the extrapelvis. The incidence of extrapelvic recurrence of patients with Grade 3 tumors was 29% ($\text{4}\text{14}$); those with deep myometrial invasion was 33% ($\text{4}\text{12}$). The overall 5 year survival and complication rate was 89% and 4% respectively: these results were comparable between pre-op RT and post-op RT groups. However, post-op RT offers the advantage of accurate surgical-pathologic staging and optimal individualization of adjuvant therapy. In addition, those who have deep myometrial invasion and/or Grade 3 tumors may require systemic therapy in view of high incidence of distant failures.     

Vaginal recurrences of endometrial carcinoma: the prognostic value of staging by a primary vaginal carcinoma system

Fifty-five of 1716 women with endometrial carcinoma seen consecutively at three institutions prior to 1986 were found to have an isolated post-hysterectomy vaginal recurrence. Their therapy included external radiation therapy (RT) and brachytherapy for 26 women, external RT alone for 17, brachytherapy only for 4, and no RT for 8. Combined external RT/brachytherapy doses ranged from 2000 to 10,000 cGy with a median of 6000 cGy. The 3- and 5-year actuarial survival rates are 48% and 31% for the entire group, and the 3- and 5-year pelvic control rates are 52% and 42%. The 5-year survival and pelvic control rates for those who received greater than or equal to 6000 cGy in total RT dose are 47% and 68%, compared with 12% and 10% for those receiving less than 6000 cGy (p = 0.002 and p = 0.004). For patients receiving their second RT course, the 5-year survival rate is 16%, compared with 48% for those not previously irradiated. The Perez modification of the International Federation of Gynecology and Obstetrics (FIGO) staging system for primary vaginal carcinoma was applied to each recurrence. There were 15 Stage I cases (vaginal mucosa), 32 Stage II cases divided between 15 Stage IIA (subvaginal infiltration) and 17 in Stage IIB (parametrial infiltration), and 8 Stage III cases (pelvic wall involvement). The 3-year actuarial survival and pelvic control rates using this staging system are: Stage I: 85%/100%; Stage II: 41%/43%, Stage IIA: 59%/53%, Stage IIB: 26%/35%; Stage III: 13%/0%. These outcome endpoints are significantly better for Stage I than Stage II patients (p = 0.01 & 0.0004) and for Stages I and IIA compared to Stages IIB and III (p = 0.0005 & 0.002). The pre-treatment variables of age, interval since hysterectomy, initial stage, and location did not predict for survival, but a higher rate of pelvic control was observed for apical than for suburethral recurrences (56% vs. 20%). Grade III histology was highly correlated with poor survival (p = 0.0006). This vaginal carcinoma staging system appears to have value in predicting treatment outcome for patients with post-hysterectomy vaginal recurrences.     

Operable Stages IB and II cervical carcinomas: a retrospective study comparing preoperative uterovaginal brachytherapy and postoperative radiotherapy

PURPOSE: To evaluate our data concerning prognostic factors and treatment toxicity in a series of operable cervical carcinomas. METHODS AND MATERIALS: Between May 1972 and January 1994, 414 patients with cervical carcinoma, staged according to the 1995 FIGO staging system (286 Stage IB1, 38 Stage IB2, 56 Stage IIA, and 34 Stage IIB with 1/3 proximal parametrial involvement), underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection (N+: n = 68). Group I included 168 patients who received postoperative radiation therapy (RT): 64 patients had low-dose-rate vaginal brachytherapy with a median total dose (MTD) of 50 Gy; 93 patients had external beam pelvic RT (EBPRT) with an MTD of 45 Gy over 5 weeks, followed by low-dose-rate vaginal brachytherapy (MTD: 20 Gy); and 11 patients had EBPRT alone (MTD: 50 Gy over 6 weeks). Group II included 246 patients treated with preoperative low-dose-rate uterovaginal brachytherapy (MTD: 65 Gy); 32 of these 246 patients also received postoperative EBPRT (MTD: 45 Gy over 5 weeks) delivered to the parametria and pelvic nodes. Mean follow-up from the beginning of treatment was 106 months. RESULTS: First events included isolated locoregional recurrences (35 patients), isolated distant metastases (27 patients), and locoregional recurrences with synchronous metastases (13 patients). The 10-year disease-free survival (DFS) rate was 88% for Stage IB1, 44% for Stage IB2, 65% for Stage IIA, and 48% for Stage IIB. Multivariate analysis showed that independent factors influencing the probability of DFS were as follows: cervical site (exocervical or endocervical vs. both endo- and exocervical, relative risk [RR]: 1.77, p = 0.047), vascular space invasion (no vs. yes, RR: 1.95, p = 0.041), age (>51 years vs. 1 cm: 83% vs. 41%, respectively, p = 0.001). The overall postoperative complication rate was 10% in Group I and 9% in Group II (p = 0.7). The rate of postoperative ureteral complications requiring surgical intervention was lower in Group I than in Group II (0.6% vs. 2.3%, respectively, p = 0.03). The overall 10-year rate for Grade 3 and 4 late radiation complications was 10.4%. Postoperative EBPRT significantly increased the 10-year rate for Grade 3 and 4 late radiation complications (yes vs. no: 22% vs. 7%, respectively, p = 0.0002). CONCLUSION: The prognosis for patients with cervical carcinoma was not influenced by the sequence of adjuvant RT (preoperative uterovaginal brachytherapy vs. postoperative RT) for Stages IB, IIA, and IIB with 1/3 proximal parametrial involvement. However, postoperative EBPRT increased the risk of late radiation complications.     

Feasibility study of Californium-252 for the therapy of stage IV cervical cancer

Twenty patients with Stage IVA and IVB cervic cancers were treated with Californium-252 (Cf) neutron brachytherapy (NT) in a feasibility trial between 1976 and 1986. Eleven patients had Stage IVA disease; nine patients had Stage IVB disease. Patient compliance with therapy was poor in four of nine patients with Stage IVB disease, and the 50% survival time was 6 months. In Stage IVA disease there were 18% 3-year survivals. For those that failed, the 50% survival time was 7.5 months. Because of the frequency of disseminated metastases, effective adjuvant therapy needs to be developed to use after the tumor debulking therapy, especially for Stage IVB disease. A single early Cf-NT implant followed by 6000 cGy of whole-pelvis fractionated radiation would accomplish this adequately for local tumor control and palliation.     

Surgery and postoperative radiation therapy in stage II endometrial carcinoma.

The traditional approach to patients with stage II endometrial carcinoma is preoperative radiation therapy (RT) followed by surgery. Currently, many patients are treated with primary surgery and postoperative RT. We retrospectively reviewed the outcome of 44 stage II (32 IIA, 12 IIB) patients who underwent surgery and postoperative RT. Nine (20%) had microscopic cervical involvement noted before surgery, and 35 (80%) had occult involvement noted postoperatively. Postoperative RT consisted of whole pelvic RT (WPRT) (50%), vaginal brachytherapy (VB) (18%), or both (32%). At a median follow-up of 40 months, the 5-year actuarial disease-free survival was 72.4%. Two patients (4%) had recurrence in the pelvis (one vagina, one lateral pelvis). Eighteen stage IIA patients treated with WPRT alone and eight stage IIA patients, without deep myometrial invasion (MI), were treated with VB alone, and remained controlled in the pelvis. Extrapelvic recurrences occurred in 12 patients (25%), primarily in those with deep MI and/or grade 2-3 disease. Our results suggest that patients with stage II endometrial carcinoma with microscopic or occult cervical involvement treated with surgery and postoperative RT have a favorable outcome. A high rate of pelvic control is achieved with RT tailored to the pathologic findings.     

Results of multifield conformal radiation therapy of nonsmall-cell lung carcinoma using multileaf collimation beams

A five-field conformal technique with three-dimensional radiation therapy treatment planning (3-DRTP) has been shown to permit better definition of the target volume for lung cancer, while minimizing the normal tissue volume receiving greater than 50% of the target dose. In an initial study to confirm the safety of conventional doses, we used the five-field conformal 3-DRTP technique. We then used the technique in a second study, enhancing the therapeutic index in a series of 42 patients, as well as to evaluate feasibility, survival outcome, and treatment toxicity. Forty-two consecutive patients with nonsmall-cell lung carcinoma (NSCLC) were evaluated during the years 1993-1997. The median age was 60 years (range 34-80). The median radiation therapy (RT) dose to the gross tumor volume was 6,300 cGy (range 5,000-6,840 cGy) delivered over 6 to 6.5 weeks in 180-275 cGy daily fractions, 5 days per week. There were three patients who received a split course treatment of 5,500 cGy in 20 fractions, delivering 275 cGy daily with a 2-week break built into the treatment course after 10 fractions. The stages of disease were II in 2%, IIIA in 40%, IIIB in 42.9%, and recurrent disease in 14.3% of the patients. The mean tumor volume was 324.14 cc (range 88.3-773.7 cc); 57.1% of the patients received combined chemoradiotherapy, while the others were treated with radiation therapy alone. Of the 42 patients, 7 were excluded from the final analysis because of diagnosis of distant metastasis during treatment. Two of the patients had their histology reinterpreted as being other than NSCLC, 2 patients did not complete RT at the time of analysis, and 1 patient voluntarily discontinued treatment because of progressive deterioration. Median follow-up was 11.2 months (range 3-32.5 months). Survival for patients with Stage III disease was 70.2% at 1 year and 51.5% at 2 years, with median survival not yet reached. Local control for the entire series was 23.3+/-11.4% at 2 years. However, for Stage III patients, local control was 50% at 1 year and 30% at 2 years. Patients who received concurrent chemotherapy had significantly improved survival (P = 0.002) and local control (P = 0.004), compared with RT alone. Late esophageal toxicity of > or =Grade 3 occurred in 14.1+/-9.3% of patients (3 of 20) receiving combined chemoradiotherapy, but in none of the 15 patients treated with RT alone. Pulmonary toxicity limited to Grades 1-2 occurred in 6.8% of the patients, and none developed > or =Grade 3 pulmonary toxicity. Patients with locally advanced NSCLC, who commonly have tumor volumes in excess of 200 cc, presenta challenge for adequate dose delivery without significant toxicity. Our five-field conformal 3-DRTP technique, which incorporates treatment planning by dose/volume histogram (DVH) was associated with minimal toxicity and may facilitate dose escalation to the gross tumor.     

Analysis of prognostic factors and patterns of recurrence in patients with pathologic stage III endometrial cancer

PURPOSE: To retrospectively assess prognostic factors and patterns of recurrence in patients with pathologic Stage III endometrial cancer. METHODS AND MATERIALS: Between 1989 and 2003, 107 patients with pathologic International Federation of Gynecology and Obstetrics Stage III endometrial adenocarcinoma confined to the pelvis were treated at our institution. Adjuvant radiotherapy (RT) was delivered to 68 patients (64%). The influence of multiple patient- and treatment-related factors on pelvic and distant control and overall survival (OS) was evaluated. RESULTS: Median follow-up for patients at risk was 41 months. Five-year actuarial OS was significantly improved in patients treated with adjuvant RT (68%) compared with those with resection alone (50%; p = 0.029). Age, histology, grade, uterine serosal invasion, adnexal involvement, number of extrauterine sites, and treatment with adjuvant RT predicted for improved survival in univariate analysis. Multivariate analysis revealed that grade, uterine serosal invasion, and treatment with adjuvant RT were independent predictors of survival. Five-year actuarial pelvic control was improved significantly with the delivery of adjuvant RT (74% vs. 49%; p = 0.011). Depth of myometrial invasion and treatment with adjuvant RT were independent predictors of pelvic control in multivariate analysis. CONCLUSIONS: Multiple prognostic factors predicting for the outcome of pathologic Stage III endometrial cancer patients were identified in this analysis. In particular, delivery of adjuvant RT seems to be a significant independent predictor for improved survival and pelvic control, suggesting that pelvic RT should be routinely considered in the management of these patients.     

The morbidity of treatment for patients with stage I endometrial cancer: results from a randomized trial

Purpose: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial.

Methods and Materials: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French–Italian glossary.

Results: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1–4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3–4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1–2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06).

Conclusion: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.     

Prognostic factors and changing trends in the treatment of stage I endometrial cancer: A clinical and histopathological study of 182 patients

Changing trends in treatment of Stage 1 endometrial carcinoma are reflected in the modalities used in the University Hospital in Groningen. From 1969 to 1979, three treatment regimes have been used in 182 patients with Stage I disease: Group A (50 patients): preoperative uterine radium packing followed by surgery six weeks later; Group B (94 patients): preoperative low dose external irradiation (14 Gray) immediately followed by surgery and an additional 40 Gray in patients who had invasion of the myometrium beyond the inner one-third; Group C (38 patients): primary surgery with post-operative radiation therapy. No significant differences were found in the 5-year actuarial survivals of 92, 90 and 88% in Groups A, B and C respectively. Most recurrences were seen in Group B (16%) as compared to 10% in Group A and 8% in Group C. Poor prognostic factors were found to be myometrial infiltration beyond the inner one-third, dedifferentiation of the tumor (Grade 2 and 3), vascular invasion, age over 60 years, and uterine length over 8 cm. The advantages of primary surgery, allowing for accurate surgical pathological examination and individualization of postoperative irradiation, are stressed.     

Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications

The poor outcome of certain patients with Stage III endometrial carcinoma has led some investigators to direct adjuvant therapy to the abdominal cavity. To better define failure patterns, a review of 126 patients with Stage III endometrial carcinoma treated at four institutions was performed. Seventy-four patients were diagnosed at surgery with pathologic Stage III disease, whereas 52 patients presented with clinical Stage III disease. Most patients received external beam irradiation to the pelvis with a variety of boost techniques. Site of disease, grade, depth of invasion, and pathology were examined for prognostic significance. Actuarial techniques were used to analyze survival and recurrences. For the 52 clinical Stage III patients, 5-year survival was 36%. The median survival of 20 patients who were treated with radiation therapy (RT) following biopsy was 9 months. Pelvic control was poor in these patients, with 16/18 evaluable patients failing locally. Thirty-two patients who underwent resection with adjunctive RT had a 5-year survival of 48%. Local failure occurred in 40% of patients, whereas 38% of patients had abdominal failure. Isolated abdominal failure was infrequent with 6% failing as isolated recurrence, and 16% failing as the only site of distant disease. For 74 pathologic Stage III patients, 5-year survival was 54%. Local failure resulted in 20% of patients, and isolated abdominal failure occurred in 7% of patients. The subset of patients with ovarian or tubal involvement included 42 patients, with a 5-year survival of 60%. Further analysis of this subset by grade and depth of myometrial penetration was found to be prognostically significant. Twenty-four patients who were Stage III because of parametrial or pelvic peritoneal involvement had a 5-year survival of 44%. Local control and survival is improved in Stage III patients treated with surgical resection. The high rate of distant metastases in both abdominal and extra-abdominal sites has significant therapeutic implications.