Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of stage IB and IIA carcinoma of the uterine cervix: final report

A prospective randomized study in selected patients with Stage IB and IIA carcinoma of the uterine cervix was carried out at Washington University between January 1966 and December 1979. Patients were randomized to be treated with irradiation alone consisting of 1000 cGy whole pelvis, additional 4000 cGy to the parametria with a step wedge midline block, and two intracavitary insertions for 7500 mgh; or irradiation and surgery, consisting of 2000 cGy whole pelvis irradiation, one intracavitary insertion for 5000-6000 mgh followed 2 to 6 weeks later by a radical hysterectomy with pelvic lymphadenectomy. A total of 40 patients with Stage IB and 16 with Stage IIA were randomized to be treated with irradiation alone. A similar group of 48 patients with Stage IB and 14 with IIA were randomized to the preoperative radiation and surgery group. The 5-year, tumor-free actuarial survival for Stage IB patients treated with radiation was 89% and with preoperative radiation and surgery 80%. In Stage IIA, the tumor-free actuarial 5-year survival was 56% for the irradiation alone group and 79% for the patients treated with preoperative radiation and radical hysterectomy. In the patients with Stage IB treated by irradiation alone only one pelvic failure combined with distant metastasis occurred, and 3 patients developed distant metastasis. In the 48 patients treated with combined therapy, there were six pelvic failures (12.5%) all combined with distant metastases and two distant metastases alone. In the 16 patients with Stage IIA treated with radiotherapy alone, there were four pelvic failures (all parametrial), three of them combined with distant metastasis. In the 14 patients treated with irradiation and surgery, two developed a pelvic recurrence, and one distant metastasis. In the preoperative radiation group, the incidence of metastatic pelvic lymph nodes was 6.3% in Stage IB and 7.1% in Stage IIA. Major complications of therapy in the patients treated with radiation alone (10%) consisted of one rectovaginal fistula, two vesicovaginal fistulas, and one rectal stricture. In the preoperative radiation group, three ureteral strictures and two severe proctitis-rectal strictures were noted (8%). The present study shows no significant difference in therapeutic results or morbidity for invasive carcinoma of the uterine cervix Stage IB or IIA treated with irradiation alone or combined with a radical hysterectomy and lymphadenectomy.     

Glassy cell carcinoma of the cervix: A bimodal treatment strategy

Glassy cell carcinoma of the cervix is a distinct clinicopathologic entity. This infrequent pathologic subtype is an aggressive biologic tumor associated with a rapid clinical course and poor outcome with conventional treatment modalities in the majority of cases. In a 12-year period from July 1976 to June 1988, 32 cases of glassy cell carcinoma of the cervix were identified. This accounted for 5.3% of all cervical carcinomas. The mean age was 10 years younger than that of other histologic subtypes. A disproportional number of patients with glassy cell carcinoma had malignancies of early clinical stages. The 5-year survival of patients with Stage IB glassy cell carcinoma of the cervix was 45% when treated with primary radical surgery in contrast to 90% for squamous cell and 78% for adenocarcinoma. When bimodal therapy with radical surgery and radical radiotherapy was used, the survival of patients with Stage IB glassy cell carcinoma improved to 87%. Survival of patients with Stage II glassy cell carcinoma of the cervix improved from 50% to 85% with combined radical surgery and radiotherapy. Despite a combination of radical surgery and radiotherapy, complications were minimal.     

The prognostic significance of tumor emboli in lymphatic or vascular spaces of the cervical stroma in Stage IB squamous cell carcinoma of the cervix

The presence of tumor emboli in lymphatic or vascular spaces within the cervical stroma in squamous cell carcinoma of the cervix has been reported by several authors to be associated with a decrease in 5-year survival. In a 10-year review of 124 radical hysterectomies for Stage IB squamous cell carcinoma of the cervix at the University of Michigan from 1970 to 1980 the presence of tumor emboli in the cervical stroma without other known risk factors did not significantly alter the 3- and 5-year survival. With the potential risks and lack of proved benefit the use of adjuvant radiotherapy or chemotherapy in this setting is not recommended.     

Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma.

There were 289 radical hysterectomies performed at Roswell Park Memorial Institute for Stage IB, IIA, and recurrent cervical cancer from 1957 to 1967. The prognostic significance of cervical lesion size, pelvic node metastases, and type of radical hysterectomy have been evaluated. Excellent 5-year survival rates for women with Stage IB cervical carcinoma were associated with cervical lesions measuring less than 3 cm and resected pelvic lymph nodes which did not contain metastatic cancer. In addition, 31% of women with recurrent cervical cancer treated by radical hysterectomy survived 5 years without recurrence.     

Nerve-sparing radical hysterectomy for stage IA2-IIB cervical cancer: 5-year survival of 501 consecutive cases

OBJECTIVE: The purpose of this study was to assess the 5-year survival and morbidity in cases with radical hysterectomy and pelvic lymphadenectomy with pre- and postoperative irradiation performed to treat Stage IA2-IIB cervical cancer. METHODS: During a 10(1/2)-year period between July 1990 and December 2000, 501 consecutive radical hysterectomies with bilateral pelvic lymphadenectomy were performed by the same gynecological surgeon in Stage IA2, IB, IIA and IIB cervical cancer. The patients were treated by pre- and postoperative irradiation as well. RESULTS: Apart from recurrence, perioperative complications were minimal with no long-term morbidity. The absolute 5-year survival rates for the patients in Stage IA2, IB1, IB2, IIA and IIB were 94.4%, 90.7%, 84.1%, 71.1%, and 55.4%, respectively. The respective 5-year survival rates for patients without or with lymph node metastasis were 94.5% and 33.3% in Stage IB2, 81.7% and 48.7% in Stage IIA and 70.2% and 36.5% in Stage IIB, respectively. CONCLUSIONS: Nerve-sparing radical hysterectomy with pelvic lymph node dissection and pre- and postoperative irradiation remains the treatment of choice for most patients with early-stage and even Stage IIB cervical cancer. The radicalism and extent of lymph node dissection and parametrial resection should be individualized and tailored to tumor- and patient-related risk factors.     

Radical surgery after preoperative intracavitary radiotherapy for Stage IB and IIA carcinoma of the uterine cervix

During the years 1970–1978 one hundred nineteen patients with Stage IB and fifty-eight patients with Stage IIA carcinoma of the cervix were treated by combined preoperative radium and Wertheim hysterectomy with lymphadenectomy at the State University Hospital in Groningen. The overall 5-year survival was 87% for Stage IB and 70% for Stage IIA. The incidence of pelvic lymphnode metastases was 14.8 and 35.4% in Stage IB and IIA, respectively. The presence of lymphnode metastases was significantly related to the presence of residual tumour in the cervix after preoperative radium treatment (P < 0.01) and was the most significant prognostic factor. The 5-year survival was 37% for those patients with node involvement as compared to 94% for those without lymphatic extension. Complications particularly concerned the urinary tract. The incidence of these complications was greatly reduced as experience grew.     

Mature Results of a Phase II Trial of Concomitant Cisplatin/Pelvic Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Cervix

Purpose:Patients with locally advanced squamous cell carcinoma of the cervix have a poor prognosis when treated by standard ratiotherapy (RT) alone. Factors such as large tumor volume or nodal disease result in pelvic and distant treatment failures. Cisplatin (CDDP), a known radiosensitizer with documented activity in squamous cell carcinomas, was used in a phase II prospective study to evaluate the efficacy of combined chemo/radiotherapy in locally advanced squamous cell carcinomas of the cervix.Method:CDDP was administered (20 mg/m²) daily × 5 at 21-day intervals with concomitant external beam and intracavity RT. Standard RT was delivered at 1.8–2.0 Gy/day, 5 fractions per week for 5 weeks. Intracavitary cesium insertions were planned to treat point A to approximately 80 Gy.Results:Fifty-nine patients were enrolled from March 1986 to July 1990. Four patients were voluntarily withdrawn, leaving 55 patients evaluable for response. Of these, 16 were Stage IB/IIA, 11 were Stage IIB, 24 were Stage III, and 4 were Stage IV. The median age of patients enrolled was 47 years (range 27–79). Median follow-up time was 65 months (range 60–113). Histopathologic confirmation of node status was available in 33 patients, of whom 45.5% (15/33) had nodal metastases. Overall response was 96% (CR = 87%, PR = 9.0%) and 3.6% had progressive disease during treatment. Forty-six patients were evaluable at 5 years for overall and disease-free survival. Calculations were based on Kaplan–Meier product limit estimates. The 5-year survival was 73% for Stage IB/IIA, 60% for Stage IIB, 67% for Stage III, and 25% for Stage IV. The disease-free survival at 5 years was 73% for Stage for IB/IIA, 50% for Stage IIB, 67% for Stage III, and 25% for Stage IV. Hematologic toxicity was severe but tolerable. No treatment-related deaths occurred.Conclusion:Concomitant CDDP/RT is a safe and tolerable method of treating patients with locally advanced squamous cell carcinoma of the cervix. Our data suggest a benefit in both disease-free and 5-year survival, particularly notable among patients with Stage III disease.     

Analysis of prognostic features in adenocarcinoma of the cervix

Uncertainties regarding the clinical behavior and management of women with primary adenocarcinoma of the cervix persist. A series of 162 patients was evaluated with emphasis on histopathology, clinical features, treatment, and survival. Sixty-seven patients underwent radical hysterectomy alone, 65 patients underwent radiation therapy alone, while the remainder were treated with combined surgery and radiotherapy. When compared to a matched series of squamous cell carcinoma patients, no statistical differences in survival could be demonstrated. Clinical stage (P less than 0.001) and lesion size (P less than 0.001) were the most important prognostic factors for the entire series. Patients with adenocarcinoma of varied histologic patterns were compared to patients with adenosquamous lesions and no statistical difference in survival could be demonstrated. Multivariate analysis of those women with Stage I adenocarcinoma of the cervix identified risk groups based on tumor grade, lesion size, and patient age. Patients in the low risk group had a 5-year survival of 89.5% while patients in the intermediate and high risk groups had 5-year survival rates of 68.4 and 37.3%, respectively. In patients with Stage I well-differentiated lesions survival was excellent, independent of lesion size.     

Radical hysterectomy as therapy for early carcinoma of the cervix

During a 13-year period, 268 radical hysterectomies and pelvic lymphadenectomies were performed for Stage IB and IIA carcinoma of the cervix at Duke University Medical Center. Fifteen percent of patients had lymph node metastasis. Substage, histologic features, grade, capillary-like space involvement, and lesion size did not appear to affect nodal status. Survival was related to lymph node metastasis, status of surgical margins, and lesion size. Judicious use of radiation therapy after hysterectomy may have improved survival in high-risk patients. These does not appear to be any contraindication to operation in this group of patients as long as the condition is deemed medically operable.     

Early stage I adenocarcinoma of the uterine cervix: Treatment results in patients with tumors 4 cm in diameter

Between 1965 and 1985, 160 patients had initial treatment at the M. D. Anderson Cancer Center for Stage I adenocarcinoma of the uterine cervix 4 cm in diameter. Of these patients, 84 were treated with radiation therapy (RT) alone, 20 were treated with external and intracavitary radiation followed by total hysterectomy (R + S), and 56 were treated with radical hysterectomy (RH). Survival rate was strongly correlated with tumor volume (P = 0.0008), lymphangiogram findings (P = 0.01), and tumor grade (P = 0.0018). Patients with a normal-appearing cervix or a small visible or palpable tumor that did not expand the cervix more than 3 cm had survival and pelvic-control rates of more than 90% after treatment with RH or RT. However, after 5 years, 45% of patients treated with RH for tumors 3–4 cm in diameter had disease recurrence in the pelvis, compared with 11% of patients treated with either RT or R + S (P = 0.025). For patients treated with RH, recurrence was also strongly correlated with findings of lymph/vascular space invasion (P = 0.0004) and poorly differentiated tumor (P = 0.018). Major complication rates were comparable for the three treatment groups. The high rate of pelvic recurrence following treatment with radical hysterectomy alone for patients with tumors >3 cm in diameter, particularly in the presence of lymph/vascular space invasion, poorly differentiated features, and/or positive nodes, should be considered in planning the primary management of patients with Stage I adenocarcinoma of the cervix.     

Cancer of the Cervix (Stages 1B, 2A and 2B): Treatment and Results

Summary: Combined methods of treatment of carcinoma of the cervix Stage 1B and 2 (A and B) are described using irradiation and surgery. In a personally conducted series of 101 patients, a.5-year survival rate of 86% for Stage 1 and 65.4% for Stage 2 was achieved. The urinary tract morbidity associated with combined methods of treatment and the modifications adopted to prevent it are described. It is concluded that the preferred method of treatment of carcinoma of the cervix Stages IB, 2A and 2B is irradiation (intracavitary + external megavoltage irradiation) followed by modified radical hysterectomy.     

Comparison of Clinical Outcome in Black and White Women Treated with Radiotherapy for Cervical Carcinoma

Background. The purpose of this investigation was to evaluate the significance of race on the cancer-specific survival outcome of women treated with radiotherapy for advanced-stage cancer of the uterine cervix.Methods. Data from 922 women with cancer of the uterine cervix treated with radiotherapy were reviewed. Patients were treated at the Mallinckrodt Institute of Radiology from 1959 through 1993. There were 576 women with clinical Stage II cancer and 346 women with clinical Stage III cancer. All women were treated following standard medical care treatment policies according to the stage of their disease. Data were analyzed by race and known treatment-related prognostic factors. Overall and cancer-specific survivals were evaluated.Results. The 5-year cancer-specific survivals for clinical Stage II were 66 and 61% (P = 0.56) for white and black women, respectively. The corresponding 5-year overall survivals were 60 and 51% (P = 0.02). The 5-year cancer-specific survivals for clinical Stage III were 38 and 47% (P = 0.34) for white and black women, respectively. The associated 5-year overall survivals were 32 and 40% (P = 0.37). No differences in treatment-related factors were identified.Conclusions. In a cancer treatment system where black and white women with clinical Stage II and III cancer of the uterine cervix are all treated with radiotherapy alone, following standard treatment policies, no significant difference in cancer-specific survival outcome is shown. Multivariate analysis revealed that clinical stage and overall treatment time are significant variables affecting the control of tumor by radiotherapy. Overall survivals for the two racial groups are different and may be related to other non-cancer-related factors.     

An Analysis of Cell Type in Patients with Surgically Staged Stage IB Carcinoma of the Cervix: A Gynecologic Oncology Group Study

The influence of cell type on recurrence-free interval (RFI) and survival after radical hysterectomy for patients with Stage IB carcinoma of the cervix was investigated. Patients with Stage IB carcinoma of the cervix (>3-mm invasion) underwent a radical hysterectomy and pelvic lymphadenectomy. Patients with involved paraaortic nodes or gross extracervical disease were excluded. Of 813 evaluable patients, 645 had squamous, 104 with adenocarcinoma, and 64 had adenosquamous cell type. The time to failure and the following clinical/pathologic characteristics were compared among the three cell types: age, Gynecologic Oncology Group performance status (PS), gross versus occult tumor, histologic grade, depth of invasion, node status, uterine extension, parametrial extension, surgical margins, and capillary–lymphatic space (CLS) involvement. A Cox proportional hazards model was used to compare the patients with adenosquamous and adenocarcinoma to those with squamous while adjusting for prognostic factors. The median age was 40 years (range, 21–87). Pelvic nodes were involved in 119 (15%) of patients. There were no significant differences between cell types in distributions of the following factors: age, PS, positive nodes, depth of invasion, uterine extension, surgical margins, or parametrial extension. There were statistically significant differences between cell types with regards to grade (P< 0.001), gross versus occult primary status (P= 0.016), and CLS involvement (P= 0.005). There was no statistically significant difference detected between cell types in crude comparisons of RFI (P= 0.29); however, there was a difference in survival (P= 0.02) with shorter survival seen in the adenosquamous cell type. After adjusting for CLS involvement, PS, depth of invasion, and clinical tumor size, survival remained worse for patients with adenosquamous primaries when compared to squamous carcinoma (P= 0.02) and adenocarcinoma (P= 0.007). In conclusion, no statistically significant differences were seen in RFI among cell types; however, in patients with Stage I carcinoma of the cervix overall survival after radical hysterectomy may be slightly worse for those with adenosquamous cell type.     

Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter

Between 1965 and 1985, 160 patients had initial treatment at the M. D. Anderson Cancer Center for Stage I adenocarcinoma of the uterine cervix less than or equal to 4 cm in diameter. Of these patients, 84 were treated with radiation therapy (RT) alone, 20 were treated with external and intracavitary radiation followed by total hysterectomy (R + S), and 56 were treated with radical hysterectomy (RH). Survival rate was strongly correlated with tumor volume (P = 0.0008), lymphangiogram findings (P = 0.01), and tumor grade (P = 0.0018). Patients with a normal-appearing cervix or a small visible or palpable tumor that did not expand the cervix more than 3 cm had survival and pelvic-control rates of more than 90% after treatment with RH or RT. However, after 5 years, 45% of patients treated with RH for tumors 3-4 cm in diameter had disease recurrence in the pelvis, compared with 11% of patients treated with either RT or R + S (P = 0.025). For patients treated with RH, recurrence was also strongly correlated with findings of lymph/vascular space invasion (P = 0.0004) and poorly differentiated tumor (P = 0.018). Major complication rates were comparable for the three treatment groups. The high rate of pelvic recurrence following treatment with radical hysterectomy alone for patients with tumors greater than 3 cm in diameter, particularly in the presence of lymph/vascular space invasion, poorly differentiated features, and/or positive nodes, should be considered in planning the primary management of patients with Stage I adenocarcinoma of the cervix.     

Stage IB carcinoma of the cervix, the Norwegian Radium Hospital, 1968-1970: results of treatment and major complications. I. Lymphedema

Different methods of treatment have been debated over the years for Stage IB carcinoma of the cervix, especially in view of the results and complications. We have reviewed the experience of the Norwegian Radium Hospital for carcinoma of the cervix, Stage IB, for the years 1968, 1969, and 1970; most of the patients receive preoperative intrauterine and intravaginal radium, followed by radical hysterectomy and pelvic lymphadenectomy; if the nodes are involved, they also receive external pelvic irradiation. During this period, 437 patients had Stage IB; the 5 year survival was 80.2% (not corrected). We focused our attention on lymphedema following such a method of treatment; of 402 patients operated upon, 23.4% developed lymphedema ranging from mild to moderate to severe; 20 patients (5%) had severe lymphedema; factors involved are analyzed.     

Primary adenocarcinoma of the cervix: treatment and results

Summary. Between 1972 and 1983,49 patients with adenocarcinoma of the cervix were treated in four ways: (i) radiotherapy alone, (ii) pre- or postoperative radiotherapy and a total abdominal hysterectomy and bilateral salpingo-oophorectomy, (iii) Wertheim's hysterectomy, and (iv) pre- or postoperative pelvic radiotherapy and Wertheim's hysterectomy. The 5-year survival results for patients with FIGO Stage I disease was 90%; with Stage II disease 60%; with Stage III disease 11% and none survived with Stage IV disease. All the patients, except one (Stage 111), with well-differentiated tumours are alive and disease-free, irrespective of the type of treatment they received whereas only one patient out of the 13 who had poorly differentiated tumour is alive and disease-free. Three patients had bowel damage, one after radiotherapy alone and two after Wertheim's hysterectomy and postoperative radiotherapy. No major surgical complications occurred in this series.     

Stage II carcinoma of the endometrium. An analysis of treatment

An analysis of 41 patients with histologically documented Stage II adenocarcinoma of the endometrium treated between 1969 and 1974 is presented. The 3-year survival for all patients was 46%. Patients treated with radiation therapy alone (tandem, ovoids, and external radiation therapy) had 29% survival while patients treated with radiation therapy and surgery had a 71% survival. For all patients, survival by grade was 80% (Grade I), 36% (Grade II), and 20% (Grade III). Among those patients with recurrent disease, 40% of cases were in the pelvis while 20% were isolated distal recurrences. Patients with stromal invasion of the cervix had a 30% survival while patients without stromal invasion had a 67% survival. An analysis of these data, along with a review of the literature, reveals that 1) hysterectomy plays a critical role in survival, 2) invasion of the cervical stroma would appear to be a requisite criteria for the establishment of Stage II disease, and 3) aggressive radiation therapy with uterine packings (Heyman capsules) should be attempted in those patients who are not surgical candidates.     

Survival data of Israeli Jewish patients with squamous cell carcinoma of the cervix treated by irradiation

During a 9-year period 61 Israeli Jewish Patients with histologically confirmed invasive squamous cell carcinoma of the uterine cervix (SUC) were treated by irradiation alone. A large proportion of the patients (44.2%) were more than 60 years old and only 27.9% were diagnosed as having stage IB disease. This is attributed to low awareness and infrequent cytologic screening. There is a trend for a large proportion of stage IB patients among those younger than 59 compared to those older than 60 years. The overall 5-year survival rate was 52.2% and the survival of patients with stage IB (72.6%) was significantly higher than in more advanced stages. In addition to clinical stage, age at diagnosis and method of irradiation also influenced survival rates.     

Primary adenocarcinoma of the cervix: treatment and results

Between 1972 and 1983, 49 patients with adenocarcinoma of the cervix were treated in four ways: (i) radiotherapy alone, (ii) pre- or postoperative radiotherapy and a total abdominal hysterectomy and bilateral salpingo-oophorectomy, (iii) Wertheim's hysterectomy, and (iv) pre- or postoperative pelvic radiotherapy and Wertheim's hysterectomy. The 5-year survival results for patients with FIGO Stage I disease was 90%; with Stage II disease 60%; with Stage III disease 11% and none survived with Stage IV disease. All the patients, except one (Stage III), with well-differentiated tumours are alive and disease-free, irrespective of the type of treatment they received whereas only one patient out of the 13 who had poorly differentiated tumour is alive and disease-free. Three patients had bowel damage, one after radiotherapy alone and two after Wertheim's hysterectomy and postoperative radiotherapy. No major surgical complications occurred in this series.     

Stage IB adenocarcinoma of the cervix: metastatic potential and patterns of dissemination

The metastatic potential patterns of dissemination have been investigated in 150 patients with Stage 1B adenocarcinoma of the cervix treated during a 20-year period from 1956 to 1977. All cases with the exception of one were treated with a combination of intracavitary radium implants followed by a radical surgical procedure with pelvic lymph node dissection. It was found that the incidence of pelvic metastases and distant recurrences and the survival rates were the same as in previously published reports for squamous cell carcinomas treated in the same manner. In one respect adenocarcinomas showed a significant difference when compared with squamous cell cancers: The incidence of residual tumor in the hysterectomy specimens after intracavitary treatment was much higher (30% versus 11%). This is considered a strong argument for surgical treatment of patients with early stages of adenocarcinoma of the cervix.