Objective
The objective of the study was to study posttherapy chemoradiation hysterectomy histology with long-term survival in bulky stage 1 B cervical cancer patients.
Study Design
Gynecologic Oncology Group protocols 71 and 123 enrolled 464 patients randomly allocated to pelvic radiation (75 Gy, n = 291) plus hysterectomy (RTH) or to pelvic radiation (75 Gy) and cisplatin (40 mg/m 2 , n = 176) plus hysterectomy (RTCH). Risk of progression and death were evaluated by posttherapy hysterectomy response (good: <10% viable; poor: ≥10% viable).
Results
Median survivor follow-up was 112 months. Relative risks of disease progression and death were 0.656 (95% confidence interval, 0.472–0.912) and 0.638 (95% confidence interval, 0.449–0.908), favoring RTCH. Good response patients (345; 74%) had similar 10 year overall survival (OS) and progression-free survival (PFS) after RTH or RTCH ( P > .47). Poor response patients after RTCH had superior OS ( P = .046) and PFS ( P = .084). Extrapelvic recurrences occurred more often in poor response patients.
Conclusion
Posttherapy viable residual disease less than 10% was associated with reduced risk of progression and cancer-related death.
The hypothesis that radiation plus single-agent chemotherapy reduces pelvic recurrence has been tested in patients with bulky stage I B invasive cervical carcinomas. A rationale for such an approach relied on the premise that chemoradiation-induced cytoreduction of cervical cancer would facilitate a less radical adjuvant hysterectomy, thus perhaps decreasing perioperative and postoperative morbidity. Presurgical chemoradiation also was assumed to treat occult micrometastases and thereby would lessen the risk of extrapelvic metastatic disease progression. Although clinical outcomes data ultimately did not support routine extrafascial hysterectomy after chemoradiation, an extrafascial hysterectomy after chemoradiation would provide an in vivo proof-of-principle biological measure of chemoradiation-induced cytoreduction of cervical cancer.
Pathological necrosis remains the most reliable method whereby an objective assessment of chemoradiation sensitivity is made, although 3 month posttherapy 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography ( F-FDG CT/PET) has emerged as an early surrogate for chemoradiation response. But before metabolic surrogates can be evaluated rigorously, an assessment of the likelihood of residual disease after chemoradiation is needed. The Gynecologic Oncology Group (GOG) has conducted 2 phase III randomized clinical trials in patients with bulky stage I B invasive cervical carcinomas allowing in vivo determination of residual disease after radiation and chemoradiation. The purpose of this retrospective study was to test the hypothesis that a radiation plus chemotherapy survival benefit in patients with bulky stage I B invasive cervical carcinomas is manifest by decreasing posttherapy residual disease.
Materials and Methods
GOG clinical trial 71 randomized patients by central telephone allocation to pelvic radiation alone or pelvic radiation plus hysterectomy. GOG clinical trial 123 randomized patients by central telephone allocation to radiation plus hysterectomy or chemoradiation plus hysterectomy. In these trials, 464 patients with bulky invasive carcinomas of the cervix were entered ( Table 1 ). Patients with cervical cancer recurrence, prior malignancies, or those not candidates for radiation were ineligible. Extraperitoneal surgical staging of lymph nodes was optional, but prior to enrollment paraaortic lymph nodes were required to be negative for metastatic disease by either extraperitoneal surgical staging or computed tomography. Written informed consent consistent with institutional, state, and federal regulations and each treating institution’s local institutional review board approval was obtained before conducting protocol treatments.
| Characteristic | Value | Treatment type | |
|---|---|---|---|
| RTH (n = 289) n (%) | RTCH (n = 175) n (%) | ||
| Age, y | ≤35 | 57 (19.7) | 40 (22.9) |
| 36-45 | 110 (38.1) | 85 (48.6) | |
| 46-55 | 76 (26.3) | 30 (17.1) | |
| 56-65 | 30 (10.4) | 9 (5.1) | |
| >65 | 16 (5.5) | 11 (6.3) | |
| Race | Black | 70 (24.2) | 36 (20.6) |
| Hispanic | 22 (7.6) | 22 (12.6) | |
| White | 166 (57.4) | 107 (61.1) | |
| Other | 10 (3.5) | 9 (5.1) | |
| Unknown | 21 (7.3) | 1 (0.6) | |
| Performance status | 0 | 233 (80.6) | 148 (84.6) |
| 1 | 49 (17.0) | 26 (14.9) | |
| 2 | 7 (2.4) | 1 (0.6) | |
| Tumor size, cm | ≤4.0 | 29 (10.0) | 14 (8.0) |
| 4.1-6.0 | 171 (59.2) | 104 (59.4) | |
| 6.1-8.0 | 81 (28.0) | 48 (27.4) | |
| ≥8.1 | 7 (2.4) | 9 (5.1) | |
| Not reported | 1 (0.3) | 0 (0.0) | |
| Tumor grade | 1 | 21 (7.3) | 14 (8.0) |
| 2 | 185 (64.0) | 94 (53.7) | |
| 3 | 77 (26.6) | 66 (37.7) | |
| Not graded | 6 (2.1) | 1 (0.6) | |
| Tumor type | Barrel | 139 (48.1) | 80 (45.7) |
| Exophytic | 150 (51.9) | 94 (53.7) | |
| Not reported | 0 (0.0) | 1 (0.6) | |
| Cell type | Adenocarcinoma | 21 (7.3) | 9 (5.1) |
| Adeno-squamous carcinoma | 16 (5.5) | 16 (9.1) | |
| Squamous cell carcinoma | 242 (83.7) | 140 (80.0) | |
| Other | 10 (3.5) | 10 (5.7) | |
Radiation therapy
On these trials, patients would receive external-beam radiation 5 days a week using opposed anteroposterior or 4-field radiation treatment fields encompassing the uterine cervix and bilateral iliac and low common iliac lymph nodes. On GOG protocol 71, patients were to receive 45 Gy to the pelvic midplane halfway between the L4 and L5 vertebral body interspace and lower one third of the obturator foramina at a daily fraction of 1.8 Gy.
On GOG protocol 123, patients were to receive 45 Gy to the pelvic midplane of fields extending at least 3 cm beyond the known extent of disease at a daily fraction of 1.8-2.0 Gy.
Following external-beam treatment in both studies, patients were to undergo 1 or 2 low-dose rate intracavitary brachytherapy using tandem and ovoid applicators to a dose of 30.0 Gy to point A. An optional parametrial boost would have been delivered to bring the point B dose to 55.0 Gy. Complete blood counts and platelet counts were to be obtained weekly.
Chemotherapy
Only patients randomly allocated to chemotherapy during radiation on GOG protocol 123 were to receive chemotherapy. Cisplatin (40 mg/m 2 ), not to exceed 70 mg total per week, was to be administered intravenously once per week during external-beam radiation for a maximum of 6 weekly cycles.
Surgery
All entered patients were to undergo standardized total extrafascial hysterectomy, 2-6 weeks (GOG 71) or 6-8 weeks (GOG 123) after completion of all radiation including brachytherapy.
Statistical analysis
Patient clinical and follow-up data were abstracted from patient charts maintained at the GOG Statistical and Data Center (Buffalo, NY) where data have been closed since October 2003 for these clinical trials. The design of this retrospective study included the desire to evaluate histopathological tumor response on long-term survival outcomes after radiation or cisplatin chemoradiation. For this study, median follow-ups were 128 months for GOG 71 and 118 months for GOG 123. For the current retrospective analysis, 464 patients were analyzed following an intent-to-treat method ( Figure 1 ). Three originally reported patients do not contribute to the current statistical analyses because of missing data.
This study retrospectively compared the original documented histopathology tumor response as assessed by central review of at least 2 GOG pathologists blinded to patient clinical, tumor, and treatment outcome variables by randomized treatment groups: either radiation plus hysterectomy (n = 289) or cisplatin chemoradiation plus hysterectomy (n = 175). The GOG Pathology Committee reviewed pathology from extrafascial hysterectomy specimens, including any persistent cancer in the cervix or adjacent tissues to assure uniform pathologic review.
The original pathological review consisted of lesion size, location, thickness, histological grade, and presence of angiolymphatic invasion. To supplement the pathological review, the surgeon was required to include in the operative note clinical findings such as observed macroscopic disease of the cervix.
For the purposes of this report, hysterectomy specimen histopathologies were scored as 1 as having a good histopathological tumor response if less than 10% of observed cancer cells appeared viable or as 2 as having a poor histopathological tumor response if 10% or greater of observed cancer cells appeared viable. A proportion of 10% or greater chosen for poor histopathological response was based on the association of 10% or greater viable tumor presence and high local and systemic relapse rate seen in pediatric osteogenic sarcoma management.
In most cases of microscopic residual disease (160/174; 92%), the amount of viable remnant tumor was obvious (greater than 10% vital or nearly all vital) to the original GOG reviewers, and an indication of the percentage of viable tumor was recorded in the original GOG histopathological assessment. These assessments by the original GOG reviewers were scored for good and poor histopathological response (investigator, C.K.). For 12 nonobvious cases, review of GOG pathologist original hand-written pathological assessment, including indications for tumor viability, and review of surgical records were done (C.K.) to classify histopathological tumor response. For 2 nonobvious cases, a GOG pathologist (F.W.A.-K.) blinded to treatment and outcome provided an independent review of histopathology for proportion of viable remnant tumor.
For each group, survival was determined from date of study entry to date of cancer-related or all-cause death or date last seen. Progression-free survival (PFS) was defined as date of study entry to date of physical or radiographic evidence of recurrent cervical cancer or death. Product-limit estimates were calculated according to Kaplan-Meier method and differences in PFS and overall survival (OS) were assessed utilizing the log-rank test. The Cox model was used to adjust for prognostic factors and to estimate hazard ratios (and 95% confidence interval [CI]) of PFS and OS. All P values reported were two-sided and P < .05 was interpreted as statistically significant.
Results
GOG protocol 71 enrolled 122 eligible patients on the radiation and hysterectomy (RTH) treatment arm that underwent hysterectomy and had histopathology available for review. GOG protocol 123 enrolled 167 eligible patients on the RTH arm and 175 eligible patients on the radiation plus cisplatin chemotherapy and hysterectomy (RTCH) arm who underwent hysterectomy and had histopathology available for review. For the 464 evaluated patients in this study, median age was 43 years (range, 21–78 years) for the RTH cohort and 40 years (range, 21–81 years) for the RTCH cohort. Patient characteristics appear in Table 1 .
In this study, the RTH cohort was older ( P = .024) and had a higher non-Caucasian proportion ( P = .002). An increased proportion of high tumor grade cancers was observed in the RTCH cohort ( P = .047). Cohorts were balanced for patient performance status, tumor size, tumor morphology type, and tumor cell type ( Table 1 ). The median total radiation treatment time was 49 days for the RTCH cohort and 49 days for the RTH cohort.
Survival and recurrence
At the time of this report, there are 50 of 289 RTH (17%) and 16 of 175 RTCH patients (9%) whose disease has recurred locally in the pelvis, cervix, or vagina ( Table 2 ). There are 54 of 289 RTH (19%) and 23 of 175 RTCH patients (13%) with extrapelvic recurrences ( Table 2 ). There have been 90 (31%) vs 30 (17%) cancer-related deaths and 108 (37%) vs 45 (26%) all-cause deaths in the RTH and RTCH cohorts, respectively. Cervical cancer-related deaths comprised the majority (78%) of observed deaths on the GOG 71 and GOG 123 clinical trials.
