Abstract
Background:
To determine whether adjuvant chemoradiation (CRT) with weekly cisplatin improves recurrence-free survival (RFS) compared to radiation (RT) in pathologically proven intermediate risk early-stage cervical cancer following radical hysterectomy and lymphadenectomy.
Methods:
Post-surgical patients with Stage I-IIA cervical cancer with pathologically noted intermediate risk factors including combinations of capillary lymphatic space (CLS) involvement, stromal invasion, and tumor size were randomly assigned in a 1:1 ratio to receive either adjuvant CRT or RT (NCT01101451). Patients received conformal RT, or Intensity Modulated Radiation Therapy. In the CRT arm, 6 weekly cycles of cisplatin 40 mg/m2 was administered during RT. RFS was the primary endpoint in randomized and eligible patients. Secondary endpoints included overall survival (OS), quality of life (QOL), and adverse events (AE).
Results:
Of the 340 randomized patients, 316 were eligible and most had FIGO (2009) stage IB1 and squamous cell carcinoma histology. 292 of 316 (92.4%) patients received 28 fractions of RT with a median dose of 50.4 Gy and a median treatment duration of 39 days. Three-year RFS was 88.5% in the CRT arm and 85.4% in the RT arm. Both RFS [hazard ratio (HR) 0.698, 95% CI 0.408–1.192, p=0.09] as well as OS [HR 0.586, 95% CI: 0.286–1.199, p = 0.07] favored CRT compared to RT alone. Grade 3 or 4 AEs occurred in 43% and 15% in the CRT and RT arms, respectively (p < 0.01). A transient decline in QOL occurred in the CRT arm compared to RT after starting treatments and recovered to pre-treatment level by 36 weeks.
Conclusion:
Although RFS and OS favored CRT, the addition of cisplatin during RT did not statistically improve RFS or OS in cervical cancer patients with intermediate pathologic risk factors following radical hysterectomy and lymphadenectomy. CRT increased grade 3 and 4 AEs with a transient decline in QOL.
Keywords: Cervical cancer, Intermediate risk, Chemo-radiation, Recurrence-free Survival
Introduction
Early-stage cervical cancer has an overall favorable prognosis following surgical resection of the primary tumor with nodal assessment (1–3). Post-operative adjuvant therapy decisions rely on categorization of patients based on pathologic findings into either low-risk where adjuvant therapy is not indicated, or intermediate and high-risk where adjuvant radiation, with or without chemotherapy, is recommended (1, 4, 5). The presence of lymph node metastasis, parametrial invasion and/or a positive resection margin following radical hysterectomy and pelvic lymphadenectomy, are considered to be high-risk features with an unacceptable risk of recurrence and adjuvant chemoradiation (CRT) is standard (5, 6). Secondary to multiple positive randomized controlled trials, cisplatin based concurrent CRT is the preferred standard treatment regimen in the curative setting and as an adjuvant therapy for post-operative patients with high-risk pathologic features (1, 5).
In comparison to high-risk pathologic factors, intermediate post-operative pathologic risk factors such as depth of stromal invasion (DSI), large tumor size, and capillary lymphatic space (CLS) involvement do not increase recurrence significantly as single factors, but combinations of them increase the risk of recurrence from 2% up to 31% (4, 7, 8). These observations were initially based on the evaluation of over 1100 patients by the Gynecologic Oncology Group (GOG) for patients with histologically proven cervical cancer undergoing radical hysterectomy with pelvic and para-aortic lymphadenectomy (9). After excluding those with nodal disease, a subsequent manuscript including 645 individuals with stage I squamous cell carcinoma noted clinical tumor size, the presence of CLS and the DSI as independent prognostic factors for worse disease free interval (7). For intermediate risk patients a combination of two factors – tumor size >4 cm, middle 1/3 or greater invasion and CLS involvement predicted a risk of recurrence of >30% after surgery (4, 7). To decrease this risk of recurrence, Sedlis and colleagues performed and reported outcomes from a randomized trial evaluating post-operative radiotherapy versus no further therapy following radical hysterectomy and nodal dissection. GOG-92 demonstrated that adjuvant radiation (RT) resulted in a significant reduction in recurrence risk with improved 2-year recurrence-free survival (RFS) of 88% as compared to 79% (p=0.008) for the no further treatment (NFT) group in patients with intermediate risk factors (Supplemental Table 1), although long-term follow-up did not demonstrate statistically superior OS for patients receiving RT, HR 0.70 (90% CI, 0.45–1.05) (4, 10).
The role of adjuvant CRT in patients with intermediate risk factors following radical surgery is not fully investigated and remains controversial. Ryu and colleagues performed a retrospective study that reported that the addition of weekly cisplatin 40 mg/m2 to standard RT was associated with a 3-year RFS of 90.5% in the RT arm as compared to 97.5% in the CRT arm suggesting a beneficial role of CRT (11). However, several retrospective studies have reported that the CRT did not demonstrate a survival benefit and only appeared to increase adverse events (AEs) in patients with intermediate risk factors (12–15). Clearly based on their retrospective nature multiple limitations including overall selection bias and the variable definition(s) of intermediate risk grouping prevent easy comparisons among studies. To decrease both acute and late radiation related toxicities, Intensity Modulated Radiation Therapy (IMRT) has been increasingly used in the post-hysterectomy setting. Following initial assessments regarding safety and decrease radiation doses to the small bowel, Radiation Therapy Oncology Group (RTOG) investigators reported confirmatory clinical trial results, demonstrating that IMRT was feasible, and associated with less gastrointestinal and urinary toxicity, in the post-operative setting in patients with both endometrial and cervical cancer (16–18).
The objective of this current randomized phase III study was to investigate whether the addition of cisplatin to standard post-operative adjuvant RT, increased RFS and overall survival (OS), and whether there is any significant change of AEs in cervical cancer patients with intermediate risk factors following radical hysterectomy and pelvic lymphadenectomy.
Patients and Methods
NRG Oncology/GOG-0263/KGOG 1008 (NCT01101451) was an open-label, randomized phase III trial (https://www.clinicaltrials.gov/search?term=NCT%2001101451). Patients with a diagnosis of FIGO (2009) stage IB-IIA cervical cancer with intermediate risk factors following radical hysterectomy and pelvic lymphadenectomy were randomly assigned, between three to eight-weeks following surgery, with equal probability to the radiation treatment group (RT arm) or weekly cisplatin-based chemoradiation treatment group (CRT arm) following written informed consent and Institutional Review Board approval.
Patients had to be older than 18 years with histologically proven squamous cell carcinoma, adeno-squamous carcinoma or adenocarcinoma. Performance of radical hysterectomy and lymphadenectomy is as described in detail in GOG-92 (4). The intermediate risk group for this study had one of several combinations of DSI, tumor size, and CLS involvement. Specifically, patients with CLS had to also have DSI of the outer/deep one-third with any size tumor, invasion of the middle one-third with a clinical tumor ≥ 2cm or superficial invasion with a clinical tumor ≥ 5cm. For patients without CLS, they required both a clinical tumor ≥ 4cm and either middle one-third or deep one-third DSI (Supplemental Table 1).
Tumor size was determined by clinical exam, the largest diameter of pathologic specimen, radiologic imaging or colposcopic measurement. DSI was measured by the fractional thickness of the cervical wall divided in thirds. CLS involvement was determined by the presence or absence of tumor cells in the lymphovascular space on the surgical specimen. H&E stained pathology slides were reviewed centrally by the GOG Pathology Committee to confirm eligibility and to confirm DSI and CLS involvement.
Patients were prospectively stratified by CLS involvement (positive vs. negative), DSI (deep vs. middle vs. superficial), performance status (0/1 vs. 2), planned radiation therapy modality (IMRT vs. 3 D conformal external beam radiation treatment RT) and cooperative groups (GOG vs. KGOG vs. other). To minimize the baseline imbalances between the two treatment arms within these 5 stratification factors, randomization was implemented using dynamic allocation.
Patients were required to have adequate baseline labs to include hematologic function: ANC ≥ 1,500/mcl, platelets ≥ 100,000/mcl; renal function: creatinine ≤ ULN or calculated creatinine clearance ≥ 60mL/min; hepatic function: bilirubin ≤ 1.5 x ULN, alkaline phosphatase and SGOT ≤ 3x ULN, and GOG performance status of 0–2. Patients with high-risk pathologic features, including nodal metastasis, positive surgical margins, parametrial involvement and/or extrauterine spread were excluded. Additionally, patients with any of the following: septicemia/severe infection, intestinal obstruction, gastrointestinal bleeding, post-operative fistula, receipt of prior chemotherapy or radiation, renal abnormalities (e.g. pelvic kidney or renal transplant, etc.) that necessitate modification of the radiation plan and a history of malignancies other than non-melanoma skin cancer in the last five years were excluded.
All patients were expected to receive adjuvant RT with external beam irradiation without brachytherapy, starting within 3–8 weeks postoperatively. In the external radiation only arm, pelvic irradiation was given with a 4-field technique with a megavoltage beam, although cobalt-60 was allowed if the SSD was > 80 cm. The prescribed radiation dose was 50.4 Gy in 28 fractions (5 fractions per week). Each patient was to be given daily fractions of 1.8 – 2.0 Gy over 4.5 – 5.5 weeks. For IMRT, credentialing by Imaging and Radiation Oncology Core (IROC) Houston was required, and the volume specifications described per RTOG consensus guidelines (19).
CRT patients received 40 mg/m2 of cisplatin (maximum total dose of 70 mg/week) weekly. Pre-hydration with 1,000 ml of normal saline was infused intravenously one hour before cisplatin. Cisplatin was diluted in 250 ml 0.9% sodium chloride and administered over one or two hours. Alternatively, cisplatin could be diluted and administered per other established institutional guidelines. Cisplatin was typically given on the first day of RT, preferably approximately four hours prior to RT, and was repeated on days 8, 15, 22, 29, and 36 of RT.
Physical examination and Pap test were performed every 3 months for 2 years, every 6 months for the next 3 years, and annually thereafter. Chest X-ray and imaging studies, including CT, MRI or PET/CT were performed every 6 months for the first three years and annually thereafter. QOL assessments included a baseline measurement completed prior to randomization, and at 3 weeks, 7 weeks, and 9 months following the first day of treatment. Patient reported outcomes (PRO) were assessed by the Functional Assessment of Cancer Therapy (FACT-G, Version 4), in a Scantron form of total number of 52 questions including 42 items of FACT-Cx, 4 items of neurotoxicity questions, 5 items of additional toxicity questions, and a brief pain questionnaire.
Recurrence was defined as the appearance of clinical, radiologic, or histologic evidence of disease since study entry. The primary endpoint was RFS, defined as the time from randomization to the date of first documented recurrence, or death from any cause, whichever occurred first. Patients alive without recurrence at the time of the reported analysis were censored on the date of last contact. OS was a secondary endpoint, defined as the time from randomization to death due to any cause. Patients alive at the time of the reported analysis were censored on the date of last contact. Evaluation of treatment efficacy for RFS and OS consisted of randomized and eligible patients, based on modified intention-to-treat principle. The analysis of adverse events included all randomized patients who received any amount of their assigned protocol therapy, where AEs were assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
The primary objective was to determine whether CRT with weekly cisplatin improved RFS compared to radiation alone. The target accrual was 360 patients. By the time of the final analysis for the primary endpoint, 54 RFS events would be expected to occur in both arms. This would provide 80% power to detect a hazard ratio of 0.498 (or a 6.3% increase in 3-year RFS in CRT arm to 93.3%) based on one-sided log-rank tests with a 5% overall significance level.
Two interim analyses were planned. The 1st interim analysis for efficacy and futility was conducted at 33% of the RFS information time, as scheduled. The 2nd interim analysis for efficacy was performed at 70% of the RFS information time, which was close to the planned 67%. The futility boundaries used the method provided by Wieand et al. (20). The efficacy boundaries were determined by an O’Brien-Fleming alpha spending function. The nominal significance levels for the 2 interim analyses and the final analysis were 0.0007, 0.0161, and 0.0451, respectively.
Cox proportional hazards (PH) modeling was used to estimate the treatment hazard ratio and its corresponding Wald confidence interval. Survival functions were estimated by the Kaplan-Meier method. For secondary analyses, one-sided tests were performed for OS analysis and toxicity at a significance level of 0.05. For exploration analyses, 2-sided tests were used with a 5% significance level. No adjustments were made for multiple testing. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).
Results
Three-hundred-forty patients were enrolled between April 2010 and April 2022, of whom 24 patients (14 on the RT and 10 on the CRT arms respectively) were ineligible upon central review (Figure 1). Overall, 316 were eligible with a median age of 46 years (range 25–88) without racial differences between the CRT and RT arms (Table 1). Most patients had FIGO (2009) stage IB1 (56%) tumors and squamous cell carcinoma was the most common histologic type (73.7%). Surgically, one hundred sixty-nine participants (53.5%) underwent laparoscopic surgical management prior to enrollment with similar rates in both treatment arms, 51.9% and 55.1% for CRT and RT respectively (p=0.57). Median clinical tumor size was 3.5cm and outer third DSI was present in 60.8% with CLS involvement present in 73.7% of patients. There was not a significant difference in selected RT modality between two arms with conformal EBRT utilized in 61.4% on the RT arm and 63.3% on the CRT arm, with a rate of IMRT of 38.6% in RT arm and 36.7% in CRT arm respectively. Finally, there was no difference in enrollment according to the cooperative groups.
Figure 1.
Consort Diagram for patients enrolled on GOG263
Table 1.
Baseline Patient Characteristics
| RT arm (n = 158) | CRT arm (n = 158) | Total (n = 316) | p-value* | |
|---|---|---|---|---|
|
| ||||
| Age (median years/range) | 46.5 (28 – 88) | 45 (25 – 78) | 46 (25 – 88) | 0.12 |
| Race | ||||
| Unknown/Not Reported | 2 (1.3%) | 6 (3.8%) | 8 (2.5%) | 0.26 |
| Asian | 79 (50.0%) | 87 (55.1%) | 166 (52.5%) | |
| Black/African American | 12 (7.6%) | 5 (3.2%) | 17 (5.4%) | |
| American Indian/Alaskan | 2 (1.3%) | 2 (1.3%) | 4 (1.3%) | |
| Native Hawaiian/Pacific | 1 (0.6%) | 0 (0.0%) | 1 (0.3%) | |
| White | 62 (39.2%) | 58 (36.7%) | 120 (38.0%) | |
| Performance status | ||||
| 0 | 138 (87.3%) | 129 (81.6%) | 267 (84.5%) | 0.15 |
| 1 | 20 (12.7%) | 27 (17.1%) | 47 (14.9%) | |
| 2 | 0 (0.0%) | 2 (1.3%) | 2 (0.6%) | |
| Histology | ||||
| Squamous cell carcinoma | 124 (78.5%) | 109 (69.0%) | 233 (73.7%) | 0.08 |
| Adenocarcinoma | 24 (15.2%) | 32 (20.3%) | 56 (17.7%) | |
| Serous | 1 (0.6%) | 0 (0.0%) | 1 (0.3%) | |
| Endometrioid | 1 (0.6%) | 0 (0.0%) | 1 (0.3%) | |
| Glassy cell carcinoma | 0 (0.0%) | 2 (1.3%) | 2 (0.6%) | |
| Adenosquamous | 8 (5.1%) | 15 (9.5%) | 23 (7.3%) | |
| Tumor grade | ||||
| 1 | 10 (6.3%) | 16 (10.1%) | 26 (8.2%) | 0.60 |
| 2 | 94 (59.5%) | 86 (54.4%) | 180 (57.0%) | |
| 3 | 46 (29.1%) | 49 (31.0%) | 95 (30.1%) | |
| Not graded | 8 (5.1%) | 7 (4.4%) | 15 (4.7%) | |
| FIGO Stage (2009) | 0.83 | |||
| I | ||||
| IB | 2 (1.3%) | 2 (1.3%) | 4 (1.3%) | |
| IB1 | 92 (58.2%) | 85 (53.8%) | 177 (56.0%) | |
| IB2 | 52 (32.9%) | 60 (38.0%) | 112 (35.4%) | |
| II | ||||
| II | 1 (0.6%) | 0 (0.0%) | 1 (0.3%) | |
| IIA | 1 (0.6%) | 1(0.6%) | 2 (0.6%) | |
| IIA1 | 7 (4.4%) | 6 (3.8%) | 13 (4.1%) | |
| IIA2 | 3 (1.9%) | 4 (2.5%) | 7 (2.2%) | |
| Tumor size(median)(cm) | 3.5 | 3.5 | 3.5 | 0.98 |
| Stromal invasion | 0.17 | |||
| Deep | 91 (57.6%) | 101 (63.9%) | 192 (60.8%) | |
| Middle | 60 (38.0%) | 55 (34.8%) | 115 (36.4%) | |
| Superficial | 7 (4.4%) | 2 (1.3%) | 9 (2.8%) | |
| CLS involvement | 0.70 | |||
| Negative | 40 (25.3%) | 43 (27.2%) | 83 (26.3%) | |
| Positive | 118 (74.7%) | 115 (72.8%) | 233 (73.7%) | |
| CLS at randomization | 0.73 | |||
| Negative | 70 (44.3%) | 67 (42.4%) | 137 (43.4%) | |
| Positive | 88 (55.7%) | 91 (57.6%) | 179 (56.6%) | |
| Stromal invasion at randomization | 0.77 | |||
| Deep | 130 (82.3%) | 128 (81.0%) | 258 (81.6%) | |
| Middle | 27 (17.1%) | 30 (19.0%) | 57 (18.0%) | |
| Superficial | 1 (0.6%) | 0 (0.0%) | 1 (0.3%) | |
| Performance status at randomization | 0.50 | |||
| 0/1 | 158 (100.0%) | 156 (98.7%) | 314 (99.4%) | |
| 2 | 0 (0.0%) | 2 (1.3%) | 2 (0.6%) | |
| Surgical approach | 0.57 | |||
| Open | 70 (44.3%) | 76 (48.1%) | 146 (52.5%) | |
| Laparoscopic | 87 (55.1%) | 82 (51.9%) | 169 (46.2%) | |
| Not reported | 1 (0.6%) | 0 (0%) | 1(0.3%) | |
| Planned RT modality at randomization | 0.73 | |||
| Conformal EBRT | 97 (61.4%) | 100 (63.3%) | 197 (62.3%) | |
| IMRT | 61 (38.6%) | 58 (36.7%) | 119 (37.7%) | |
| Cooperative group at randomization | 0.65 | |||
| GOG | 85 (53.8%) | 81 (51.3%) | 166 (52.5%) | |
| KGOG | 72 (45.6%) | 74 (46.8%) | 146 (46.2%) | |
| Other | 1 (0.6%) | 3 (1.9%) | 4 (1.3%) | |
RT; radiation treatment only, CRT; concurrent chemo-radiation treatment, NS; not significant, FIGO; International Federation of Gynecologic Oncology, CLS; capillary lymphatic space involvement, EBRT; external beam radiation treatment, IMRT; intensity modulated radiation treatment, GOG; Gynecologic Oncology Group, KGOG; Korean Gynecologic Oncology Group
: observations with missing values were included for discrete-type variables and excluded for continuous variables.
Wilcoxon rank-sum tests: age, tumor size.
(Exact) chi-square tests: (race), (histology), (tumor grade), FIGO stage (I vs II), CLS involvement, (stromal invasion), CLS involvement at randomization, (stromal invasion at randomization), (performance status at randomization), (surgical approach), planned RT modality at randomization, (cooperative group at randomization).
Exact Spearman rank correlation coefficient test: performance status.
In the RT arm, 99.4% (157/158 patients) of patients completed planned therapy, while only 84.8% (134/158 patients) of patients in CRT arm completed planned therapy (p < 0.01) (Table 2). In CRT arm, most patients (90.5%) received at least 4 cycles of cisplatin and 71.5% of patients completed all 6 cycles. The number of fractions of RT, total dose of radiation, and duration of RT were significantly lower in the CRT arm compared to the RT arm. However, the compliance with radiation therapy between the two arms was not statistically different (69% in RT arm 65.2% in CRT arm, respectively, p=0.41) with both arms having similar rates of minor and major deviations in administered radiation therapy.
Table 2.
Study Treatment Outcomes
| RT arm (n = 158) | CRT arm (n = 158) | Total (n = 316) | p-value* | |
|---|---|---|---|---|
|
| ||||
| Reason off protocol therapy | < 0.001 | |||
| Completion of planned protocol therapy | 157 (99.4%) | 134 (84.8%) | 291 (92.1%) | |
| Patient withdrawal / refusal | 0 (0%) | 14 (8.9%) | 14 (4.4%) | |
| Toxicity | 0 (0%) | 2 (1.3%) | 2 (0.6%) | |
| Other | 1 (0.6%) | 8 (5.1%) | 9 (2.8%) | |
| Cycles of cisplatin | NA | |||
| 0 | 5 (3.2%) | |||
| 1 | 3 (1.9%) | |||
| 2 | 1 (0.6%) | |||
| 3 | 6 (3.8%) | |||
| 4 | 4 (2.5%) | |||
| 5 | 26 (16.5%) | |||
| 6 | 113 (71.5%) | |||
| Number of fractions | 0.001 | |||
| 28 times | 154 (97.5%) | 138 (87.3%) | 292 (92.4%) | |
| Less than 28 times | 4 (2.5%) | 20 (12.7%) | 24 (7.6%) | |
| Total radiation dose | 0.001 | |||
| < 50.4 Gy | 4 (2.5%) | 20 (12.7%) | 24 (7.6%) | |
| ≥ 50.4 Gy | 154 (97.5%) | 138 (87.3%) | 292 (92.4%) | |
| RT duration (days) | 0.03 | |||
| Median | 39 | 38.5 | 39 | |
| Min - Max | 31 – 53 | 0 – 64 | 0 – 64 | |
| Radiation therapy compliance | 0.41 | |||
| Acceptable | 109 (69.0%) | 103 (65.2%) | 212 (67.1%) | |
| Minor violation | 37 (23.4%) | 38 (24.1%) | 75 (23.7%) | |
| Major violation | 2 (1.3%) | 7 (4.4%) | 9 (2.8%) | |
| Not reviewed | 10 (6.3%) | 10 (6.3%) | 20 (6.3%) | |
| Survival status | 0.18 | |||
| Dead - disease-related | 16 (10.1%) | 9 (5.7%) | 25 (7.9%) | |
| Dead - neither treatment or disease | 4 (2.5%) | 1 (0.6%) | 5 (1.6%) | |
| Dead - undetermined | 0 (0.0%) | 2 (1.3%) | 2 (0.6%) | |
| Alive - without recurrence | 126 (79.7%) | 135 (85.4%) | 261 (82.6%) | |
| Alive - with recurrence | 12 (7.6%) | 11 (7.0%) | 23 (7.3%) | |
| Lost to follow-up | 0.58 | |||
| Temporary | 5 (3.2%) | 8 (5.1%) | 13 (4.1%) | |
| Temporary delay | 5 (3.2%) | 9 (5.7%) | 14 (4.4%) | |
| Permanent | 39 (24.7%) | 36 (22.8%) | 75 (23.7%) | |
| No | 109 (69.0%) | 105 (66.5%) | 214 (67.7%) | |
RT; radiation treatment only, CRT; concurrent chemo-radiation treatment, NS; not significant, NA; not applicable,
: observations with missing values were included for discrete-type variables and excluded for continuous variables.
Wilcoxon rank-sum test: RT duration.
Exact chi-square tests: reason off protocol therapy, radiation therapy compliance, survival status, lost to follow-up
Fisher’s exact tests: number of fractions (dichotomized), total radiation dose (dichotomized).
As of the cutoff date for the final statistical analysis on April 2, 2024, and with a median follow-up of 76.5 months (IQR: 50.3–107.7 months), there were 55 RFS events (32 cases in RT arm and 23 cases in CRT arm), and 32 deaths (20 cases in RT arm and 12 cases in CRT arm) (Table 2). Three-year RFS estimates for the CRT and RT arms were 88.5% (95% CI: 82% – 93%) and 85.4% (95% CI: 79% - 90%) respectively, and the RFS hazard ratio estimate for CRT vs RT was 0.698 (95% CI: 0.408 – 1.192) with a log-rank 1-sided p-value of 0.09 (Figure 2A). The estimated OS hazard ratio for the CRT vs. RT arm was 0.586 (95% CI: 0.286 – 1.199) with a log-rank 1-sided p-value of 0.07 (Figure 2B). With 32 deaths, the trial had 44.7% power to detect an OS HR of 0.586 using a 1-sided log-rank test at the 5% significance level.
Figure 2.
a) Recurrence-Free Survival (RFS) by Kaplan-Meier method per randomized therapy (3-year RFS: 88.5% in CRT arm and 85.4% in RT arm respectively, p = 0.09).
b) Overall Survival (OS) by Kaplan-Meier method per randomized therapy (3-year OS: 97.2% in CRT arm and 90.3% in RT arm respectively, p = 0.07).
c) Forest plot for recurrence-free survival treatment effect by subgroup analyses. Confidence intervals should not be used to reject or not reject the null hypothesis of a treatment effect.
RT; radiation treatment only, CRT; concurrent chemo-radiation treatment, CI; confidence interval, RFS; recurrence free survival, OS; overall survival, CLS; capillary lymphatic space involvement, Strata: stratification used at randomization, IMRT; intensity modulated radiation treatment, XRT; external beam radiation treatment, GOG; Gynecologic Oncology Group, KGOG; Korean Gynecologic Oncology Group
The recurrence rate was not different between the two arms (15.8% in RT arm and 12.7% in CRT arm), and there was not a significant difference in pattern of recurrence (distant, loco-regional or combined) between the arms (Supplemental Table 2). In subgroup analyses of RFS, when patients were treated with conformal external radiotherapy (as opposed to IMRT), there appeared to be a trend favoring CRT treatment as compared to RT treatment with a HR of 0.47 (95% CI: 0.24 – 0.92) (Figure 2C). In addition, a Cox PH regression indicated a potential interaction between treatment and RT modality with a p-value of 0.04. Moreover, while no statistically significant outcomes were present, the HR point estimates for the subgroups all favored CRT, other than the use of IMRT (HR 1.74, 95% CI 0.63–4.81) which favored RT alone. No grade 5 AEs were reported. Patients in the CRT arm experienced a higher incidence of grade 3 or 4 AEs than the RT arm (42.9% vs. 15.3%, 1-sided p < 0.01 by Fisher’s exact test) (Supplemental Table 3). In terms of specific AEs, patients in the CRT arm experienced a higher incidence of grade 3 or 4 neutropenia (1-sided p < 0.01), leukopenia (1-sided p < 0.01), and thrombocytopenia than the RT arm (1-sided p: 0.0549) (3).
PRO assessments demonstrated a decline in QOL per the FACT-CX after starting treatments with the patients on CRT arm reporting worse outcomes. This observed decline in QOL was more pronounced in the CRT treatment arm although it ultimately improved by week 36. Moreover, measured QOL outcomes were greater than baseline for both treatment arms by 36 weeks (Supplemental Figure 1).
Discussion
This prospective, randomized international trial demonstrated improved RFS and OS with cisplatin-based CRT as compared to RT alone for cervical cancer patients with intermediate risk pathologic factors following radical hysterectomy and pelvic lymphadenectomy, although the differences were not statistically significant. The trial had rigorous radiographic and clinical interval follow-up. The 3-year RFS estimates for the CRT and RT arms were similar at 88.5% and 85.4% respectively, with the RFS hazard ratio estimate for CRT vs. RT of 0.698 (95% CI: 0.408 – 1.192; log-rank 1-sided p-value of 0.09). Moreover, patients on the CRT arm experienced an increase of grade 3 and 4 AEs as well as a transient decline in measured QOL. In a planned subset, we found improved outcomes for those on the CRT arm as compared to RT alone in patients receiving traditional conformal EBRT compared to IMRT.
Although intermediate risk cervical cancer has utilized a standard set of criteria for over twenty years, the recurrence risk model estimates utilized may in fact be too low to show a benefit from addition of concurrent chemotherapy. Since this study was an all-comer population, there was no biomarker to enrich the population to those at further increased risk other than traditional pathologic risk factors (4, 7). Nonetheless, the current study used identical criteria to GOG-92, which again noted a two-year RFS of 88% in RT arm (4) and accordingly, the 3-year RFS of 85.4% in RT arm in this study is consistent (Figure 2A). Moreover, while the LACC trial noted harm with the performance of minimal invasive radical hysterectomy for patients with early-stage cervical cancer, the rates of minimally invasive surgery prior to registration were similar for both arms thus unlikely to impact outcomes (21).
Like many aspects in risk stratification for adjuvant therapy decisions, alternative criteria exist to define increased recurrence risk in post-operative cervical cancer patients. Samlal and colleagues evaluated nearly 200 patients with Stage IB and IIA cervical cancer that underwent radical hysterectomy with pelvic lymph node dissection from their institution with pathologically negative pelvic lymph nodes (22). Retrospective review identified that the following: adenocarcinoma histology, tumor diameter (≥ 3cm), depth of cervical invasion (≥1 0mm) and outer two-thirds cervical stromal invasion predicted an increased risk of recurrence. Specifically, the presence of 2 or more risk factors was associated with a 5-year disease-free interval of 81% as compared to 98% when only a single factor was present. Similarly, Ryu and colleagues also utilized a ‘four-factor model’, which defined the intermediate-risk group according to the presence of any two of four risk variables: tumor size ≥ 3cm, DSI, CLS involvement, and adenocarcinoma /adenosquamous histology (23). In this large multi-institutional retrospective study including 2,158 patients, the ‘Four factor model’ showed a better performance for prediction of recurrence and survival compared to other criteria. Nonetheless, most consider the ‘Sedlis criteria’ as the gold standard based on its use and results from a randomized perspective clinical trial, justifying evaluation in the current study; however, the Sedlis trial did not incorporate preoperative MRI, which may have led to misclassification of patients’ risk status. Modern imaging may allow for more precise preoperative staging and risk stratification, which could influence both patient selection treatment recommendations. A more rigorously staged cohort may have field different estimates of the benefit of adjuvant radiation.
Originally, this study was designed with a planned sample size of 534 participants with a projected 10% lost to follow-up. Secondary to slower than projected accrual, the sample size was adjusted in November of 2017 to target 342 eligible and evaluable patients which required 54 RFS events. Moreover, based on continued slow accrual the trial was ultimately closed to accrual with 316 eligible patients. Importantly, the change in sample size must be taken into context in that although, neither RFS nor OS was statistically superior, it remains possible that an incorrect decision of not rejecting the null hypothesis of no difference between the treatment arms is present when in fact CRT was superior to RT alone was made. Although not powered for an OS endpoint difference between the two treatment arms, the design with a one-sided alpha of 0.05 and a power of 0.8, the observed OS HR of 0.586 would require 87 OS events.
The current study is unique in its composition in that the overall proportion of Asian patients was 52%, which was much higher than that of 7.9% in GOG-92 study. Nonetheless, while the impact of this aspect of the clinical trial is unique, it seems unlikely that racial differences alone would impact survival, especially considering the randomized study design. The distribution of intermediate risk factor such as CLS involvement, DSI, and tumor size was not significantly different from GOG-92 study, and well balanced between RT and CRT arms. Although differences were noted in the pathologic variables of CLS and stromal invasion, based upon reported status for randomization and on subsequent pathology review, the proportions remained similar for both variables in both treatment arms and thus are both referenced (Table 1). Although rates of CLS involvement at randomization were lower (56.6%) than upon further review (73.7%), rates in both treatment arms and both conditions were statistically similar. Similarly, deep stromal invasion was reported more commonly at randomization (81.6%) than upon further review (60.8%), although again these rates were statistically similar.
From a radiation standpoint, a striking difference of the current study, as compared to the GOG 92-trial, is that this study allowed IMRT. IMRT is increasingly adopted as the standard of care in the adjuvant treatment of cervical cancer dues to its dosimetric advantages and improved toxicity profile. While randomized comparisons in cervical cancer are limited, available evidence supports the use of IMRT to enhance tolerability and maintain oncologic efficacy (18, 24). IMRT seemed to favor RT alone per subgroup analysis (Figure 2C), while participants receiving standard conformal RT seemed to do better on the CRT arm with a HR of 0.47 (0.24–0.92). The exact reason for differential outcomes with different radiation techniques is not currently known, although significant dosimetry benefits were reported for IMRT, which appear to translate clinically into reduced treatment toxicities initially in phase II trials (17, 25). IMRT has demonstrated reduced toxicity compared to conventional 3D conformal radiation in multiple studies. Notably, phase III trials such as RTOG 1203 (TIME-C) and the PARCER trial have shown that IMRT leads to significantly improved patient-reported outcomes (PROs) and lower rates of gastrointestinal and genitourinary toxicity in the postoperative and definitive settings (18, 24, 26). Our study was not powered to determine if chemotherapy could make up for less conformal RT techniques, but we hypothesize that both IMRT and conformal RT treated the tumor specific targets at risk. Although IMRT improved the therapeutic ratio by reducing toxicities, it has not been shown to eliminate the need for systemic therapy in intermediate-risk cervical cancer. The ongoing evaluation of concurrent chemoradiation in GOG 263 is aimed at determining whether chemotherapy improves disease control, irrespective of radiation technique.
There were significantly lower number of administered fractions of radiation, total radiation dose, and shorter RT duration in CRT arm than in RT arm, which may be secondary to AEs from adding weekly cisplatin chemotherapy (Table 2). However, despite the differences of RT factors, the final compliance to RT was similar (compliance of 69% in RT arm and 65.2% in CRT arm, respectively, p = 0.41). Compared to the 11% major violation rate of RT in GOG-92 study, the major violation rate was only 2.8% in the current study. Presumptively, more active and perhaps even improved management of AEs and supportive care may be responsible for mitigating the violation rate and contribute to the increased of compliance to RT as compared to GOG-92.
It was suggested that weekly cisplatin administration in CRT may have a systemic effect to control distant metastasis. However, this study demonstrated no statistical difference in either distant (11.4% and 6.3% in RT and CRT arm, respectively) or loco-regional metastasis (4.4% and 5.7% in RT and CRT arm, respectively), indicating minimal effect of weekly cisplatin to prevent distant metastasis (Supplemental Table 2). More grade 3 and 4 AEs of hematologic toxicity such as anemia, neutropenia, and thrombocytopenia occurred in CRT arm than in RT arm (15.3% in RT arm vs 42.9% in CRT arm, p < 0.01) (Supplemental Table 3). AEs may decrease the compliance of treatment, but it was generally tolerable and recovered by conventional supportive therapy restricting significant impact to survival outcome (Supplemental Table 3). PRO assessments demonstrated a decline in QOL after starting treatments in CRT arm, with recovery to pre-treatment level by 36 weeks (Supplemental Figure 1). Additional evaluations of overall QOL are the subject of a separate an ongoing evaluation of data from this clinical trial.
Currently and to the best of our knowledge, there was only one randomized prospective study prior to the current study in patients with intermediate risk factors following radical hysterectomy and lymphadenectomy (4). Secondary to the time gap of 25 years between the two studies, multiple factors such as development of new RT modality like IMRT, new imaging techniques, and improved supportive care may have contributed to an increase of survival and eventually lessen the role and potential of CRT in intermediate risk cervical cancer. As designed, NRG Oncology/GOG-263 was a superiority trial, and thus negative results do not mean the non-inferiority of CRT to RT. Finally, the open-label STARS evaluated patients similar to our study with one of three treatment strategies following radical hysterectomy including RT alone, CRT with cisplatin or sequential chemotherapy with two cycles of paclitaxel and cisplatin both prior to and following radiation (27). Although randomized, patient characteristics were variable including nodal metastasis rates for instance, with outcomes improved for the sequential chemotherapy and radiation arm as compared to RT alone or the CRT arm. This novel, but not currently utilized approach, was clearly not included in our study.
In conclusion, NRG Oncology/GOG-263/KGOG 1008 demonstrated that weekly cisplatin-based CRT improved outcomes in terms of both RFS and OS for patients, although neither improvement was statistically significant. CRT was associated with an increase in grade 3 and 4 toxicities with a transient decrease of QOL as assessed by PRO in cervical cancer patients with intermediate risk factors following radical hysterectomy and pelvic lymphadenectomy. Nonetheless, with improved outcomes noted in the subset of patients based on radiation techniques, future study to investigate the role of technological advancements in RT for cervical cancer patients with intermediate risk factors is needed.
Supplementary Material
Supplemental Figure 1. The Quality of Life (QOL) as measured by patient-reported FACT-Cx TOI scores between CRT and RT group demonstrated a decline of QOL after starting treatments with the patients on CRT group reporting the worst. QOL of CRT group recovered and exceeded pre-treatment level by 36 weeks.
RT; radiation treatment only, CRT; concurrent chemo-radiation treatment
Research Highlights.
Three-year recurrence free survival exceeded 85% for both patient groups, regardless of therapy approach.
Although not statistically significant, the addition of chemotherapy was associated with an improved RFS and OS.
In planned sub-group analysis, IMRT appeared to benefit patients more for those not receiving chemotherapy with radiation.
Acknowledgements
The authors would like to thank all the patients, and their families, that enrolled on this trial as well as the participating sites and the NRG Oncology Regulatory and Statistical Centers.
We appreciate the contribution of patients and collaborators for participating in this study, along with all investigators and site personnel. Aside from the authors listed in the manuscript, we list all the name and country of international collaborators below.
Gangnam Severance Hospital (Korea), Shikoku Cancer Center (Japan), Ohio State University Comprehensive Cancer Center (USA), Women’s Cancer Center of Nevada (USA), University of Cincinnati (USA), Nebraska Methodist Hospital (USA), Tohoku University School of Medicine (Japan), Saint Joseph’s Hospital and Medical Center (USA), University of New Mexico (USA), University of Iowa Hospitals and Clinics (USA), University of Texas Southwestern Medical Center (USA), University of Kansas Medical Center (USA), Summa Akron City Hospital/Cooper Cancer Center (USA), Kagoshima City Hospital (Japan), Kyung Hee University Hospital at Gangdong (Korea), Yonsei University Health System-Severance Hospital (Korea), Parkview Regional Medical Center (USA), The New York Methodist Hospital (USA), Abington Memorial Hospital-Asplundh Cancer Pavilion (USA), Walter Reed National Military Medical Center (USA), Woman’s Hospital (USA), State University of New York (USA), Downstate Medical Center (USA), Southwest Gynecologic Oncology Associates Inc (USA), Memorial Hermann Texas Medical Center (USA), Avera Cancer Institute (USA), Kure National Hospital (Japan), The Mark H Zangmeister Center (USA), Inha University (Korea), Northeast Georgia Medical Center (USA), Baystate Medical Center (USA), Western Pennsylvania Hospital (USA), Intermountain Medical Center (USA), CoxHealth South Hospital (USA), St. Johns Mercy Medical Center (USA), Greenville Health System Cancer Institute-Faris (USA), Interim LSU Public Hospital (USA), Good Samaritan Hospital-Cincinnati (USA), University of Mississippi Medical Center (USA), LDS Hospital (USA), Olive View-University of California Los Angeles Medical Center (USA), Seattle Cancer Care Alliance (USA), Abramson Cancer Center of The University of Pennsylvania (USA), Indiana University Hospital/Melvin and Bren Simon Cancer Center (USA), University of New Mexico (USA), Cleveland Clinic Foundation (USA), Saint Luke’s University Hospital-Bethlehem Campus (USA), Memorial Sloan Kettering Cancer Center (USA), Memorial Sloan Kettering Cancer Center Rockville Centre (USA), Wheeling Hospital / Schiffler Cancer Center (USA), Loyola University Medical Center (USA), Case Western Reserve University (USA), John Muir Medical Center-Concord Campus (USA), Iwate Medical University School of Medicine (Japan), Niigata University Medical & Dental Hospital (Japan), Medical College of Wisconsin (USA), Pikeville Medical Center (USA), Pomona Valley Hospital (USA), Catholic University of Korea-Seoul Saint Mary’s Hospital (Korea), National Cancer Center-Korea (Korea), John B Amos Cancer Center (USA), Jackson Memorial Hospital (USA), University of Missouri - Ellis Fischel (USA), Avera Cancer Institute (USA), University Medical Center Brackenridge (USA), Dartmouth-Hitchcock Medical Center (USA), University of Rochester (USA), Mercy Cancer Center (USA), West Michigan Cancer Center (USA), Fairview-Southdale Hospital (USA), Mercy Hospital - Coon Rapids (USA), Greenville Health System Cancer Institute-Seneca (USA), Florida Hospital Cancer Institute CCOP (USA), Adena Regional Medical Center (USA), Presbyterian Rust Medical Center/Jorgensen Cancer Center (USA), Memorial University Medical Center (USA), Alaska Women’s Cancer Care (USA), Saint Luke’s Mountain States Tumor Institute-Twin Falls (USA), Swedish Medical Center-First Hill (USA), Riverside Methodist Hospital (USA).
Funding
This study was supported by National Cancer Institute grants to NRG Oncology U10CA180822 (NRG Oncology Statistics and Data Management Center) and U10CA180868 (NRG Oncology Operations), as well as LAPS UG1 CA233330.
This manuscript is the result of funding in whole or in part by the National Institutes of Health (NIH). It is subject to the NIH public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH.
CONFLICT OF INTEREST
Dr. Charles A. Leath’s institution received grant support from NIH Grants NIH UG1 233330 and P50 CA098252 and Contacted Research – Agenus and Seattle Genetics. He received a Lecture Honorarium from Merck. He also received travel support from Merck. He also participated in the Scientific Advisory Boards for Merck and Seattle Genetics.
Dr. Jyoti Mayadev received grants from NCI R50, NCI r01, and Curebound award for clinical research in cervical cancer. She also received consulting fees from Varian Medical Systems, Merck and Primmmune in an Advisory role. She received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Varian Medical Systems, Merck and Primmune for Advisory roles. She received payment for expert testimony, about 5K expert fees. She received support for attending meets and /or travel from NRG Oncology. She has patents planned, issued or pending for Vaginal Stenosis Dilator device US PATENT. She holds leadership or fiduciary role in other board, society, committee or advocacy group paid or unpaid from ABS, BOD, GOG-F BOD.
Dr. Robert Mannel is a Group Chair for NRG and receives salary support paid to institution. He is also a Senior Vice President of GOG Foundation Board – salary support paid to institution.
Dr. Dana Chase received consulting fees from GSK, Astra Zeneca, Merck, Eisai, Pfizer and Abbvie. She also received payment for honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, Astra Zeneca, Merck, Eisai, Pfizer and Abbvie.
Dr. William Small Jr received consulting fees from GSK for consultation on KNB2 data in endometrial cancer. He also received travel support for attending NRG Oncology meetings. He has a leadership role with NRG Oncology, serving as Co- Chair of the Publications Committee.
Dr. Bradley Monk received personal consulting fees from AstraZeneca, Biotech, Corcept, DSI, Eisai, Eli Lilly, Genmab/Seagen/Pfizer, GOG Foundation, GSK, Immunogen/Abbvie, Incyte, Karyopharm, Merck, Mersana, Mural/Alkermes, Myriad, Natera, Novartis, Novocure, OncoC4, Panavance, Pharma&, ProfoundBio/Genmab, Regeneron, Roche/Genentech, Sutro, Tubulis, Verastem, Zentalis and Zymeworks. He also received honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, BioNtech, Corcept, DSI, Easai, Eli Lilly, Genmab/Seagen/Pfizer, GOG Foundation, GSK, Immunogen/Abbvie, Incyte, Karyopharm, Merck, Mersana, Mural/Alkermes, Myriad, Natera, Novartis, Novocure, OncoC4, Panavance, Pharma&, ProfoundBio/Genmab, Regeneron, Roche/Genentech, Sutro, Tubulis, Verastem, Zentalis, Zymeworks, AstraZeneca and BioNtech. He received payments from AstraZeneca, Eisai, ImmunoGen/Abbvie, Lilly, MSD and Tesaro/GSK for serving on Speakers’ Bureau.
All other co-authors have no Conflicts of Interest to declare.
Footnotes
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Associated Data
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Supplementary Materials
Supplemental Figure 1. The Quality of Life (QOL) as measured by patient-reported FACT-Cx TOI scores between CRT and RT group demonstrated a decline of QOL after starting treatments with the patients on CRT group reporting the worst. QOL of CRT group recovered and exceeded pre-treatment level by 36 weeks.
RT; radiation treatment only, CRT; concurrent chemo-radiation treatment