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Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer
Gynecologic Oncology 128 (2013) 288–293
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer☆ Michael R. Folkert a, Karin K. Shih b, Nadeem R. Abu-Rustum b, Elizabeth Jewell b, Marisa A. Kollmeier a, Vicky Makker c, Richard R. Barakat b, Kaled M. Alektiar a,⁎ a b c
Department of Radiation Oncology, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA Department of Surgery, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA Department of Medicine, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
H I G H L I G H T S ► Intensity-modulated radiation therapy (IMRT) is a radiation treatment modality that allows for relative sparing of normal tissues. ► Postoperative IMRT with concurrent chemotherapy was feasible in intermediate- and high-risk cervical cancer. ► Toxicity and oncologic outcomes were excellent.
a r t i c l e
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Article history: Received 21 August 2012 Accepted 9 November 2012 Available online 15 November 2012 Keywords: Cervical cancer Chemoradiation IMRT Postoperative Intermediate or high risk
a b s t r a c t Objective. According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. Methods. From 1/2004 to 12/2009, 34 patients underwent radical hysterectomy and pelvic lymph node dissection (28 median nodes were removed) for early stage cervical cancer. Median dose of postoperative pelvic IMRT was 50.4 Gy (range, 45–50.4). All patients received concurrent cisplatin. Results. With a median follow-up of 44 months, 3 patients have recurred; 1 vaginal recurrence, 1 regional and distant, and 1 distant. The 3- and 5-year disease-free survival (DFS) was 91.2% (95% CI, 81.4–100%) and overall survival (OS) was 91.1% (95% CI, 81.3–100%). All failures and all deaths were in the high-risk group (n=3/26). There was 32.3% G3–4 hematologic toxicity, 2.9% acute G3 gastrointestinal toxicity, and no acute G3 or higher genitourinary toxicity. There were no chronic G3 or higher toxicities. Conclusions. Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. Toxicity was minimal even in the setting of an aggressive trimodality approach. Data from this study and emerging data from the Phase II RTOG study (0418) demonstrate the advantages of postoperative IMRT in early stage cervical cancer. © 2012 Elsevier Inc. All rights reserved.
Introduction Intensity-modulated radiation therapy (IMRT) permits the delivery of highly conformal therapeutic radiation doses to oncologic targets while constraining the dose to healthy tissue. According to national surveys, the use of IMRT has been steadily increasing in many subsites [1–3]; after genitourinary (GU), head and neck, and central nervous
☆ There are no funding sources to disclose. None of the authors have conflicts to disclose. None of the authors have a personal or institutional financial interest in the materials or devices described in this submission. ⁎ Corresponding author at: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Fax: +1 212 639 8876. E-mail address: [email protected] (K.M. Alektiar). 0090-8258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2012.11.012
system disease, the treatment of gynecologic malignancies is the fourth most common area in which IMRT is utilized. While dose escalation and economic competition are cited as major reasons for the increasing adoption of IMRT, the leading reason has been to permit normal tissue sparing and optimize delivery of conventional doses [2]. Despite this increasing trend in utilization of IMRT in the treatment of gynecologic cancers, the breadth of the supporting literature remains limited. Most of the data focuses on the advantages of IMRT over conventional radiation (RT) in terms of toxicity [4–9]. Therefore, there is still reluctance to adopt IMRT as standard practice, citing paucity of data on oncologic outcome. Few studies have investigated the outcomes of IMRT in cervical cancer; however, these studies generally include a mix of definitive and adjuvant IMRT, or are confounded by variations in the use of adjuvant chemotherapy and/or the use of additional
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intravaginal RT [10,11]. The purpose of the current study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. Methods Patients For the purposes of this study, all patients who underwent definitive surgery including Class III radical hysterectomy and pelvic lymph node dissection for International Federation of Gynecology and Obstetrics (FIGO) stages IA–IIA intermediate- and high-risk cervical cancer followed by concurrent chemotherapy and postoperative external beam radiation therapy using IMRT techniques from January 2004 to December 2009 were included. Patients were classified as intermediate risk based on a combination of the following factors: lymphovascular involvement, stromal invasion, and tumor size [12], and high-risk if they had features including positive pelvic nodes, positive parametrial involvement, or positive surgical margins [13]. All patients received postoperative IMRT and concurrent chemotherapy and no patients received intravaginal RT as part of their treatment. Patients who underwent any aspect of their trimodality care (surgery, chemotherapy, or radiation therapy) at an outside institution were excluded; all treatments performed were of curative intent. This retrospective study was approved by our institutional Internal Review Board. There were 34 consecutive patients who met these inclusion criteria and were eligible for IMRT. Radiation therapy All patients in this study underwent computed tomography (CT)-based simulation and planning, using custom immobilization in the supine position. Patients were given intravenous (IV) and small bowel contrast; rectal contrast (50 cm3 diluted barium) was applied using a rectal catheter to outline the rectosigmoid and rectum, and vaginal contrast (15–20 cm3 diluted barium) was instilled to outline the vaginal cuff as shown in Fig. 1.
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Contouring is performed in a manner similar to the Radiation Therapy Oncology Group (RTOG) [14,15]; for lymphatics, the internal, external, and common iliac vessels and presacral lymph nodes are contoured and two consecutive 7 mm expansions are applied to create a “pelvic lymph node planning target volume (PTV)” and “presacral PTV.” The superior extent of the nodal PTV is the L4–L5 interspace; for a paraaortic field, the superior extent of the nodal PTV is the T12–L1 interspace. The inferior extent of the nodal PTV includes presacral lymph nodes to the level of S3 posteriorly and includes the external iliac nodes to the inguinal ligament. In terms of the “vaginal clinical target volume (CTV),” unlike the RTOG, where motion is accounted for by simulating with both a full and an empty bladder and incorporating elements of both scans, our institution accounts for motion with generous margins. The vaginal cuff contour (including the proximal two-thirds of the vagina) is expanded initially by 2 cm to generate the “vaginal cuff CTV,” and then an additional 1 cm expansion is applied to create the “vaginal cuff PTV.” The pelvic lymph node, presacral, and vaginal cuff PTVs are then collectively used to plan the prescribed dose delivery. All patients treated in this study were treated with IMRT external beam radiation therapy techniques; no patients received intravaginal RT. All but one patient were treated with pelvic fields; one was treated with an extended field due to positive paraaortic nodes. Treatment plans were generated using our in-house treatment-planning system (Top Module, New York, NY, USA). Typical normal tissue constraints are as follows: ≤45 Gy to bowel or D05% ≤ 50 Gy, no hot spots; ≤45 Gy to femurs or max point dose ≤52 Gy and D05% 50 Gy; ≤33% V18 Gy to kidneys (each kidney separately); ≤50 Gy max point dose to cauda; D05% ≤50.4 Gy to the bladder not contained within the PTV, no hot spots; and D05% ≤ 50.4 Gy to the rectum not contained within the PTV. Target criteria were designed to provide uniform coverage to the PTV and avoid underdosage; these treatment criteria were specified such that the PTV Dmax should be ≤110%, D95% should be ≥98%, and V95% should be ≥98%; the presacral PTV Dmax should be less than the hot spots in the other nodal and vaginal PTVs. It should be noted that the coverage is very consistent with that provided by conventional fields; IMRT differs in that it constrains normal tissues to the doses described above. The median dose of postoperative pelvic IMRT was 50.4 Gy in 28 fractions (range, 45–50.4).
Fig. 1. Axial view of planning computed tomography scan; the bladder is outlined in white and the rectum is outlined in black; the white arrow marks the vaginal contrast demarcating the vaginal cuff.
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Chemotherapy All patients received cisplatin-based chemotherapy administered concurrently with radiation treatment. IV cisplatin was administered weekly at a dose of 40 mg/m 2. When 5-fluorouracil (5-FU) was added to cisplatin, 5-FU was dosed at 4000 mg/m 2 by continuous infusion over 96 h on days 1 through 4 of each week. Assessment/follow-up All patients were monitored while on treatment with a minimum of once-weekly status check by the treating radiation oncologist and medical oncologist. In addition, weekly complete blood counts and chemistries were assessed. Follow-up evaluation included assessment with physical examination, imaging, Pap smears, complete blood counts, and basic chemistries. All patient follow-up was performed at the primary institution. Grading of toxicity was based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, with the highest grade of any observed toxicity reported for each patient; gastrointestinal, genitourinary, and vaginal toxicity, as well was lymphedema and sacral insufficiency fractures, were scored at the time of follow-up. Hematologic toxicities were scored on the basis of complete blood counts (CBC) taken during treatment and at each follow-up visit. Statistics All outcome measurements were measured from time to definitive surgery to time of event. Overall survival (OS) was defined as the time of death from any cause. Overall disease-free survival (DFS) was defined as the time to any local (vaginal), regional (pelvic), or distant failure; local/regional progression-free survival and distant progression free survival were defined as the time to first clinical or pathological evidence of vaginal/pelvic or distant disease recurrence, respectively. Patients were censored at the date of last follow-up or death. Outcomes were estimated using the Kaplan–Meier method and cumulative incidence functions [16]; confidence intervals at median follow-up times were calculated using Wilson's interval with continuity correction [17]. Log-rank tests and Cox proportional hazards regression models were used for univariate analysis. Statistical analysis was performed using SPSS v.20.0.0 (SPSS Inc.). Results Patients The mean age was 44 (range, 22.8–81.4). The majority of patients underwent an open hysterectomy (27/34; 79.4%); 4 patients (11.8%) underwent laparoscopic abdominal hysterectomy and two patients (5.9%) underwent robotic hysterectomy. All patients underwent pelvic lymph node dissection; 28 median nodes were removed (range, 11–53). There were 22/34 (64.7%) patients who had positive pelvic nodes. Para-aortic node sampling was performed in 20/34 (58.8%) patients; there were 3.5 median nodes (range, 1–14). There were 1/34 (2.9%) patients who had positive para-aortic nodes. There were 2 (5.9%) stage IA2, 23 (67.6%) stage IB1, 6 (17.6%) stage IB2, and 3 (8.8%) stage IIA patients. Histological breakdown was 50% squamous, 35.3% adenocarcinoma, and 14.7% adenosquamous. Of the 34 patients, 26 (76.5%) were high risk and 8 (23.5%) were intermediate risk based on Gynecologic Oncology Group (GOG) risk stratification. All patients received concurrent chemotherapy; 32 (94.1%) used weekly cisplatin (40 mg/m2 × 5 cycles), and 2 (5.9%) used cisplatin and 5-FU (Table 1). The full chemotherapy course as planned was received by 32 of 34 patients (94%); of the 2 patients who did not receive the full course, 1 patient (3%) received 4 of a planned 5 cycles due to GI/GU irritation, and 1 patient (3%) was limited to 3 cycles due to preexisting renal insufficiency.
Table 1 Patient characteristics. N (%) Mean age (range in years) Age ≤ 50 Age > 50 Histology Squamous Adenocarcinoma Adenosquamous Clinical stage IA2 IB1 IB2 IIA Type of surgery Open hysterectomy Laparoscopic Robotic Lymphovascular space invasion Yes No Lymph node procedure Pelvic dissection Para-aortic sampling Median lymph nodes removed (range) Pelvic Para-aortic Patients with positive lymph nodes Pelvic Para-aortic Margin status Negative Positive Risk group Intermediate High Extent of radiotherapy Pelvic Pelvic and para-aortic Type of chemotherapy Cisplatin Cisplatin + 5-fluorouracil
44 years (22.8–81.4) 23 (67.6%) 11 (32.4%) 17 (50%) 12 (35.3%) 5 (14.7%) 2 (5.9%) 23 (67.6%) 6 (17.6%) 3 (8.8%) 27 (79.4%) 4 (11.8%) 2 (5.9%) 31 (91.2%) 3 (8.8%) 34 (100%) 20 (58.8%) 28 (11–53) 3.5 (1–14) 22 (64.7%) 1 (2.9%) 31 (91.2%) 3 (8.8%%) 8 (23.5%) 26 (76.5%) 33 (97.1%) 1 (2.9%) 32 (94.1%) 2 (5.9%)
Outcomes Of the 34 patients in this study, three (8.8%) recurred, all of whom were high-risk patients. One patient had isolated vaginal cuff recurrence for which chemotherapy was recommended. One patient had synchronous relapse in her right pelvic side wall, abdominal wall, and liver, and was treated with carboplatin/paclitaxel-based chemotherapy and palliative surgical resection, and one patient recurred in the liver and was treated with carboplatin/paclitaxel-based chemotherapy. Thus, the rate of vaginal recurrence was 2.9% (1/34), pelvic side wall recurrence was 2.9% (1/34), and distant relapse was 5.9% (2/34). There were no para-aortic recurrences. The median time to local recurrence was 14.3 months and to distant recurrence 12.4 months. With a median follow-up of 44 months, the 3- and 5-year recurrence rate was 6% (95% CI, 0–14.2%) for both local/regional and distant failures. The 3- and 5-year DFS was 91.2% (95% CI, 81.4–100.0%). The 3- and 5-year OS was 91.1% (95% CI, 81.3–100%) (Fig. 2). Of the 34 patients, three have died, all following disease recurrence; the median time to death was 24.6 months, and the median time from recurrence to death was 10.3 months (range, 6.4–15.1 months). There was no death from other causes. Univariate analysis was performed to identify if any correlation existed between outcome and potential prognostic factors recorded in this cohort. Factors assessed were age > 50, histology, type of surgery performed, clinical stage, and risk group. Using log-rank tests on the Kaplan–Meier curves generated for these risk subgroups, no factor was found to be a significant predictor of local/regional control, DFS, or OS (Table 2).
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Fig. 2. Disease-free and overall survival.
Toxicity All (100%) patients had some degree of hematological toxicity (Grade 1, 88.2%; Grade 2, 67.6%; Grade 3, 29.4%; and Grade 4, 2.9%). The only hematologic Grade 4 toxicity observed occurred in a patient with a hemoglobin value during treatment of 6.3 g/dL; this was remediated with a transfusion. Acute gastrointestinal (GI) toxicity was seen in 31 (91.2%) patients (Grade 1, 73.5%; Grade 2, 23.5%; and Grade 3, 2.9%). The acute Grade 3 GI toxicity was diarrhea requiring IV hydration in 1 patient. Acute GU toxicity was observed in 12 (35.3%) patients (Grade 1 20.6%, Grade 2 14.7%). Chronic GI toxicity occurred in 5 (14.7%) patients, all Grade 1; there were no small bowel obstructions observed in this study population. Chronic GU toxicity occurred in 5 (14.7%) patients (Grade 1 11.8%, Grade 2 2.9%). Chronic vaginal toxicity (dryness and stenosis) occurred
in 13 (38.2%) patients, all Grade 1. Lower extremity edema occurred in 13 (38.2%) patients; (Grade 1 23.5%, Grade 2 14.7%). There were 2 (5.9%) sacral insufficiency fractures; 1 Grade 1 and 1 Grade 2 (Table 3). Discussion The role of postoperative pelvic RT combined with chemotherapy for intermediate and high risk cervical cancer is well established on the basis of two randomized trials [12,13,18]. While this treatment has been shown to have a significant impact on the risk of local recurrence and duration of disease-free survival, as well as survival benefit in high-risk patients, it is not without its morbidity. The conventional “4-field box” technique used in these studies is considered sufficient to deliver conformal radiation dose to the target at risk but also results in significant exposure to other organs in the pelvis. In intermediate risk patients, Sedlis et al. [12] observed 3 (2.3%) gastrointestinal
Table 2 Outcomes analysis by factor. Factor
3-Year local/regional control (95% CI)
Overall
94% (85.8–100%)
Age ≤50 >50
95.7% (87.1–100%) 90.9% (73.5–100%)
.618
91.3% (79.5–100%) 90.9% (73.5–100%)
.999
91.3% (79.5–100%) 90.9% (73.5–100%)
.989
Histology Squamous Non-squamous
93.8% (81.6–100%) 94.1% (83.7–100%)
1
88.2% (72.6–100%) 92.3% (77.5–100%)
.552
88.2% (72.6–100%) 94.1% (82.7–100%)
.564
Type of surgery Open Minimally invasive
96.3% (89.1–100%) 85.7% (59.3–100%)
.320
92.6% (82.6–100%) 85.7% (59.3–100%)
.320
92.6% (82.6–100%) 85.7% (59.3–100%)
.616
Stage IA2–IB1 IB2–IIA
96% (88.2–100%) 88.9% (67.9–100%)
.393
96% (88.2–100%) 77.8% (50–100%)
.086
95.8% (87.6–100%) 77.8% (50–100%)
.088
GOGa risk group Intermediate High
100% 92.1% (81.5–100%)
a
GOG: Gynecologic Oncology Group.
P value
3-Year disease-free survival (95% CI)
P value
91.2% (81.4–100%)
.423
100% 88.5% (75.9–100%)
3-Year overall survival (95% CI)
P value
91.1% (81.3–100.0%)
.327
100% 88.3% (75.5–100%)
.323
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Table 3 Acute and chronic toxicity of postoperative cervical intensity-modulated radiation therapy. ANC = absolute neutrophil count, GI = gastrointestinal; GU = genituourinary; Gyn = gynecological; Hgb = hemoglobin; Plt = platelets; SI = sacral insufficiency. Grade 1 (%)
Grade 2 (%)
Grade 3 (%)
Grade 4 (%)
Acute adverse effects GI, diarrhea GI, proctitis GI, enteritis GU, cystitis GU, frequency Hematologic, ANC Hematologic, Hgb Hematologic, Plt Post-surgical edema
13 (38.2%) 22 (64.7%) 5 (14.7%) 6 (17.6%) 2 (5.9%) 0 17 (50%) 19 (55.9%) 8 (23.5%)
3 (8.8%) 5 (14.7%) 2 (5.9%) 5 (14.7%) 0 7 (20.6%) 9 (26.5%) 0 0
0 1 (2.9%) 0 0 0 4 (11.8%) 3 0 0
0 0 0 0 0 0 1 (2.9%) 0 0
Chronic adverse effects GI, diarrhea GI, proctitis GU, frequency Gyn, any Hematologic, any Lower extremity edema SI fracture
5 (14.7%) 1 (2.9%) 4 (11.8%) 13 (38.2%) 0 8 (23.5%) 1 (2.9%)
0 0 1 (2.9%) 0 0 5 (14.7%) 1 (2.9%)
0 0 0 0 0 0 0
0 0 0 0 0 0 0
(GI) and 4 (3.1%) GU Grades 3–4 toxicities in 128 assessable patients receiving postoperative RT. In high-risk patients, Peters et al. [13] reported Grades 3–4 diarrhea in 12 (9.8%) patients and small bowel obstruction in 2 (1.6%) in the chemoradiation group. In comparison, there were 7 (6.3%) patients with Grades 3–4 diarrhea and 1 (0.9%) patient with small-bowel obstruction in the RT alone group. In the current study using IMRT, Grades 3–4 acute GI complications were observed in 1 (2.9%) patient. No acute Grades 3–4 GU or chronic Grades 3–4 toxicities were observed. Hasselle et al. [11] reported on 111 patients with stages I–IVA cervical cancer treated with IMRT. In the subset of 22 patients treated with postoperative RT, of which 12 (55%) received concurrent chemotherapy, they observed 1 patient (5%) with Grades 3–4 acute GI toxicity; no acute GU or chronic Grades 3–4 toxicities were observed. Chen et al. [10] reported on a group of 54 patients with cervical cancer, who were treated with adjuvant chemoradiation in the postoperative setting consisting of 50.4 Gy IMRT and cisplatin, as well as 6 Gy intravaginal RT in three fractions. In terms of acute toxicity, they observed no Grade 3 or higher GI or GU toxicities. There was 1 (1.8%) chronic Grade 3 GU toxicity. Reporting on lymphedema after radical hysterectomy and postoperative radiation has been sparse. In the current study, the rate of Grades 1–2 lymphedema was 38.2%. In comparison, a study by Ohba et al. [19] reported rates as high as 50% in the setting of postoperative pelvic radiation after systematic lymphadenectomy for cervical cancer. Hematologic toxicity resulting from irradiation of the pelvis in conjunction with marrow-suppressing chemotherapy has been the topic of several studies [4,20]; Sedlis et al. [12] reported 3 (2.3%) patients with Grades 3–4 acute hematologic toxicity in the arm receiving adjuvant radiation therapy; Peters et al. [13] reported Grades 3–4 hematologic toxicities including anemia in 4 (3.3%) patients, leukopenia in 43 (35.2%), granulocytopenia in 35 (28.7%), and thrombocytopenia in 1 (0.8%) in the chemoradiation group. In comparison, Grades 3–4 granulocytopenia and leukopenia were seen in 3 (2.7%) patients and 1 (0.9%) patient, respectively, in the adjuvant RT-alone group. In the current study using IMRT, Grades 3–4 acute hematologic toxicity was observed in 11 (32.3%) patients. Of these 11 patients, 10 (29.4%) patients had leukopenia (including 4/10 granulocytopenic) and 4 (11.7%) patients had anemia. The only Grade 4 hematological toxicity was anemia in one patient, which was corrected by transfusion. In Chen et al. [10], they observed 3 (6%) acute Grades 3–4 hematologic toxicities. Mell et al. [4] reported on 37 patients with cervical cancer treated
with IMRT and concurrent cisplatin, of which 22 (59.4%) patients were early stage; they observed Grades 3–4 hematological toxicities including anemia in 3 (8.1%) patients, granulocytopenia in 1 (2.7%) patient, and leukopenia in 4 (10.8%) patients. Comparison to a historical control group should always be exercised with caution, but interim reports from the ongoing RTOG trial [14], “A phase II study of intensity modulated radiation therapy (IMRT) to the pelvis ± chemotherapy for post-operative patients with either endometrial or cervical carcinoma,” provides corroboration for our results. For a group of 40 patients with cervical cancer treated with adjuvant chemoradiation, Klopp et al. [21] described significantly decreased rates of Grade 4 or higher hematologic toxicity (0% in the IMRT vs. 18% in the conventional comparison, P = .002). While the toxicity profile of postoperative pelvic IMRT seems to compare very favorably with conventional RT, it could be argued that the tight conformality attained by IMRT may adversely impact oncologic outcome. For intermediate-risk patients, the update of GOG 92 [18] showed PFS at 3 years to be approximately 86% and OS to be approximately 88%. In the Intergroup study [13] for high-risk patients, the estimated PFS at 3 years with chemoradiation was 84% and OS was 88%. With a median follow-up of 44 months in the current study, the 3- and 5-year OS was 91.1% (95% CI, 81.3– 100.0%) and the PFS was 91.2% (95% CI, 81.4–100.0%). Hasselle et al. [11] reported 3-year DFS and OS rates of 95.2% (95% CI, 86.7–100%) and 100% (95% CI, 80.3–100%) for the postoperative subset of 22 patients in their cohort with a median follow-up time of 27 months. Chen et al. [10,22] reported 3-year rates of locoregional control, DFS, and OS of 93% (95% CI, 86.5–99.5%), 78% (95% CI, 64.7–91.3%), and 98% (95% CI, 94–100%), respectively, in 54 patients treated postoperatively with a median follow-up of 20 months. Preliminary data from the RTOG 0418 trial (median follow-up of 32 months) [23] demonstrated 2-year DFS and OS rates of 86.9% (95% CI, 71.2–94.3%) and 94.6% (95% CI, 80.1–98.6%), respectively. When evaluating the outcomes and toxicity data presented in this study, it must be recognized that they are subject to the biases and limitations of a retrospective review of a single-institution experience. Every effort was made to ensure that the cohort presented was as homogeneous as possible; patients with any aspect of their treatment performed at an outside institution were excluded. Ultimately, confirmation of these results will come from the results of cooperative group studies such as the RTOG 0418 trial. In conclusion, based on this study, oncologic outcomes with postoperative pelvic IMRT and concurrent chemotherapy in early stage cervical cancer were excellent, with 3- and 5-year local control, DFS, and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. The morbidity profile was also very favorable, even in the setting of an aggressive trimodality approach. Data from this study as well as the emerging data from the Phase II RTOG study (0418) highlights the advantages of postoperative IMRT in the management of early stage cervical cancer. Conflict of interest statement The authors have no conflicts of interest to disclose.
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apy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606-13. RTOG 0418. A phase II study of intensity modulated radiation therapy (IMRT) to the pelvis ± chemotherapy for post-operative patients with either endometrial or cervical carcinoma. Small Jr W, Mell LK, Anderson P, Creutzberg C, De Los Santos J, Gaffney D, et al. Consensus guidelines for delineation of clinical target volume for intensitymodulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys 2008;71:428-34. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Statist Assoc 1958;53:457-81. Wilson E. Probable inference, the law of succession, and statistical inference. J Am Statist Assoc 1927;22:209-12. Rotman M, Sedlis A, Piedmonte MR, Bundy B, Lentz SS, Muderspach LI, et al. A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 2006;65:169-76. Ohba Y, Todo Y, Kobayashi N, Kaneuchi M, Watari H, Takeda M, et al. Risk factors for lower-limb lymphedema after surgery for cervical cancer. Int J Clin Oncol 2011;16:238-43. Lujan AE, Mundt AJ, Yamada SD, Rotmensch J, Roeske JC. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516-21. Klopp A, Moughan J, Portelance L, Miller B, Salehpour M, D'Souza D, et al. Hematologic toxicity on RTOG 0418: a phase II study of post-operative IMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys 2010;78:S121. Chen MF, Tseng CJ, Tseng CC, Kuo YC, Yu CY, Chen WC. Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys 2007;67:1438-44. Portelance L, Moughan J, Jhingran A, Miller B, Salehpour M, D'Souza D, et al. A phase II multi-institutional study of postoperative pelvic intensity modulated radiation therapy (IMRT) with weekly cisplatin in patients with cervical carcinoma: two year efficacy results of the RTOG 0418. Int J Radiat Oncol Biol Phys 2011;81:S3.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer☆ Michael R. Folkert a, Karin K. Shih b, Nadeem R. Abu-Rustum b, Elizabeth Jewell b, Marisa A. Kollmeier a, Vicky Makker c, Richard R. Barakat b, Kaled M. Alektiar a,⁎ a b c
Department of Radiation Oncology, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA Department of Surgery, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA Department of Medicine, Memorial-Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
H I G H L I G H T S ► Intensity-modulated radiation therapy (IMRT) is a radiation treatment modality that allows for relative sparing of normal tissues. ► Postoperative IMRT with concurrent chemotherapy was feasible in intermediate- and high-risk cervical cancer. ► Toxicity and oncologic outcomes were excellent.
a r t i c l e
i n f o
Article history: Received 21 August 2012 Accepted 9 November 2012 Available online 15 November 2012 Keywords: Cervical cancer Chemoradiation IMRT Postoperative Intermediate or high risk
a b s t r a c t Objective. According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. Methods. From 1/2004 to 12/2009, 34 patients underwent radical hysterectomy and pelvic lymph node dissection (28 median nodes were removed) for early stage cervical cancer. Median dose of postoperative pelvic IMRT was 50.4 Gy (range, 45–50.4). All patients received concurrent cisplatin. Results. With a median follow-up of 44 months, 3 patients have recurred; 1 vaginal recurrence, 1 regional and distant, and 1 distant. The 3- and 5-year disease-free survival (DFS) was 91.2% (95% CI, 81.4–100%) and overall survival (OS) was 91.1% (95% CI, 81.3–100%). All failures and all deaths were in the high-risk group (n=3/26). There was 32.3% G3–4 hematologic toxicity, 2.9% acute G3 gastrointestinal toxicity, and no acute G3 or higher genitourinary toxicity. There were no chronic G3 or higher toxicities. Conclusions. Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. Toxicity was minimal even in the setting of an aggressive trimodality approach. Data from this study and emerging data from the Phase II RTOG study (0418) demonstrate the advantages of postoperative IMRT in early stage cervical cancer. © 2012 Elsevier Inc. All rights reserved.
Introduction Intensity-modulated radiation therapy (IMRT) permits the delivery of highly conformal therapeutic radiation doses to oncologic targets while constraining the dose to healthy tissue. According to national surveys, the use of IMRT has been steadily increasing in many subsites [1–3]; after genitourinary (GU), head and neck, and central nervous
☆ There are no funding sources to disclose. None of the authors have conflicts to disclose. None of the authors have a personal or institutional financial interest in the materials or devices described in this submission. ⁎ Corresponding author at: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Fax: +1 212 639 8876. E-mail address: [email protected] (K.M. Alektiar). 0090-8258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2012.11.012
system disease, the treatment of gynecologic malignancies is the fourth most common area in which IMRT is utilized. While dose escalation and economic competition are cited as major reasons for the increasing adoption of IMRT, the leading reason has been to permit normal tissue sparing and optimize delivery of conventional doses [2]. Despite this increasing trend in utilization of IMRT in the treatment of gynecologic cancers, the breadth of the supporting literature remains limited. Most of the data focuses on the advantages of IMRT over conventional radiation (RT) in terms of toxicity [4–9]. Therefore, there is still reluctance to adopt IMRT as standard practice, citing paucity of data on oncologic outcome. Few studies have investigated the outcomes of IMRT in cervical cancer; however, these studies generally include a mix of definitive and adjuvant IMRT, or are confounded by variations in the use of adjuvant chemotherapy and/or the use of additional
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intravaginal RT [10,11]. The purpose of the current study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. Methods Patients For the purposes of this study, all patients who underwent definitive surgery including Class III radical hysterectomy and pelvic lymph node dissection for International Federation of Gynecology and Obstetrics (FIGO) stages IA–IIA intermediate- and high-risk cervical cancer followed by concurrent chemotherapy and postoperative external beam radiation therapy using IMRT techniques from January 2004 to December 2009 were included. Patients were classified as intermediate risk based on a combination of the following factors: lymphovascular involvement, stromal invasion, and tumor size [12], and high-risk if they had features including positive pelvic nodes, positive parametrial involvement, or positive surgical margins [13]. All patients received postoperative IMRT and concurrent chemotherapy and no patients received intravaginal RT as part of their treatment. Patients who underwent any aspect of their trimodality care (surgery, chemotherapy, or radiation therapy) at an outside institution were excluded; all treatments performed were of curative intent. This retrospective study was approved by our institutional Internal Review Board. There were 34 consecutive patients who met these inclusion criteria and were eligible for IMRT. Radiation therapy All patients in this study underwent computed tomography (CT)-based simulation and planning, using custom immobilization in the supine position. Patients were given intravenous (IV) and small bowel contrast; rectal contrast (50 cm3 diluted barium) was applied using a rectal catheter to outline the rectosigmoid and rectum, and vaginal contrast (15–20 cm3 diluted barium) was instilled to outline the vaginal cuff as shown in Fig. 1.
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Contouring is performed in a manner similar to the Radiation Therapy Oncology Group (RTOG) [14,15]; for lymphatics, the internal, external, and common iliac vessels and presacral lymph nodes are contoured and two consecutive 7 mm expansions are applied to create a “pelvic lymph node planning target volume (PTV)” and “presacral PTV.” The superior extent of the nodal PTV is the L4–L5 interspace; for a paraaortic field, the superior extent of the nodal PTV is the T12–L1 interspace. The inferior extent of the nodal PTV includes presacral lymph nodes to the level of S3 posteriorly and includes the external iliac nodes to the inguinal ligament. In terms of the “vaginal clinical target volume (CTV),” unlike the RTOG, where motion is accounted for by simulating with both a full and an empty bladder and incorporating elements of both scans, our institution accounts for motion with generous margins. The vaginal cuff contour (including the proximal two-thirds of the vagina) is expanded initially by 2 cm to generate the “vaginal cuff CTV,” and then an additional 1 cm expansion is applied to create the “vaginal cuff PTV.” The pelvic lymph node, presacral, and vaginal cuff PTVs are then collectively used to plan the prescribed dose delivery. All patients treated in this study were treated with IMRT external beam radiation therapy techniques; no patients received intravaginal RT. All but one patient were treated with pelvic fields; one was treated with an extended field due to positive paraaortic nodes. Treatment plans were generated using our in-house treatment-planning system (Top Module, New York, NY, USA). Typical normal tissue constraints are as follows: ≤45 Gy to bowel or D05% ≤ 50 Gy, no hot spots; ≤45 Gy to femurs or max point dose ≤52 Gy and D05% 50 Gy; ≤33% V18 Gy to kidneys (each kidney separately); ≤50 Gy max point dose to cauda; D05% ≤50.4 Gy to the bladder not contained within the PTV, no hot spots; and D05% ≤ 50.4 Gy to the rectum not contained within the PTV. Target criteria were designed to provide uniform coverage to the PTV and avoid underdosage; these treatment criteria were specified such that the PTV Dmax should be ≤110%, D95% should be ≥98%, and V95% should be ≥98%; the presacral PTV Dmax should be less than the hot spots in the other nodal and vaginal PTVs. It should be noted that the coverage is very consistent with that provided by conventional fields; IMRT differs in that it constrains normal tissues to the doses described above. The median dose of postoperative pelvic IMRT was 50.4 Gy in 28 fractions (range, 45–50.4).
Fig. 1. Axial view of planning computed tomography scan; the bladder is outlined in white and the rectum is outlined in black; the white arrow marks the vaginal contrast demarcating the vaginal cuff.
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Chemotherapy All patients received cisplatin-based chemotherapy administered concurrently with radiation treatment. IV cisplatin was administered weekly at a dose of 40 mg/m 2. When 5-fluorouracil (5-FU) was added to cisplatin, 5-FU was dosed at 4000 mg/m 2 by continuous infusion over 96 h on days 1 through 4 of each week. Assessment/follow-up All patients were monitored while on treatment with a minimum of once-weekly status check by the treating radiation oncologist and medical oncologist. In addition, weekly complete blood counts and chemistries were assessed. Follow-up evaluation included assessment with physical examination, imaging, Pap smears, complete blood counts, and basic chemistries. All patient follow-up was performed at the primary institution. Grading of toxicity was based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, with the highest grade of any observed toxicity reported for each patient; gastrointestinal, genitourinary, and vaginal toxicity, as well was lymphedema and sacral insufficiency fractures, were scored at the time of follow-up. Hematologic toxicities were scored on the basis of complete blood counts (CBC) taken during treatment and at each follow-up visit. Statistics All outcome measurements were measured from time to definitive surgery to time of event. Overall survival (OS) was defined as the time of death from any cause. Overall disease-free survival (DFS) was defined as the time to any local (vaginal), regional (pelvic), or distant failure; local/regional progression-free survival and distant progression free survival were defined as the time to first clinical or pathological evidence of vaginal/pelvic or distant disease recurrence, respectively. Patients were censored at the date of last follow-up or death. Outcomes were estimated using the Kaplan–Meier method and cumulative incidence functions [16]; confidence intervals at median follow-up times were calculated using Wilson's interval with continuity correction [17]. Log-rank tests and Cox proportional hazards regression models were used for univariate analysis. Statistical analysis was performed using SPSS v.20.0.0 (SPSS Inc.). Results Patients The mean age was 44 (range, 22.8–81.4). The majority of patients underwent an open hysterectomy (27/34; 79.4%); 4 patients (11.8%) underwent laparoscopic abdominal hysterectomy and two patients (5.9%) underwent robotic hysterectomy. All patients underwent pelvic lymph node dissection; 28 median nodes were removed (range, 11–53). There were 22/34 (64.7%) patients who had positive pelvic nodes. Para-aortic node sampling was performed in 20/34 (58.8%) patients; there were 3.5 median nodes (range, 1–14). There were 1/34 (2.9%) patients who had positive para-aortic nodes. There were 2 (5.9%) stage IA2, 23 (67.6%) stage IB1, 6 (17.6%) stage IB2, and 3 (8.8%) stage IIA patients. Histological breakdown was 50% squamous, 35.3% adenocarcinoma, and 14.7% adenosquamous. Of the 34 patients, 26 (76.5%) were high risk and 8 (23.5%) were intermediate risk based on Gynecologic Oncology Group (GOG) risk stratification. All patients received concurrent chemotherapy; 32 (94.1%) used weekly cisplatin (40 mg/m2 × 5 cycles), and 2 (5.9%) used cisplatin and 5-FU (Table 1). The full chemotherapy course as planned was received by 32 of 34 patients (94%); of the 2 patients who did not receive the full course, 1 patient (3%) received 4 of a planned 5 cycles due to GI/GU irritation, and 1 patient (3%) was limited to 3 cycles due to preexisting renal insufficiency.
Table 1 Patient characteristics. N (%) Mean age (range in years) Age ≤ 50 Age > 50 Histology Squamous Adenocarcinoma Adenosquamous Clinical stage IA2 IB1 IB2 IIA Type of surgery Open hysterectomy Laparoscopic Robotic Lymphovascular space invasion Yes No Lymph node procedure Pelvic dissection Para-aortic sampling Median lymph nodes removed (range) Pelvic Para-aortic Patients with positive lymph nodes Pelvic Para-aortic Margin status Negative Positive Risk group Intermediate High Extent of radiotherapy Pelvic Pelvic and para-aortic Type of chemotherapy Cisplatin Cisplatin + 5-fluorouracil
44 years (22.8–81.4) 23 (67.6%) 11 (32.4%) 17 (50%) 12 (35.3%) 5 (14.7%) 2 (5.9%) 23 (67.6%) 6 (17.6%) 3 (8.8%) 27 (79.4%) 4 (11.8%) 2 (5.9%) 31 (91.2%) 3 (8.8%) 34 (100%) 20 (58.8%) 28 (11–53) 3.5 (1–14) 22 (64.7%) 1 (2.9%) 31 (91.2%) 3 (8.8%%) 8 (23.5%) 26 (76.5%) 33 (97.1%) 1 (2.9%) 32 (94.1%) 2 (5.9%)
Outcomes Of the 34 patients in this study, three (8.8%) recurred, all of whom were high-risk patients. One patient had isolated vaginal cuff recurrence for which chemotherapy was recommended. One patient had synchronous relapse in her right pelvic side wall, abdominal wall, and liver, and was treated with carboplatin/paclitaxel-based chemotherapy and palliative surgical resection, and one patient recurred in the liver and was treated with carboplatin/paclitaxel-based chemotherapy. Thus, the rate of vaginal recurrence was 2.9% (1/34), pelvic side wall recurrence was 2.9% (1/34), and distant relapse was 5.9% (2/34). There were no para-aortic recurrences. The median time to local recurrence was 14.3 months and to distant recurrence 12.4 months. With a median follow-up of 44 months, the 3- and 5-year recurrence rate was 6% (95% CI, 0–14.2%) for both local/regional and distant failures. The 3- and 5-year DFS was 91.2% (95% CI, 81.4–100.0%). The 3- and 5-year OS was 91.1% (95% CI, 81.3–100%) (Fig. 2). Of the 34 patients, three have died, all following disease recurrence; the median time to death was 24.6 months, and the median time from recurrence to death was 10.3 months (range, 6.4–15.1 months). There was no death from other causes. Univariate analysis was performed to identify if any correlation existed between outcome and potential prognostic factors recorded in this cohort. Factors assessed were age > 50, histology, type of surgery performed, clinical stage, and risk group. Using log-rank tests on the Kaplan–Meier curves generated for these risk subgroups, no factor was found to be a significant predictor of local/regional control, DFS, or OS (Table 2).
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Fig. 2. Disease-free and overall survival.
Toxicity All (100%) patients had some degree of hematological toxicity (Grade 1, 88.2%; Grade 2, 67.6%; Grade 3, 29.4%; and Grade 4, 2.9%). The only hematologic Grade 4 toxicity observed occurred in a patient with a hemoglobin value during treatment of 6.3 g/dL; this was remediated with a transfusion. Acute gastrointestinal (GI) toxicity was seen in 31 (91.2%) patients (Grade 1, 73.5%; Grade 2, 23.5%; and Grade 3, 2.9%). The acute Grade 3 GI toxicity was diarrhea requiring IV hydration in 1 patient. Acute GU toxicity was observed in 12 (35.3%) patients (Grade 1 20.6%, Grade 2 14.7%). Chronic GI toxicity occurred in 5 (14.7%) patients, all Grade 1; there were no small bowel obstructions observed in this study population. Chronic GU toxicity occurred in 5 (14.7%) patients (Grade 1 11.8%, Grade 2 2.9%). Chronic vaginal toxicity (dryness and stenosis) occurred
in 13 (38.2%) patients, all Grade 1. Lower extremity edema occurred in 13 (38.2%) patients; (Grade 1 23.5%, Grade 2 14.7%). There were 2 (5.9%) sacral insufficiency fractures; 1 Grade 1 and 1 Grade 2 (Table 3). Discussion The role of postoperative pelvic RT combined with chemotherapy for intermediate and high risk cervical cancer is well established on the basis of two randomized trials [12,13,18]. While this treatment has been shown to have a significant impact on the risk of local recurrence and duration of disease-free survival, as well as survival benefit in high-risk patients, it is not without its morbidity. The conventional “4-field box” technique used in these studies is considered sufficient to deliver conformal radiation dose to the target at risk but also results in significant exposure to other organs in the pelvis. In intermediate risk patients, Sedlis et al. [12] observed 3 (2.3%) gastrointestinal
Table 2 Outcomes analysis by factor. Factor
3-Year local/regional control (95% CI)
Overall
94% (85.8–100%)
Age ≤50 >50
95.7% (87.1–100%) 90.9% (73.5–100%)
.618
91.3% (79.5–100%) 90.9% (73.5–100%)
.999
91.3% (79.5–100%) 90.9% (73.5–100%)
.989
Histology Squamous Non-squamous
93.8% (81.6–100%) 94.1% (83.7–100%)
1
88.2% (72.6–100%) 92.3% (77.5–100%)
.552
88.2% (72.6–100%) 94.1% (82.7–100%)
.564
Type of surgery Open Minimally invasive
96.3% (89.1–100%) 85.7% (59.3–100%)
.320
92.6% (82.6–100%) 85.7% (59.3–100%)
.320
92.6% (82.6–100%) 85.7% (59.3–100%)
.616
Stage IA2–IB1 IB2–IIA
96% (88.2–100%) 88.9% (67.9–100%)
.393
96% (88.2–100%) 77.8% (50–100%)
.086
95.8% (87.6–100%) 77.8% (50–100%)
.088
GOGa risk group Intermediate High
100% 92.1% (81.5–100%)
a
GOG: Gynecologic Oncology Group.
P value
3-Year disease-free survival (95% CI)
P value
91.2% (81.4–100%)
.423
100% 88.5% (75.9–100%)
3-Year overall survival (95% CI)
P value
91.1% (81.3–100.0%)
.327
100% 88.3% (75.5–100%)
.323
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Table 3 Acute and chronic toxicity of postoperative cervical intensity-modulated radiation therapy. ANC = absolute neutrophil count, GI = gastrointestinal; GU = genituourinary; Gyn = gynecological; Hgb = hemoglobin; Plt = platelets; SI = sacral insufficiency. Grade 1 (%)
Grade 2 (%)
Grade 3 (%)
Grade 4 (%)
Acute adverse effects GI, diarrhea GI, proctitis GI, enteritis GU, cystitis GU, frequency Hematologic, ANC Hematologic, Hgb Hematologic, Plt Post-surgical edema
13 (38.2%) 22 (64.7%) 5 (14.7%) 6 (17.6%) 2 (5.9%) 0 17 (50%) 19 (55.9%) 8 (23.5%)
3 (8.8%) 5 (14.7%) 2 (5.9%) 5 (14.7%) 0 7 (20.6%) 9 (26.5%) 0 0
0 1 (2.9%) 0 0 0 4 (11.8%) 3 0 0
0 0 0 0 0 0 1 (2.9%) 0 0
Chronic adverse effects GI, diarrhea GI, proctitis GU, frequency Gyn, any Hematologic, any Lower extremity edema SI fracture
5 (14.7%) 1 (2.9%) 4 (11.8%) 13 (38.2%) 0 8 (23.5%) 1 (2.9%)
0 0 1 (2.9%) 0 0 5 (14.7%) 1 (2.9%)
0 0 0 0 0 0 0
0 0 0 0 0 0 0
(GI) and 4 (3.1%) GU Grades 3–4 toxicities in 128 assessable patients receiving postoperative RT. In high-risk patients, Peters et al. [13] reported Grades 3–4 diarrhea in 12 (9.8%) patients and small bowel obstruction in 2 (1.6%) in the chemoradiation group. In comparison, there were 7 (6.3%) patients with Grades 3–4 diarrhea and 1 (0.9%) patient with small-bowel obstruction in the RT alone group. In the current study using IMRT, Grades 3–4 acute GI complications were observed in 1 (2.9%) patient. No acute Grades 3–4 GU or chronic Grades 3–4 toxicities were observed. Hasselle et al. [11] reported on 111 patients with stages I–IVA cervical cancer treated with IMRT. In the subset of 22 patients treated with postoperative RT, of which 12 (55%) received concurrent chemotherapy, they observed 1 patient (5%) with Grades 3–4 acute GI toxicity; no acute GU or chronic Grades 3–4 toxicities were observed. Chen et al. [10] reported on a group of 54 patients with cervical cancer, who were treated with adjuvant chemoradiation in the postoperative setting consisting of 50.4 Gy IMRT and cisplatin, as well as 6 Gy intravaginal RT in three fractions. In terms of acute toxicity, they observed no Grade 3 or higher GI or GU toxicities. There was 1 (1.8%) chronic Grade 3 GU toxicity. Reporting on lymphedema after radical hysterectomy and postoperative radiation has been sparse. In the current study, the rate of Grades 1–2 lymphedema was 38.2%. In comparison, a study by Ohba et al. [19] reported rates as high as 50% in the setting of postoperative pelvic radiation after systematic lymphadenectomy for cervical cancer. Hematologic toxicity resulting from irradiation of the pelvis in conjunction with marrow-suppressing chemotherapy has been the topic of several studies [4,20]; Sedlis et al. [12] reported 3 (2.3%) patients with Grades 3–4 acute hematologic toxicity in the arm receiving adjuvant radiation therapy; Peters et al. [13] reported Grades 3–4 hematologic toxicities including anemia in 4 (3.3%) patients, leukopenia in 43 (35.2%), granulocytopenia in 35 (28.7%), and thrombocytopenia in 1 (0.8%) in the chemoradiation group. In comparison, Grades 3–4 granulocytopenia and leukopenia were seen in 3 (2.7%) patients and 1 (0.9%) patient, respectively, in the adjuvant RT-alone group. In the current study using IMRT, Grades 3–4 acute hematologic toxicity was observed in 11 (32.3%) patients. Of these 11 patients, 10 (29.4%) patients had leukopenia (including 4/10 granulocytopenic) and 4 (11.7%) patients had anemia. The only Grade 4 hematological toxicity was anemia in one patient, which was corrected by transfusion. In Chen et al. [10], they observed 3 (6%) acute Grades 3–4 hematologic toxicities. Mell et al. [4] reported on 37 patients with cervical cancer treated
with IMRT and concurrent cisplatin, of which 22 (59.4%) patients were early stage; they observed Grades 3–4 hematological toxicities including anemia in 3 (8.1%) patients, granulocytopenia in 1 (2.7%) patient, and leukopenia in 4 (10.8%) patients. Comparison to a historical control group should always be exercised with caution, but interim reports from the ongoing RTOG trial [14], “A phase II study of intensity modulated radiation therapy (IMRT) to the pelvis ± chemotherapy for post-operative patients with either endometrial or cervical carcinoma,” provides corroboration for our results. For a group of 40 patients with cervical cancer treated with adjuvant chemoradiation, Klopp et al. [21] described significantly decreased rates of Grade 4 or higher hematologic toxicity (0% in the IMRT vs. 18% in the conventional comparison, P = .002). While the toxicity profile of postoperative pelvic IMRT seems to compare very favorably with conventional RT, it could be argued that the tight conformality attained by IMRT may adversely impact oncologic outcome. For intermediate-risk patients, the update of GOG 92 [18] showed PFS at 3 years to be approximately 86% and OS to be approximately 88%. In the Intergroup study [13] for high-risk patients, the estimated PFS at 3 years with chemoradiation was 84% and OS was 88%. With a median follow-up of 44 months in the current study, the 3- and 5-year OS was 91.1% (95% CI, 81.3– 100.0%) and the PFS was 91.2% (95% CI, 81.4–100.0%). Hasselle et al. [11] reported 3-year DFS and OS rates of 95.2% (95% CI, 86.7–100%) and 100% (95% CI, 80.3–100%) for the postoperative subset of 22 patients in their cohort with a median follow-up time of 27 months. Chen et al. [10,22] reported 3-year rates of locoregional control, DFS, and OS of 93% (95% CI, 86.5–99.5%), 78% (95% CI, 64.7–91.3%), and 98% (95% CI, 94–100%), respectively, in 54 patients treated postoperatively with a median follow-up of 20 months. Preliminary data from the RTOG 0418 trial (median follow-up of 32 months) [23] demonstrated 2-year DFS and OS rates of 86.9% (95% CI, 71.2–94.3%) and 94.6% (95% CI, 80.1–98.6%), respectively. When evaluating the outcomes and toxicity data presented in this study, it must be recognized that they are subject to the biases and limitations of a retrospective review of a single-institution experience. Every effort was made to ensure that the cohort presented was as homogeneous as possible; patients with any aspect of their treatment performed at an outside institution were excluded. Ultimately, confirmation of these results will come from the results of cooperative group studies such as the RTOG 0418 trial. In conclusion, based on this study, oncologic outcomes with postoperative pelvic IMRT and concurrent chemotherapy in early stage cervical cancer were excellent, with 3- and 5-year local control, DFS, and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. The morbidity profile was also very favorable, even in the setting of an aggressive trimodality approach. Data from this study as well as the emerging data from the Phase II RTOG study (0418) highlights the advantages of postoperative IMRT in the management of early stage cervical cancer. Conflict of interest statement The authors have no conflicts of interest to disclose.
Acknowledgments The authors would like to thank Lawrence A. Herman, who provided editorial assistance in the preparation of the final version of this manuscript. References [1] Loiselle C, Koh WJ. The emerging use of IMRT for treatment of cervical cancer. J Natl Compr Canc Netw 2010;8:1425-34. [2] Mell LK, Mehrotra AK, Mundt AJ. Intensity-modulated radiation therapy use in the U.S., 2004. Cancer 2005;104:1296-303.
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