Arch Gynecol Obstet DOI 10.1007/s00404-015-3712-3
GYNECOLOGIC ONCOLOGY
Five years’ experience treating locally advanced cervical cancer with concurrent chemoradiotherapy: results from a single institution J. Khalil1 • H. El Kacemi1 • M. Afif1 • T. Kebdani1 • N. Benjaafar1
Received: 12 January 2015 / Accepted: 1 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Introduction Cervical cancer is the second most common cause of female cancer death. In Morocco it is the second most common cancer, our department recruits more than 500 patients each year and proximally half of the cases are diagnosed at an advanced stage. Patients and methods Between January 2008 and December 2008, all patients with diagnosis of locally advanced cervical cancer referred to our department and treated with concurrent chemoradiotherapy were retrieved. We analyzed outcomes for this particular population; overall survival, local control, and toxicities, we also retrieved prognostic factors influencing outcomes for this population. Results The overall survival rate for the cohort was 68 % at 2 years, and reached 47 % at 5 years. The overall LC rate was 71 % at 2 years and 58 % at 5 years. The most important prognostic factors for OS and LC were the pretreatment hemoglobin, the tumor size, total duration of treatment, and the use of brachytherapy. For OS, the presence of enlarged lymph nodes was also important. For & J. Khalil [email protected] & N. Benjaafar [email protected] H. El Kacemi [email protected] M. Afif [email protected] T. Kebdani [email protected] 1
National Cancer Institute, Mohamed V University, Rabat, Morocco
LC, the number of chemotherapy’s courses was important. Of the included patients, 20 % experienced late grade 3 or 4 toxicity. Conclusion The results of our study have shown that despite all the treatment strategies available, locally advanced cervical cancer is associated with bad outcomes. In this cohort, the most important prognostic factors were the pretreatment hemoglobin level and the tumor size. Keywords Locally advanced cervical cancer Concurrent chemoradiotherapy Prognostic factors Abbreviations FIGO Federation of gynecology and obstetrics O.S Overall survival L.C Local control P.F.S Progression-free survival C.T Computed tomography MRI Magnetic resonance imaging EORTC European oncology and radiation therapy center RTOG Radiation therapy oncology group EBRT External beam radiation GOG Gynecologic oncology group NACT Neoadjuvant chemotherapy R.S Radical surgery LACC Locally advanced cervical cancer
Introduction Cervical cancer is one of the most widespread gynecological malignancies in women worldwide; it is also the second most common cause of female cancer death [1]. The incidence is even greater in developing countries, as an example, in Morocco cervical cancer is the second most
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common cancer in the country and is the third most common cause of death [2]. Cervical cancer is diagnosed at an advanced stage in more than half of the cases. Local control is particularly compromised in this population and is the major cause of death [3]. Treatment for uterine cervix cancer is related to the stage of the disease. As for locally advanced cervical cancer, concurrent chemoradiotherapy has been established to be the primary treatment of choice. In 1980 the high chemo-sensitivity of this cancer was quite evident and well recognized, since chemotherapy started to be strongly recommended especially after the National Cancer Institute Alert in 1999 [4], showing a 30–50 % decrease in risk of death; chemotherapy concomitantly with radiation has become the standard of care in women with cervical cancer. There have been many controversies concerning the management of locally advanced cervical cancer especially that it accounts for almost 60 % of all diagnosed cervical cancers tumors and is associated with a low 2- and 5-year overall survival ranging from 59 to 41 % [5]. In this population with advanced stage many factors have been associated with bad prognosis such as the tumor size and stage, the presence of positive lymph nodes, and the hemoglobin level. Some of the available data suggest a benefit from adding chemotherapy to the primary treatment in improving cancer outcomes [6, 7]. However, the available data do not recommend additional chemotherapy other than its use concomitantly with radiation as a standard of care for this particular population.
Materials and methods Data collection The National cancer institute of Morocco is a referral center specializing in oncology treatment and contains six major departments; surgery, external beam radiation and brachytherapy, medical oncology, radiology, pathology, and palliative and intensive care department. Most referrals are from within the north and east areas of the country. All women treated for cervical cancer in our institute between January 2008 and December 2008 were identified. Our study included only women with cervical cancer staged as IIB–IVA according to the International Federation of Gynecology and Obstetrics (FIGO) who were treated with primary chemoradiotherapy. For each patient, the case notes were evaluated to collect information retrospectively for the main outcome measures: overall survival (OS), local control (LC), and toxicity. For each patient, the following data were also collected for analysis of the prognostic factors: age, tumor stage,
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tumor size, histologic type, presence of lymphadenopathy, pretreatment hemoglobin level, mean hemoglobin during treatment, number of cycles of chemotherapy, external beam RT dose, total dose of HDR brachytherapy when given, and overall treatment time. Patients During the study period, 387 patients were identified; primary treatment consisted on radiation therapy in all the patients from the cohort. Chemotherapy was delivered concomitantly with radiation in all the cases. Of the 387 patients, we excluded 84 patients. 80 of them did not complete the planned treatment and 4 of them had received a neoadjuvant chemotherapy which was not a part of the inclusion criteria. Eventually, 303 patients treated with concomitant chemoradiotherapy were included in our study. Statistical analysis The Kaplan–Meier method was used to analyze OS and LC. Univariate analysis was performed using the log–rank test. Multivariate analysis was performed using the Cox proportional hazards model. A Statistical Package for Social Sciences package (SPSS) was used for analysis. Follow-up Patients were followed up for 5 years by radiation oncologists. If clinical suspicion of recurrence was present, additional investigation included examination under anesthesia whenever it was needed, biopsy, magnetic resonance imaging, or computed tomography scan. The median follow-up was 5 years.
Results Clinico-pathologic criteria in the studied patients: (Table 1) The mean age for the whole group of patients in this study was 47.7 (range 26–78 years), and the median age was 46 years. A maximum duration of symptoms prior to presentation of 24 months, and a minimum of 2 months with a mean duration of 5 ± 2.4 months was noted. Duration of symptoms was strongly correlated with stage at presentation by simple linear regression (p \ 0.001). The most common presenting symptoms were vaginal bleeding (298 patients, 98.3 %), vaginal discharge (278 patients, 92 %), pelvic pain (25 patients, 8.3 %), constipation (11 patients, 3.8 %), and dysurea (6 patients, 2 %). The mean size was
Arch Gynecol Obstet Table 1 Clinico-pathologic criteria and workup results for the studied patients Age
47.7 (26–78 years)
Duration of symptoms
5 ± 2.4 mouths
Symptom profile Vaginal bleeding
98.2 %
298
Vaginal discharge
92 %
278
Pelvic pain
8.3 %
25
Constipation
3.8 %
11
Dysurea
2%
Tumor size
4.87 cm (2.8–10 cm)
Vaginal involvement
49 %
181
Parametrial involvement Histopathological type
58 %
243
Squamous carcinoma
78 %
294
Adenocarcinoma
17 %
73
5%
19
Primitive iliac
47 %
182
External iliac
68 %
244
Internal iliac
5%
221
Obturator chain
18 %
89
Adenosquamous carcinoma
6
Positive ADP by CT and/or MRI
of the patients had an evaluation of thoracic metastases either by a chest X-ray which was performed in 65 % of the cases or a CT chest performed in 35 % of the cases. Radiological workup revealed 71 % cases of metastatic lymph nodes; 43 % in the primitive iliac chain, 13, 18, 56, 68 % in the presacral, obturator, internal, and external iliac chains. There were 34 % of positive Para-aortic lymph nodes. Biological workup All of our patients had a blood cell account and a dosage of the urea and the creatinine levels: the hemoglobin level was below 12 g/dl in 63 % of the cases and 34 % of them had a renal failure with a creatinine clearance of less than 60 ml/m2. Treatment modalities and results (Table 2)
4.87 cm (2.8–10 cm). Extension into the vagina was reported in 49 % of the cohort, it concerned the upper third in 10 % of the cases, the lower and the medial third in 13 and 31 % of the studied cohort. The parametrium was involved in 58 % of the cases; it concerned both sides in 42 % of the cases. Squamous carcinoma was the most histopathological type reported in our series and concerned 78 % of the patients; adenocarcinoma and adenosquamous carcinoma represented 17 and 5 % of the cohort.
All of our patients had primary chemoradiation as it was one of the inclusion criteria. Radiation therapy was delivered either as a combination of external beam radiation therapy (EBRT) and brachytherapy or as EBRT alone when brachytherapy was not feasible. 58 % of the studied cohort ended up receiving a total dose of 70 Gy with the combination of EBRT and brachytherapy, while 42 % received the same dose with EBRT alone as they were not candidate for brachytherapy; in fact, 14 % of them had a lower vaginal involvement and 18 % had either a cervicoisthmique or a uterus involvement, which in both cases were not covered by our brachytherapy applicators; 10 % of the studied cohort had a poor response with a gross residual volume not amenable to be treated with brachytherapy. When given alone radiation therapy was delivered in two phases of treatment to a total dose of 70 Gy. CT-based treatment planning and conformal blocking were both used in this setting. A fusion with MRI images was realized whenever MRI was available. In the first phase, volume included the gross disease, parametria, uterosacral ligaments, and a vaginal margin of 3 cm from the gross disease. Concerning the nodal volume,
Workup results
Table 2 Treatment modalities
Presacral chain
13 %
65
Para-aortic ADP
34 %
143
\12 g/dl
63 %
224
[12 g/dl
42 %
162
[60 [30 and \60
64 % 21 %
248 93
\30
13 %
46
Hemoglobin level
Creatinin clearance
Radiological workup In addition to the physical exam, 72 % of the cohort had an abdomino-pelvic CT to evaluate the loco regional extent and 32 % of them had a pelvic MRI along with abdominal CT. In only 3 % of the cases, no additional workup was performed because of their altered performance status. All
EBRT Alone In combination with brachytherapy Chemotherapy Concomitant
100 %
303
42 %
127
58 % 100 %
176 303
100 %
303
Cisplatin
87 %
264
Carboplatin
13 %
39
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for patients with negative nodes on radiologic imaging, the radiation volume included the entirety of the external iliac, internal iliac, and obturator nodal basins. For those deemed at higher risk of lymph node involvement (bulky tumors; suspected or confirmed nodes confined to the low true pelvis), the radiation volume was increased to cover the common iliacs as well. In patients with documented common iliac and/or para-aortic nodal involvement, extendedfield pelvic and para-aortic radiotherapy was used, up to the level of the renal vessels (or more cephalad as directed by involved nodal distribution). A total dose of 46 Gy was delivered with a box technique using four fields (anterior– posterior and two laterals); conformal blocking was used in all the cases to maximally spare the bowel and bladder and normal bone structures. The second phase consisted on a boost of 24 Gy delivered to the gross tumor volume defined by MRI when available; otherwise, the volume includes the whole cervix. A margin of 2 cm is then added. When feasible, brachytherapy was performed using intracavitary approach, with an intrauterine tandem and vaginal colpostats. Depending on the patient and tumor anatomy, the vaginal component of brachytherapy was delivered using either ovoids or ring applicators (combined with the intrauterine tandem). Ovoids were used in 42 % of the cases while ring applicators were used in 16 % of the cases; ring applicators were reserved for patients with lesions limited to the cervix with an intact vagina. MRI imaging immediately preceding brachytherapy was realized in 38 % of the case as a tool to help the delineation of the residual tumor. In all of the cases, brachytherapy was initiated toward the latter part of the EBRT treatment. An additional dose of 14–20 Gy was systematically delivered to any proven positive lymph nodes. Platinum-based regimen was the protocol used for all the cases. Weekly Cisplatin (40 mg/m2) was the most used regimen. Carboplatine was prescribed only in 13 % of the cases for whom renal failure (\30 ml/m2) was diagnosed before starting the treatment. Therapeutic results Radiotherapy compliance All of the 303 patients included in the study completed the planned radiotherapy treatment as it was one of the inclusion criteria. Two hundred and sixty-eight patients (97.3 %) completed external beam radiotherapy as planned without any interruptions. Three patients died during external beam radiotherapy. One patient, who had bulky stage IIIB disease died of pulmonary embolism that was misdiagnosed. The second patient developed cutaneous metastases during second week of chemotherapy and died
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consecutively. As to the third patient, he developed a neutropenic sepsis during the third week of chemoradiotherapy, and died 1 week later. The median time to start radiotherapy was 42 days (range 1–110 days). The median overall treatment time was 62 days (range 36–107 days). Chemotherapy compliance Chemotherapy was given as outpatient treatment. The antiemetic regimen consisted of Ondansetron 8 mg, given intravenously before chemotherapy, followed by dexamethasone 1 mg/kg orally one time a day for 5 days. Of the five planned cycles of concurrent cisplatin chemotherapy, 256 patients (84.5 %) received four or more cycles. Of these, 238 patients (78.5 %) completed all five cycles and 11 patients (3.6 %) had four cycles. The main reason for patients having reduced number of cycles was acute hematologic toxicity. Of the patients who completed fewer than four cycles, 32 (10.5 %) had received only three cycles because of renal failure, 15 (4.9 %) received between two and one cycle mainly because of side effects especially nausea and vomiting in 10 % of the cases. Treatment toxicities Acute toxicities (Table 3) 74 % of the admitted patients were closely monitored; they had a weekly evaluation along with a blood cell account and a dosage of urea and creatinine levels. We could not find any data concerning the remaining patients. The most common acute adverse effects were gastrointestinal (n = 184; 60.7 %) (diarrhea in 68 women, and nausea and vomiting in 123 women), hematological (n = 139; 46 %), infections (n = 88; 29 %), and skin reactions (n = 109; 36 %). The most common hematological toxicity was anemia (n = 126; 41.6 %); 117 women developed grade 1 or 2 toxicity, and 80 women developed grade 1 or 2 neutropenia. The most common acute grade 3 or 4 toxicity was hematological (n = 42; 13.8 %), with 27 (9 %) women experiencing grade 3 or 4 neutropenia, 9 women experiencing grade 3 or 4 anemia, and 6 women experiencing grade 3 or 4 thrombocytopenia. No women died from hematological toxicity, and it was reversible in all the cases. Twelve women (4 %) had acute grade 3 or gastrointestinal toxicity, and eight (2 %) women developed thromboembolic complications. Six deaths of treatment-related toxicity were noted. Death was related to neutropenic septicemia in two cases, peritonitis in one case and colon perforation in three cases.
Arch Gynecol Obstet Table 3 Treatment-related acute toxicities
Gastrointestinal
Table 4 Treatment-related late toxicities
%
n
% = 20.5
N = 62
60.7
184
Gastrointestinal
Diarrhea
22.4
68
Grade 1 or 2
3.3
10
Nausea–vomiting
40.6
123
Grade 3 or 4
5
15
Hematologic toxicities
51
197
Neutropenia
11.3
34
Grade 1 or 2
6
18
Grade 1 or 2
2.3
7
Grade 3 or 4
4
12
Grade 3 or 4
9
27
Thromboembolic
Anemia
Genitourinary
41.6
126
Grade 1 or 2
0.3
1
Grade 1 or 2
38.6
117
Grade 3 or 4
2
6
Grade 3 or 4
3
9
2.6 0.6
8 2
Grade 1 or 2 Grade 3 or 4
Thrombopenia Grade 1 or 2 Grade 3 or 4 Renal insufficiency Radio cystitis
Renal 4.6 5.6
14 17
2
6
Musculoskeletal
19
58
Grade 1 or 2
1
3
Grade 3 or 4
0.6
2
37
112
Grade 1
7
21
Grade 2
21
63
Grade 3
9
28
Late toxicities (Table 4) Late complications were defined as occurring more than 3 months after the first day of radiotherapy. Late grade 3 or 4 complications were noted in 46 cases. The late toxicity experienced by these women is documented below in Table 4. Of these 46 patients, 32 patients with severe late toxicity were treated to full-dose EBRT without brachytherapy. OS and LC (Figs. 1 and 2) The overall 2-year survival rate for the cohort was 72 %, and the overall 5-year survival rate was 57 %. The overall LC rate was 71 % at 2 years and 61 % at 5 years. Although tumor size was not found to be an independent prognostic factor for LC, we observed a difference in LC for patients with different tumor sizes. At 2 years, the LC rate was 78 % (95 % confidence interval [CI], 68–86 %) for patients with tumors \4 cm and 59 % (95 % CI, 39–76 %) in patients with tumors [4 cm. At 5 years, the LC rate was 67 % (95 % CI, 46–76 %) and 48 % (95 % CI, 30–68 %) for these groups, respectively. Univariate analysis The univariate analysis examined prognosis factors affecting the aforementioned variables. OS was significantly
affected by the pretreatment hemoglobin (p = 0.015), tumor size (p = 0.017), and total treatment duration. According to Exp(B), we found a 1.6 times reduction in OS for the range of 8–10 g/dl of the pretreatment hemoglobin and a 2.5 times reduction in OS for patients with a tumor size of 4–6 cm when compared with \4 cm. The presence of pelvic lymphadenopathy was also found to be a significant prognostic factor (p = 0.03). OS was in fact reduced by a factor of 2.4. OS was significantly reduced (p = 0.02) when the total treatment duration exceeded 55 days. For LC, the pretreatment hemoglobin level was again a prognostic indicator (p = 0.018), so was the tumor size with a decrease of LC by a factor of 1.8 with a tumor size of 4 cm and above. The use of brachytherapy for the tumor boost was also found to be a significant factor influencing the LC; a decrease of LC by a factor of 2.1 in the absence of brachytherapy was noted. The number of cycles of chemotherapy completed (p = 0.032) was also a significant factor for LC. Other factors were also found in our analysis but could not reach significant values; young age and histological type were identified with non-significant p (Table 5). Multivariate analysis The only independently significant variables that were identified in the multivariate analysis were tumor size (p = 0.047) and pretreatment hemoglobin level (p = 0.016) (Table 6).
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Arch Gynecol Obstet Fig. 1 Five year overall survival for the studied cohort
Fig. 2 Local control for the studied cohort
Discussion Cervical cancer is a major health problem. Worldwide, it accounts for 287,000 deaths in 2008, and this number is expected to rise up to 410,000 by 2030 [8, 9]. Despite the worldwide implementation of prevention and early detection strategies, including the Papanicolaou smear test, human papillomavirus (HPV) testing, and vaccines, approximately 30 % of newly diagnosed cases are categorized as ‘‘locally advanced disease’’ [10]. Furthermore, 50 % of patients with locally advanced disease are expected to relapse within the first 2 years after initial
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treatment [11]. Advanced cervical cancer has been reported to be associated with low overall survival and local control rates despite a well-conducted concurrent chemoradiotherapy. In fact, tumor relapse’s rate is around 50–70 % in LACC [12]. In our series, tumor relapse’s rate was around 60 %. Tumor size, hemoglobin level, and the presence of pelvic lymphadenopathy are the most reported indicators influencing outcomes in LACC. A retrospective study by Mark et al. showed that a hemoglobin level of less than 10 g/dl is associated to a low survival rate. Girinski et al. [13] found that the hemoglobin level before the treatment was not a significant indicator but it significantly affects
Arch Gynecol Obstet Table 5 Univariate analysis for prognostic factors p
Risk or Exp(B)
Exp(B) CI 95 %
Pretreatment hemoglobin
p = 0.015
0.615
0.519–0.862
Tumor size
p = 0.017
0.745
0.456–0.789
Total treatment duration
p = 0.03
0.876
0.617–0.945
Presence of pelvic adenopathy
p = 0.02
0.634
0.523–0.767
Number of cycles of chemotherapy (\4)
p = 0.032
0.786
0.456–0.865
Table 6 Multivariate analysis for prognostic factors p
Risk or Exp(B)
Exp(B) CI 95 %
Pretreatment hemoglobin
p = 0.016
0.575
0.523–0.762
Tumor size
p = 0.047
0.865
0.523–0.678
outcomes during radiotherapy, in their retrospective study that included 386 patients treated at the Gustave-Roussy institute; anemia during radiotherapy led to a relative risk of local relapse of 1.6 and metastatic relapse of 1.8 [14]. Tumor volume defined as ‘‘Bulky’’ is not well established in the literature; it is in some situations defined as 4 cm, 5 cm and very often as 6 cm [15]. Perez et al. [15] found that stage IIIB was associated to a high rate of metastatic relapse when compared with stage IIIA and bellow. Finally, available data suggest that patients with positive lymph nodes are at a higher risk of developing relapses [16, 17]. In our series, tumor size and pretreatment hemoglobin level were identified as independent prognostic factors. Data from Atahan et al. [18] showed overall treatment time to be a significant prognostic factor for survival; a decrease in overall survival was reported in increased total treatment durations ([55 h). In our series, OS was in fact reduced by a factor of 2.4. OS was significantly reduced (p = 0.02) when the total treatment duration exceeded 55 days. Concurrent chemoradiation is considered to be the standard of care for this category [19, 20]. In 1999, a randomized phase III trial conducted by Morris et al. at the MD Anderson cancer center included 401 patients with advanced cervical cancer and compared radiotherapy alone with the combination of chemotherapy (Platine- and 5FUbased regimen) and radiation. At 5 years, PFS was 67 % with the association of chemotherapy and radiation while it reached only 40 % with radiotherapy alone (p \ 0.001). Overall survival rates were respectively 73 and 58 % (p = 0.004) [21]. These results were confirmed by other randomized trials that concerned this particular population
[22–26]; toxicity among these trials was considered to be acceptable. Hence concurrent radiochemotherapy is the treatment of choice for locally advanced cervical cancer. Currently, acceptable concurrent cisplatine-based regimens are either weekly Cisplatine or the combination of 5FUCisplatine [19, 20, 24–26]. Other associations have been evaluated to improve outcomes in advanced cervical cancer; in a recent international phase III randomized trial, the combination of cisplatine/gemcitabine concomitantly with radiotherapy followed by two additional cycles of the same regimen of chemotherapy was associated with an improved rates of PFS and OS when compared with the standard treatment [27]. However, these results are controversial because in one hand there were changes in its statistical design and in the other hand the superiority of this combination was associated with unresolved toxicity issues [27–29]. Nedaplatin is a synthetic analog of cisplatin that has also been evaluated in the concurrent chemoradiation setting. In a pilot phase II trial, weekly nedaplatin concurrently with radiation achieved an ORR of 90 %, a 3-year PFS of 58.7 %, and an OS of 78.0 % [30]. Non-platinum-containing regimens have been widely explored. The feasibility of concurrent radiotherapy and paclitaxel administration was evaluated in a pilot study with 20 patients (13 new cases, stage IIB–III, and 7 with pelvic recurrences) and complete regression was reported in 63 % [31]. In a subsequent randomized phase II trial, weekly cisplatin was compared to weekly paclitaxel as concurrent chemotherapy with standard RT in patients with stage IB2–IVA disease or with postsurgical pelvic recurrence, as results weekly paclitaxel did not provide any clinical advantage over weekly cisplatin [32]. A multiagent regimen that included paclitaxel, ifosfamide, and cisplatin (TIP) has been also evaluated in two different settings: bulky and locally advanced cervical cancer and recurrentpersistent disease [33]. Finally, the combination of paclitaxel and vinorelbine was associated with significant hematologic toxicity [34]. Mitomycin C is another drug that has been tested in locally advanced cervical cancer; its use concurrently with radiotherapy was first evaluated in a randomized trial including 160 patients, and better results were seen in the mitomycin arm when compared with radiation alone [35]. The combination of 5FU and Mitomycin C concurrently with radiotherapy was then evaluated in four trials, two of them comparing the combination with RT alone [36], and the other two comparing the combination with Mitomycin C alone [36, 37] suggesting better results with the combination over infusional 5FU concurrently with RT [37]. In a validation phase I cohort, intravenous topotecan was used with cisplatin concurrently with pelvic radiation and intracavitary brachytherapy with tolerable toxicities and good results [38, 39]. The safety and feasibility of concurrent radiation therapy with weekly
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irinotecan in patients with locally advanced disease were evaluated in two small phase II trials, suggesting promising efficacy and tolerable adverse events [40, 41]. More recently, induction chemotherapy followed by concurrent chemoradiation or surgery alone, and also preoperative concurrent chemoradiation and adjuvant chemotherapy to concurrent chemoradiation have been implemented in the therapeutic armamentarium in an effort to optimize local control and also to minimize the risk for metastatic disease. Between 1983 and 1995, 20 pilot studies were conducted to determine the efficacy of neoadjuvant chemotherapy preceding radical surgery treatment, showing an overall response of 77.5 %. A recent Cochrane review and a randomized GOG study have questioned this association and compared NACT ? RS versus RS alone [42, 43]. However, available data are very difficult to interpret. On one hand, the Cochrane review has assembled data on both early (IB1) and locally advanced stages, and it is commonly known that the greatest benefit of NACT is essentially seen on locally advanced cervical cancer (LACC) [6, 42, 44–47]. On the other hand, Cisplatin dosage reported was different among different studies, which is considered to be an important bias. A recent ongoing trial planned by EORTC (55994EORTC) comparing NACT ? RS versus CT/RT in stage IB2–IIB cervical is awaited and will answer to this particular question. In 2000, Peters et al. advocated another treatment strategy in a GOG protocol; it consisted of adding 3–4 cycles of chemotherapy after completion of CT/RT. A recent meta-analysis showed larger benefits in trials in which additional chemotherapy was administered after CT/RT, with an absolute improvement of 19 % at 5 years [28]. Although these encouraging results, concomitant chemotherapy and radiation are still the treatment of choice for locally advanced cervical cancer, and other options are still under investigation.
Conclusion In our country cervical cancer is mostly diagnosed at an advanced stage, despite all the efforts made to improve treatment options, outcomes are still poor. As in the literature, our review found that hemoglobin level, tumor size and presence of positive lymph nodes are indicators of bad prognosis in this particular population. Newer treatment options are still under investigation to enhance LC, and eventually OS. Conflict of interest We declare not having any competing interests. Informed consent Written informed consent was obtained from the patient for publication of this case report and accompanying images.
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A copy of the written consent is available for review by the Editor-inChief of this journal.
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definitive radio- therapy. Int J Radiation Oncology Biol Phys 60:249–257 Atahan Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up N. Colombo1,2, S. Carinelli3, A. Colombo4, C. Marini5, D. Rollo1 and C. Sessa5,6, on behalf ofthe ESMO Guidelines Working Group* NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesÒ) Cervical Cancer Version 2014 Morris M, Eifel PJ, Lu J et al (1999) Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high risk cervical cancer. N Engl J Med 340:1137–1143 Keys Henry M, Bundy Brian N, Stehman Frederick B, Muderspach Laila I (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340(15):1154–1161 Roberts WS, Kavanagh JJ, Greenberg H (1989) Concomitant radiation therapy and chemotherapy in the treatment of advanced squamous carcinoma of the lower female genital tract. Gynecol Oncol 34:183–186 Rose Peter G, Bundy Brian N, Watkins Edwin B, Thigpen Tate J (1999) Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340(15):1144–1153 Gaffney DK, Erickson-Wittmann BA, Jhingran A et al (2011) ACR Appropriateness Criteria(R) on advanced cervical cancer expert panel on radiation oncology-gynecology. Int J Radiat Oncol Biol Phys 81:609–614 Monk BJ, Tewari KS, Koh W-J (2007) Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 25:2952–2965 Duenas-Gonzalez A, Zarba JJ, Patel F et al (2011) Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29:1678–1685 Thomas G (2011) Are we making progress in curing advanced cervical cancer. J Clin Oncol 29:1654–1656 Rose PG, Degeest K, McMeekin S, Fusco N (2007) A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 107:274–279 Yokoyama Y, Takano T, Nakahara K et al (2008) A phase II multicenter trial of concurrent chemoradiotherapy with weekly nedaplatin in advanced uterine cervical carcinoma: Tohoku gynecologic cancer unit study. Oncol Rep 19(6):1551–1556 Cerrotta A, Gardani G, Cavina R et al (2002) Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose. Eur J Gynaecol Oncol 23(2):115–119 Geara FB, Shamseddine A, Khalil A, Abboud M, Charafeddine M, Seoud M (2010) A phase II randomized trial comparing radiotherapy with concurrent weekly cisplatin or weekly paclitaxel in patients with advanced cervical cancer. Radiat Oncol 5(1), article 84 Zanetta G, Fei F, Mangioni C (2000) Chemotherapy with paclitaxel, ifosfamide, and cisplatin for the treatment of squamous cell
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cervical cancer: the experience of Monza. Semin Onvcol 27(1, supplement):23–27 Mundt AJ, Rotmensch J, Waggoner SE, Yamada D, Langhauser SC, Fleming GF (2001) Phase I trial of concomitant vinorelbine, paclitaxel, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies. Gynecol Oncol 82(2):333–337 Roberts KB, Urdaneta N, Vera R (2000) Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix. Int J Cancer 90(4):206–223 Nguyen PD, John B, Munoz AK, Yazigi R, Graham M, Franklin P (1991) Mitomycin-C/5-FU and radiation therapy for locally advanced uterine cervical cancer. Gynecol Oncol 43(3):220–225 Ludgate SM, Crandon AJ, Hudson CN, Walker Q, Langlands AO (1988) Synchronous 5-fluorouracil, mitomycin-C and radiation therapy in the treatment of locally advanced carcinoma of the cervix. Int J Radiat Oncol Biol Phys 15(4):893–899 John M, Flam M, Caplan R et al (1996) Final results of a phase II chemoradiation protocol for locally advanced cervical cancer: RTOG 85-15. Gynecol Oncol 61(2):221–226 Christie DR, Bull CA, Gebski V, Langlands AO (1995) Concurrent 5-fluorouracil, mitomycin C and irradiation in locally advanced cervix cancer. Radiother Oncol 37(3):181–189 Fabbro M, Gladieff L, Guichard F et al (2010) Phase I study of irinotecan and cisplatin in combination with pelvic radiotherapy in the treatment of locally advanced cervical cancer: a GINECO trial. Gynecol Oncol 117(2):276–280 Suntornpong N, Chansilp Y, Pattaranutaporn P, Thephamongkhol K (2003) Concurrent radiation therapy and irinotecan in stage IIIB cervical cancer. J Med Assoc Thail 86(5):430–435 Rydzewska L, Tierney J, Vale CL, Symonds PR (2010) Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev 1:CD007406 (Review) Chen H, Liang C, Zhang L, Huang s, Wu X (2008) Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: a randomized study. Gynecol Oncol 110:308–315 Benedetti-Panici P, Greggi S, Colombo A, Amoroso M, Smaniotto D, Giannarelli D, Amunni G et al (2002) Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20(1):179–188 Namkoong SE, Park JS, Kim JW (1995) Comparative study of the patients with locally advanced stages I and II cervical cancer treated by radical surgery with and without preoperative adjuvant chemotherapy. Gynecol Oncol 59:136–142 Cho YH, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH (2009) Comparative study of neoadjuvant chemotherapy before radical hysterectomy and radical surgery alone in stage IB2–IIA bulky cervical cancer. J Gynecol Oncol 20(1):22–27 Gong L, Lou JY, Wang P, Zhang JW, Liu H, Peng ZL (2012) Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2–IIB cervical cancer. Int J Gynaecol Obstet 117(1):23–26 Sardi JE, Sananes C, Giaroli A et al (1998) Neoadjuvant chemotherapy in cervical carcinoma stage IIB: a randomized controlled trial. Int J Gynecol Cancer 8:441–450
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GYNECOLOGIC ONCOLOGY
Five years’ experience treating locally advanced cervical cancer with concurrent chemoradiotherapy: results from a single institution J. Khalil1 • H. El Kacemi1 • M. Afif1 • T. Kebdani1 • N. Benjaafar1
Received: 12 January 2015 / Accepted: 1 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Introduction Cervical cancer is the second most common cause of female cancer death. In Morocco it is the second most common cancer, our department recruits more than 500 patients each year and proximally half of the cases are diagnosed at an advanced stage. Patients and methods Between January 2008 and December 2008, all patients with diagnosis of locally advanced cervical cancer referred to our department and treated with concurrent chemoradiotherapy were retrieved. We analyzed outcomes for this particular population; overall survival, local control, and toxicities, we also retrieved prognostic factors influencing outcomes for this population. Results The overall survival rate for the cohort was 68 % at 2 years, and reached 47 % at 5 years. The overall LC rate was 71 % at 2 years and 58 % at 5 years. The most important prognostic factors for OS and LC were the pretreatment hemoglobin, the tumor size, total duration of treatment, and the use of brachytherapy. For OS, the presence of enlarged lymph nodes was also important. For & J. Khalil [email protected] & N. Benjaafar [email protected] H. El Kacemi [email protected] M. Afif [email protected] T. Kebdani [email protected] 1
National Cancer Institute, Mohamed V University, Rabat, Morocco
LC, the number of chemotherapy’s courses was important. Of the included patients, 20 % experienced late grade 3 or 4 toxicity. Conclusion The results of our study have shown that despite all the treatment strategies available, locally advanced cervical cancer is associated with bad outcomes. In this cohort, the most important prognostic factors were the pretreatment hemoglobin level and the tumor size. Keywords Locally advanced cervical cancer Concurrent chemoradiotherapy Prognostic factors Abbreviations FIGO Federation of gynecology and obstetrics O.S Overall survival L.C Local control P.F.S Progression-free survival C.T Computed tomography MRI Magnetic resonance imaging EORTC European oncology and radiation therapy center RTOG Radiation therapy oncology group EBRT External beam radiation GOG Gynecologic oncology group NACT Neoadjuvant chemotherapy R.S Radical surgery LACC Locally advanced cervical cancer
Introduction Cervical cancer is one of the most widespread gynecological malignancies in women worldwide; it is also the second most common cause of female cancer death [1]. The incidence is even greater in developing countries, as an example, in Morocco cervical cancer is the second most
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common cancer in the country and is the third most common cause of death [2]. Cervical cancer is diagnosed at an advanced stage in more than half of the cases. Local control is particularly compromised in this population and is the major cause of death [3]. Treatment for uterine cervix cancer is related to the stage of the disease. As for locally advanced cervical cancer, concurrent chemoradiotherapy has been established to be the primary treatment of choice. In 1980 the high chemo-sensitivity of this cancer was quite evident and well recognized, since chemotherapy started to be strongly recommended especially after the National Cancer Institute Alert in 1999 [4], showing a 30–50 % decrease in risk of death; chemotherapy concomitantly with radiation has become the standard of care in women with cervical cancer. There have been many controversies concerning the management of locally advanced cervical cancer especially that it accounts for almost 60 % of all diagnosed cervical cancers tumors and is associated with a low 2- and 5-year overall survival ranging from 59 to 41 % [5]. In this population with advanced stage many factors have been associated with bad prognosis such as the tumor size and stage, the presence of positive lymph nodes, and the hemoglobin level. Some of the available data suggest a benefit from adding chemotherapy to the primary treatment in improving cancer outcomes [6, 7]. However, the available data do not recommend additional chemotherapy other than its use concomitantly with radiation as a standard of care for this particular population.
Materials and methods Data collection The National cancer institute of Morocco is a referral center specializing in oncology treatment and contains six major departments; surgery, external beam radiation and brachytherapy, medical oncology, radiology, pathology, and palliative and intensive care department. Most referrals are from within the north and east areas of the country. All women treated for cervical cancer in our institute between January 2008 and December 2008 were identified. Our study included only women with cervical cancer staged as IIB–IVA according to the International Federation of Gynecology and Obstetrics (FIGO) who were treated with primary chemoradiotherapy. For each patient, the case notes were evaluated to collect information retrospectively for the main outcome measures: overall survival (OS), local control (LC), and toxicity. For each patient, the following data were also collected for analysis of the prognostic factors: age, tumor stage,
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tumor size, histologic type, presence of lymphadenopathy, pretreatment hemoglobin level, mean hemoglobin during treatment, number of cycles of chemotherapy, external beam RT dose, total dose of HDR brachytherapy when given, and overall treatment time. Patients During the study period, 387 patients were identified; primary treatment consisted on radiation therapy in all the patients from the cohort. Chemotherapy was delivered concomitantly with radiation in all the cases. Of the 387 patients, we excluded 84 patients. 80 of them did not complete the planned treatment and 4 of them had received a neoadjuvant chemotherapy which was not a part of the inclusion criteria. Eventually, 303 patients treated with concomitant chemoradiotherapy were included in our study. Statistical analysis The Kaplan–Meier method was used to analyze OS and LC. Univariate analysis was performed using the log–rank test. Multivariate analysis was performed using the Cox proportional hazards model. A Statistical Package for Social Sciences package (SPSS) was used for analysis. Follow-up Patients were followed up for 5 years by radiation oncologists. If clinical suspicion of recurrence was present, additional investigation included examination under anesthesia whenever it was needed, biopsy, magnetic resonance imaging, or computed tomography scan. The median follow-up was 5 years.
Results Clinico-pathologic criteria in the studied patients: (Table 1) The mean age for the whole group of patients in this study was 47.7 (range 26–78 years), and the median age was 46 years. A maximum duration of symptoms prior to presentation of 24 months, and a minimum of 2 months with a mean duration of 5 ± 2.4 months was noted. Duration of symptoms was strongly correlated with stage at presentation by simple linear regression (p \ 0.001). The most common presenting symptoms were vaginal bleeding (298 patients, 98.3 %), vaginal discharge (278 patients, 92 %), pelvic pain (25 patients, 8.3 %), constipation (11 patients, 3.8 %), and dysurea (6 patients, 2 %). The mean size was
Arch Gynecol Obstet Table 1 Clinico-pathologic criteria and workup results for the studied patients Age
47.7 (26–78 years)
Duration of symptoms
5 ± 2.4 mouths
Symptom profile Vaginal bleeding
98.2 %
298
Vaginal discharge
92 %
278
Pelvic pain
8.3 %
25
Constipation
3.8 %
11
Dysurea
2%
Tumor size
4.87 cm (2.8–10 cm)
Vaginal involvement
49 %
181
Parametrial involvement Histopathological type
58 %
243
Squamous carcinoma
78 %
294
Adenocarcinoma
17 %
73
5%
19
Primitive iliac
47 %
182
External iliac
68 %
244
Internal iliac
5%
221
Obturator chain
18 %
89
Adenosquamous carcinoma
6
Positive ADP by CT and/or MRI
of the patients had an evaluation of thoracic metastases either by a chest X-ray which was performed in 65 % of the cases or a CT chest performed in 35 % of the cases. Radiological workup revealed 71 % cases of metastatic lymph nodes; 43 % in the primitive iliac chain, 13, 18, 56, 68 % in the presacral, obturator, internal, and external iliac chains. There were 34 % of positive Para-aortic lymph nodes. Biological workup All of our patients had a blood cell account and a dosage of the urea and the creatinine levels: the hemoglobin level was below 12 g/dl in 63 % of the cases and 34 % of them had a renal failure with a creatinine clearance of less than 60 ml/m2. Treatment modalities and results (Table 2)
4.87 cm (2.8–10 cm). Extension into the vagina was reported in 49 % of the cohort, it concerned the upper third in 10 % of the cases, the lower and the medial third in 13 and 31 % of the studied cohort. The parametrium was involved in 58 % of the cases; it concerned both sides in 42 % of the cases. Squamous carcinoma was the most histopathological type reported in our series and concerned 78 % of the patients; adenocarcinoma and adenosquamous carcinoma represented 17 and 5 % of the cohort.
All of our patients had primary chemoradiation as it was one of the inclusion criteria. Radiation therapy was delivered either as a combination of external beam radiation therapy (EBRT) and brachytherapy or as EBRT alone when brachytherapy was not feasible. 58 % of the studied cohort ended up receiving a total dose of 70 Gy with the combination of EBRT and brachytherapy, while 42 % received the same dose with EBRT alone as they were not candidate for brachytherapy; in fact, 14 % of them had a lower vaginal involvement and 18 % had either a cervicoisthmique or a uterus involvement, which in both cases were not covered by our brachytherapy applicators; 10 % of the studied cohort had a poor response with a gross residual volume not amenable to be treated with brachytherapy. When given alone radiation therapy was delivered in two phases of treatment to a total dose of 70 Gy. CT-based treatment planning and conformal blocking were both used in this setting. A fusion with MRI images was realized whenever MRI was available. In the first phase, volume included the gross disease, parametria, uterosacral ligaments, and a vaginal margin of 3 cm from the gross disease. Concerning the nodal volume,
Workup results
Table 2 Treatment modalities
Presacral chain
13 %
65
Para-aortic ADP
34 %
143
\12 g/dl
63 %
224
[12 g/dl
42 %
162
[60 [30 and \60
64 % 21 %
248 93
\30
13 %
46
Hemoglobin level
Creatinin clearance
Radiological workup In addition to the physical exam, 72 % of the cohort had an abdomino-pelvic CT to evaluate the loco regional extent and 32 % of them had a pelvic MRI along with abdominal CT. In only 3 % of the cases, no additional workup was performed because of their altered performance status. All
EBRT Alone In combination with brachytherapy Chemotherapy Concomitant
100 %
303
42 %
127
58 % 100 %
176 303
100 %
303
Cisplatin
87 %
264
Carboplatin
13 %
39
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for patients with negative nodes on radiologic imaging, the radiation volume included the entirety of the external iliac, internal iliac, and obturator nodal basins. For those deemed at higher risk of lymph node involvement (bulky tumors; suspected or confirmed nodes confined to the low true pelvis), the radiation volume was increased to cover the common iliacs as well. In patients with documented common iliac and/or para-aortic nodal involvement, extendedfield pelvic and para-aortic radiotherapy was used, up to the level of the renal vessels (or more cephalad as directed by involved nodal distribution). A total dose of 46 Gy was delivered with a box technique using four fields (anterior– posterior and two laterals); conformal blocking was used in all the cases to maximally spare the bowel and bladder and normal bone structures. The second phase consisted on a boost of 24 Gy delivered to the gross tumor volume defined by MRI when available; otherwise, the volume includes the whole cervix. A margin of 2 cm is then added. When feasible, brachytherapy was performed using intracavitary approach, with an intrauterine tandem and vaginal colpostats. Depending on the patient and tumor anatomy, the vaginal component of brachytherapy was delivered using either ovoids or ring applicators (combined with the intrauterine tandem). Ovoids were used in 42 % of the cases while ring applicators were used in 16 % of the cases; ring applicators were reserved for patients with lesions limited to the cervix with an intact vagina. MRI imaging immediately preceding brachytherapy was realized in 38 % of the case as a tool to help the delineation of the residual tumor. In all of the cases, brachytherapy was initiated toward the latter part of the EBRT treatment. An additional dose of 14–20 Gy was systematically delivered to any proven positive lymph nodes. Platinum-based regimen was the protocol used for all the cases. Weekly Cisplatin (40 mg/m2) was the most used regimen. Carboplatine was prescribed only in 13 % of the cases for whom renal failure (\30 ml/m2) was diagnosed before starting the treatment. Therapeutic results Radiotherapy compliance All of the 303 patients included in the study completed the planned radiotherapy treatment as it was one of the inclusion criteria. Two hundred and sixty-eight patients (97.3 %) completed external beam radiotherapy as planned without any interruptions. Three patients died during external beam radiotherapy. One patient, who had bulky stage IIIB disease died of pulmonary embolism that was misdiagnosed. The second patient developed cutaneous metastases during second week of chemotherapy and died
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consecutively. As to the third patient, he developed a neutropenic sepsis during the third week of chemoradiotherapy, and died 1 week later. The median time to start radiotherapy was 42 days (range 1–110 days). The median overall treatment time was 62 days (range 36–107 days). Chemotherapy compliance Chemotherapy was given as outpatient treatment. The antiemetic regimen consisted of Ondansetron 8 mg, given intravenously before chemotherapy, followed by dexamethasone 1 mg/kg orally one time a day for 5 days. Of the five planned cycles of concurrent cisplatin chemotherapy, 256 patients (84.5 %) received four or more cycles. Of these, 238 patients (78.5 %) completed all five cycles and 11 patients (3.6 %) had four cycles. The main reason for patients having reduced number of cycles was acute hematologic toxicity. Of the patients who completed fewer than four cycles, 32 (10.5 %) had received only three cycles because of renal failure, 15 (4.9 %) received between two and one cycle mainly because of side effects especially nausea and vomiting in 10 % of the cases. Treatment toxicities Acute toxicities (Table 3) 74 % of the admitted patients were closely monitored; they had a weekly evaluation along with a blood cell account and a dosage of urea and creatinine levels. We could not find any data concerning the remaining patients. The most common acute adverse effects were gastrointestinal (n = 184; 60.7 %) (diarrhea in 68 women, and nausea and vomiting in 123 women), hematological (n = 139; 46 %), infections (n = 88; 29 %), and skin reactions (n = 109; 36 %). The most common hematological toxicity was anemia (n = 126; 41.6 %); 117 women developed grade 1 or 2 toxicity, and 80 women developed grade 1 or 2 neutropenia. The most common acute grade 3 or 4 toxicity was hematological (n = 42; 13.8 %), with 27 (9 %) women experiencing grade 3 or 4 neutropenia, 9 women experiencing grade 3 or 4 anemia, and 6 women experiencing grade 3 or 4 thrombocytopenia. No women died from hematological toxicity, and it was reversible in all the cases. Twelve women (4 %) had acute grade 3 or gastrointestinal toxicity, and eight (2 %) women developed thromboembolic complications. Six deaths of treatment-related toxicity were noted. Death was related to neutropenic septicemia in two cases, peritonitis in one case and colon perforation in three cases.
Arch Gynecol Obstet Table 3 Treatment-related acute toxicities
Gastrointestinal
Table 4 Treatment-related late toxicities
%
n
% = 20.5
N = 62
60.7
184
Gastrointestinal
Diarrhea
22.4
68
Grade 1 or 2
3.3
10
Nausea–vomiting
40.6
123
Grade 3 or 4
5
15
Hematologic toxicities
51
197
Neutropenia
11.3
34
Grade 1 or 2
6
18
Grade 1 or 2
2.3
7
Grade 3 or 4
4
12
Grade 3 or 4
9
27
Thromboembolic
Anemia
Genitourinary
41.6
126
Grade 1 or 2
0.3
1
Grade 1 or 2
38.6
117
Grade 3 or 4
2
6
Grade 3 or 4
3
9
2.6 0.6
8 2
Grade 1 or 2 Grade 3 or 4
Thrombopenia Grade 1 or 2 Grade 3 or 4 Renal insufficiency Radio cystitis
Renal 4.6 5.6
14 17
2
6
Musculoskeletal
19
58
Grade 1 or 2
1
3
Grade 3 or 4
0.6
2
37
112
Grade 1
7
21
Grade 2
21
63
Grade 3
9
28
Late toxicities (Table 4) Late complications were defined as occurring more than 3 months after the first day of radiotherapy. Late grade 3 or 4 complications were noted in 46 cases. The late toxicity experienced by these women is documented below in Table 4. Of these 46 patients, 32 patients with severe late toxicity were treated to full-dose EBRT without brachytherapy. OS and LC (Figs. 1 and 2) The overall 2-year survival rate for the cohort was 72 %, and the overall 5-year survival rate was 57 %. The overall LC rate was 71 % at 2 years and 61 % at 5 years. Although tumor size was not found to be an independent prognostic factor for LC, we observed a difference in LC for patients with different tumor sizes. At 2 years, the LC rate was 78 % (95 % confidence interval [CI], 68–86 %) for patients with tumors \4 cm and 59 % (95 % CI, 39–76 %) in patients with tumors [4 cm. At 5 years, the LC rate was 67 % (95 % CI, 46–76 %) and 48 % (95 % CI, 30–68 %) for these groups, respectively. Univariate analysis The univariate analysis examined prognosis factors affecting the aforementioned variables. OS was significantly
affected by the pretreatment hemoglobin (p = 0.015), tumor size (p = 0.017), and total treatment duration. According to Exp(B), we found a 1.6 times reduction in OS for the range of 8–10 g/dl of the pretreatment hemoglobin and a 2.5 times reduction in OS for patients with a tumor size of 4–6 cm when compared with \4 cm. The presence of pelvic lymphadenopathy was also found to be a significant prognostic factor (p = 0.03). OS was in fact reduced by a factor of 2.4. OS was significantly reduced (p = 0.02) when the total treatment duration exceeded 55 days. For LC, the pretreatment hemoglobin level was again a prognostic indicator (p = 0.018), so was the tumor size with a decrease of LC by a factor of 1.8 with a tumor size of 4 cm and above. The use of brachytherapy for the tumor boost was also found to be a significant factor influencing the LC; a decrease of LC by a factor of 2.1 in the absence of brachytherapy was noted. The number of cycles of chemotherapy completed (p = 0.032) was also a significant factor for LC. Other factors were also found in our analysis but could not reach significant values; young age and histological type were identified with non-significant p (Table 5). Multivariate analysis The only independently significant variables that were identified in the multivariate analysis were tumor size (p = 0.047) and pretreatment hemoglobin level (p = 0.016) (Table 6).
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Arch Gynecol Obstet Fig. 1 Five year overall survival for the studied cohort
Fig. 2 Local control for the studied cohort
Discussion Cervical cancer is a major health problem. Worldwide, it accounts for 287,000 deaths in 2008, and this number is expected to rise up to 410,000 by 2030 [8, 9]. Despite the worldwide implementation of prevention and early detection strategies, including the Papanicolaou smear test, human papillomavirus (HPV) testing, and vaccines, approximately 30 % of newly diagnosed cases are categorized as ‘‘locally advanced disease’’ [10]. Furthermore, 50 % of patients with locally advanced disease are expected to relapse within the first 2 years after initial
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treatment [11]. Advanced cervical cancer has been reported to be associated with low overall survival and local control rates despite a well-conducted concurrent chemoradiotherapy. In fact, tumor relapse’s rate is around 50–70 % in LACC [12]. In our series, tumor relapse’s rate was around 60 %. Tumor size, hemoglobin level, and the presence of pelvic lymphadenopathy are the most reported indicators influencing outcomes in LACC. A retrospective study by Mark et al. showed that a hemoglobin level of less than 10 g/dl is associated to a low survival rate. Girinski et al. [13] found that the hemoglobin level before the treatment was not a significant indicator but it significantly affects
Arch Gynecol Obstet Table 5 Univariate analysis for prognostic factors p
Risk or Exp(B)
Exp(B) CI 95 %
Pretreatment hemoglobin
p = 0.015
0.615
0.519–0.862
Tumor size
p = 0.017
0.745
0.456–0.789
Total treatment duration
p = 0.03
0.876
0.617–0.945
Presence of pelvic adenopathy
p = 0.02
0.634
0.523–0.767
Number of cycles of chemotherapy (\4)
p = 0.032
0.786
0.456–0.865
Table 6 Multivariate analysis for prognostic factors p
Risk or Exp(B)
Exp(B) CI 95 %
Pretreatment hemoglobin
p = 0.016
0.575
0.523–0.762
Tumor size
p = 0.047
0.865
0.523–0.678
outcomes during radiotherapy, in their retrospective study that included 386 patients treated at the Gustave-Roussy institute; anemia during radiotherapy led to a relative risk of local relapse of 1.6 and metastatic relapse of 1.8 [14]. Tumor volume defined as ‘‘Bulky’’ is not well established in the literature; it is in some situations defined as 4 cm, 5 cm and very often as 6 cm [15]. Perez et al. [15] found that stage IIIB was associated to a high rate of metastatic relapse when compared with stage IIIA and bellow. Finally, available data suggest that patients with positive lymph nodes are at a higher risk of developing relapses [16, 17]. In our series, tumor size and pretreatment hemoglobin level were identified as independent prognostic factors. Data from Atahan et al. [18] showed overall treatment time to be a significant prognostic factor for survival; a decrease in overall survival was reported in increased total treatment durations ([55 h). In our series, OS was in fact reduced by a factor of 2.4. OS was significantly reduced (p = 0.02) when the total treatment duration exceeded 55 days. Concurrent chemoradiation is considered to be the standard of care for this category [19, 20]. In 1999, a randomized phase III trial conducted by Morris et al. at the MD Anderson cancer center included 401 patients with advanced cervical cancer and compared radiotherapy alone with the combination of chemotherapy (Platine- and 5FUbased regimen) and radiation. At 5 years, PFS was 67 % with the association of chemotherapy and radiation while it reached only 40 % with radiotherapy alone (p \ 0.001). Overall survival rates were respectively 73 and 58 % (p = 0.004) [21]. These results were confirmed by other randomized trials that concerned this particular population
[22–26]; toxicity among these trials was considered to be acceptable. Hence concurrent radiochemotherapy is the treatment of choice for locally advanced cervical cancer. Currently, acceptable concurrent cisplatine-based regimens are either weekly Cisplatine or the combination of 5FUCisplatine [19, 20, 24–26]. Other associations have been evaluated to improve outcomes in advanced cervical cancer; in a recent international phase III randomized trial, the combination of cisplatine/gemcitabine concomitantly with radiotherapy followed by two additional cycles of the same regimen of chemotherapy was associated with an improved rates of PFS and OS when compared with the standard treatment [27]. However, these results are controversial because in one hand there were changes in its statistical design and in the other hand the superiority of this combination was associated with unresolved toxicity issues [27–29]. Nedaplatin is a synthetic analog of cisplatin that has also been evaluated in the concurrent chemoradiation setting. In a pilot phase II trial, weekly nedaplatin concurrently with radiation achieved an ORR of 90 %, a 3-year PFS of 58.7 %, and an OS of 78.0 % [30]. Non-platinum-containing regimens have been widely explored. The feasibility of concurrent radiotherapy and paclitaxel administration was evaluated in a pilot study with 20 patients (13 new cases, stage IIB–III, and 7 with pelvic recurrences) and complete regression was reported in 63 % [31]. In a subsequent randomized phase II trial, weekly cisplatin was compared to weekly paclitaxel as concurrent chemotherapy with standard RT in patients with stage IB2–IVA disease or with postsurgical pelvic recurrence, as results weekly paclitaxel did not provide any clinical advantage over weekly cisplatin [32]. A multiagent regimen that included paclitaxel, ifosfamide, and cisplatin (TIP) has been also evaluated in two different settings: bulky and locally advanced cervical cancer and recurrentpersistent disease [33]. Finally, the combination of paclitaxel and vinorelbine was associated with significant hematologic toxicity [34]. Mitomycin C is another drug that has been tested in locally advanced cervical cancer; its use concurrently with radiotherapy was first evaluated in a randomized trial including 160 patients, and better results were seen in the mitomycin arm when compared with radiation alone [35]. The combination of 5FU and Mitomycin C concurrently with radiotherapy was then evaluated in four trials, two of them comparing the combination with RT alone [36], and the other two comparing the combination with Mitomycin C alone [36, 37] suggesting better results with the combination over infusional 5FU concurrently with RT [37]. In a validation phase I cohort, intravenous topotecan was used with cisplatin concurrently with pelvic radiation and intracavitary brachytherapy with tolerable toxicities and good results [38, 39]. The safety and feasibility of concurrent radiation therapy with weekly
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irinotecan in patients with locally advanced disease were evaluated in two small phase II trials, suggesting promising efficacy and tolerable adverse events [40, 41]. More recently, induction chemotherapy followed by concurrent chemoradiation or surgery alone, and also preoperative concurrent chemoradiation and adjuvant chemotherapy to concurrent chemoradiation have been implemented in the therapeutic armamentarium in an effort to optimize local control and also to minimize the risk for metastatic disease. Between 1983 and 1995, 20 pilot studies were conducted to determine the efficacy of neoadjuvant chemotherapy preceding radical surgery treatment, showing an overall response of 77.5 %. A recent Cochrane review and a randomized GOG study have questioned this association and compared NACT ? RS versus RS alone [42, 43]. However, available data are very difficult to interpret. On one hand, the Cochrane review has assembled data on both early (IB1) and locally advanced stages, and it is commonly known that the greatest benefit of NACT is essentially seen on locally advanced cervical cancer (LACC) [6, 42, 44–47]. On the other hand, Cisplatin dosage reported was different among different studies, which is considered to be an important bias. A recent ongoing trial planned by EORTC (55994EORTC) comparing NACT ? RS versus CT/RT in stage IB2–IIB cervical is awaited and will answer to this particular question. In 2000, Peters et al. advocated another treatment strategy in a GOG protocol; it consisted of adding 3–4 cycles of chemotherapy after completion of CT/RT. A recent meta-analysis showed larger benefits in trials in which additional chemotherapy was administered after CT/RT, with an absolute improvement of 19 % at 5 years [28]. Although these encouraging results, concomitant chemotherapy and radiation are still the treatment of choice for locally advanced cervical cancer, and other options are still under investigation.
Conclusion In our country cervical cancer is mostly diagnosed at an advanced stage, despite all the efforts made to improve treatment options, outcomes are still poor. As in the literature, our review found that hemoglobin level, tumor size and presence of positive lymph nodes are indicators of bad prognosis in this particular population. Newer treatment options are still under investigation to enhance LC, and eventually OS. Conflict of interest We declare not having any competing interests. Informed consent Written informed consent was obtained from the patient for publication of this case report and accompanying images.
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A copy of the written consent is available for review by the Editor-inChief of this journal.
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