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British Journal of Radiology (2005) 78, 821-826
© 2005 British Institute of Radiology
doi: 10.1259/bjr/13147816
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Treatment results and prognostic analysis of radical radiotherapy for locally advanced cancer of the uterine cervix

H Yamashita, MD, K Nakagawa, MD, M Tago, MD, K Shiraishi, MD, N Nakamura, MD and K Ohtomo, MD

Department of Radiology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study investigated treatment results and prognostic factors in radical radiotherapy for stage IIB-IVA cervical cancer. This is a retrospective analysis of 71 patients with cancer of the uterine cervix treated radically with external beam radiotherapy and high-dose-rate intracavitary brachytherapy between June 1991 and May 2004. In 47/71 (66%) of patients' chemotherapy was combined with radiotherapy. All 71 patients were retrospectively analysed. The median follow-up time was 34.8 months. The median age was 57 years (range 26–78 years) There were 21 patients (30%) in stage IIB, 3 (4%) stage IIIA, 40 (56%) stage IIIB, and 7 (10%) stage IVA. The 5-year overall survival rate was 83.5%, 77.0%, and 42.9% for stage IIB, III, and IVA, respectively. Federation Internationale de Gynocologie et d'Obstetrique (FIGO) classification stage and pelvic and para-aortic nodal status significantly affected survival in univariate analysis, but no treatment-related factor was found to be significant in multivariate analysis. In this study para-aortic nodal status was the most important prognostic factor in the radical radiotherapy of cervical cancer.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Cervical cancer is the most common gynaecological cancer in Japan, with an estimated 15 new cases per 100 000 females every year. High dose-rate intracavitary brachytherapy (HDR-ICBT) in combination with external beam irradiation (EBRT) has become an acceptable treatment for carcinoma of the cervix [1]. HDR-ICBT has been widely used in treatment of uterine cervical cancer in Asia and Europe [2–13]. Despite some criticism of HDR-ICBT [14], its use has been increasing in the USA [15, 16].

Recently published randomized clinical trials demonstrated a significant improvement in pelvic disease control and survival when concurrent chemotherapy consisting of cisplatin (CDDP)-containing regimens was added to radiotherapy (RT) in patients with locally advanced cervical cancer [17–19]. These results have led to significant changes in the standard treatment of cervical cancer. In our department, we have used CDDP-based chemotherapy combined with RT since July 2000. However, a Phase III clinical study from Canada showed no significant benefit from adding chemotherapy to radiation alone [20]. Although chemoradiation has also been used in Japan for advanced cervical cancer, there is a big difference between Euro-American and Japanese radiotherapeutic techniques. There may also be differences in tolerated doses of antitumour agents. Therefore, the effectiveness of this treatment method needs to be assessed in a Japanese context. Previous studies of various neoadjuvant chemotherapeutic regimens have failed to show, when compared with radiotherapy alone, any benefit in survival.

In this retrospective study we assessed the results of radical radiotherapy for cervical cancer in our department over the past 14 years, with particular emphasis on the methods of treatment.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
Between June 1991 and May 2004, a total of 71 patients were treated for the International Federation of Gynaecology and Obstetrics classification (FIGO) stage IIB, III, and IVA carcinoma of the cervix with intracavitary RT (ICRT) at our department. Patients were previously untreated and had a histological diagnosis of squamous cell carcinoma, or adenocarcinoma in FIGO stages IIB (n=21), IIIA (n=3), IIIB (n=40), and IVA (n=7). Patients with adenocarcinoma (n=5), and patients who underwent external beam RT at other institutions (n=30) were not excluded. Patients treated palliatively (i.e. Stage IVB) (n=3) and patients treated post-operatively were excluded. Median age was 57 years (range 26–78 years). 38 patients were treated with concurrent chemoradiation therapy (cCRT) and compared with 24 and 9 patients treated with RT alone and neoadjuvant chemotherapy (NAC), respectively. Most of the patients in this series were in stage IIB and IIIB. Table 1Go shows the patients' characteristics.


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  		Table 1. Patient characteristics

 
Patients were evaluated with a physical and pelvic examination without anaesthesia, routine blood counts, blood chemistry profile, chest radiograph, intravenous urogram and barium enema. CT scan and MRI were used only for detecting lymphadenopathy. Pelvic and para-aortic lymph nodes greater than 10 mm in minimum diameter were considered to be enlarged by CT and MRI. Neither lymphangiography nor surgical evaluation of lymph nodes were performed.

EBRT
Concurrent chemotherapy was added to RT in these patients. The majority of patients received EBRT using a linear accelerator with a photon-beam-energy of 6 MV to the whole pelvis with the four-field box technique for a total dose of 30.6 Gy in 17 fractions (3.4 weeks, 1.8 Gy fractions from Monday to Friday). The irradiated volume was to include the whole uterus, the paracervical, parametrium and uterosacral regions, as well as the external iliac, hypogastric and obturator lymph node. Minimum margins were the upper margin of L-5 (superiorly), the lower margin of the obturator foramen or the lowest extension of the disease (inferiorly), and 1.5–2.0 cm beyond the lateral margins of the bony pelvis and its widest plane (laterally). For the lateral fields, the anterior margin was the anterior edge of the symphysis or 3 cm in front of the sacral promontory. The posterior margin was the S2–S3 interspace or the posterior border of the uterine cervix assessed by CT for treatment planning plus a 2 cm margin. After that, a midline block, 4 cm in width at midplane, was inserted with the anteroposterior parallel two-field technique for a dose of 19.8 Gy in the last 11 fractions. This did not extend to the top of the pelvic field.

12 patients who had para-aortic lymph node involvement received whole pelvic irradiation plus para-aortic irradiation using 4-fields box or conformal technique.

Patients with inadequate response to treatment were treated with additional radiotherapy: 7 patients (1 patient: IIIB, 6 patients: IVA) received boost RT with rotational or conformal techniques to a dose of 20 Gy in 10 fractions, and 2 patients with stage IIIB received 10 Gy in 5 fractions.

ICBT
Four or five intracavitary Cobalt-60 (60Co) (from June 1991 to February 1999, n=23) or iridium-192 (192Ir) (from July 2000 to present, n=48) insertions were performed weekly 3–4 weeks after starting EBRT. High-dose-rate intracavitary therapy was used. Brachytherapy was delivered using after-loading applicators placed in the uterine cavity and vagina. A Manchester system applicator (Nucleotron microSelectron HDR source) has been used since July 2000, and prior to that a handmade applicator was used. The dose distribution was calculated for each individual patient and placement. Applications were usually done under intravenous anaesthesia with O2 saturation monitoring. Anterior and posterior vaginal packing was used in an attempt to displace the bladder and rectum from the applicators. All the applicator insertions, radiographs and treatments were performed in a dedicated brachytherapy suite equipped with imaging equipment. There was therefore no need to move patients during the ICBT procedure. Patients were treated in the dorsal lithotomy position. A purpose-built external fixation device was used to prevent applicator movement. Point A was defined on radiographs as being 2 cm superior (along the tandem) to the flange abutting the external cervical os and 2 cm lateral from the axis of the tandem. Source loading corresponded to the Manchester System for uterine cervical cancer [21]. According to the Manchester system, the dose at point A was comprised of a tandem/ovoid ratio=1.8. Over a distance of one third from the tip of the tandem, weightings of the source were 1.5 times. No planned optimization was done. HDR-ICBT was performed once a week with a daily dose of 6 Gy at point A. Since there are 2 point A doses, right and left, and these are not exactly the same, we chose the lower point A dose, not the mean of the both, for the reference dose for certain patients. The rectal, bladder and vaginal reference points were determined according to the guidelines in ICRU Report 38 [22]. The ICRU rectal and bladder reference doses were calculated routinely from July 2000.

Treatment schedules
In our department, EBRT preceded ICBT. A midline block was inserted after the first application of ICBT. Standard protocol of treatment at our institution consists of whole-pelvic radiotherapy (WPRT) of 20 Gy plus WPRT with a midline block (MB) of 30 Gy plus ICRT of 24 Gy in 4 fractions for stage II, WPRT of 30 Gy plus WPRT with MB of 20 Gy plus ICRT of 24 Gy in 4 fractions for stage IIB with a bulky mass and stage III, and WPRT of 40 Gy plus WPRT with MB of 10 Gy plus ICRT of 18 Gy in 3 fractions for stage IIIB with a bulky mass and stage IVA. The most frequent schedule in our department was a WPRT of 30.6 Gy or 30 Gy followed by HDR-ICBT of 24 Gy and WPRT of 19.8 Gy or 20 Gy with MB (39 patients, 55%) (Table 2Go). No EBRT was given on the same day as ICBT.


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  		Table 2. Treatment schedules

 
Chemotherapy
We have routinely used concurrent CDDP-based chemotherapy combined with RT since July 2000. In the case of advanced age, poor renal or heart function, or patients' refusal of chemotherapy, patients were treated with RT-alone. All 47 patients received cisplatin- or nedaplatin-based chemotherapy combined with RT. 38 patients out of 47 received CCRT. 29 patients out of 38 received CDDP (n=29) or nedaplatin (n=1) (75 mg m–2 in a bolus infusion on days 1, 22 and 43) either combined with or without 5-fluorouracil (1000 mg m–2/24 h by continuous infusion from days 2–5, 23–26 and 44–47). Seven patients out of 37 received weekly CDDP (n=4) (30 mg m–2 week–1) or nedaplatin (n=3) (20 mg m–2 week–1). One patient out of 25 received concurrent daily low-dose CDDP (10 mg body–1 day–1). Nine patients received NAC before RT. Seven out of nine patients received a BOMP (bleomycin, vincristine, mitomycin C and CDDP) regimen. The other two patients received intra-arterial CDDP-based NAC.

Follow-up
Both radiation and gynaecological oncologists followed-up the treated patients. The patients were seen every month for the first year, every 2–3 months for the next 2 years, and 3–12 months afterward. Patients without regular visits were followed-up via telephone. No patients were lost to follow-up. Follow-up procedures included pelvic examination, palpation of supraclavicular nodes, cervical Papanicolaou smear, and review of serum squamous cell carcinoma antigen value. When central and/or parametrial recurrence was suspected by pelvic examination and/or Papanicolaou smear, a biopsy was taken for confirmation. Intravenously enhanced chest, abdominal and pelvic CTs were performed annually. Other imaging studies, such as MRI, ultrasound and bone scintigraphy, were not routinely performed. Late complications were graded in accordance with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2.0, especially for bladder and bowel complications.

Statistical analysis
Statistical analyses were performed using StatView Dataset File version 5.0J for Windows computers (Cary, NC). OS was calculated from the first date of EBRT. Survival time was plotted using the Kaplan-Meier method. Differences in the incidences of toxicities were analysed by the chi-squared test. Differences in survival by treatment were evaluated using the log-rank test. Proportional hazards model was used in univariate and multivariate analysis.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Median follow-up time for all 71 patients was 34.8 months (range 2.4–147.0 months) and 24.0 months (range 2.4–146.2 months) for the surviving 52 patients. No patients were lost to follow-up.

Patients
All patients had a Karnovsky performance status of at least 80%. Overall radiation treatment times varied between 21 and 93 days (median 43 days). In 11 patients (15%) overall treatment time was longer than 8 weeks. The maximum tumour diameter assessed by MRI ranged from 20 mm to 75 mm with a median diameter of 40 mm.

Dose and BED
The median cumulative point A dose (sum of the EBRT midline dose and point A dose of ICRT) was 48.1 Gy (range 39.1–63.2 Gy). The biological effective dose (BED) was calculated to the tumour ({alpha}/{beta}=10) and late-responding tissue ({alpha}/{beta}=3) for both EBRT and HDR-ICBT [23]. The total BED values to point A and ICRU reference points (rectum and bladder) were the summation of those of EBRT and HDR-ICBT. Median cumulative values of point A BED were 74.5 Gy10 (range 62.1–111 Gy10) for early-responding tissue, and 121 Gy3 (range 95–170 Gy3) for late-responding tissue. Median calculated doses at ICRU reference points from single ICBT were 4.2 Gy (range 2.6–6.8 Gy) for the rectum and 4.5 Gy (range 2.5–8.0 Gy) for the bladder. Dose at reference points exceeded point A doses in seven treatments (16%) for the rectal dose and in nine treatments (20%) for the bladder dose. The sum of the EBRT midline dose and the reference point dose from ICBT were 39.1–63.2 Gy (median 48.9 Gy) at the rectum and 95.0–121.0 Gy (median 120 Gy) at the bladder.

Survival
When we closed this analysis, 52 patients out of 71 were alive. 15 patients died from recurrent disease. Three patients (stage IIB: 1 patient and IVA: 2 patients) died from coincidental disease. One patient (stage IVA) had treatment-related-death (the patient died from septic shock during adjuvant chemotherapy). Table 3Go shows outcomes according to FIGO stage. The 5-year overall survival rate was 83.5%, 77.0% and 42.9% for stage IIB, III, and IVA, respectively (Figure 1Go). Tables 3 and 4GoGo show the 5-year outcomes according to stage and several factors, respectively. In univariate analysis, FIGO stage and pelvic and para-aortic nodal status significantly affected the survival (Figures 2 and 3GoGo), but no treatment-related factor was found to be significant in multivariate analysis.


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  		Table 3. 5-year outcomes due to stage

 


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  		Figure 1. Overall survival by stage.

 

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  		Table 4. The 5-year survival outcomes due to several factors

 


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  		Figure 2. Overall survival between pelvic lymph node (PLN) positive and negative.

 


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  		Figure 3. Overall survival between para-aortic lymph node (PALN) positive and negative.

 
The 5-year overall survival rates for CCRT, NAC and RT-alone were 79.2%, 53.3% and 74.6%, respectively; this difference between these two treatments was not statistically significant (p=0.4276) (Table 4Go). The difference in overall survival rates between these two treatments for stage III and IVA patients was not also statistically significant (p=0.9230).

Late complications (complications that persisted or occurred for more than 60 days after treatment)
Grade 3+ toxicity occurred in eight patients. Six patients were in stage IIIB and 2 patients in stage IVA. Five patients were treated with CRT and three patients with RT alone. The treatment-related death was in a patient with Stage IVA disease. Each of the following seven complications occurred in seven different individual patients: intestinal obstruction (Grade 4), bloody stool (Grade 3), pelvic abscess (Grade 4), urethritis followed by anal bleeding (Grade 3), cystitis (Grade 3), vesico-vaginal fistula (Grade 4), and rectal ulcer followed by strangulated and adhesive intestinal obstruction (Grade 4).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In a French Cooperative Group study of 1875 patients who received RT according to Fletcher's guidelines, Barillot and colleagues [24] reported a 5-year survival rate of 70%, 45% and 10% in patients having stage IIB, IIIB and IVA tumours, respectively. 5-year survival rates of 65–75%, 35–50% and 15–20% have been reported in patients who received RT alone for stage IIB, IIIB and IV tumours, respectively [25–30]. In our department, the 5-year overall survival rate for stage IIB, III and IVA were 83.5%, 77.0% and 42.9%, respectively.

Para-aortic nodal metastasis is the most significant prognostic factor in patients with locally advanced cervical cancer [31]. In our analysis, pelvic and para-aortic nodal status were also important prognostic factors (Figure 3Go). The American Brachytherapy Society recommends keeping the total treatment duration to less than 8 weeks because prolongation of total treatment duration can adversely affect local control and survival [32–35]. In our study, this factor did not affect survival (p=0.4939).

Dose at reference points exceeded point A doses in seven treatments (16%) for the rectal dose and in nine treatments (20%) for the bladder dose. However, Grade 3+ toxicity did not occur in these patients. Our results suggest that the dose at reference points might not predict late complications.

In our experience, RT alone without chemotherapy showed favourable results. The 5-year overall survival rate was 70.6%, disease free survival rate 53.8%, and cause-specific survival rate 79.2%. Our study showed that survival is not compromised by using RT alone. Recently, five randomized trials performed by the Gynaecologic Oncology Group, Radiation Therapy Oncology Group and the South West Oncology Group studying CDDP-based chemoradiation have demonstrated a significant survival advantage [17–19, 36, 37]. Three of the trials compared CDDP-based CCRT with RT-alone and two trials compared CDDP-based CCRT to RT with hydroxyurea. In all of the trials, CDDP-based chemotherapy administered concurrently with RT was more effective at reducing the risk of death by 30–50%. Acute toxicities, principally neutropenia and gastrointestinal, were more common with CRT, but were transient and the rates of late complications were similar. Based on the results of these five randomized trials, the National Cancer Institute released a Clinical Announcement stating that CDDP-based chemotherapy, as used in these trials (i.e. concurrently with RT), as the new standard of therapy for cervical cancer. There is one negative study on cisplatin concurrent with RT in locally advanced cervical cancer from a study by Pearcey et al in Canada [20]. They criticized the American trials (GOG 85 [18], GOG 120 [17]), on the basis that the treatment results from the control group were worse than historical RT results, and that one of the reasons was that overall treatment times, at 9 weeks, were unusually and inappropriately prolonged. The chemotherapy was simply compensating for proliferation occurring during treatment and would have shown no benefit had shorter overall treatment times been used in the control arms.

CRT has also been used in Japan for advanced uterine cervical cancer. Considering the difference in bodily habitus between Japanese and Western women and local anatomical differences, we do not know whether these protocols can, without modification, be safely applied to Japanese women. There may be a difference in the tolerated dose of antitumour agents. In 2000, multi-institute retrospective analysis from Japan also concluded that, compared with radiation alone, combined chemoradiation was not of benefit. [38]. Additionally, it should be remembered that HDR-ICBT is the mainstay of treatment in Japan. In our department, though many patients (n=47) received combined RT and chemotherapy, we could not demonstrate any significant benefit. In Japanese women, the benefits from including chemotherapy in RT for locally advanced cervical cancer are probably minimal. The effectiveness of this treatment method needs to be assessed in clinical trials in a Japanese population.

Additionally, several randomized controlled trials and a meta-analysis [39] demonstrate that patients with locally advanced cervical cancer who receive NAC prior to definitive RT may actually do worse than a group receiving RT alone. In our study, NAC was inferior to CCRT or RT-alone in 5-year overall survival.

Our analysis showed that the most important prognostic factor in radical RT for cervical cancer was para-aortic nodal status.

Received for publication January 6, 2005. Revision received February 14, 2005. Accepted for publication March 4, 2005.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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