Clinical Outcome for Chemoradiotherapy in Carcinoma of the Cervix
Article Outline
Abstract
Aims
Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone.
Materials and methods
Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40
mg/m2 weekly with radiotherapy, (the neoadjuvant dose was 60mg/m2 3 weekly). External beam radiotherapy was given to the pelvis (40–45Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5–32.5Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15–20Gy/8–10 fractions).
Results
The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% (P=0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant (P=0.14).
Conclusion
There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.
Key words: Cervix carcinoma, chemoradiotherapy, outcome, survival, toxicity
Introduction
Carcinoma of the cervix is the second most common cancer to affect females worldwide and is the most common cause of cancer-related death in developing countries [1]. In the UK, the incidence of cervical cancer has fallen over the last few years, which may be secondary to the UK screening programme for cervical intraepithelial neoplasia and education in sexual health. This has been associated with a significant fall in mortality, but survival rates for the UK as a whole compared with other European countries and International Federation of Gynecology and Obstetrics (FIGO) statistics continue to be low 2, 3.
In February 1999, the US National Cancer Institute issued a clinical alert stating that ‘strong consideration should be given to adding chemotherapy to radiation therapy in the treatment of cervical cancer’ [4]. This was unprecedented in that it was issued before the publication of five randomised phase III trials 5, 6, 7, 8, 9 that showed that platinum chemotherapy given concurrently with radiotherapy improved 3-year survival by 8–19%. This survival benefit was seen in women with locally advanced cancer, FIGO stages IB2–IVA.
At the Christie Hospital in Manchester, concurrent chemoradiation was introduced as standard treatment for locally advanced cervical cancer in 2000. This study looked at the treatment outcomes (survival and toxicity) and compared the results with the results from 183 patients from the same institution treated in 1993 [included in the national audit of cervix cancer outcomes, 5-year overall survival 49% (Fig. 1) and grade 3 and 4 toxicity 3.4%] [10].
Fig. 1
Five-year survival from the 1993 national audit.
Materials and Methods
Patient Selection and Characteristics
Between July 2000 and December 2003, 75 patients with cervical carcinoma were treated with concurrent chemoradiation. Patients were entered on to a prospective database, but case notes were reviewed retrospectively. The median age of the patients was 47 years (range 23–74 years). All patients had World Health Organization performance status 0–2 at presentation, adequate renal function as measured by isotope glomerular filtration rate >60ml/min and a haemoglobin level maintained above 11g/dl. Twelve women had FIGO stage I disease (16%), 28 (37.3%) had stage II, 27 (36%) had stage III, six (8%) had stage IV and two (2.7%) patients had recurrent disease after surgery. Sixty-two women (82.7%) had squamous cell carcinomas, nine (12%) adenocarcinomas, two (2.7%) adenosquamous carcinomas, one (1.3%) other, and one (1.3%) with unknown histology. Of the squamous cell carcinomas, four (5.3%) were well differentiated, 28 (37.3%) were moderately well differentiated and 26 (34.7%) were poorly differentiated. All patients were staged with examination under anaesthesia and magnetic resonance imaging of the abdomen and pelvis. Thirty-three (44%) patients were found to have positive pelvic lymph nodes, 35 (46.7%) had negative pelvic lymph nodes and the lymph node status was unknown in seven (9.3%) patients. All patients were treated with chemoradiation. The details are given below. The patient characteristics for the 1993 cohort and the current cohort are given in Table 1.
Table 1. Comparison of patient characteristics from the 1993 cohort with the current cohort
| 1993 (n=183) | Current (n=75) | |
|---|---|---|
| Stage at presentation | ||
| I | 45 (24.5%) | 12 (16%) |
| II | 71 (39%) | 28 (37.3%) |
| III | 51 (28%) | 27 (36%) |
| IV | 16 (8.5%) | 6 (8%) |
| Postoperative recurrence | – | 2 (2.7%) |
| Median age (range) | 57.4 years (21–90 years) | 47 years (23–74 years) |
| Histology | ||
| Squamous cell carcinoma | 131 (71.5%) | 62 (82.7%) |
| Adenocarcinoma | 11 (6%) | 9 (12%) |
| Adenosquamous carcinoma | 15 (8%) | 2 (2.7%) |
| Other | – | 1 (1.3%) |
| Unknown | 26 (14.5%) | 1 (1.3%) |
| Nodal status | ||
| Positive | 40 (21.9%) | 33 (44%) |
| Negative | 20 (10.9%) | 35 (46.7%) |
| Unknown | 123 (67.2%) | 7 (9.3%) |
| Postoperative patients | 44 (24%) | 2 (2.7%) |
Radiotherapy
Patients were treated with a combination of external beam radiotherapy followed by brachytherapy. If brachytherapy was not possible, an external beam boost was given. External beam radiotherapy was delivered using 8–18 Mv photons using a four-field technique. Node-positive patients were planned using computed tomography planning and all other patients were planned on the simulator. Patients were treated supine and for the patients planned on the simulator, a radio-opaque marker was placed at the lower extent of visible disease. The superior border for node-negative patients was at the top of the true pelvis, and for node-positive patients at the L4–5 intervertebral space to include the common iliac nodes. The inferior border was situated midway through the obturator foraminae ensuring there was an adequate margin below disease. Laterally the field was 1cm outside the bony pelvis, anteriorly midway through the symphysis pubis and posteriorly at the S2–3 junction. A typical volume for node-negative patients was 1500–1600cm3. The planning target volume for node-positive patients was larger at 1800–1900cm3. No shielding was used. Node-positive patients with a larger field received 40Gy/20 fractions/4 weeks and node-negative patients received 45Gy/20 fractions/4 weeks. Brachytherapy was given using the Manchester system using low dose rate caesium in remote afterloading equipment. The dose was dependent on the external beam dose and rectal readings taken at the time of insertion. If patients had initially received 40Gy to the pelvis, they received a further 32.5Gy to point A, and patients who had received 45Gy received 22.5Gy to point A. Patients who had failed insertion were given a computed tomography planned external beam boost (15–20Gy/8–10 fractions).
Biological equivalent doses were calculated. Patients receiving 40Gy/20 fractions/4 weeks followed by a brachytherapy dose of 32.5Gy had a biological equivalent dose of 87.4Gy and patients receiving 45Gy/20 fractions/4 weeks followed by a brachytherapy dose of 22.5Gy had a biological equivalent dose of 87Gy. Rectal dose readings were made using an ionisation chamber in the lower rectum with the applicators in place with caesium pellets inserted into the applicators to simulate the treatment positions. The dose rate was kept below two-thirds the dose rate to point A. Direct measurements of bladder dose have not been used in Manchester after they were shown to not be helpful in a study of bladder base dose in a series of patients undergoing intracavitary treatment [11]. No patients received para-aortic radiation or parametrial boosts. All patients completed phase I within 30 days. Seventy-three patients completed their treatment in fewer than 50 days. The other two patients completed their treatment within 56 and 59 days. This delay was due to failed insertions and both patients received a computed tomography planned external beam boost.
Chemotherapy
All patients were World Health Organization performance status 0–2 and all had adequate renal function with a glomerular filtration rate >60ml/min. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was because of waiting list problems, which subsequently improved during the study period. Neoadjuvant chemotherapy was given as cisplatin 60mg/m2. Concurrent treatment was given as weekly cisplatin 40mg/m2 (maximum dose 70mg). Patients were reviewed weekly during their treatment with assessment of gastrointestinal symptoms, blood tests and creatinine clearance. Thirty-two (42.7%) patients received all four cycles of concurrent chemotherapy, 26 (34.7%) received three cycles, 14 (18.6%) received two cycles and three (4%) managed only one cycle. This was due to increased gastrointestinal toxicity, renal impairment or neutropenia.
Statistics
Survival and disease-free survival rates were analysed using Kaplan–Meier methods. Stage distribution was assessed using the chi-squared test. Toxicity was assessed using Fisher's exact test. No patients were lost to follow-up. The median follow-up was 57 months (range 24–88 months).
Results
Survival and Progression
The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60% (Fig. 2). The 3-year disease-free survival rate was 63.6%, with an estimated 5-year disease-free survival rate of 55% (Fig. 3). Compared with the cohort of 183 patients from the Christie Hospital in the 1993 audit, there was a trend towards improved survival from 49 to 60% (P=0.06).
Fig. 2
Overall survival.
Fig. 3
Disease-free survival with chemoradiation.
Survival with respect to stage is shown in Table 2. A chi-squared test was carried out, which showed that there was no difference in stage groupings between the two cohorts (P=0.39). The 3-year overall local disease-free survival was 77% and the distant disease-free survival was 72%. Local disease-free survival was defined as patients who remained disease free within the radiation fields and distant disease-free survival was defined as patients who remained free of distant metastases.
Table 2. Three-year survival with respect to stage
| Overall survival | DFS | Local DFS | Distant DFS | |
|---|---|---|---|---|
| Stage 1 | 83% | 67% | 83% | 83% |
| Stage 2 | 74% | 71% | 78% | 74% |
| Stage 3 | 70% | 66% | 74% | 76% |
| Stage 4 | 33% | 17% | 83% | 20% |
Survival with respect to nodal status is shown in Table 3 and Fig. 4. There was no difference in 3-year overall survival between node-positive and node-negative patients. There was, however, a significant difference in disease-free survival (both local and distant) between the two groups.
Table 3. Three-year survival with respect to nodal status
| Node negative | Node positive | |
|---|---|---|
| 3-year overall survival | 70% | 66% |
| 3-year DFS | 68% | 54% |
| 3-year local DFS | 82% | 69% |
| 3-year distant DFS | 78% | 62% |
Fig. 4
Survival with respect to nodal status.
Survival with respect to chemotherapy is shown in Table 4. There was a significant difference in 3-year overall survival between the patients who received concurrent chemotherapy alone and patients who received neoadjuvant and concurrent chemotherapy.
Table 4. Three-year survival with respect to chemotherapy
| Concurrent alone | Neoadjuvant and concurrent | |
|---|---|---|
| 3-year overall survival | 75% | 64% |
| 3-year DFS | 68% | 58% |
| 3-year local DFS | 83% | 68% |
| 3-year distant DFS | 72% | 72% |
Twenty-two patients developed distant metastases. Seven patients developed metastases in more than one site. In total, there were 30 recorded events in this time period (Table 5).
Table 5. Sites of metastases
| Site of metastases | Number of patients |
|---|---|
| Para-aortic nodes | 12 |
| Supraclavicular fossa nodes | 2 |
| Mediastinal nodes | 1 |
| Liver | 3 |
| Lung | 6 |
| Bone | 3 |
| Brain | 2 |
| Skin | 1 |
Late Toxicity
Late toxicity was defined as that occurring more than 90 days after the first day of radiotherapy. It was scored using the Franco-Italian glossary [12]. This describes five grades of increasing severity (0–4). Grade 0 has no complications, grade 1 mild and grade 2 moderate complications with patients able to maintain normal activity. Grade 3 is severe complications requiring surgery or causing permanent damage and grade 4 is complications resulting in death due to treatment.
There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. Of the patients with grade 3 toxicity (Fig. 5), three (4%) had bowel toxicity requiring surgery (one patient with a rectal fistula, one with a sigmoid stricture and one with small bowel obstruction after surgery for urinary diversion after presenting with hydronephrosis due to stage IV disease), three (4%) had bladder toxicity and one (1.3%) had vaginal stenosis. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%. However, using Fisher's exact test, there was no statistical difference between the two cohorts (P=0.14).
Fig. 5
Grade 3 toxicity.
Discussion
The publication of five randomised trials 5, 6, 7, 8, 9 followed by two large meta-analyses 13, 14 has resulted in concurrent chemoradiation for locally advanced cervical cancer becoming the gold standard treatment. Green et al. [13] showed a 12% absolute benefit in survival and Lukka et al. [14] showed an estimated survival benefit of 11%. Our study has shown an estimated improved survival benefit of 11% in an unselected patient population outside a research setting. This comparison was not randomised and was made with the patients treated with radiotherapy alone in the same centre as part of the 1993 national audit [10]. The national survival figures for the UK as a whole at that time were 47%. A recent publication by King et al. from Birmingham [15] showed a 3-year survival of 87%. In our study, the 3-year survival rate was 70%. However, in the Birmingham series, 38% of patients had early tumours defined as FIGO IIA or less, and 28% of all patients had surgery as their primary treatment. In our study, 84% of patients received chemoradiotherapy as their primary definitive treatment, and only 16% of all patients received surgery before chemoradiation. This difference in stage between the two series probably accounts for the difference in 3-year survival (87% vs 70%).
Grigsby et al. [16] have also recently reported a 5-year overall survival estimate of 81% in patients treated with chemoradiotherapy compared with 85% in patients treated with radiotherapy alone. However, the numbers in the radiotherapy alone arm were small at n=16. They also reported that there was no difference in overall survival in lymph node-negative patients stated by 18-fluorodeoxyglucose positron emission tomography (18-FDG PET) by FDG-PET treated by radiotherapy with or without chemotherapy. In our series there was no difference in the 3-year overall survival rate between node-positive and node-negative patients (70% vs 66%), but there was a difference in survival when comparing these results with the cohort of patients treated in the 1993 national audit and therefore both node-positive and node-negative patients benefited from chemoradiation. As expected there was a difference in disease-free survival between node-negative and node-positive patients (68% vs 54%), with the largest difference seen in the distant disease-free survival group (78% vs 62%). None of the patients in our series underwent staging with FDG-PET, which is not standard in the UK at present, although it may be useful in staging locally advanced disease 17, 18, 19. All the patients in our series underwent staging with magnetic resonance imaging and will therefore have been more accurately staged than the 1993 cohort. In this series, there was a significant difference in 3-year overall survival and disease-free survival between patients who received concurrent chemotherapy alone and patients who received neoadjuvant and concurrent chemotherapy. Survival was much better in the concurrent only group (overall survival 76% vs 64% and disease-free survival 68% vs 57%). Neoadjuvant chemotherapy was used as there was a long waiting list to commence radiotherapy in Manchester at the time. This waiting list improved during the study period and 56% of patients received concurrent chemotherapy alone. There are no data on the use of neoadjuvant chemotherapy before chemoradiation. The only data available are on the use of neoadjuvant chemotherapy before surgery or radiation alone [20]. A possible explanation for this may be the importance of overall treatment time in the treatment of cervical cancer. The risk of prolongation of treatment time has been reported as an estimated loss of local control ranging from 0.3 to 1.6% per day of treatment prolongation [21]. This was reported in relation to radiotherapy for cervical cancer and there are no data for chemotherapy. Radiobiological models show that increased waiting time to commencing radiotherapy can have an adverse effect on tumour control and there is plenty of evidence that shows that delay in starting radiotherapy leads to reduced local control and hence metastases and reduced survival 22, 23, 24, 25, 26.
Looking at all the published data, there is no doubt that the addition of concomitant chemotherapy to radiotherapy improves survival outcomes, but what is not yet clear is the effect on late toxicity. Acute toxicity is increased, but with careful monitoring and evaluation of the patient during treatment is manageable. Other series 15, 27 have shown an increase in thrombotic events in patients undergoing chemoradiation. We had no thromboembolic events in our study population. It is difficult to separate this from the increased thromboembolic risk of just having a pelvic malignancy. There are few data available on late toxicity 5, 6, 8, 14, 28. In the meta-analysis by Lukka et al. [14] of the eight randomised studies included, late toxicity data were only reported in four. None of the studies detected a significant increase in late toxicity with the addition of cisplatin chemotherapy to radiotherapy. The late toxicity rate was reported as 12%, which is higher than the 8% rate of grade 3 complications reported by Denton et al. [10] in the UK national audit in 1993 of patients treated with radiotherapy alone. The recorded late toxicity rate from this centre in the 1993 national audit was 3.4%, which was significantly lower than the UK average. A meta-analysis of 19 trials by Kirwan et al. [28] reported 11 toxic deaths, eight acute (sepsis) and three late (small bowel obstruction, ureteric fibrosis and pulmonary embolus). A recent UK series presented by Tan and Zahra [29] reported a late grade 3 and 4 toxicity rate of 18.3%, with three toxic deaths (4%).There were no toxic deaths in our study. In this series, however, our late toxicity rate increased from 3.4 to 9%, but this was not statistically significant. There was one case of vaginal stenosis in a patient who did not use the vaginal dilators as recommended, so excluding this, the bladder and bowel late toxicity rate was 8%. The patients who developed grade 3 late toxicity all presented with very advanced disease and it is recognised that advanced stage of disease is associated with morbidity. In addition, increasing survival probably leads to increasing reporting of late toxicity. Altering treatment-related factors may reduce late toxicity, such as using conformal or intensity-modulated radiotherapy techniques or decreasing the dose per fraction. However, the fractionation used here was 2Gy/fraction in the node-positive patients and 2.25Gy/fraction in the node-negative patients. The rate of late toxicity (8% grade 3 bowel and bladder toxicity) in the chemoradiation patients was lower than the 12% internationally and similar to the 8% of the UK national audit, who were treated with radiotherapy alone. This implies that higher doses per fraction do not seem to be associated with a higher rate of treatment morbidity.
Twenty-two patients developed distant metastases. Metastases were seen in unusual sites (bone, brain, skin). This may be as a result of the increased survival. The distant disease-free survival rate was the same in both the concurrent only and the neoadjuvant and concurrent chemotherapy groups. Overall the concurrent group had an improved survival compared with the neoadjuvant and concurrent group. There are no data looking at adjuvant chemotherapy in this cohort of patients and this may be an area of potential future research to determine if the addition of adjuvant chemotherapy after definitive chemoradiotherapy could reduce the recurrence rates and, hence, improve overall survival further. However, it will be important to review these figures again in 5 years to assess whether the improvement seen is sustained.
Conclusion
The addition of chemotherapy to radical radiotherapy outside a research setting has shown a trend towards improved overall and disease-free survival. There was also a trend towards increasing toxicity, which may become significant with longer follow-up. The site orientated e network of the Royal College of Radiologists is planning to undertake a further national audit of cervix cancer outcomes to include patients treated with chemoradiotherapy and this may provide us with further data.
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PII: S0936-6555(08)00444-5
doi:10.1016/j.clon.2008.10.014
© 2008 The Royal College of Radiologists. Published by Elsevier Inc. All rights reserved.
