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British Journal of Radiology (2004) 77, 581-587
© 2004 British Institute of Radiology
doi: 10.1259/bjr/63967203
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Full Paper

Adding concurrent low dose continuous infusion of cisplatin to radiotherapy in locally advanced cervical carcinoma: a prospective randomized pilot study

M Garipagaoglu, MD1, F Kayikçioglu, MD2, M F Köse, MD2, M Adli, MD3, K H Gülkesen, MD4, Z Koçak, MD5 and G Tulunay, MD2

1 Akdeniz University Medical School, Radiation Oncology Department, Antalya, 2 SSK Ankara Maternity Hospital, Gynaecologic Oncology Department, Ankara, 3 Harran University Hospital, Medical School, Radiation Oncology Department, Sanliurfa, 4 Akdeniz University Medical School, Biostatistics Department, Antalya and 5 Trakya University Medical School, Radiation Oncology Department, Edirne, Turkey


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Pre-treatment evaluation
 Results
 Discussion
 Conclusion
 References
 
The tolerability and efficacy of the continuous infusion of cisplatin during radiotherapy was studied by tumour response, survival and pelvic control, in carcinoma of the cervix. 44 patients with stage IIB–IIIB cervical carcinoma were prospectively randomized into two groups: radiation alone (control group) versus radiation plus cisplatin (study group). While there was no significant difference in diarrhoea and urinary complication scores, emesis and appetite changes were significantly greater in the study group. Tumour responses were no different at the end of the treatment and 3 months after completion of treatment. After 40 months median follow-up, 40/44 patients were assessed (one had a second primary tumour and three were lost to follow-up). Persistent disease was found in 3 patients: one in the study arm and two in the control arm. Recurrence was seen in 10 patients in the first 2 years. 5-year pelvic control rates were; 69.4% and 63.9% (p=0.7), survival rates were 52.0% and 48.9% (p=0.7) and disease-free survival rates were 67.5% and 58.7% (p=0.3) for the control and the study groups, respectively. Although the continuous infusion of cisplatin during radiotherapy was well tolerated, this additional treatment did not appear to show an improvement in pelvic control, survival, or disease-free survival.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Pre-treatment evaluation
 Results
 Discussion
 Conclusion
 References
 
Carcinoma of the cervix is the most common female cancer and is one of the major causes of cancer deaths in females in the developing world [1, 2]. The majority of the patients present with advanced disease [1, 3, 4] due to a low screening rate [5, 6].

Local failure is a major problem in advanced cervical carcinoma [7–11]. Increased radiation doses improve local control but the tolerance of surrounding tissues limits the radiation dose [12]. Attempts to improve local control such as hypoxic cell sensitizers [13, 14], hyperbaric oxygen [15], neutron therapy [16], and altered fractionation schedules [17] have met with limited or no success. The combination of chemotherapy and radiation has been used to improve pelvic control and survival. Most of the studies with neoadjuvant [18–21] and adjuvant [22] chemotherapy did not increase survival. The maximum benefit was obtained with concurrent chemoradiotherapy using cisplatin based chemotherapy [23–28], fluorouracil [29, 30] and hydroxyurea [31]. Cisplatin is the most effective chemotherapeutic agent in the treatment of cervical carcinoma [22, 26, 28, 32, 33]. The overall rate of objective response before radiation ranges from 31% to 100%, and the complete response rate is 0–25% [18, 22, 33]. In neoadjuvant studies, cisplatin based combination regimens showed no difference compared with single agent cisplatin in tumour response rate, median duration of response and survival [26, 28, 33].

The objective of this prospective randomized pilot study was to test the tolerability and efficacy judged by tumour response, survival and pelvic control of continuous infusion of cisplatin during radiotherapy, in carcinoma of the cervix.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Pre-treatment evaluation
 Results
 Discussion
 Conclusion
 References
 
Patient selection
Patients with biopsy proven squamous cell carcinoma of the cervix, FIGO stages IIB or IIIB, tumour size=>ge;4 cm, with adequate haematological, renal and hepatic functions, Karnofsky performance status of >80%, and no prior chemotherapy, radiotherapy or pelvic surgery, were eligible.

This study was approved by the Institutional Ethics Committee.


   Pre-treatment evaluation
Top
 Abstract
 Introduction
 Patients and methods
 Pre-treatment evaluation
Results
 Discussion
 Conclusion
 References
 
All patients underwent cystoscopy, proctosigmoidoscopy, intravenous pyelography and pelvic examination under general anaesthesia. Abdominal CT or lymphangiography was not performed to evaluate para-aortic lymph nodes. A full blood count, liver and renal chemistry (blood urea nitrogen, creatinine, creatinine clearance) and a chest radiograph were obtained.

Treatment protocol
Between January 1996 and March 1997, 44 patients with inoperable cervical carcinoma were prospectively randomized into 2 groups, according to stage, age and tumour diameter (Table 1Go). As seen in Table 1Go, patients were further divided according to involvement of bilateral or unilateral parametria and pelvic side walls. The control group received radiation alone and the study group received radiation plus continuous cisplatin infusion.


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  		Table 1. Patient characteristics

 
Cisplatin 20 mg per square metre per day was administered as a continuous intravenous infusion, from Monday to Saturday, in the first and fourth week of external beam radiotherapy (Figure 1Go). The patients received antiemetic treatment [5] and 0.9% saline solution 2 litres each day during chemotherapy.



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  		Figure 1. Treatment protocol for the study group (RT, radiotherapy; CP, cisplatin; Lab, complete blood count, renal and hepatic function tests).

 
External radiotherapy (ERT) was given to the whole pelvis, using Co 60 and anteroposterior, posteroanterior fields, 2 Gy daily to 46–50 Gy. Brachytherapy (BT) was carried out with either high dose rate (HDR) Co 60 or HDR Ir 192, an average 2 weeks after completion of ERT, with two 10 Gy fractions to point A. Radiotherapy (external and BT) was given at the Ankara University School of Medicine Department of Radiation Oncology.

Study parameters and follow-up
Patients were seen at weekly intervals during treatment. Acute urinary, gastrointestinal and haematological complications were scored according to the modified RTOG (Radiation Therapy Oncology Group) system. The scores were based on the patient's subjective complaints, objective examination findings and treatment of symptoms. The emesis scores of the study group and the control group were both compared during the week that the study group of patients received chemotherapy and the week that the patients did not receive chemotherapy.

Tumour sizes were measured by physical examination prior to treatment on the last day (at the second BT fraction) and 3 months after completion of radiation therapy by the same physician. The percentage response rates for the groups were compared. Greater than 90% response was defined as complete response, 50–89% response was defined as partial response and less than 50% was evaluated as stable disease.

Patients were followed up at 3 month intervals after completion of treatment. Pelvic examination, cervical cytology, complete blood count and renal function test were performed at each follow up visit. Imaging studies were done if there was a suspicion of recurrence or distant metastasis. Pelvic control, overall survival (OS) and disease-free survival (DFS) rates of both groups were compared.

Statistics
Acute treatment complications and response rate were compared using the Mann-Whitney U test. The Kaplan Meier test was used to calculate pelvic control, OS and DFS rates. The Log rank test was used to compare the pelvic control and survival rates of the groups. Power analysis of comparison of survival in two groups was performed with the help of a web application in John Hopkins University Bloomberg School of Public Health website (http://www.jhsph.edu/research/centers/cct/javamarc).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Pre-treatment evaluation
 Results
Discussion
 Conclusion
 References
 
All 44 patients completed the treatment as planned. Persistent disease was found in 3 patients: one in the study group and 2 in the control group. After 40 (3–62) months median follow-up 40 of 44 patients were assessable (one case had second primary tumour and 3 cases were lost to follow-up). When the analysis was done, 17 of the assessable 40 patients had died, 8 in the control group and 9 in the study group.

The emesis score was found to be significantly greater in the study group than in the control group during chemotherapy (p=0.0001). There was no significant difference during the week the study group did not receive chemotherapy (p=0.1); and there was no significant difference in diarrhoea (p=0.5) and urinary complication scores (p=0.2). Decrease of appetite was significantly greater in the study group (p=0.01).

Neutropenia and nephrotoxicity occurred in one 67-year-old patient in the study group. She had neutropenia in the second week of treatment. The white blood count (WBC) was 1100 mm–3. After using colony stimulating factor (CSF) for 5 days her WBC increased to 7000 mm–3. Her blood urea nitrogen (BUN) and creatinine levels were increased in the third week of treatment. After hydration, the patient recovered. She had a mild electrolyte imbalance but she did not develop chronic renal insufficiency. Because of this complication, radiotherapy was discontinued for 1 week.

Pelvic examination was undertaken in all patients but due to the subjective nature of pelvic examination the tumour diameter could not be accurately estimated in some patients. Therefore the response rate was evaluated in 42 patients at the end of treatment and 36 patients 3 months after completion of treatment. The tumour response of the study group did not significantly differ from the control group both at the end of the treatment (p=0.052) and 3 months after completion of treatment (p=0.3).

Recurrence was seen in 10 patients of whom 6 were in the control group and 4 were in the study group (Table 2Go). The number of patients with residual and recurrent disease according to treatment are given in Table 2Go; the majority of the failures were in the pelvis. All the recurrences were seen in the first 2 years; mean recurrence times were 9 months in the control and 11 months in the study group.


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  		Table 2. Characteristics of the patients with recurrence and residual disease. *Alive with disease; {dagger}Alive, cured

 
The salvage treatment was chemotherapy in 9 patients and surgery in 1 patient. Three patients did not receive further treatment. Only 1 of 13 cases with recurrent or residual disease was salvaged successfully, and in this case residual disease was treated by surgery. One patient was alive with recurrent disease treated by chemotherapy.

The 5-year pelvic control rate, OS and DFS were 66.27%, 51.3% and 63.24%, respectively, for the whole group. There was no significant difference between the study and the control groups in terms of 5-year pelvic control (p=0.7) (Figure 2aGo), survival (p=0.7) (Figure 2bGo) and DFS (p=0.3). 5-year pelvic control rates were 69.4% and 63.9%, the survival rates were 52.0% and 48.9% and the DFS rates were 67.5% and 58.7% for the control and the study groups, respectively.



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  		Figure 2. Pelvic control rate (a) and survival rate (b).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Pre-treatment evaluation
 Results
 Discussion
Conclusion
 References
 
A total of 200 mg m–2 continuous infusion cisplatin was administered to 22 patients, without requiring any dose adjustment, during radiotherapy for cervical carcinoma. The reported compliance rate for weekly 40 mg m–2 cisplatin bolus was 70–85% [34], for 3 weekly 75 mg m–2 cisplatin bolus and continuous 5 fluorouracil was 68–70% [26], and for 3 weekly 100 mg m–2 cisplatin bolus was 85% [27]. The Gynecologic Oncology Group (GOG) conducted a study with 3 arms one of which included consecutive daily 20 mg m–2 cisplatin bolus in the first and fourth week of radiotherapy [33]. This was closed early due to the inconvenience of daily routine treatment. Sood et al reported the results of a similar study in which 5 consecutive daily 20 mg m–2 cisplatin bolus were given in the first and fourth week of radiotherapy [35]. This resulted in 80% of Grade III–IV haematological complication. On the other hand 60% of patients included in the same study received both pelvic and para-aortic radiotherapy. Concurrent chemotherapy and pelvic–para-aortic radiotherapy caused higher gastrointestinal and haematological complication rates [36, 37]. All the patients included in the current study, were hospitalized for socioeconomic reasons. The low treatment toxicity of this protocol can be explained by the lower toxicity with continuous infusion of cisplatin compared with bolus infusion, radiotherapy confined to the pelvis and hospitalization. Better tolerance [38] especially lower rate of bone marrow suppression with continuous infusion of cisplatin than bolus infusion, was reported in head and neck cancer patients receiving concurrent radiotherapy [39]. It appears that continuous infusion of cisplatin can be administered safely to inoperable cervical carcinoma patients receiving radiation therapy. The most significant important side effect was emesis, but it was successfully managed by one of the 5 hydroxytryptamine (5HT3) antagonists. Renal and haematological toxicity occurred in only one patient.

Using pelvic examination to estimate tumour size is subjective. Although estimation could not be carried out in all patients, tumour response was higher in the study group than the control group at the end of treatment. Nevertheless, this difference disappeared at 3 months after treatment. The response rates increased from the end of the treatment to 3 months after treatment in both the study and the control groups; most patients who had persistent disease at the end of treatment, achieved complete response at 3 months after treatment, but there was no further improvement after 3 months. Perez and Kaufman [40, 41] pointed out that tumour regression continues until 3 months after treatment; therefore tumour response 3 months after treatment is a good predictor for treatment outcome. This is in agreement with the results presented here.

The majority of treatment failures were seen in the pelvis, in the irradiated area, which is consistent with other studies [7–10]. An analysis of the patterns of failure reveals that 72% of those who failed had pelvic tumour as a component of the first site of failure [9]. Because the pelvis is the major treatment failure site, an increase in pelvic control leads to an increase in survival [40, 42, 43]. The main reason for using concurrent chemotherapy and radiotherapy is to improve control of the pelvis rather than extrapelvic disease [30, 43]. Although there were some negative studies [29, 34, 44, 45] most of the previous studies reported increased pelvic control rates by the addition of concomitant chemotherapy [23–28]. However, the addition of concurrent continuous infusion of cisplatin to radiotherapy did not provide improvement in pelvic control in this study.

Although, survival and DFS rates, were comparable with reported results [26, 27, 34], there is a need for improvement. Most of the previous studies reported an increased survival, DFS and progression-free survival when using concurrent radiotherapy and cisplatin-based chemotherapy [26–28]. The reported survival benefit was around 10–15% [26–28] and, according to a meta-analysis, OS benefit was around 12% [30, 43]. On the contrary, this pilot study did not show benefit for either survival or DFS with the addition of concurrent cisplatin to radiotherapy. The statistical comparison of survival in the two groups showed that the number of patients in the present study was inadequate to detect a difference.

The benefit of concurrent chemotherapy is more marked in early stages than advanced stages [30]. Locally advanced disease includes extrapelvic disease, lymph node metastasis and bulky tumour. The patients of the current study were mainly at an advanced stage, but para-aortic lymph nodes were not evaluated before randomization. Most of the published studies reporting increased survival included only para-aortic node negative patients [26–28]. Improvement in pelvic control and survival rates were not seen in the trials which did not evaluate para-aortic lymph nodes surgically [34, 45]. Perhaps undetected extrapelvic disease is another reason for chemotherapy failing to contribute in this series.

A reduction in distant metastasis rate was not seen in single trials using short-term concurrent chemotherapy during radiation [26–28]. However, meta-analysis has shown a significant reduction in the distant metastasis rate [30]. There was no difference in the occurrence of extrapelvic failure in this study.

The ERT fraction size was 2 Gy, and as far as we know this is the only study using 2 Gy daily fraction of ERT and concurrent chemotherapy that did not cause excessive toxicity. BT could not be performed in 4–12% of the patients in previous studies [26–28, 33, 34]. All patients' tumour responses in the current study were sufficient to allow BT application. We suggest that local failure is related to the 2 week break before starting BT. As reported previously, extended total treatment time causes treatment failure [46, 47], therefore we do not support a 2 week break before BT.

The median ERT time was 38 days, which did not differ between groups. Because of 2 week breaks before starting BT the median total radiotherapy time was 61 and 62 days (8.8 weeks) which was similar in both groups. The optimal radiotherapy time is ≤8 weeks [40, 47]. The total treatment time was slightly longer than optimal, slightly less than the positive chemoradiotherapy study reported by Whitney which was 9.1 weeks [26]. Although the total radiotherapy time of the current study was longer than Pearcey's whole group, it was close to the HDR arm, which was 55 days [34]. Pearcey suggested that the additive effect of chemoradiotherapy is noticeable only when total radiotherapy time is prolonged. The extended total treatment time did not lead to a better combined modality outcome in the current study, contrary to Pearcey's claim. As pointed out by Rose and Bundy [43], the hypothesis that the enhanced effect of cisplatin-based chemoradiotherapy arose from the extended radiation time, should be approached cautiously.

The American Brachytherapy Society (ABS) recommended using a minimum total of 75 Gy to point A with ERT and HDR BT, 5 times 6 Gy fractions, to achieve optimum tumour control [48]. The fractionation of the current study is 2 times 10 Gy which is different from the suggested fractionation. The radiobiologically equivalent doses to tumour and normal tissues were calculated, without considering the time effect, using the linear quadratic formula; with {alpha}/{beta} values of 10 Gy for the tumour and 3 Gy for normal tissues. The calculated biologic equivalent dose (BED) values without considering the time effect for tumour and normal tissue were 48 and 90 for the ABS suggested fractionation (5 times 6 Gy) and 40 and 86 for the current study (2 times 10 Gy), respectively. Both radiobiologically equivalent doses for tumour and normal tissue were less than the ABS suggested fractionation. Furthermore, the median total point A dose in the current study was 70 (66–70) Gy, less than the recommended dose. The Canadian National Study's [34] HDR arm also had less than the recommended point A dose. They analysed the group as a whole and did not evaluate the effectiveness of chemoradiotherapy separately in the HDR arm. Pearcey [34] claimed that the benefit of chemoradiotherapy was enhanced when using insufficient radiation doses, and criticized previous positive chemoradiotherapy trials for using less than optimal radiation dose. However contrary to his claim, insufficient radiation dose and concurrent combination chemotherapy did not enhance treatment outcome in the current study. Furthermore, in another non-randomized study that used less than optimal point A dose, no difference between chemoradiotherapy and radiation alone arms was reported [35]. Therefore, the relation of total point A dose and increase in survival and pelvic control rate in treatment protocols using chemoradiotherapy should be investigated further.

There is no established optimum schedule for the use of cisplatin. The GOG study for testing the effect of cisplatin doses 100 mg, 50 mg weekly and 20 mg x 5 days showed that the effectiveness, and most of the acute and late effects, were the same, while emesis was less in the 20 mg x 5 day group [33]. Moreover, a dose–response relationship was not seen. The additional benefit of the combination of other drugs such as topotecan [49, 50] or hypoxic cell sensitizers such as tirapazamine [51] or retinoids [52] to concurrent cisplatin based chemoradiotherapy has been investigated.

The continuous infusion of cisplatin is more effective than bolus as a radiosensitizer [31, 53]. Furthermore, continuous infusion has a lower suppressive effect than bolus on the bone marrow [38]. Salem et al [39] reported that cisplatin (dose 20 mg per square metre per 24 hours, 5 days, continuous infusion, at 3-week intervals) and radiation could be used concurrently in head and neck carcinomas [39]. It was assumed that the tumour biology of squamous cell carcinomas of the cervix and head and neck are similar. In order to avoid serious acute side effects and to avoid reduction of the cisplatin dose, a similar schedule was chosen in the current study. However, as far as we know, there is no experience of low dose continuous infusion of cisplatin in cervical carcinomas. Low dose continuous infusion of cisplatin is used mostly in testicular carcinomas and lymphomas which have a good blood supply. In contrast, cervical squamous cell carcinomas often have necrotic areas and a poor blood supply, therefore a relatively low daily cisplatin dose and dose intensity could be responsible for the failure of cisplatin to benefit in this series.


   Conclusion
Top
 Abstract
 Introduction
 Patients and methods
 Pre-treatment evaluation
 Results
 Discussion
 Conclusion
References
 
Continuous infusion cisplatin can be administered safely to patients with inoperable cervical carcinoma in combination with radiation therapy. There was no benefit in pelvic control, survival or DFS. We assume that the negative result of this pilot study is related to insufficient patient numbers and inadequate extrapelvic disease evaluation. There is evidence to support the use of concurrent cisplatin based chemotherapy and radiation in locally advanced carcinoma of the cervix, but investigations are still needed to determine the optimum chemotherapy schedule and dose of radiation.


   Footnotes
 
Drs Garipagaoglu, Adli and Koçak were working at Ankara University School of Medicine Department of Radiation Oncology during the whole radiotherapy schedule. Back

Received for publication June 23, 2003. Revision received November 24, 2003. Accepted for publication December 10, 2003.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Pre-treatment evaluation
 Results
 Discussion
 Conclusion
 References
 

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