1 Instituto Nacional de Cancerología, Mexico City; 2 Unidad de Investigación Biomédica en Cancer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
Received 9 January 2003; revised 9 April 2003; accepted 11 April 2003
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Abstract |
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Our aim was to evaluate the efficacy and safety of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with weekly cisplatin for locally advanced cervical carcinoma.
Patients and methods:
Forty-three patients staged as IB2IIIB were treated with three 21-day courses of carboplatin (area under the timeconcentration curve 6 mgmin/ml) and paclitaxel at 175 mg/m2 by 3-h infusion both on day 1 followed by radical type III hysterectomy and adjuvant radiation concurrent with 6-weekly doses of cisplatin at 40 mg/m2. Response rate, resectability, toxicity and survival were evaluated.
Results:
From December 2000 to June 2001, 43 patients were recruited. All were evaluated for response and toxicity to neoadjuvant chemotherapy. A total of 129 courses were administered. Clinical responses were seen in 41 patients (95%) [95% confidence interval (CI) 89.2% to 100%] with four (9%) complete and 37 (86%) partial. Forty-one patients underwent surgery (resectability 95%); pathologically complete or near-complete responses were seen in seven (17%) and eight (20%), respectively, positive surgical margins in five (12%), and positive pelvic lymph nodes in eight (20%). Twenty-six patients were scheduled for adjuvant chemoradiation. External radiation was delivered for 42.8 days (range 3361), with a mean dose of 49.3 Gy (range 4656), and a median of five cisplatin courses (two to six). The mean dose of brachytherapy was 32 Gy (range 25.535.6). Neoadjuvant therapy was well-tolerated with neutropenia grade 3 and 4 in 12% and 3% of the courses, respectively. Toxicity to adjuvant chemoradiation was mainly hematological and gastrointestinal, mostly grades 1/2. A total of 39 patients completed all scheduled treatment. At a median follow-up of 21 months (range 326), the projected overall survival in the intention-to-treat analysis was 79% (95% CI 62% to 88%).
Conclusions:
The triple modality of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with cisplatin is a highly active treatment for locally advanced cervical carcinoma with acceptable toxicity.
Key words: cervical carcinoma, concomitant chemoradiation, neoadjuvant chemotherapy, radical hysterectomy
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Introduction |
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Earlier attempts to improve the prognosis of these patients included the use of neoadjuvant chemotherapy followed by radiation. However, this sequential modality failed to improve the prognosis, most probably because of the cross-resistance between chemotherapy and radiation [3]. More recently, seven of eight prospective randomized phase III trials have shown the superiority of chemotherapy delivered concurrently with radiation, compared with standard radiation [411]. Nevertheless, the absolute benefit in survival is only 12% according to a meta-analysis of concurrent chemoradiation trials [12].
On the other hand, several studies have evaluated the role of radical surgery after neoadjuvant chemotherapy. The main rationale of this approach is that surgery may bypass the cross-resistance between chemotherapy and radiation delivered sequentially; thus the disease remaining after chemotherapy could in theory be more effectively treated with surgery. Interestingly, phase III randomized trials demonstrate the superiority of this neoadjuvant approach over radiation alone [1315]. However, because of the superiority of concurrent chemoradiation over radiation alone [12], neoadjuvant chemotherapy should now be compared with standard chemoradiation. Pending confirmation from prospective randomized phase III trials, data from two consecutive phase II studies comparing neoadjuvant chemotherapy and surgery versus standard chemoradiation suggest that both modalities are similar in terms of survival [16]. Even assuming that these two modalities are equally effective, newer approaches should be tested in order to improve the prognosis of locally advanced cervical cancer patients.
In order to get the maximum benefit from the neoadjuvant chemotherapy and surgery modality there are two issues that should be addressed. One is to determine the optimal management of patients who do not achieve a major response to induction chemotherapy, and are therefore not able to undergo radical hysterectomy. These patients are usually treated with radiation alone and have a poor prognosis, compared with those able to undergo surgery [1720]. Thus, maximum effort should be made to submit these patients for surgery, as the tumor cells remaining after induction chemotherapy will most likely be resistant to radiation. Nevertheless, despite the use of a highly active program of induction chemotherapy, a proportion of patients cannot undergo surgery and the use of chemoradiation instead of radiation alone as local treatment might have a good chance of control [21]. A second issue is to prevent the failures in patients who undergo radical hysterectomy. In a literature review of all trials of neoadjuvant chemotherapy and surgery, some patients have been treated with adjuvant pelvic radiation [22]; however, the benefit of adjuvant radiation in this setting is yet to be proved [23]. In contrast, the single study reported of concomitant adjuvant chemoradiation has shown positive results [4], which makes it logical to employ concurrent chemoradiation instead of radiation alone as adjuvant treatment for the locally advanced cases submitted to induction chemotherapy and surgery. In this regard, we have previously reported that postoperative chemoradiation is feasible in this patient population [24].
We report the results of a phase II trial of multimodality treatment of locally advanced cervical carcinoma using carboplatin and paclitaxel as neoadjuvant chemotherapy, followed by radical surgery and adjuvant cisplatin chemoradiation.
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Patients and methods |
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Clinical staging was performed by a multidisciplinary team of physicians (at least three examiners to reach consensus) and included pelvic examination, drawing a detailed map of the lesion, chest X-ray, cystoscopy, rectosigmoidoscopy and intravenous pyelogram. The status of the para-aortic lymph nodes was not assessed. During neoadjuvant chemotherapy, complete blood cell counts and biochemical profiles were performed at days 14 and 21 of each of the three cycles.
Treatment consisted of intravenous carboplatin at a dose giving an area under the timeconcentration curve of 6 mg×min/ml (based on calculated creatinine clearance) diluted in 500 ml 5% glucose administered over 1 h, followed by paclitaxel at 175 mg/m2 administered over 3 h, both drugs on day 1. Conventional premedication for paclitaxel was used. A total of three 21-day courses were administered. Chemotherapy was withheld in case of disease progression. In both cases, patients were taken to immediate locoregional treatment. Dose modifications were not allowed but could be delayed for 1 week when the platelet and neutrophil counts were <100 000/mm3 or <1500/mm3, respectively. Patients could receive full supportive care, including transfusions (to keep hemoglobin ³9 g/dl), antibiotics, antiemetics, steroids, anti-diarrheals and analgesics when appropriate. The prophylactic use of colony-stimulating growth factors was not allowed.
Patients who received at least two courses of chemotherapy were evaluated for response to neoadjuvant chemotherapy. This was performed at the end of chemotherapy using standard criteria. Complete response was defined as the complete disappearance of all measurable disease. Partial response was recorded as >50% reduction in the product of the two longest perpendicular diameters of all measurable lesions. No response or stable disease was defined as <50% decrease in the product of the two longest perpendicular diameters of the measurable lesions. Progressive disease was defined as >25% increase in the product of the two longest perpendicular diameters of one measurable lesion (even with the regression of other lesions) or the appearance of new ones. The evaluation was performed by three examiners.
After neoadjuvant chemotherapy all patients except those with progression to neoadjuvant treatment were submitted to radical type III hysterectomy. Patients in whom hysterectomy was not performed received definitive standard pelvic radiation with external beam (50 Gy, 2 Gy daily from Monday to Friday) and one or two applications of brachytherapy with cesium sources to deliver at least 85 and 55 Gy to points A and B, respectively, plus concomitant 6-weekly doses of cisplatin at 40 mg/m2 during external beam radiation. Postoperative chemoradiation was performed in all cases with positive surgical margins, one or more positive pelvic lymph node and those with disease in parametria (high-risk factors for recurrence), as well as those cases whose residual disease contained vascular or lymphatic permeation and/or deep of invasion to the middle or internal thirds of the cervical stroma (intermediate-risk factors for recurrence). In the adjuvant setting, the dose of pelvic external beam radiation was 50 Gy followed by a 3035 Gy dose to the vaginal mucosa using intravaginal brachytherapy with cesium sources. Cisplatin was administered during external radiation as described above. During chemoradiation (definitive or adjuvant), complete blood cell counts and serum creatinine were performed weekly. Transfusions were allowed to keep hemoglobin ³9 g/dl.
Toxicity to neoadjuvant chemotherapy and chemoradiation were evaluated according to the WHO and Radiation Therapy Oncology Group criteria, respectively.
Follow-up procedures included pelvic examination and vaginal cytology starting 3 months after the completion of all treatment and every 3 months thereafter. Computed tomography scans and other image studies were performed as indicated.
Survival was considered from the date of diagnosis until death or last visit. Survival curves were constructed according to the KaplanMeier estimator [25].
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Results |
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The overall treatment and final responses of patients are shown in Table 3.
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Toxicity to chemoradiation
Chemoradiation was well tolerated. Table 5 shows that the most frequent toxicity was leukopenia grade 1 in 44% of patients, grade 2 in 35% and grade 3 in 6%. Neutropenia grade 1, 2 and 3 was present in 29%, 24% and 6% of patients, respectively. Thrombocytopenia grades 1 and 2 were observed in 11% and 6%, respectively. Grade 3 upper and lower intestinal toxicities were observed in 6% and 18% of patients, respectively. Genitourinary and skin toxicity were mainly grade 1/2. A the time of this analysis none of the patients has presented late toxicity.
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The remaining four patients have relapsed and died; two with pelvic/systemic relapse, one with local recurrence (pelvic) and one with intra-abdominal recurrence. All operated patients who have progressed or died of recurrent disease showed only partial pathological response (macroscopic residual tumor, positive pelvic nodes or positive surgical margins. In the intention-to-treat analysis, the projected overall survival is 79% (95% CI 62% to 88%) (Figure 1). Currently, all living patients are disease free.
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Discussion |
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In this study, we report the results of a multimodality treatment incorporating neoadjuvant chemotherapy, radical surgery and adjuvant chemoradiation for previously untreated locally advanced cervical carcinoma. Our results suggest that this approach is feasible, produces manageable toxicity and is promising.
Neoadjuvant chemotherapy has become the standard of care or a promising modality in several solid tumors, but in cervical carcinoma it remains an experimental therapy. In this tumor type, the modality of local treatment after induction chemotherapy used is important. Despite the lack of randomized trials comparing radiation with radical surgery after induction chemotherapy, emerging data from a large number of neoadjuvant trials suggest that surgical resection could be better as it bypasses the cross-resistance between chemotherapy and radiation [1720]. Previous studies have shown that the resectability of locally advanced cervical tumors depends very much on the response to induction chemotherapy [22]. Also, the benefit on survival of neoadjuvant chemotherapy in solid tumors is mostly limited to patients with complete clinical or pathological response; therefore, the employment of an effective induction scheme of chemotherapy seems necessary in order to obtain better survival figures [2628].
In this study, we combined the use of carboplatin and paclitaxel. This scheme has not been tested previously in cervical carcinoma, but it is known that both agents have a high cytotoxic activity as single agents in preclinical and clinical studies of cervical cancer [2932]. On the other hand, the combination of cisplatin and paclitaxel has demonstrated significant activity in cervical cancer patients with advanced or recurrent disease achieving response rates between 40% and 50% [3335]. Here we decided to use carboplatin instead of cisplatin because both have comparable activity against cervical cancer cells [29], carboplatin has a more favorable toxicity profile and because cisplatin was to be used concurrently with radiation in the postoperative setting. The results of this study show that when used as first-line treatment this combination is highly active, with a 95% overall response rate, although only four cases had complete clinical response. Interestingly, there was a lack of concordance between the clinical and pathological assessment of the response as we observed in a previous study using gemcitabinecisplatin [36]. Thus, seven (17%) and eight (20%) of the patients showed complete or near-complete pathological response, respectively. These results compare favorably with earlier regimes such as cisplatinvincristinebleomycin; cisplatinbleomycin, cisplatinifosfamide, and many others [22], as well as with new combinations such as cisplatinnavelbine [37] and cisplatinirinotecan [38] in untreated cervical carcinoma patients. The combination of cisplatin and paclitaxel has been tested in advanced or recurrent cervical carcinoma yielding response rates between 45% and 47%, which are clearly inferior to the present rates, but these results are not comparable, due to differences in the treated patient population. There has only been one study of cisplatin, ifosfamide and paclitaxel performed in untreated patients [39]. Zanetta et al. [39] reported the treatment of 37 patients with locally advanced disease, most IB2/IIA, using three 21-day courses of paclitaxel 175 mg/m2 given over 3 h on day 1, cisplatin 50 mg/m2 (75 mg/m2 in 10 patients), ifosfamide 5 g/m2 in a 24-h continuous infusion and mesna. The overall clinical response rate was 84% and the pathological responses in 34 patients who underwent surgery were 16% and 18% pathological and near-complete pathological complete responses, which are almost identical to the present study. However, this three-drug combination proved to be more toxic with grade 3/4 neutropenia and thrombocytopenia in 71% and 10.5% of cases, respectively. Thus, our results confirm that the combination of carboplatin and paclitaxel is very active and devoid of significant toxicity in the neoadjuvant setting.
The rationale for the use of surgical consolidation after induction chemotherapy is to avoid the cross-resistance between chemotherapy and subsequent radiation; therefore, every effort should be made to operate on patients with a poor response to induction chemotherapy. However, response to chemotherapy is not the sole factor determining operability; the aggressiveness of the surgical team also plays an essential role. In our previous studies of neoadjuvant chemotherapy the operability rate was between 60% and 70% [24, 36]; here we were able to perform radical hysterectomy in 95% of cases. This high surgical rate was due to the fact that operability was defined intraoperatively; thus some cases with partial response to chemotherapy that preoperatively looked inoperable by pelvic examination were actually able to be resected.
The role of adjuvant or postoperative radiation or chemoradiation is well-determined in early-stage patients treated by radical hysterectomy. In the Gynecology Oncology Group 92 study performed in early-stage surgically treated patients with intermediate-risk factors for recurrence, patients received, or not, radiation alone and the results showed a significant benefit in the risk of relapse [23]. On the other hand, in high-risk (node-positive, parametrial infiltration and positive surgical margins) adjuvant concurrent chemoradiation prolongs survival compared with radiation alone [4]. However, in locally advanced patients who have received preoperative chemotherapy, the role of adjuvant treatment is yet to be determined. Sardi et al. reported a benefit in survival in two separate studies for patients in stages IIB [13] and IIIB [14] in which they used adjuvant radiation for all operated patients, whereas the results from the Italian group who only used adjuvant radiation in a subset of patients showed no significant difference in IIIB patients [15]. These results suggest that adjuvant radiation may play a role, which could be even greater if radiation were administered with concurrent chemotherapy.
In a previous study by our group, in which patients were treated with neoadjuvant gemcitabinecisplatin followed by surgery, among the 23 patients who underwent radical type III hysterectomy, six achieved a complete pathological response, three showed a microscopic residue and the remaining 14 displayed macroscopic tumor in the surgical specimen [40]. All these patients were left with no additional treatment at a median follow-up of 26 months [36]; most of the relapses (16 of 17) have occurred in the group with macroscopic residual disease. Based on this, in the present study we treated with adjuvant radiation concomitant with weekly cisplatin all patients except those with complete or near-complete pathological response. Adjuvant chemoradiation in this setting proved to be well-tolerated with no unexpected acute toxicity. Moreover, so far none of the patients has presented late toxicity.
The follow-up of this study is rather short; however, the figure of 79% survival is encouraging. However, it is remarkable that even with this aggressive multimodality treatment that may overtreat some patients, nine patients died of either progression or relapse. This underscores the fact that locally advanced cervical carcinoma is a very aggressive disease that may require the combination of the three main therapeutic modalities presently available.
Finally, it is important to consider that the biological behavior of cervical carcinoma may differ among populations from different geographical areas, this phenomenon being linked to the association of this tumor with the human papilloma virus [41]. Thus, it seems desirable that the treatment of cervical cancer should be tailored to the different populations according to their specific tumors biological characteristics.
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Footnotes |
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References |
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