Concurrent daily cisplatin and extended-field radiation therapy for carcinoma of the cervix

Authors


Takashi Uno, MD, Department of Radiology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuou-ku, Chiba 260-8670, Japan. Email: unotakas@faculty.chiba-u.jp

Abstract

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m2, which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4–55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m2 (range, 200–240 mg/m2). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m2 during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m2.

Randomized studies have demonstrated that concurrent cisplatin-based chemoradiotherapy significantly improves treatment outcome compared with radiation therapy alone for patients with locally advanced uterine cervical cancer(1–5). In addition, two meta-analyses have confirmed the therapeutic benefit of concurrent chemoradiotherapy(6,7). Concurrent chemoradiotherapy is therefore now considered to be a standard treatment for locally advanced uterine cervical cancer.

A surgical staging study by the Gynecologic Oncology Group has shown a correlation between the incidence of nodal involvement with advancing tumor stage(8). The pattern of lymphatic spread in cervical cancer appears to be orderly, and patients with high pelvic lymph nodes have high propensity for para-aortic nodal metastases. Thus, many patients with advanced-stage harbor occult para-aortic lymph node metastases. Results of a Radiation Therapy Oncology Group (RTOG) phase III study demonstrated that elective para-aortic irradiation reduced extrapelvic recurrence and improved survival(9). The RTOG further compared elective para-aortic irradiation versus pelvic radiation therapy with concurrent chemotherapy(1,5). Although the addition of chemotherapy to pelvic radiation therapy improved the survival, the combination did not reduce the risk of para-aortic recurrence.

Extended-field radiation therapy (EFRT), treating the pelvic and para-aortic nodal area in contiguity, has been used as a local-regional treatment in patients with locally advanced cervical cancer and/or positive para-aortic lymph node metastases. Several studies have shown the feasibility of a concurrent chemoradiotherapy using EFRT(10,11). However, the toxicity of concurrent chemoradiotherapy using EFRT is substantial and depends on chemotherapy regimens and radiation therapy technique. This study was initiated prospectively to evaluate feasibility of concurrent EFRT and chemotherapy with daily cisplatin dose of 8 mg/m2, which was determined in the previous phase I study using pelvic radiotherapy(12).

Materials and methods

Between 2003 and 2005, 15 women with cervical cancer were treated with concurrent low-dose daily cisplatin and EFRT. Patient characteristics are shown in Table 1. The median age was 51 years (range, 26–61 years). The histology was squamous cell carcinoma in 11 and adenocarcinoma in 4. All patients were staged according to the staging system of the FIGO. Patients were also evaluated for extrapelvic disease with abdominopelvic computed tomography (CT) without influencing FIGO stage allocation. Surgical staging or lymphangiography was not used in this patient population. Twelve patients were treated without surgery. Of those, as for radiation therapy, eight patients underwent combined external beam radiation therapy and intracavitary brachytherapy for curative intent, and four patients received external beam radiation therapy alone. FIGO stages of these patients were IB2 in one, IIA in one, IIB in three, and IIIB in seven. A maximum tumor diameter determined on pelvic magnetic resonance imaging ranged from 50 to 80 mm, with a median of 64 mm. All these 12 patients had multiple para-aortic or high common iliac lymph node metastases detected by CT before the initiation of the treatment. Three other patients were treated with adjuvant chemoradiotherapy after surgery due to pathologically confirmed common iliac lymph node metastases. All three patients had FIGO IB1 tumor. This study was in accordance with the Declaration of Helsinki (2001). All patients gave their written informed consent.

Table 1.  Patient characteristics
Number of patients15
Age (years)
 Median51
 Range26–61
Histology
 Squamous cell carcinoma11
 Adenocarcinoma4
Stage
 IB13
 IB21
 IIA1
 IIB3
 IIIB7
Radiation therapy
 EFRT + brachytherapy8
 EFRT alone4
 Adjuvant EFRT3

Radiation therapy

For all patients, radiation therapy was delivered using a linear accelerator with a 10-MV photon beam, and all patients underwent three-dimensional (3D) radiation treatment planning. Patients were positioned on the couch of the CT simulator (AcQSIM, Picker PQ2000 CT, Philips Medical Systems, Andover, MA) in a supine position. CT images were acquired in spiral mode using 1.5 pitch and 3-mm slice thickness during quiet respiration from above the diaphragm to the ischial tuberosities. A virtual simulation was performed based on the full 3D CT anatomical data that were obtained. The treatment planning and dose distribution calculation with tissue heterogeneity correction were performed using a 3D treatment planning system (FOCUS version 3.2.1 or Xio version 4.3.1, CMS, St. Louis, MO). Radiation therapy targets were defined according to the International Commission on Radiation Units and Measurements Report Number 50 and 62. The gross tumor volume (GTV) consisted of all areas of known gross disease. The clinical target volume (CTV) included all areas of gross and potentially microscopic disease, and included the upper half of the vagina, parametria, uterus if present, and regional lymph node regions (common, internal and external iliacs, and para-aortic regions). The CTV in the para-aortic region was contiguous with the pelvic lymph node stations and generously encompassed the aorta and the inferior vena cava with at least a 1.5-cm margin. Although the upper border might be individualized depending on the patient’s known extent of the disease, the superior CTV border was usually at the level of L1. The planning target volume, corresponding to a field of EFRT, included the CTV plus a 10-mm margin to account for patient motion and setup uncertainty. Each beam was individually conformed to the target volume using a multileaf collimator. Radiation therapy was delivered conventionally using a standard two- or four-field technique with a fractional daily dose of 1.8–2.0 Gy at the isocenter. Generally, the dose prescribed for CTV was 40–45 Gy. After that, the GTV was boosted to 50.4–55 Gy. For eight patients, EFRT was followed by low–dose rate intracavitary brachytherapy with 1- to 2-week interval. For these patients, a 4-cm width central shielding was used after 41.4–45 Gy to decrease the dose to the rectum and the bladder by parallel-opposed anteroposterior-posteroanterior fields. No central shielding was used for seven patients treated with external beam radiation therapy alone.

Chemotherapy

All patients received concurrent low-dose daily cisplatin from the start day of EFRT. Daily cisplatin, at 8 mg/m2 in 100 mL of normal saline, was administered intravenously over 30 min, and was completed in 1 h before radiation therapy. Postchemotherapy, daily hydration was performed with 1 L of normal saline given over 2 h. Chemotherapy was not delivered during brachytherapy. All patients were admitted to the hospital during the course of concurrent chemoradiotherapy

Toxicity evaluation and patient follow-up

During the course of chemoradiotherapy, patients were evaluated weekly by clinical assessments including treatment-related toxicities and pelvic examinations. A complete blood count and chemistry profiles such as renal and liver function tests were conducted weekly. Acute toxicities, measured from the initiation of treatment to 60 days after completion, were graded by the Common Terminology Criteria for Adverse Events version 3.0. Cisplatin was suspended if grade 3 thrombocytopenia appeared simultaneously with grade 3 leukopenia or any grade 4 hematologic toxicity was observed. Radiation therapy was suspended if grade 4 hematologic toxicity appeared or in the event of grade 4 radiation-related gastrointestinal toxicity. After the completion of radiation therapy, patients were evaluated at 1- to 3-month intervals by radiation oncologists and gynecological oncologists. Radiologic studies, serum markers, and blood chemistries were ordered at the discretion of the treating oncologists.

Results

A total dose of cisplatin ranged from 200 to 240 mg/m2, with a median of 224 mg/m2. In 14 of 15 patients (93%), daily cisplatin could be administered continuously as planned with no interruption or dose modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. All patients completed planned radiation therapy. A total dose of EFRT ranged from 40 to 45 Gy. A total dose to GTV ranged from 50.4 to 55 Gy. The total length of external beam radiation therapy ranged from 32 to 42 days, with a mean length of 38 days. No delay in radiation therapy could be observed. Acute toxicities are shown in Table 2. Moderate to severe hematologic toxicities were common. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Those two patients who experienced grade 4 leukopenia after the end of radiation therapy required granulocyte colony–stimulating factor. Despite lowered cell counts, both patients completed treatment without requiring an interruption in scheduled radiotherapy. Grade 3 thrombocytopenia was observed in three patients including one after treatment. One of the two patients who had grade 3 thrombocytopenia during the course of chemoradiotherapy experienced simultaneous grade 3 leukopenia. Grade 2 or worse anemia was observed in 12. As for nonhematologic toxicities, mild to moderate gastrointestinal events are frequent. Grade 1–2 diarrhea and nausea/vomiting were observed in 13 patients and 14 patients, respectively. Although gastrointestinal events were well managed by medication, most patients developed anorexia, which became worse toward the end of EFRT. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Renal toxicity was uncommon. There was no treatment-related death.

Table 2.  Acute toxicities
ToxicityGrade
01234
Hematologic
 Leukopenia01482
 Thrombocytopenia29130
 Anemia12930
Gastrointestinal
 Diarrhea09420
 Nausea/vomiting05910
Renal (laboratory)
 Creatinine131100

At the time of the data analysis, with a median follow-up of 12 months, ten patients are alive with no evidence of disease, four patients are alive with disease, and one died of disease. Of eight patients who underwent combined EFRT and intracavitary brachytherapy for curative intent, seven patients are alive with no evidence of disease, whereas one patient developed supraclavicular lymph node metastasis. Of four patients who received EFRT alone due to bulky local-regional disease, one died of disease due to disseminated disease including local-regional recurrence, two experienced extrafield recurrence, and one is still alive with no evidence of disease. None of three patients who received adjuvant EFRT developed recurrence. Although local-regional control data must be interpreted cautiously in this small heterogeneous patient population with shorter follow-up, only one patient experienced infield failure in this study.

Discussion

A Gynecologic Oncology Group study using surgical staging for patients with cervical cancer revealed that the incidences of occult para-aortic metastases were 6%, 16%, and 25% for FIGO stage I, II, and III, respectively(8). Based on this considerable histologic evidence of occult nodal metastasis, RTOG initiated a phase III study examining a role of prophylactic para-aortic irradiation for patients with bulky IB/IIA and IIB cervical cancer(10). The RTOG study demonstrated that elective para-aortic irradiation reduced extrapelvic recurrence and improved survival. To eradicate micrometastases outside the irradiation fields, while sensitizing infield tumor cells to radiation, RTOG further compared EFRT versus pelvic radiotherapy with concurrent chemotherapy using cisplatin and fluorouracil(1). Although the addition of chemotherapy to pelvic radiotherapy improved the survival, the combination did not eliminate the risk of para-aortic recurrence. The subgroup analysis of the study showed that survival benefit was more enhanced in patients with FIGO IB–IIB, while it was only modest in patients with more advanced disease that has a higher incidence of para-aortic metastasis. This has led to a reexamination of the role of EFRT. An important issue, however, is the toxicity of concurrent chemoradiotherapy using a large irradiation field. The feasibility of a combination of cisplatin and EFRT has been studied with a wide variation of radiation doses, fractionations, and chemotherapy regimens (10,11,13,14). In general, concurrent cisplatin-based chemotherapy and EFRT produce substantial acute toxicities. Single-institution studies have reported 52% acute grade 3–4 hematologic toxicities and 24% acute grade 3–4 gastrointestinal toxicities with concurrent single-agent cisplatin and EFRT(14). With regard to the schedule of cisplatin administration in that study, daily dose of 20 mg/m2 for 5 days were given during the first and the fourth weeks of EFRT to the planned total dose of 200 mg/m2. Prospective phase II cooperative group trials have reported 49% grade 3–4 acute bowel toxicity with the delivery of concurrent chemotherapy and EFRT using two-drug combination of cisplatin and 5-fluorouracil(15). These results suggested that most frequently used chemotherapy regimen with the pelvic radiotherapy is too toxic to deliver when EFRT is performed. Based on the evidence that no advantage has been demonstrated for combination chemotherapy over single-agent cisplatin, Chung et al.(16) used a moderate dose of single-agent cisplatin (median total dose of 120 mg/m2 during radiotherapy) concurrently with EFRT to reduce toxicities. Although their data are promising, it remains to be answered that whether the cisplatin dose can be altered to reduce acute toxicities without diminishing efficacy. In case of concurrent chemoradiation using pelvic radiotherapy, weekly dose of cisplatin as a single agent is usually set at 40 mg/m2(2,3). Otherwise, cisplatin is combined with 5-fluorouracil. In head and neck cancer treatment, it was suggested that a cumulative cisplatin dose of approximately 200 mg/m2 might be sufficient to yield a beneficial antitumor effect independent of the schedule(17). Ninety percent of patients in the pivotal trials, where 40 mg/m2 of weekly cisplatin was combined with pelvic radiation therapy, could have received four or more weekly dose of cisplatin(2,3). In the present study, we demonstrated that, by using low-dose daily administration, a cumulative cisplatin dose of greater than 200 mg/m2 during radiotherapy could be achieved. Although moderate to severe hematologic toxicities are common, administration of cisplatin had to be interrupted in only one patient for only 3 days. The incidence of severe acute toxicity was quite similar to that seen for Chung et al.’s study(16). Thus, we consider that this regimen is feasible. Results of the present study warrant further studies using concurrent EFRT and daily cisplatin for local-regional advanced cervix cancer. In addition to therapeutic gain, of course, other factors such as patient’s convenience and treatment expense should also be considered. As for reduction of acute toxicities, advantage of modern radiation therapy techniques such as intensity-modulated radiation therapy (IMRT) over conventional two- or four-field technique is already reported in the treatment of pelvic and para-aortic irradiation(18,19). Gerszten et al.(20) showed feasibility of concurrent weekly cisplatin and EFRT using IMRT. However, definition of the target volume differs considerably from study to study, and the planning target volume used in the IMRT study was apparently smaller than that contoured based on lymphangiogram findings(19,21–23). Thus, by using IMRT technique, whether or not adequate dose of cisplatin can be more easily administered with less toxicity during EFRT is still unclear and awaits further examination. Target volume delineation, especially the pelvic and para-aortic lymph nodes, should be standardized urgently in modern radiation therapy.

Ancillary