grams, survival by stage has not changed significantly over the past 15 years [1, 2]. Forty to fifty percent of patients treated for invasive cervical cancer eventually.
Annals of Oncology 7: 511-516, 1996. O 1996 Kluwer Academic Publishers. Tainted in the Netherlands.
Original article Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix E. Pras,1 P. H. B. Willemse,2 H. Boonstra,4 H. Hollema,3 M. A. A. M. Heesters,1 B. G. Szabo,1 H. W. A. de Bruijn,4 J. G. Aalders4 & E. G. E. de Vries2 Departments of * Radiotherapy, Netherlands
2
Medical Oncology,
3
Pathology and * Gynecological Oncology, University Hospital Groningen, The
68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local reBackground: The feasibility of concurrent chemotherapy and currence free survival for group I and II are, respectively, radiotherapy for advanced primary carcinoma of the cervix 69% versus 38% (P < 0.003), 67% versus 38% (P < 0.005) was evaluated and the results were compared to historical and 84% versus 43% (P< 0.0001). Two patients in each group developed posttreatment enteritis. controls. Patients and methods: In a single institution study, patients Conclusions: Radiotherapy with concurrent carboplatin (n — 74) with primary cervical carcinoma received 3 cycles and 5-fluorouracil resulted in a better overall survival, discarboplatin/5-fluorouracil concurrent with radiotherapy, fol- ease free survival and local disease free survival compared to lowed by salvage hysterectomy (group I). Treatment results historical controls. The toxicity of this schedule did not exwere compared with those of a historical control group ceed that of radiation alone in historical controls. (n - 39) (group n), treated similarly but without chemotherapy. Key words: carboplatin, cervical cancer, chemotherapy, Results: In group I median follow-up is 28 months (12- 5-fluorouracil, radiotherapy Summary
Although cisplatin is the most active drug in cervical cancer, its analog carboplatin will achieve 15%-25% Although the overall mortality of carcinoma of the response when used as a single agent and 26%-60% uterine cervix has been markedly reduced by the wide- combined with other drugs [6-18]. spread availability of effective cytologic screening proFor the (neo-)adjuvant setting, there is no agreement grams, survival by stage has not changed significantly on the optimal drug or drug combination, the timing or over the past 15 years [1, 2]. Forty to fifty percent of the sequence of chemotherapy and irradiation. The patients treated for invasive cervical cancer eventually most marked effects are found when chemotherapy relapse and the prognosis of these patients is extremely given simultaneously with radiotherapy. Cisplatin is a poor with only 6% of patients surviving more than 3 well-known radio-sensitizer [18]. Carboplatin shares years [3]. the radio-sensitizing potential with cisplatin in experiThe results of surgery in the early stages of invasive mental systems [19]. 5-Fluorouracil also has radiation cervical cancer have hardly changed [4]. Modern radio- enhancer capacities in vitro and clinically [20]. therapy techniques have achieved better local control Based on these data, a study was initiated combining than in older series [1, 5]. However, depending on simultaneous radio- and chemotherapy, its main aim tumor stage and size, radiotherapy may fail in 10%- being the improvement of local control. A combination 50%. This has stimulated the design of studies combin- of carboplatin and 5-FU was expected to induce less ing radiotherapy and chemotherapy. Combination with gastrointestinal and renal toxicity with moderate chemotherapy might improve local control and en- myelotoxicity than the reported side effects of cisplatin hance radiation effects, simultaneously affecting sub- in this setting. The use of this combination has not been clinical metastases [6]. reported earlier for patients with cervical carcinoma. A The value of chemotherapy has been most exten- group of patients which was treated previously in the sively studied in patients with metastatic disease. Single same institution with the same radiotherapeutic schedagents will result in remissions in 10%—25% of pa- ule without chemotherapy served as a control group. In tients, but the duration of most responses is limited and both groups, an additive hysterectomy was considered this will have only a modest effect upon survival [6]. after completion of combined treatment. Introduction
512 Patients and methods Patients with FIGO bulky stage IB and HA disease (>4 cm), and tumors stage I B , III and FVA were eligible for this single institution study. Entry criteria comprised a histopathologic proven diagnosis of primary carcinoma of the uterine cervix; age younger than 70 years with no past history of malignancy, no prior surgery, radiotherapy or chemotherapy. Patients with a WHO performance status 3 and 4 were excluded, as were patients with a leukocyte count 120 u.mol/1 and/or creatinine clearance 4 cm. Eight patients in linear accelerator. The 'box' technique was used comprising an group I had enlarged pelvic lymph nodes on CT-scan, anterior, posterior and two lateral fields. The superior limit of the which is a poor prognostic parameter. Enlarged paraantero-posterior fields was the upper border of the fourth lumbar aortic nodes were absent on the CT-scan. vertebra, the lower limit was the lower margin of the obturator foramen (or, in stage I1I-A, the distal vagina). The lateral margin was The median follow-up for group I at evaluation is 28 2 cm lateral from the transverse diameter of the pelvic brim. For the months (range: 12-68+ months), and for group II 23 lateral fields, the ventral limit was the upper margin of the symphysis months (range 14-90+ months). and the dorsal limit was the front of the os coccyx. Radiation was In group I all patients completed the full course of given by 1.8 Gy daily fractions, five days per week for a total dose of 45 Gy. All fields were treated daily. Two weeks after completing the radiotherapy without interruption. Treatment was well external beam irradiation, a second examination under general tolerated. Leukocyte nadir grade I occurred in 18 anaesthesia was performed and if technically feasible, a 137Cesium (25%), grade H in 34 (46%), grade m in 20 (27%), and application of 17.5 Gy to point A, was repeated after one week for a grade IV in two patients (3%). Thrombocytopenia total dose of 35 Gy. If brachytherapy was impossible or inappropriate in case of tumor extension into the parametria or lymph nodes, grade I was observed in 58 (78%), grade II in 12 (16%), patients received an additional external boost of 35 Gy over 2 weeks grade in in one and grade IV in two patients. In 22/ for a total dose of 70.2 Gy. 222 (10%) chemotherapy cycles carboplatin was delayed 1 week for insufficient leucocyte recovery at the Chemotherapy start of a cycle. Cycle 3 was deleted in one patient for grade IV thrombocytopenia. No bleeding or leukoPatients in group I received chemotherapy comprising 3 cycles of penic fever were observed. Nausea and vomiting were carboplatin and 5-FU. Carboplatin, 300 mg/m2, was dissolved in 250 mL 5% glucose and given over 30 min intravenously (i.v.) on day mild (gTade 0: 35%; grade I: 37%; grade II: 28%), nor 1. 5-FU, 600 mg/m2, was dissolved in 2 1 normal saline and ad- was there enhanced diarrhea due to chemotherapy. ministered a continuously i.v. days 2-5. Cycles were repeated after One patient died suddenly at home after completion of 28 days for a total of 3 during the first, fifth and ninth week of treat- treatment but before tumor evaluation. She was known ment. Dose modifications only concerned carboplatin. If at the start to have suffered a prior myocardial infarction. In a secof the second or third cycle the leukocyte count remained below 2.5 x lO'/l, the chemotherapy administration was postponed 1 week. If ond patient there occurred one silent recurrent myo-
513 Table 2. Results of histopathological evaluation, and site of tumor relapse in group I.
Table 1. Patient characteristics at diagnosis. Group
P-value Evaluation
Tumor response
Follow-up NED
Number of patients Age (years) Mean Range FIGO stage IB HA IIB IHB Tumor size 4 cm Histology at diagnosis Squamous Adenosquamous Small-cell Neuro-endocrine Adenocarcinoma Radiation boost External Brachytherapy Combined Hysterectomy
74
39
47 28-73
58 29-78
7 5 44
3 5 24
i 17
2 5
15 (20%) 59 (80%)
13 (33%) 26 (66%)
60 3 5 2 4
30 2 4
25 38 11 43
16 23 19
pCR
