CONTINUOUS-INFUSION OF CARBOPLATIN DURING CONVENTIONAL RADIOTHERAPY TREATMENT IN ADVANCED SQUAMOUS CARCINOMA OF THE CERVIX UTERI IIB-IIIB (UICC) - A PHASE I II AND PHARMACOKINETIC STUDY/

Objective: A prospective, single-arm phase-I/II trial performed to ass ess the efficacy and toxicity of the concomitant use continuous infusi on of low-dose carboplatin and pelvic conventional radiotherapy in pat ients with locally advanced squamous cell carcinoma of the cervix. Mat erials and Methods: Between January and July 1994, a total of 12 patie nts consecutively diagnosed to have squamous cell carcinoma of the cer vix uteri stages IIB-IIIB UICC-TNM (five patients, IIB; and seven pati ents, IIIB) entered the study. All patients were evaluated by a gyneco logist and a radiation oncologist and were submitted to standard pretr eatment staging procedures. Radiation was delivered with 10-MeV photon beams with the shrinking-field technique. The patients received 2 Gy radiotherapy daily, 5 fractions per week, up to a planned total of 60 Gy in 6 weeks to the primary tumor and 46 Gy in 4 weeks to the whole p elvis. Irradiation was performed using four fixed orthogonal fields. O ne intracavitary insertion, 8 Gy to point A (dose rate, 1.1 Gy/h), was performed immediately after external pelvic irradiation. Carboplatin (12 mg/m(2)/day) was also administered in a continuous infusion, start ing 1 day before the first fraction of radiotherapy. The platinum in p lasma and urine, as well as the platinum concentration in the cytosols of lymphocytes and tumor, was measured weekly. Results: A complete re sponse was seen in nine (75%) of the 12 patients. Of the nine patients who achieved a complete remission, only one had subsequent failure in the pelvis. The total pelvic failure rate was 33.3% (four of 12 patie nts). With a median follow-up time of 20 months, the actuarial surviva l rate at 24 months was 64.8%. All patients completed the treatment wi thout major protocol violations. Grade-2 leukopenia (in nine patients) and grade-1 nausea and vomiting (in five) were the most common acute toxicities. There was one grade-3 hematologic toxicity. Grade-3 late c omplications were observed in 16.6% of cases (two of 12 patients). On days 28 and 42 of the treatment, the mean total platinum plasma concen trations were 491 mu g/L (SD = 129) and 672 mu g/L (SD = 160), and the ultrafilterable fraction was 8-10%. At the same time points, the conc entration in lymphocytes was constant at 21 picograms (pg) platinum/ly mphocyte. The levels of platinum concentration measured on days 14 and 28 in the cytosols of tumor cells were 0.3 mu g/g (SD = 0.1) and 0.93 mu g/g (SD = 0.2). Conclusion: The combination of continuous infusion of carboplatin and radiotherapy at the aforementioned doses in patien ts with locally advanced cervical carcinoma resulted in a relatively l ow frequency of significant acute and late complications. Platinum in normal tissue (picograms per lymphocyte) was stable from week 1 of tre atment, whereas the platinum steady state in plasma and in tumor cells was not reached in 6 weeks and was below that required in vitro to pr oduce radiopotentiation. Further studies to determine the optimal dose of carboplatin and irradiation are needed prior to the initiation of phase-III studies.