Radiation carboplatin

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin. 

The Southwest Oncology Group (SWOG) conducted a phase II trial with continuous thoracic radiation to a total dose of 61 Gy and simultaneous daily cisplatin (5 mg/m2) and found acceptable toxicity (130). Another trial utilized a split-course of thoracic radiation therapy to a total dose of 50 Gy and simultaneous daily continuous infusion cisplatin (5 mg/m2) and found a 35 % 2-yr survival rate with relatively mild toxicity (131). Weekly doses of carboplatin were administered with continuous thoracic irradiation to a total dose of 60 Gy in a phase II trial that resulted in a 45% response rate (132). 

Douple EB, Richmond RC, O Hara J A, Coughlin CT. Carboplatin as a potentiator of radiation therapy. Cancer Treat Revs 1985 12(Suppl A) lll-124. 

Coughlin CT, Richmond RC. Biologic and clinical developments of cisplatin combined with radiation concepts, utility, projections for new trials and the emergence of carboplatin. Semin Oncol 1989 16(Suppl 6) 31—43. 

Jeremie B, Shibamoto Y, Stanisavljevic B, Milojevic L, Milicic B, Nikolie N. Radiation therapy alone or with concurrent low-dose either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck a prospective randomized trial. Radiotherap Oncol 1997 43 29-37. 

Choy et al. have published two further phase II trials of concurrent paclitaxel and carboplatin. In both trials the two drugs were administered weekly with paclitaxel at a dose of 50 mg/m2 and carboplatin at a dose of 2 AUC. The first of these trials, LUN-56 (60), combined these two drugs with once daily radiation to adose of 66 Gy and the second trial, LUN-63 (61), used hyperfractionated radiation to a total dose of 69.6 Gy directed at the primary tumor. They have shown similar promising results in patient populations where 70% have stage IIIB disease. LUN-56, which enrolled40 patients, showed a 76% response rate and 1-, 2-, and 3-yr median survivals of 54,46, and 32% 43 patients were enrolled on LUN-63. In this trial there was a 79% response rate and a median survival of 14.3 mo. Encouraging 1- and 2-yr survivals of 61% and 35% were seen. 

Lau et al. have reported on their experience of administering radiation with taxol dosed twice a week for locally advanced nonsmall-cell lung cancer (53). Their phase II trial was conducted combining low-dose radiosensitizing chemotherapy with concurrent radiation followed by consolidation chemotherapy (62). The induction chemoradiation consisted of paclitaxel, 30 mg/m2 iv over 1 h, twice weekly for 6 wk carboplatin, AUC of... 

Socinski et al. have reported on their phase I/II experience with dose-escalated thoracic radiation in the setting of a combined modality approach to locally advanced NSCLC (55,64). Two cycles of carboplatin and paclitaxel (AUC 6 and 225 mg/m2/3h q21d) were followed on d 43 by weekly carboplatin and paclitaxel (AUC 2 and 45 mg/ m2/3h x 6) and thoracic radiotherapy (TRT), 50 Gy was delivered to the prechemotherapy tumor volume and areas of suspected microscopic spread in the mediastinum with a 1.0-2.0 cm margin. Boost volumes included the primary tumor volume and all radiographically positive nodes with a 1.0 cm margin. The total dose of radiation was escalated through four cohorts of patients 60,66,70,74 Gy without reaching any of the planned toxicity endpoints. The overall response to the therapy was 50% (3% CR, 47%... 

PR) and median survival was 26 mo. The 3-yr survival probability is 0.47 (64). Because dose escalation was limited to 74 Gy without reaching a maximally tolerated dose, a further trial is underway to find the true MTD of dose-escalated thoracic radiation with concurrent carboplatin-paclitaxel-based chemotherapy. 

A similar small phase II trial from Germany has reported on seven patients receiving concurrent chemoradiation for transitional cell carcinoma of the bladder with cisplatin and paclitaxel (96). The authors conclude that this combination is at least feasible given an acceptable acute toxicity profile and reasonable efficacy. Another small series is reported by Nichols et al. (97) where eight patients received radiation with concurrent paclitaxel and carboplatin in an attempt at bladder preservation. Three of the patients remain free of distant metastases, and local recurrence has occurred in three. 

Amorino GP, Hamilton VM, Choy H. Enhancement of radiation effects by combined docetaxel and carboplatin treatment in vitro. Radiat Oncol Investig 1999 7(6) 343-352. 

Socinski M A, Rosenman JG, Schell MJ, et al. Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B nonsmall-cell lung carcinoma a modified Phase I trial. Cancer 2000 89(3) 534-542. 

Choy H, Akerley W, Safran H, et al. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol 1998 16(10) 3316-3322. 

Lau D, Leigh B, Gandara D, Edelman M, Morgan R, Israel V, Lara P, Wilder R, Ryu J, Doroshow J. Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel consolidation for stage III non-small-cell lung cancer a California Cancer Consortium phase II trial. J Clin Oncol 2001 19(2) 442-447. 

Choy H, DeVore RF, Porter LL, et al. Phase I trial of outpatient weekly docetaxel (DTX) Carboplatin (CBDCA) and concurrent thoracic radiation therapy (TRT) for stage III unresectable non-small-cell lung cancer A Vanderbilt Cancer Center Affiliate Network (VCCAN) Trial. Pro Am Soc Clin Oncol 1999 18 475a (abstract 1833). 

K. Radiation therapy and concomitantpaclitaxel/carboplatin chemotherapy formuscle invasive transitional cell carcinoma of the bladder a well-tolerated combination. Int J Cancer 2000 90(5) 281-286. 

Meluch AA, Hainsworth JD, Gray JR, et al. Preoperative combined modality therapy with paclitaxel, carboplatin, prolonged infusion 5-fluorouracil, and radiation therapy in localized esophageal cancer preliminary results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J Sci Am 1999 5 (2) 84-91. 

Suntharalingam M, Haas ML, Conley BA, et al. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2000 47( 1 ) 49—56. 

A randomized study comparing carboplatin/5-FU/radiotherapy vs radiotherapy in patients with locally advanced oropharyngeal carcinoma was recently reported by the French Group of Radiation Oncology for HNC (GORTEC) (54). Two hundred twenty-six patients were randomized to conventional radiotherapy or identical radiotherapy combined with three cycles of the 4-d regimen of carboplatin (70 mg/m2/d) and continuous infusion 5-FU (600 mg/m2/d) on d 1,22, and 43 of radiation. Increased mucositis was reported in the combined modality arm 67% vs 36%. No difference in skin toxicity was... 

Jacobs MC, Eisenberger M, Oh MC, et al. Carboplatin (CBDCA) and radiotherapy for stage IV carcinoma of the head and neck a phase I-II study. Int J Radiat Oncol Biol Phys 1989 17 361-363. 

Other trials attempted to improve the results of sequential chemoradiation by using newer ChT agents and/or intensifying the RT component by the use of accelerated fractionation, based on the success of the British CHART regimen. A phase II trial of paclitaxel and carboplatin followed by hyperfractionated accelerated radiation therapy (HART) to... 

Gy tidin 3 wkgave a 1-yr survival of 59% and a severe acute esophagitis rate of 63% (64). At the time of the report, the median survival had not yet been reached. On the basis of this trial, ECOG phase III trial 2597 is comparing the HART regimen to standard radiation, both preceded by paclitaxel/carboplatin. 

After phase I trials had determined the safety of paclitaxel doses of 45-50 mg/m2/ wk and carboplatin of AUC 2/wk concurrent with standard RT of 66 Gy/7 wk, phase II trials yielded encouraging survival results (69). Acute esophageal grade III or greater toxicity was high (30-50%) however, most patients fully recovered from these acute effects. Choy extended the experience with concurrent radiation and paclitaxel/ carboplatin using hyperfractionated radiation to 69.6 Gy and observed a 1-yr survival of 63% (70). 

WagnerH, AntoniaS, Shaw G, et al. Induction Chemotherapy with Carboplatin and Paclitaxel followed by Hyperfractionated Accelerated Radiation for Patients with Unresectable Stage IIA and IIB Non-Small-Cell Lung Cancer. Proc Am Soc Clin Oncol 1998 17 469a (abstr). 

Jeremic B, Shibamoto Y, Acimovic L, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage M non-small cell lung cancer a randomized study. J Clin Oncol 1996 14 1065-1107. 

North American prospective trials of radiation sensitizers for cervical cancer have focused on the use of cisplatin, fluorouracil, and hydroxyurea. However, a number of other drugs also hold promise as effective radiation sensitizers for cervical cancer, including mitomycin C, epirubicin, paclitaxel, and carboplatin. 

Muderspach et al. (31) reported the results of a pilot study of concurrent carboplatin (30 mg/m2 twice weekly) with radiation in 22 patients with stage IIA (>4 cm) to IIIB disease. The most significant chemotherapy-related side effects were grade 3 neutropenia and anemia. The authors reported 19 complete responders to this regimen, although only 11 patients were alive and disease-free at the time of their report. Because cisplatin... 

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