Paclitaxel and radiation

Experiments in which tumor xenografts were treated with paclitaxel and radiation in hypoxic and noroxic conditions were pursued (46). It was found that the creation of hypoxic conditions greatly reduced the efficacy of paclitaxel in its enhancement of radioresponse. Measurements of tumor oxygenation using Eppendorf histographs confirmed that the median tumor P02 increased from the control value of 6.8 mmHg to... 

Concurrent therapy for the treatment of more than three brain metastases using paclitaxel and radiation has been explored in a phase III trial (144). The hypothesis here being that high-dose paclitaxel in combination with cranial radiation should improve local control while providing systemically active amounts of chemotherapy. Unfortunately, there was no statically significant improvement in survival seen. There is certainly a place to further explore the benefits and toxicides experienced with concurrent taxane-based therapy with radiation in metastatic disease. The role of the taxanes in concurrent chemoradiotherapy with sarcomas and pediatric tumors has not been explored at this time. 

Formenti SC, Symmans WF, Volm M, et al. Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 1999 9(2 Suppl l) 34-42. 

Sunwoo JB, Herscher LL, Kroog GS, et al. Concurrent paclitaxel and radiation in the treatment of locally advanced head and neck cancer. J Clin Oncol 2001 19(3) 800-811. 

Fig. 1. (A) Study design of concurrent Cl 5-Fduorouracil and radiation in LABC. (B) Study design of concurrent paclitaxel and radiation in LABC.

Fig. 2. Recovering wet desquamation after completion of concurrent paclitaxel and radiation in a patient who presented with stage IIIB breast cancer.

Formenti S, et al. Low HER 2/NEU Gene Expression is Associated with Pathological Response to Primary Paclitaxel and Radiation in Locally Advanced Cancer (LABC). Proceedings of ASTRO 2000 63. 

Bauer J, Chakravarthy A, Rosenbluth J, Mi D, Seeley E, Granja-Ingram N, Olivares M, Kelley M, Mayer I, Meszoely I, Means-Powell J, Johnson K, Tsai C, Ayers G, Sanders M, Schneider R, Formenti S, Caprioli R, Pietenpol J (2010) Proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation. Clin Cancer Res 16(2) 681-690. doi 10.1158/1078-0432.CCR-09-1091... 

In the case of pacUtaxel it has been tested whether the enhanced killing by the combination of paclitaxel and radiation is connected to the presence of oxygen. 

Fig. 2. The radiation sensitizing effects of paclitaxel and concurrent ionizing radiation in a human lung cancer cell line, HL-60. From ref. 40.

Other suggested mechanisms for the increased radiosensitization seen with both paclitaxel and docetaxel include an increased alpha component of DNA damage and the fact that docetaxel is toxic for S-phase cells that are maximally radiation resistant (41,42). 

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. 

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. 

The lack of data reinforces the need to conduct randomized trials in the area of carcinoma of the bladder, and given the radiosensitizing action of the taxanes, they are worthy of consideration in these protocols. The RTOG phase I/II trial looking at concurrent cisplatin, paclitaxel, and hyperfractionated radiation with selective bladder preservation and adjuvant chemotherapy is ongoing and it may serve as the basis for future randomized trials in the area (98). 

The initial experience with the taxanes and especially with paclitaxel in the realm of combined modality therapy has had a substantial impact on the treatment of cancers both in the United States and worldwide. Paclitaxel delivered in concert with radiation provides a classical model of the development of clinically applicable treatment strategies from laboratory-based studies. The initial in vitro works of Tishler (39) and Choy (40) have translated in a very tangible way into approaches that are clinically applicable and in the next generation of randomized clinical trials their efficacy will be compared to more traditional chemotherapies in the combined modality setting. While the experience to date with both paclitaxel and docetaxel has been largely positive, the mortality rates in many of the solid tumor types remind us that much more needs to be done. 

Rathmann J, Leopold KA, Rigas JR, et al. Daily paclitaxel and thoracic radiation therapy for non-small cell lung cancer preliminary results. Semin Radiat Oncol 1999 9(2 Suppl 1) 130—135. 

Choy H, Akerley W, Safran H, et al. Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol 1994 12(12) 2682-2686. 

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. 

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. 

GOG-9804 Phase I/II Study of Extended Field Radiation Therapy With Concurrent Paclitaxel and Cisplatin Chemotherapy in Patients With Previously Untreated Carcinoma of the Cervix Metastatic to the Para-aortic Lymph Nodes. Study Protocol, http //www.cancer.gov/search/clinical trials... 

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. 

Safran H, King TP, Choy H, et al. Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer a phase I study. J Clin Oncol 1997 15(3) 901-907. 

Safran H, Moore T, IannittiD, etal. Paclitaxel and concurrent radiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2001 49(5) 1275-1279. 

Kies ME, Haraf D, Rosen F, Stenson K, List M, Brockstein B, Chung T, Mittal B, Pelzer H, Portugal L, Rademaker A, Weichselbaum R, Vokes EE. Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer. J Clin Oncol 2001 19 1961-1969. 

Langer CJ, Ruffer J, Rhodes H, et al. Phase II Radiation Therapy Oncology Group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2001 51 113-119. 

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... 

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