Biological basis for the interaction of chemotherapeutic agents and radiation therapy

Abstract

The ultimate goal of combining chemotherapy and radiotherapy is to improve the therapeutic ratio. When chemotherapy is combined with radiotherapy, improved therapeutic effects may occur as a result of the following: (1) spatial cooperation; (2) enhancement of tumor response with less or no enhancement of normal tissue injury, and (3) diminution of normal tissue injury with less or no diminution of tumor response. Possible mechanisms of interaction between chemotherapeutic agents and radiation that result in an enhanced effect include (1) changes in the slope of the dose response curve, (2) decreased accumulation or inhibition of repair of sublethal damage, (3) decreased recovery from potentially lethal damage, (4) perturbation in cell kinetics with an increase of proportion of cells in the sensitive cell cycle phase and proliferative state, (5) decreased tumor bulk and improved blood supply leading to reoxygenation and recruitment and increased radiosensitivity and chemosensitivity, and (6) increased drug delivery and uptake. The combined effects may be influenced by (1) tumor and normal tissue type, (2) drug type, (3) drug dose and schedule, (4) time sequence between drug and radiation administration, (5) radiation dose and fractionation schedule, and (6) radiation dose rate. Most experimental and clinical data suggest that enhanced tumor effects most often result from simple additivity and therefore do not require direct interaction between drug and radiation, whereas enhanced normal tissue effects are observed most often when drugs are administered in close temporal proximity to radiation. Thus, for the optimal therapeutic effect, it would seem more advantageous to administer chemotherapeutic drugs and radiation in a sequential or alternating manner rather than simultaneously.

Post-operative pharyngocutaneous fistula after laryngectomy

“…Although chemotherapy alone has been reported to increase wound complications in patients with advanced-stage resectable head and neck carcinoma (7,8), wound complications were much increased when combined with radiotherapy (20,21,22). Weber et al reported that the incidence of post-laryngectomy PCF was higher among patients who underwent chemoradiotherapy (30%) compared with radiotherapy alone (15%) (23).…”

“…We conclude that both RT and chemotherapy produce adeverse effects on PCF formation and healing with a synergistic or additive interaction when used together. Thus, chemotherapeutic agents combined with irradiation not only kill more tumor cells but also interferes with tissue repair (22). In addition to the direct damage to the pharyngeal tissue, a stricture of the cervical esophagus as a result of fibrosis due to concurrent chemoradiotherapy might be a cause of PCF.…”

The efficacy of concurrent cisplatin and 5-flurouracil chemotherapy and radiation therapy for locally advanced cancer of the uterine cervix

“…The theoretical advantages of CCRT were that the chemotherapy agent may be effective in eradicating the subclinical metastasis and act as a radiosensitizer. 5 The representative chemotherapy drugs used for CCRT were cisplatin, 5-fluorouracil (5-FU), hydro- xyurea, ifosfamide, mitomycin-C, and bleomycin. 6 In the late 1990s, five randomized prospective studies reported the superiority of CCRT to radiation alone in the treatment of locally advanced or high-risk cervical cancer.…”

A Preliminary Results of a Randomized Trial Comparing Monthly 5-flourouracil and Cisplatin to W eekly Cisplatin A lone Combined with Concurrent Radiotherapy for Locally Advanced Cervical Cancer

“…Concurrent chemoradiotherapy has the theoretical advantages of avoiding any delay in the initiation of radiotherapy, which is the main treatment modality, shortening the overall treatment time, preventing repopulation of the tumor and cross resistance to therapy, as well as radiosensitizing the effect of chemotherapeutic agents compared with neoadjuvant therapy (14,15). Concurrent chemoradiation has been proved to achieve more favorable clinical outcome in many organs, including bladder, head and neck malignancies (16,17).…”