ABSTRACT: Gemcitabine(Drug information on gemcitabine) (Gemzar) is a novel deoxycitidine drug that has demonstrated promising single-agent activity in non–small-cell lung cancer and has been proven to be a potent radiosensitizer. Although the exact mechanism of the radiosensitizing effect is unknown, several studies have focused on the drug’s effect on deoxyadenosine triphosphate (dATP) pool depletion or cell-cycle manipulation. A number of trials have evaluated this feature of gemcitabine by combining chemotherapy and radiation in various doses and schedules, and those studies are described in this article. Gemcitabine appears to be a promising agent to be combined with radiation therapy. However, further clinical trials are needed to define optimal doses, toxicity, and efficacy. [ONCOLOGY 14(Suppl 4):20-25, 2000]
Introduction
Recent research in lung cancer therapy has focused on combining radiation with chemotherapy in an attempt to improve patient outcome by controlling the tumor systemically with drug therapy while simultaneously attacking it locally with radiation. This approach is supported further by the now-established concept of radiation enhancement, whereby chemical agents have been shown to enhance the antitumor efficacy of radiation.[1,2] Several classes of drugs have demonstrated in vitro radiation enhancement activity; they include the taxanes, platinum analogs, topoisomerase inhibitors, and gemcitabine (Gemzar).[1-3] This newer approach to anticancer therapy offers hope of improved response rates and survival for patients with a variety of solid tumors, including lung cancer.
Gemcitabine is a novel deoxycitidine analog. It is particularly promising in combined chemoradiation regimens due to its efficacy in a wide range of solid tumors and its desirable safety profile.[4-10] Gemcitabine also has documented radiation-sensitizing capabilities, as established in vitro and in clinical studies.[11] It is approved for use in combination with cisplatin(Drug information on cisplatin) (Platinol) for the first-line treatment of patients with inoperable, locally advanced stage IIIA or IIIB, or metastatic stage IV non–small-cell lung cancer (NSCLC). This article will discuss preclinical studies investigating the mechanisms of gemcitabine’s radiation-sensitizing capabilities and preclinical and clinical trials designed to quantify and establish the safety and efficacy of gemcitabine plus radiation in the treatment of non–small-cell lung cancer. It will then consider the new and exciting directions into which gemcitabine research may lead.
Mechanism of Action
The mechanism by which gemcitabine sensitizes cells to radiation therapy is not well understood. The radiosensitizing activity of gemcitabine has been examined in a variety of human tumor cell lines. Shewach et al first proposed a mechanism of action based on their study of HT-29 human colon carcinoma cells during exposure to the combination of gemcitabine and radiation. They found gemcitabine to be a potent radiosensitizer, even when delivered at noncytotoxic doses over a long period. On biochemical and metabolic analyses, they consistently observed rapid depletion of cellular pools of deoxyadenosine triphosphate (dATP), independent of measures of the other nucleotides, deoxyguanosine triphosphate (dGTP) and deoxycitidine triphosphate (dCTP).[12,13] They also noted that the cytotoxicity of gemcitabine may be related to the effect of its metabolite, gemcitabine triphosphate, on DNA replication.[14]
Gemcitabine triphosphate has been identified as both an inhibitor and a substrate of DNA synthesis—two actions that are documented features of other antimetabolites with proven radiosensitizing potential. Subsequent research from the same group uncovered similar dATP pool depletion in pancreatic, colorectal, and other solid tumor cell lines, with an equivalent advantage incurred with radiation therapy.[11,15] Thus, the researchers concluded that dATP pool depletion contributes to improved response to radiation therapy in the presence of gemcitabine.
Additional research has yielded other proposed mechanisms for gemcitabine’s radiation-enhancing activity. Lawrence and colleagues observed that maximum radiosensitization occurs when gemcitabine-induced nucleotide pool depletion is accompanied by cell-cycle redistribution into the S-phase. [11,16] Milas et al have suggested a mechanism whereby gemcitabine eliminates radioresistant S-phase cells while synchronizing the rest of the tumor-cell population into a more radiosensitive phase of the cell cycle.[17] Furthermore, there is some evidence that gemcitabine may alter the threshold for cellular apoptosis in response to radiation.[18] As research continues, the relative impact of each of these potential mechanisms on gemcitabine’s radiosensitizing efficacy should become clear.
Radiation Enhancement
In 1994, Shewach and colleagues described the results of a study in which they exposed HT-29 human colon carcinoma cells to noncytotoxic concentrations (10 nmol/L) of gemictabine prior to radiation therapy. They found that gemcitabine was a potent radiosensitizer in this setting (radiation enhancement ratio, 1.8), with maximum effect achieved if cells were irradiated immediately after having been exposed to drug for 16 to 24 hours.[12] Radiation sensitization occurred in a dose- and time-dependent fashion.
Subsequent studies evaluated the cytotoxic efficacy of gemcitabine plus radiation in HT-29 cells using higher doses of drug (0.1 µmol/L and 3 µmol/L) but at a reduced exposure (2 hours).[16] This attempt to better reproduce clinically relevant gemcita-bine concentrations revealed that sensitization is apparent at 4 hours after treatment and is sustained for up to 2 days: At 24 and 48 hours after exposure, the enhancement ratio for 0.1 µmol/L of gemcitabine was 1.8 and 1.4, respectively; that of the 3-µmol/L dose was 3.0 and 1.4, respectively. By 72 hours, the effect had disappeared.
Gemcitabine also was tested in SW-620 human colon cancer cells[16] and Panc-1 and BxPC-3 human pancreatic cell lines,[18] and again exhibited radiosensitization activity at noncytotoxic levels of drug. Furthermore, Zhang and colleagues exposed human breast cancer cells (MDA-MB 231 cell lines) to 24 hours of 10- to 20-nM gemcitabine prior to radiation. At these mildly cytotoxic concentrations, an enhancement ratio of 1.47 to 1.58 was recorded, and at 1-hour exposure to higher 1- to 2- µmol/L doses, the enhancement ratio was 1.45–1.54.[19]
Potent Radiosensitizing Agent
Radiosensitizing Activity of GemcitabineIn summary, gemcitabine has been found to be a potent radiosensitizing agent. Several possible mechanisms for gemcitabine’s radiosensitizing activity have been discovered in preclinical studies (Figure 1), including dNTP pool perturbation, cell-cycle redistribution, and reduction of the apoptotic threshold for radiation. In fact, all three of these factors may play a role in gemcitabine’s influence on radiation, in which case DNA damage caused by radiation cannot be properly repaired, resulting in increased cell death through induction of apoptosis.
The average enhancement ratio of gemcitabine is ³ 1.5 and sensitization persists for at least 72 hours. These theories and others will be further investigated as basic research into gemcitabine activity continues, and the extensive documentation of the improved sensitivity of human cancer cell lines to radiotherapy after exposure to gemcitabine will be substantiated in clinical trials.
Approach to the Study of Combination Chemoradiotherapy
Given the predominant role of radiation therapy and the proven activity of gemcitabine in the management of lung cancer, mixing gemcitabine-based chemotherapy with a radiation regimen is a rational concept that can be expected to improve outcome related to the benefits of both modalities. Yet, because the combined impact of the two modalities may produce excessive toxicities, it is important to carefully select regimens of both radiation and chemotherapy so as to control the therapeutic ratio of radiotherapy both in tumor and normal tissue, without a parallel increase in treatment morbidity. Although there has been limited clinical experience published to date with chemoradiotherapy using gemcitabine, the available data will be reviewed in this article.
The combination of gemcitabine-based chemotherapy plus radiation needs to be evaluated from several perspectives, as follows:
(1) What is the benefit/risk of adding radiotherapy to a chemotherapy regimen?
(2) With radiotherapy as the base for local tumor control, does chemotherapy with gemcitabine proffer benefit?
(3) Is it safe and effective to give gemcitabine and radiotherapy concurrently?
In the first case, research would focus on a strategy for maximizing the impact of systemic drug therapy and then would assess the additive value of supplementing with irradiation. For instance, a phase I study would compare a maximum dose of gemcitabine with escalating doses of radiation to determine the appropriate dose of radiation in view of radiotherapy-driven toxicities. A phase II trial of the same comparison would follow to assess the supplemental effect on local tumor control when radiotherapy is added. Conversely, a trial designed to optimize local control with radiotherapy would use escalating doses of gemcitabine with a high radiation volume to isolate the maximum tolerated dose and then compare outcome in the radiation alone and radiation plus chemotherapy groups. Studies of each of these scenarios have been carried out.
