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
ABSTRACT: 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]
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. It is approved for use in combination with 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.
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.
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. Furthermore, there is some evidence that gemcitabine may alter the threshold for cellular apoptosis in response to radiation. As research continues, the relative impact of each of these potential mechanisms on gemcitabine’s radiosensitizing efficacy should become clear.
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. 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). 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 and Panc-1 and BxPC-3 human pancreatic cell lines, 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.
Radiosensitizing Activity of Gemcitabine
In 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.
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.
Several studies that have evaluated the activity of concurrent gemcitabine and radiotherapy have achieved essentially equivalent results.[20-26] Scalliet and colleagues performed the first trial examining concurrent administration of gemcitabine and radiotherapy. In this trial, eight male patients with stage IIIA/B NSCLC (mean age, 58.5 years) received 1,000 mg/m² gemcitabine for 6 weeks. Radiation was administered in 2-Gy fractions over 5 days per week to a total of 60 Gy and delivered to the visible primary tumor, with a 2.0- to 2.5-cm margin. The radiation field included the mediastinal, hilar, or supraclavicular lymph node regions or the entire lung if the lesion was extensive.
Patients received a median radiotherapy volume of 4,795 cm³, followed by a boost dose (median, 2,182 cm³). This large radiation exposure resulted in significant esophageal and pulmonary toxicity (including grade 3 to 5 acute lung toxicity, late lung toxicity, and damage to the pharynx/esophagus), which necessitated early termination of the study.
An independent audit of the data by Turrisi concluded that the toxicities were directly and closely correlated with the volume of tissue irradiated.[Turrisi, personal communication, 1997] However, the fact that objective responses were observed in six patients (one complete response and five partial responses) and stable disease in one led investigators to conclude that the combined gemcitabine/radiotherapy regimen was effective and warranted further study to establish an appropriate radiation schedule that would minimize lung and esophageal toxicities.
Gemcitabine Dose-"Escalation" Scheme
In a more recent trial, Gregor and coworkers designed a combined modality protocol to determine the optimal dose and schedule of gemcitabine in the presence of radiation. With 18 chemonaive patients with stage IIIA and IIIB NSCLC enrolled (mean age, 63 years; performance status [PS] < 3), the investigators delivered a standard regimen of radiotherapy along with weekly gemcitabine. Gemcitabine was administered as a 30-minute infusion starting at 300 mg/m² (which is a subtoxic dose in most studies) and “escalated” in cohorts of three to six patients. A unique escalation scheme was employed for the first six dose levels of the study; ie, dosing was increased by prolonging the number of days that the patient would be receiving the drug, rather than by escalating the dose of each infusion (Table 1). At dose levels 7 and 8, the infusion dose was increased to 450 mg/m² and 600 mg/m², respectively.
The prescribed radiotherapy regimen was established in an attempt to minimize damage to lung tissue, and consisted of 60 Gy delivered as 2-Gy fractions 5 days per week for 6 weeks to a maximum lung volume of 2,000 cm³. Radiation was initiated within 2 hours of the start of gemcitabine infusion. Toxicity evaluations included both early and late toxicities, necessitating a relatively slow transition to successive cohorts. Six cohorts have completed treatment to date with no evidence of dose-limiting toxicities that might define the maximum-tolerated dose (MTD). The trial is ongoing, with gemcitabine being administered at the 450-mg/m² dose.
The Radiation Therapy Oncology Group (RTOG) is planning a phase I trial (RTOG L0017) that will examine two gemcitabine-based combination chemotherapy regimens combined with radiation in patients with unresected stages IIIA and IIIB NSCLC without evidence of hematogenous metastases. The goal will be to determine the MTD of gemcitabine combined with carbo-platin (Paraplatin) at an area under the curve (AUC) of 2, or of gemcitabine combined with paclitaxel (Taxol) when administered concurrently with radiotherapy. Radiation will be administered in daily fractions of 1.8 Gy for 5 days per week followed by a boost to the primary and involved nodes. A total dose of 63 Gy will be delivered in 34 fractions over 7 weeks.
Dose-Escalation Schema for Proposed Radiation Therapy Oncology Group Trial L0017
Both combination chemotherapies will be delivered as 1-hour infusions on days 1, 8, 22, 29, and 43 of the radiation schedule, with doses increasing in cohorts of three patients as shown in Table 2. It is expected that the results of this trial will establish the feasibility and potential of concurrent radiation and combination chemotherapy in patients with advanced NSCLC, who have a good prognosis. Study results will be widely anticipated.
The Cancer and Leukemia Group B (CALGB) has studied the impact of administering sequential chemotherapy followed by chemotherapy plus concomitant radiation. Chemotherapy- and radiotherapy-naive patients with unresectable stage III NSCLC (median age, 61 years and PS < 2) were randomly assigned to three treatment groups of at least 60 patients each. In each group, patients received two 21-day cycles of induction chemotherapy with gemcitabine/cisplatin, vinorelbine (Navelbine)/cisplatin, or paclitaxel/cisplatin followed by two cycles of combined modality therapy.
As such, all patients received cisplatin 80 mg/m² days 1, 22, 43, 64, and were randomized to receive one of the following in addition: gemcitabine 1,250 mg/m² on days 1, 8, 22, 29, and 600 mg/m² on days 43, 50, 64, 71; vinorelbine 25 mg/m² on days 1, 8, 15, 22, 29, and 15 mg/m² on days 43, 50, 64, 71; paclitaxel 225 mg/m² (30-h infusion) on days 1 and 22 and 135 mg/m² on days 43 and 64. A radiation dose of 2 Gy per day was initiated on day 43 and continued to a total dose of 66 Gy.
Toxicity was evaluated individually for the chemotherapy and combined modality treatment arms of the trial. During the induction chemotherapy phase of this regimen (cycles 1 and 2), grade 3 and 4 toxicity was primarily limited to granulocytopenia, which occurred in 49%, 50%, and 55% of patients in the gemcitabine, paclitaxel, and vinorelbine arms, respectively. In the combined chemoradiotherapy phase, grade 3/4 toxicities included granulocytopenia in 49%, 48%, and 27% of patients receiving gemcitabine, paclitaxel, and vinorelbine, respectively, along with thrombocytopenia in 55%, 6%, and 0% and esophagitis in 49%, 35%, and 24% of these patients.
Response to Three Regimens of Combined Modality in Cancer and Leukemia Group B Trial 9431
Dyspnea occurred infrequently and at equivalent rates among the groups, although one patient receiving vinorelbine died during treatment due to respiratory insufficiency. Response rates were also equivalent between groups (Table 3); the overall response rates were 63%, 50%, and 59% in patients receiving gemcitabine, paclitaxel, and vinorelbine, respectively. Median progression-free survival ranged from 7.9 to 12.5 months and overall survival from 14.1 to 17.7 months, accounting for median 1-year survival rates of 63%, 63%, and 67%. There was no statistically significant difference in any parameter among the three treatment groups.
Based on these results, the investigators concluded that all three regimens were safe as induction therapy and in combination with radiation. The higher rate of esophagitis in the gemcitabine arm may be related to the doses used, and warrants further investigation in clinical trials to establish the MTD and appropriate radiation volumes before the regimen can be recommended for widespread use.
These trial results are representative of the overall experience with gemcitabine in combination with radiation therapy. The most compelling detail in the research carried out to date is the relative safety of the combined modality regimen, especially in view of the well-established highly toxic interactions between a variety of chemotherapeutic agents (eg, mitomycin and cisplatin) and radiation therapy.
The current database on the safety of therapy with gemcitabine followed by radiation therapy includes results from 1,200 patients, or 12% of the subjects enrolled in single-agent and combination chemotherapy trials who received radiation therapy after the trial closed.
These data are supported by a general safety information database from poststudy follow-ups or general reports on drug safety. In this accumulated treatment experience, there has been no documented radiation toxicity warranting treatment discontinuation associated with sequential gemcitabine/radiation therapy. Furthermore, radiation toxicity did not appear to be dependent on the treatment-free interval, so whether radiation was administered for 2 days, 12 days, or 1 month following chemotherapy, there has been no clear indication of enhanced radiation toxicity.
In the CALGB study, despite higher rates of esophagitis associated with gemcitabine/cisplatin treatment, toxicity was not amplified to such an extent as to eliminate the regimen from further consideration in the treatment of NSCLC. In fact, despite esophagitis, pulmonary toxicity was not significantly enhanced, and the authors concluded that the regimen provided appealing locoregional control and a favorable median survival. The regimen, therefore, warrants further study in order to isolate a less toxic regimen of drug and radiation so as to minimize adverse events.
In the CALGB trial, patients receiving cisplatin (80 mg/m² on days 1 and 22) plus gemcitabine (1,250 mg/m² on days 1, 8, 22, and 29) as induction therapy followed by combined-modality therapy (cisplatin 80 mg/m² on days 43 and 64 plus gemcitabine 600 mg/m² on days 43, 50, 64, and 71 with concurrent radical radiation) experienced no significant increase in radiation toxicity, and there was no indication of a time-dependent relationship between the chemo- and radiotherapy-induced complication rate.
Current clinical experience has established gemcitabine as an effective agent in the treatment of NSCLC, and one with proven radiation-sensitizing potential. Combination regimens using gemcitabine plus radiotherapy have been associated with improved response compared with radiation alone, reflecting an enhancement ratio of approximately 1.5 to 2.0. The enhanced radiation sensitivity persists for at least 48 hours and up to 72 hours after gemcitabine exposure.
In clinical studies where confounding factors can complicate conclusions about the effects of individual drugs or different treatment modalities on treatment outcome, there is still indication of the safety and efficacy of gemcitabine combined with radiation. In some combined-modality treatment trials, large radiation volumes rather than the presence or dosage of gemcitabine appear to have been responsible for any excesses in toxicity.
Furthermore, the data in the available safety database do not indicate enhanced toxicity among patients who entered trials and had prior radiation. Reports that may suggest such a relationship have proven to reflect, on closer examination, the use of multiple chemotherapeutic agents that have a recognized relationship to enhanced postradiation toxicity, or that fall into a time frame that links the toxicity more logically to radiation, than to the addition of drug therapy.
No data generated thus far have indicated any worsening of radiation-induced toxicities when combined-modality therapy is used. Therefore, gemcitabine with radical radiation is being investigated currently in clinical trials to identify its value in the curative treatment of NSCLC.
The potential relationship between radiation and enhanced postradiation toxicity generated by concomitant or sequential cytotoxic treatment will be clarified by continued long-term surveillance of patients receiving gemcitabine plus radiation.
1. Levine M: The action of colchicine on cell division in human cancer animal, and plant tissue. Ann NY Acad Sci 51:1365-1408, 1951.
2. Skipper HG, Chapman JB, Bell M: The antileukemic action of combinations of certain known antileukemic agents. Cancer Res 11:109-111, 1951.
3. DeVita VT, Hellman S, Rosenberg SA, (eds): Cancer: Principles & Practice of Oncology, 5th ed. Philadelphia, Lippincott-Raven, 1997.
4. Carmichael J, Possinger K, Phillip P, et al: Advanced breast cancer: A phase II trial with gemicitabine. J Clin Oncol 13:2731-2736, 1995.
5. Shapiro JD, Milward MJ, Rischin D, et al: Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. Gynecol Oncol 63:89-93, 1996.
6. Lund B, Hansen O, Theilade K, et al: Phase II study of gemcitabine (2Â´,2Â´-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530-1533, 1994.
7. Perng R-P, Chen Y-M, Jing-Liu J, et al: Gemcitabine vs the combination of cisplatin and etoposide in patients with inoperable nonâsmall-cell lung cancer in a phase II randomized study. J Clin Oncol 15:2097-2102, 1997.
8. Manegold C, Berman B, Chemaissani A, et al: Single-agent gemcitabine vs cisplatin-etoposide: Early results of a randomized phase II study in locally advanced or metastatic nonâsmall-cell lung cancer. Ann Oncol 8:525-529, 1997.
9. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347-353, 1996.
10. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997.
11. Lawrence TS, Eisbruch A, McGinn CJ, et al: Radiosensitization by gemcitabine. Oncology 13 (10 suppl 5):55-60, 1999.
12. Shewach DS, Hahn TM, Chang E, et al: Metabolism of 2Â´,2Â´-difluoro-2Â´-deoxycitidine and radiation sensitization of human colon carcinoma cells. Cancer Res 54:3218-3223, 1994.
13. Shewach DS, Lawrence TS: Radiosensitization of human tumor cells by gemcitabine in vitro. Semin Oncol 22(suppl 11):68-71, 1995.
14. Shewach DS, Lawrence TS: Gemcitabine and radiosensitization in human tumor cells. Invest New Drugs 14(3):257-263, 1996.
15. Shewach DS, Lawrence TS: Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 23(5 suppl 10):65-71, 1996.
16. Lawrence TS, Eisbruch A, Shewach DS: Gemcitabine-mediated radiosensitization. Semin Oncol 24(2 suppl 7):S7-24âS7-28, 1997.
17. Milas L, Fujii T, Hunter N, et al: Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res 59(1):107-114, 1999.
18. Lawrence TS, Chang EY, Hahn TM, et al: Radiosensitization of pancreatic cancer cells by 2Â´,2Â´-difluoro-2Â´-deoxycytidine. Int J Radiat Oncol Biol Phys 34:867-872, 1996.
19. Zhang XL, Yang SL, Ashamalla H, et al: Gemcitabine-induced radiosensitization of human breast cancer cells (abstract 1732). Proc Am Soc Clin Oncol 17:449a, 1998.
20. Goor C, Scalliet P, Van Meerbeek J, et al: A phase II study combining gemcitabine with radiotherapy in stage III NSCLC (abstract 481). Ann Oncol 7:101, 1996.
21. Data on file, Eli Lilly and Company, Indianapolis.
22. Gonzalez E, Sanchez-Rovira P, Jaen A, et al: Phase I study of concomitant gemcitabine with radiotherapy in stage III NSCLC. Eur J Cancer 35(suppl 4):A1054, 1999.
23. Groen HJM, Gregor A, van Putten JWG, et al: Phase I study of gemcitabine (G) and high-dose thoracic radiation (RT) in stage III nonâsmall-cell lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 19:2123a, 2000.
24. Blackstock AW, Richards FR, Lovelace JR, et al: Twice-weekly gemcitabine and concurrent thoracic radiotherapy-A phase I/II study in patients with advanced nonâsmall-cell lung cancer (abstract 1918). Proc Am Soc Clin Oncol 18:497a, 1999.
25. Zinner R, Fossella FV, Komaki R, et al: Phase I trial of concurrent gemcitabine (G) plus chest radiotherapy (XRT) followed by consolidation systemic chemotherapy with G plus cisplatin (CDDP) for patients with stage III and medically inoperable stage II nonâsmall-cell lung cancer (abstract 1798). Proc Am Soc Clin Oncol 18:466a, 1999.
26. Goss G, Lochrin C, Perry G, et al: A phase I study of gemcitabine and cisplatin with concurrent curative irradiation in stage III nonâsmall-cell lung cancer (NSCLC) (abstract 1986). Proc Am Soc Clin Oncol 18:515a, 1999.
27. Vokes EE, Leopold KA, Herndon JE, et al: A randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy and concomitant chemoradiotherapy for unresectable stage III nonâsmall-cell lung cancer (CALGB study 9431) (abstract 1771). Proc Am Soc Clin Oncol 18:459a, 1999.