Gemcitabine (Gemzar), a novel deoxycytidine analog, has demonstrated activity in a broad spectrum of solid tumors, including pancreatic, lung, ovarian, bladder, and breast cancers.[1-7] Gemcitabine has several properties that favor its inclusion as a component of combined-modality therapy, including its tolerance as a single agent and encouraging single-agent activity with response rates of approximately 20% (range: 20% to 22.5% for three large phase II trials) in the treatment of non-small-cell lung cancer. In addition, when combined with a platinum agent (cisplatin [Platinol], carboplatin [Paraplatin]), gemcitabine has demonstrated response rates against non-small-cell lung cancer in the range of 30% to 60%. Because gemcitabine is a potent radiosensitizer, combining gemcitabine with radiation is a logical approach to address the need to optimize both systemic and locoregional control of non-small-cell lung cancer.
The earliest study of gemcitabine with radiation was conducted in 1994 to 1995 in a phase II trial for stage IIIA/B non-small-cell lung cancer patients. In this study, patients received standard doses of gemcitabine (1,000 mg/m2/wk for 6 weeks) with radical radiotherapy. Radiation was administered as 2 Gray (Gy)/fraction, 5 d/wk, up to 60 Gy over 6 weeks to the primary tumor, and mediastinal, hilar, and supraclavicular lymph nodes regions. Eight male patients with stage IIIA/B non-small-cell lung cancer with a mean age of 58.5 years were enrolled in the study before it was stopped due to unacceptable toxicity. The estimated median patient volume in the initial large-field radiation fields for these eight patients was 4,795 mL. The estimated median radiation treatment volume for the cone-down fields was 2,182 mL. While treatment volumes are not routinely calculated in most combined-modality trials, these volumes are considered substantially larger than most treatment volumes for stage III non-small-cell lung cancer patients.
Seven patients had a > 50% reduction in the primary tumor, and four out of five patients also responded in the nodes. There were three treatment-related deaths (two attributed to pulmonary toxicity and one to hemorrhage from radiation necrosis), and three patients suffered from pneumonitis or severe esophagitis due to acute radiation toxicity; two suffered other serious side effects of radiation. An analysis of this trial revealed two major factors that contributed to high levels of toxicity: large radiation treatment volumes and the concurrent delivery of both full-dose gemcitabine and full-dose radiation.
Dose and Schedule
Gregor and colleagues conducted a phase I trial to determine the optimal dose and administration schedule of gemcitabine combined with high-dose radiotherapy for non-small-cell lung cancer patients. Patients received gemcitabine at 300 mg/m2/d concurrently with a planned radiation treatment volume of ≤ 2,000 mL with a constant dose and fractionation of radiation at 60 Gy delivered in 30 daily fractions. Thirteen stage IIIA/B patients with a mean age of 63 years and a performance status (PS) < 3 have been enrolled in this ongoing study (6 patients had PS 0, and 7 had PS 1). Gemcitabine at all dose levels was infused over 30 minutes within 2 hours of radiation.
Grade 3/4 lymphopenia was observed in all 13 patients (with data up through level 4). Of grade 3 toxicities, one patient experienced acute pulmonary toxicity and one experienced delayed pulmonary toxicity, respectively, at dose level 1, and one patient had acute laryngeal toxicity at dose level 3. Of the 12 patients evaluable for response, there were two complete and three partial responses for an overall response rate of 42%; two additional patients await confirmation of response. The maximal tolerated dose has not yet been reached. Patients are currently being enrolled at dose level 5 (gemcitabine at 300 mg/m2 on days 1, 8, 15, 22, and 29). Patients in cohort 7 will have gemcitabine increased to 450 mg/m2. The authors concluded that this regimen of concurrent gemcitabine plus radiation appeared to be active and well tolerated thus far.
Phase II Trial
Recently, the Cancer and Leukemia Group B (CALGB) reported the results of a randomized phase II multi-institutional trial of patients with unresectable stage III non-small-cell lung cancer. A total of 187 patients with a PS < 2 and a median age of 61 years (range: 30 to 81 years) were randomized to receive one of three cisplatin-based combinations (gemcitabine, paclitaxel [Taxol], or vinorelbine [Navelbine]) as induction therapy, followed by concomitant chemoradiation. This trial was designed to establish the feasibility of each of the three arms and to assess response rate, survival time, toxicities, and pattern of failure (locoregional vs systemic). The final results of this trial will allow for the selection of an investigational arm for future phase III studies.
Patients in this study received gemcitabine induction therapy for two cycles with gemcitabine at 1,250 mg/m2 on days 1, 8, 22, and 29 plus cisplatin at 80 mg/m2 on days 1 and 22. Induction treatment was followed by radiation (2 Gy/d up to 66 Gy) with concomitant gemcitabine at 600 mg/m2 on days 43, 50, 64, and 71 plus cisplatin at 80 mg/m2 on days 43 and 64.
Median Follow-Up Results
At a median follow-up of 9 months, the median survival for all patients was 18 months, and the 1-year survival probability was 66% (95% confidence interval [CI], 58% to 75%). The median progression-free survival was 10 months (range: 7.8 to 13.2 months). This study demonstrated that gemcitabine plus cisplatin could be administered as induction therapy without resulting in overlapping toxicities that would affect concurrent administration of gemcitabine/cisplatin with radiation. It also demonstrated the feasibility of administering gemcitabine at 600 mg/m2 and cisplatin at 80 mg/m2 concomitantly with radiation.
The investigators concluded that the regimens in all three arms were safe as induction chemotherapy, and provided enhanced efficacy in combination with high-dose radiotherapy. Additional studies must be conducted to further refine these combinations and to better assess their safety when used with concurrent radiation therapy.
Recent advances in scanning techniques, including computed tomography (CT) and positron emission tomography (PET) scanning, in conjunction with the increasing availability of sophisticated three-dimensional conformal treatment planning, have assisted radiation oncologists in developing radiation strategies that reduce the exposure of normal tissue to radiation and increase the radiation dose uniformity to the target. These recent advances in treatment planning techniques continue to improve techniques that reduce the size of treatment volumes to normal tissue, while increasing the targeted irradiation of the primary tumor. The exciting advances in radiation planning and treatment modalities thus improve the outlook for novel radiosensitizers, such as gemcitabine, to be incorporated more effectively into future treatment-planning options.
Further testing of gemcitabine-based combinations with concurrent radiation is currently underway. The Radiation Therapy Oncology Group (RTOG) has recently proposed a phase I, two-arm trial of novel combinations of gemcitabine with concurrent radiation (RTOG 00-17). These trials will form the foundation for future development of gemcitabine-based combinations in this setting. Included in the study design are detailed analyses of the radiation fields and volumes, as well as their relationship to the observed toxicity and efficacy in both arms of this trial. These data should provide a clear direction for the optimal techniques of incorporating gemcitabine in the setting of concurrent radiation.
Numerous trials are underway to identify the optimal doses and schedules of concurrent gemcitabine and radiation among patients with non-small-cell lung cancer. The data reported by other investigators demonstrated that several significant factors contribute to the potential toxicities and efficacy of gemcitabine/radiation combinations. The dose of both gemcitabine and radiation, the schedule and sequencing of both gemcitabine and radiation, and the volume of irradiated tissue all play critical roles in influencing the toxicity and efficacy when gemcitabine is combined with radiation.
Initial attempts to combine gemcitabine and radiation revealed the need to manage carefully the fields and volume of radiation, as well as the dose level of gemcitabine. As demonstrated in this early trial, the potential for gemcitabine and radiation to affect normal tissue must be addressed in the treatment-planning design of future trials in order to optimize the radiosensitizing properties of gemcitabine.
The CALGB trial marks a significant recent advance in the attempt to define more accurately feasible doses of gemcitabine with radiation. In this randomized, multi-institutional coooperative group trial, Vokes and coworkers demonstrated that the combination of gemcitabine and cisplatin could be successfully given as induction chemotherapy without overlapping toxicities that would affect the concurrent administration of gemcitabine/cisplatin with radiation. Although this trial was not designed with the statistical power to provide valid comparisons between arms, the efficacy observed in the three arms was similar. In addition, several ongoing phase I and II trials appear to be validating the conclusion that it is feasible to combine gemcitabine with concurrent radiation.
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