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					                             Annals of Oncology Advance Access published June 9, 2006

                                                                                                                                   Annals of Oncology
review                                                                                                                    doi:10.1093/annonc/mdl117

Gemcitabine and radiation therapy in non-small
cell lung cancer: state of the art
F. Mornex & N. Girard
Department of Radiotherapy-Oncology, Centre Hospitalier Lyon-Sud, Lyon, France

Received 24 March 2006; revised 25 April 2006; accepted 25 April 2006

Stage III non-small cell lung cancer (NSCLC) treatment is evolving. There are several choices available regarding
which chemotherapy to use and how to optimally combine them with radiotherapy. Gemcitabine (GemzarÒ,
Eli Lilly and Company, Indianapolis, USA) is a chemotherapeutic agent with activity in NSCLC, and preclinical
studies have shown that gemcitabine is a potent radiosensitizer. These two characteristics make gemcitabine
a potential option when treating patients with stage III NSCLC. This review article describes the efficacy and
tolerance of gemcitabine when combined with radiation in those patients. Gemcitabine used concurrently with
radiation, as an induction regimen before radiation, and as a consolidation regimen after radiation is reviewed.

Key words: gemcitabine, radiotherapy, chemotherapy, chemoradiation, non-small cell lung cancer

introduction                                                                     gemcitabine and radiation therapy
The treatment of stage III non-small cell lung cancer (NSCLC)                    Gemcitabine is one of the newer generation compounds that has
is based on local and systemic control of the disease [1].                       shown activity in phase II trials in NSCLC as both a single agent
Chemotherapy has an obvious role in systemic control;                            [4] and in combination with other cytotoxic agents [2, 5, 6].
however, it can also lend a hand in local control.                               Several phase III studies have confirmed the efficacy of
Many chemotherapeutic agents have been shown to                                  gemcitabine in stage IV NSCLC [7].
radiosensitize tumor cells or enhance the local effects of                          Preclinical data have shown that gemcitabine is a potent
radiation.                                                                       radiosensitizer. The mechanism by which gemcitabine causes
   Over the years, the treatment modality has evolved from                       radiation enhancement is not completely understood, but it is
radiation alone to using a cisplatin-based regimen prior to                      likely that several mechanisms play a part in the radiation-
radiation to using a cisplatin-based regimen concurrently                        enhancing effects of the drug. These include depletion of
with radiation [1]. As our knowledge has increased on how to                     dATP pools after gemcitabine administration, elimination
deliver radiation more effectively and safely, investigators are                 of the radio resistant S-phase cells and redistribution of
determining how to optimally use chemotherapy in conjunction                     surviving cells into a more sensitive component, lowering of
with radiation.                                                                  the radiation-induced apoptotic threshold, and/or oxygenation
   The approval of newer generation drugs has further widened                    of tissue from shrinking tumor cells [8–10].
the scope of available options. Several large randomized phase                      The timing of gemcitabine administration and radiation is
III studies were conducted to determine the best drug                            important for the optimization of radiosensitization. An in vitro
combination for advanced stage NSCLC [2, 3]. The results of                      study by Huang and Hittelman was aimed at finding the
these studies have shown that most platinum-based                                duration of gemcitabine-induced radiosensitization, and
combinations are comparable in terms of efficacy with similar                     chromosome repair was altered for 24 to 48 h following drug
median and 1-year survival times. Because of this plateau in                     administration [11]. The effects of gemcitabine-mediated
survival, investigators are incorporating other treatment                        radiation sensitization can be expected to last 24 to 72 h.
modalities in the hope of improving outcomes; however, with                         The scheduling of gemcitabine administration and radiation
radiation, questions remain about the order in which                             is also important for the optimization of radiosensitization. Two
chemotherapy and radiation should be given and which                             preclinical studies compared weekly with twice-weekly
chemotherapy should be used.                                                     gemcitabine. Mason et al. studied daily, twice-weekly, and
                                                                                 weekly gemcitabine followed by radiation in a murine sarcoma
                                                                                 model. All three schedules had equivalent enhancement of
                                      ´                    ´
Correspondence to: Prof. F. Mornex, Departement de Radiotherapie-Oncologie,
                                                                                 radiation; however, only the weekly schedule resulted in a slight
Centre hospitalier Lyon-Sud, 165, Chemin du Grand Revoyet, 69495 Pierre-Benite
cedex, France. Tel: (+33) 478864253; Fax: (+33) 478864265;                       protection of jejunal stem cells [10]. Fields et al. evaluated
E-mail:                                             weekly and twice-weekly gemcitabine given with daily radiation

ª 2006 European Society for Medical Oncology
review                                                                                                                          Annals of Oncology

in a murine head and neck squamous cell carcinoma model. The                    due to acute radiation toxicity (pneumonitis or severe
twice-weekly schedule was found to have a higher therapeutic                    esophagitis), and another two had other serious side effects.
index compared to the weekly schedule [12].                                        Based on the experience of this trial, several guidelines were
                                                                                formulated for the concurrent use of gemcitabine with
                                                                                radiation. First, the gemcitabine dose must be reduced. In
gemcitabine given concurrently with                                             subsequent studies, investigators gave gemcitabine at weekly
                                                                                doses ranging from 150 to 300 mg/m2 (or twice-weekly at
radiation                                                                       35 mg/m2) with concurrent total doses of radiation up to
On the basis of preclinical and clinical studies, it is expected that           63 Gy without unexpected toxicities. Second, the radiation
gemcitabine given concurrently with radiation may produce                       treatment field needs to be minimized. The 3-dimensional (3D)
radiation enhancement; however, the initial study of                            conformal radiation should be used whenever possible. Also, the
gemcitabine with concurrent radiation [13] ended with                           planning treatment volume (PTV) should be less than 2000 cm3.
undesirable results due to multiple factors. It was originally                     Weekly gemcitabine in combination with daily radiation is
hypothesized that since gemcitabine and 5-fluorouracil (5-FU)                    among the better studied regimens. In phase II evaluation, the
are structurally similar, they would react to radiation in a similar            gemcitabine dose ranged from 125 mg/m2 to 600 mg/m2, and
manner; therefore, a phase I dose-finding study was not                          the radiation dose used in the majority of studies was 1.8 to
completed for gemcitabine because full-dose 5-FU showed no                      2.0 Gy/day (Table 1). Gemcitabine in combination with
excessive toxicity when it was combined with radiation. In                      platinum agents has also been evaluated (Table 1).
the initial study, eight patients with stage IIIa/IIIb NSCLC received              The Cancer and Leukemia Group B (CALGB) study 9431 [14]
full-dose gemcitabine (1000 mg/m2) with 60 Gy of radiation in                   was a three-arm phase II study evaluating chemotherapy
large treatment volumes (according to the Radiation Therapy                     induction followed by concurrent chemoradiotherapy. The
Oncology Group [RTOG] guidelines at the time). The results were                 three arms were gemcitabine and cisplatin (arm 1), paclitaxel
intriguing: seven of the eight patients (87%) responded at the                  and cisplatin (arm 2), and vinorelbine and cisplatin (arm 3).
primary tumor, and four of five patients (80%) responded                         The induction phase used full doses of each regimen followed by
at nodal sites. The toxicity, however, was unacceptable: three                  modified doses in the concurrent phase. In arm 1, the induction
patients had treatment-related deaths (two from pulmonary                       phase used gemcitabine 1250 mg/m2 on days 1 and 8 with
toxicity, 1 from hemorrhage), three patients had complications                  cisplatin 80 mg/m2 on day 1 every 21 days. The concurrent

Table 1. Selected studies of gemcitabine given concurrently with radiation

Primary            Phase N     Population         Chemotherapy                          Radiation           Efficacy              Acute grade 3–4
investigator                                      regimen                               regimen                                  toxicity
Scalliet, 1998     II       8 Stage IIIa: 50%     Gemcitabine 1000 mg/m2                2 Gy/day for        87.5%                 Hematological: 25%
                              Stage IIIb: 50%       weekly · 6 weeks (NOT                 total of 60 Gy      response rate       Pneumonitis: 75%
                                                    RECOMMENDED)                                                                  Oesophagitis: 50%
                                                                                                                                  Toxic death: 38%
Fossella, 2001a    I      21 Stage II–III         Gemcitabine 125–190 mg/m2             1.8 Gy/day for        Estimated 55 week   Hematological: not
                                                    weekly · 7 weeks                       total of 63 Gy       median survival     reported
                                                                                                                                  Oesophagitis: 30%
Blackstock, 2001   I      17 Stage IIIa: 82%      Gemcitabine 10–50 mg/m2               1.8–2.0 Gy/day        88% response        Hematological: 12%
                             Stage IIIb: 18%        twice weekly · 6 weeks                 for total of 60 Gy   rate and 13 month Pneumonitis: 24%
                                                                                                                median survival   Oesophagitis: 18%
Vokes, 2002b       II     62 Stage IIIa: 63%      Gemcitabine 600 mg/m2                 2 Gy/day for          74% response rate,  Hematological: 53%
                             Stage IIIb: 37%        day 1, 8 plus cisplatin 80 mg/m2       total of 66 Gy       18.3 month        Pneumonitis: 14%
                                                    day 1 every 21 days · 2 cycles                              median survival   Oesophagitis: 52%
Trodella, 2003     II     39 Stage IIIa/N2        Gemcitabine 350 mg/m2                 1.8 Gy/day or 1.2     85% response rate   Hematological: 3%
                                                    weekly · 5 weeks                       Gy BID for total                       Pneumonitis: 0%
                                                                                           of 50.4 Gy                             Oesophagitis: 0%
van Putten, 2003 I        27 Stage IIIa: 14 pts Gemcitabine 300–450 mg/m2               2 Gy/day for          63% response        Hematological: 0%
                             Stage IIIb: 13 pts   weekly · 6 weeks                         total of 60 Gy       rate and 61 week  Pneumonitis: 3%
                                                                                                                median survival   Oesophagitis: 3%
Choy, 2005c        I      27 Stage IIIa/IIIb      Gemcitabine 450 mg/m2                 1.8–2.0 Gy/day        Not reported        All: 30%
                                                    day 1, 8 plus carboplatin              for total 63 Gy
                                                    AUC=2 day 1, 8 every
                                                    21 days · 2 cycles
  This study included a consolidation phase of full dose gemcitabine and cisplatin.
  This study included an induction phase of full dose gemcitabine and cisplatin.
  This study included a consolidation phase of full dose gemcitabine and carboplatin.

2 | Mornex & Girard
Annals of Oncology                                                                                                                   review
phase used gemcitabine 600 mg/m2 on days 1 and 8 with                            of radiation therapy are resolved. There have been published
cisplatin 80 mg/m2 on day 1 every 21 days for two cycles                         results of full-dose gemcitabine (both as a single agent and in
along with 2 Gy/day of radiation. It is interesting to note that                 combination with a platinum agent) administered following
the 600-mg/m2 concurrent gemcitabine dose was not                                a radiation regimen. The results seen in these studies do
supported by phase I data. Although the design of the study did                  not indicate enhanced toxicity with gemcitabine following
not allow for a statistical comparison among the arms, the                       radiation therapy.
median survival times for arms 1, 2, and 3 (18.3, 14.8, and                         Gemcitabine used as consolidation therapy has been studied
17.7 months, respectively) and response rates (74%, 67%, and                     in several trials. In this setting, single-agent gemcitabine and
73%, respectively) were clinically similar, with the gemcitabine                 gemcitabine in combination with cisplatin, carboplatin,
arm having a numerically higher 3-year survival rate (28%                        docetaxel, and vinorelbine have been evaluated (Table 2). It is
versus 19% for arm 2 and 23% for arm 3). The arm 1 toxicities                    difficult to analyze the toxicities because the primary focus of
reported during the concurrent phase revealed higher                             these trials was either induction or concurrent chemotherapy,
hematologic and gastrointestinal toxicities compared with                        and as such, the results for the consolidation phase were not
studies that used a lower gemcitabine dose. The authors                          discussed. However, the toxicity profile of gemcitabine in
concluded that induction chemotherapy followed by                                situations where gemcitabine was administered after radiation
concomitant chemoradiotherapy in patients with unresectable                      does not appear to be different than that of radiation-naıve ¨
stage III disease was safely administered at the studied schedule                patients, except for instances of radiation recall [15]. Radiation
and dose. The authors noted that the gemcitabine arm had                         recall events are usually cutaneous or mucosal reactions or
the most severe toxicity profile in the concurrent phase of the                   pneumonitis in the treatment field of prior radiotherapy that are
trial; a potential explanation for this would be the use of                      precipitated by drug treatment; these events have been reported
a higher gemcitabine dose.                                                       with many cytotoxic drugs, such as doxorubicin, etoposide,
                                                                                 paclitaxel, and tamoxifen [16]. The cutaneous reports were
gemcitabine given sequentially after                                             primarily skin erythema and pruritus [15–18], while the
                                                                                 noncutaneous reactions included hepatic necrosis [19], optic
radiation                                                                        neuritis, brainstem radio necrosis, lymphangitis [18], and
If a gemcitabine-based regimen is planned after radiation,                       abdominal wall tenderness [18, 20]. In general, radiation recall
initiation of gemcitabine should not begin until the acute effects               events have been rarely reported with gemcitabine

Table 2. Selected studies of gemcitabine given sequentially after radiation

Primary investigator   Phase    N    Population          Consolidation regimen                  Efficacy                   Acute grade 3–4 toxicity
Vinolas, 2000d         II       33   Stage IIIa: 15%     Gemcitabine 1000 mg/m2                 13.8 month median         Hematological: 70%
                                     Stage IIIb: 85%       day 1, 8, 15 plus either:              survival, 62% 1-year    Pneumonitis: 0%
                                                           Carboplatin 400 mg/m2                  survival and 19%        Oesophagitis: 34%
                                                           day 1 or cisplatin 100 mg/m2           2-year survival
                                                           day 1 every 28 days · 2 cycles
Fossella, 2001c        I        21   Stage II–III        Gemcitabine 1000 mg/m2                 Estimated 55 week         Not reported
                                                           day 1, 8, 15 plus cisplatin            median survival
                                                           60 mg/m2 day 1 · 4 cycles
Boyd-Sirard, 2002a     II       16   Stage   IIIa: 56%   Gemcitabine 1000 mg/m2                 Not reported              Hematological: 69%
                                     Stage   IIIb: 44%     6 doses over 56 days                                           Other: not reported
Featherstone, 2002f    I        11   Stage   IIIa: 45%   Gemcitabine 1200 mg/m2                 68 weeks median           Hematological: not reported
                                     Stage   IIIb: 55%     day 1, 8 plus vinorelbine 30 mg/m2     survival                Pneumonitis: 27%
                                                           day 1, 8 · 1 cycle                                             Oesophagitis: 18%
                                                                                                                          Toxic death: 18%
Zwitter, 2002b         I-II     23   Stage IIIb          Gemcitabine 1250 mg/m2                 51% 1-year                Hematological: 17%
                                                           day 1, 8 · 1 cycle or gemcitabine      survival and 43%        Pneumonitis: 0%
                                                           1250 mg/m2 day 1, 8 plus cisplatin     2-year survival         Oesophagitis: 13%
                                                           70 mg/m2 day 1 · 1–4 cycles
Garrido, 2005e         II       31   Stage IIIa: 3%      Gemcitabine 1200 mg/m2                 Not reported              Hematological: 22%
                                     Stage IIIb: 97%       day 1, 8 plus docetaxel 40 mg/m2                               Pneumonitis: 4%
                                                           day 1, 8 every 21 days · 2 cycles                              Oesophagitis: 22%
  This study included an induction phase of full–dose paclitaxel and carboplatin, and a concurrent phase of paclitaxel and carboplatin with radiation.
  This study included an induction phase of full dose gemcitabine and cisplatin, and a concurrent phase of single–agent gemcitabine with radiation.
  This study included a concurrent phase of single–agent gemcitabine with radiation.
  This study included an induction phase or full dose gemcitabine with either cisplatin or carboplatin, and a concurrent phase of vinorelbine with
either cisplatin or carboplatin.
  This study included a concurrent phase of docetaxel with carboplatin and radiation.
  This study included an induction phase of full dose gemcitabine and vinorelbine, and a concurrent phase of gemcitabine and vinorelbine with radiation.

                                                                                                                     doi:10.1093/annonc/mdl117 | 3
review                                                                                                          Annals of Oncology

administration; however, if observed, gemcitabine should be        futures directions for gemcitabine and
discontinued, and a treatment of glucocorticoids or non-           radiation in NSCLC
steroidal anti-inflammatory agents and supportive therapy
including antihistamines should be administered [16, 18].          The treatment of stage III NSCLC is advancing. The results of
Complete resolution occurs in about a half of patients, while      key studies are reshaping how to administer radiation and
others require prolonged corticoid treatment.                      chemotherapy. These studies have focused on how radiation
                                                                   and chemotherapy can be most effectively combined.
                                                                      The goal of the Locally Advanced Multimodality Protocol
                                                                   (LAMP) trial [30] was to determine the optimal order that
gemcitabine given sequentially before                              radiation and chemotherapy should be given in patients with
                                                                   unresected stage III NSCLC. There were three arms of the
radiation                                                          study that included chemotherapy followed by radiation,
If a gemcitabine-based regimen is planned prior to radiation,      chemotherapy followed by radiation concurrent with
there should be a break of at least 1 week before the start of     chemotherapy, and radiation concurrent with chemotherapy
radiation to minimize the potential for unanticipated              followed by chemotherapy. The chemotherapy used in this
radiosensitization. According to preclinical studies, the          trial was paclitaxel and carboplatin, while the dose of radiation
radiation-enhancing effects of gemcitabine typically last 24 to    was 63 Gy. The arm of radiation concurrent with
72 h. In an emergency situation, it may be necessary to            chemotherapy followed by chemotherapy showed the longest
administer radiation therapy immediately following the             median survival time along with the most grade 3 esophagitis
cessation of gemcitabine; however, there are no data               and overall lung toxicities. The authors concluded that this
regarding the effects of gemcitabine and palliative radiation      arm should serve as the core for future trials.
therapy to the central nervous system.                                RTOG 9410 [31] was planned to compare induction
   Full-dose gemcitabine-based combinations have been studied      chemotherapy with concurrent chemotherapy in patients with
in the induction setting in several trials. The majority of        stage II and III NSCLC. There were three arms of the study,
published data is with gemcitabine and cisplatin [14, 19–22],      which included chemotherapy followed by radiation,
although there are also published studies of gemcitabine and       chemotherapy concurrent with standard radiation, and
carboplatin [23–28], vinorelbine [29], and triplet therapy with    chemotherapy concurrent with hyperfractionated radiation.
paclitaxel and a platinum agent [30–32]. Most studies used         The chemotherapy used in this trial was cisplatin and
two to three cycles of induction. The CALGB study 9431             vinblastine, except for the hyperfractionated arm, which used
initiated concurrent radiotherapy 2 weeks following
                                                                   cisplatin and etoposide. The hyperfractionated arm improved
induction therapy [14].
                                                                   local control, but it did not improve survival. The
   In randomized studies, the combination of gemcitabine and
                                                                   chemotherapy with standard radiation arm produced
cisplatin has been compared with another cisplatin-based
                                                                   a statistically significant longer median survival than the
combination, either with etoposide, vinorelbine, or paclitaxel
                                                                   sequential arm. The sequential arm had higher rates of grade
[14, 19–22]. The gemcitabine dose used in most of these
                                                                   3 and 4 nonhematologic toxicities, although late toxicity
studies was 1250 mg/m2 on days 1 and 8, while the cisplatin
                                                                   rates were similar across all arms.
dose ranged from 50 to 100 mg/m2 on day 1 every 21 days. Of
                                                                      Southwest Oncology Group (SWOG) study 9504 [32] was
note, one non-randomized study began with cisplatin 100
                                                                   a single-arm study that evaluated consolidation therapy
mg/m2 and was later amended to 70 mg/m2 due to cisplatin-
related nonhematologic toxicities [22]. In all of the randomized   following concurrent chemoradiation in patients with stage IIIb
studies, the response rates of gemcitabine and cisplatin after     NSCLC. The concurrent regimen was cisplatin and etoposide
induction were numerically similar to that of the comparator       given with 61 Gy of radiation; the consolidation therapy was
arms. The response rates ranged from 40 to 60%. The toxicities     a standard docetaxel regimen. The median survival was 26
seen with the gemcitabine with cisplatin induction regimen         months. Grade 4 neutropenia was seen in more than half the
were similar to those seen when the combination was given          patients during consolidation docetaxel. Even though the results
without radiation in metastatic NSCLC. The primary toxicities      need to be substantiated in a phase III setting, this trial is
were neutropenia, thrombocytopenia, anemia, nausea, and            encouraging because the survival endpoints are some of the
vomiting.                                                          highest historically seen in stage IIIb NSCLC patients.
   In studies evaluating the combination of gemcitabine and           On the basis of these results and those of other studies, the
carboplatin administered before radiation therapy [23–28],         standard use of chemotherapy and radiation is evolving into
the gemcitabine doses have ranged from 1000 to 1250 mg/m2 on       concurrent usage with or without consolidation chemotherapy.
days 1 and 8 with the carboplatin dose ranging from AUC of         Gemcitabine was not included in any of the studies referred
5.0 to 5.2 on day 1 every 21 days. Response rates ranged from      to above; however, as reviewed in this article, gemcitabine
30% to 65%, which were similar to those in the gemcitabine         has been used in similar trial settings.
with cisplatin studies. The toxicities seen were also similar to      The initial study of gemcitabine and radiation produced
the toxicities associated with gemcitabine and cisplatin, except   unacceptable results. Lessons were learned from this study, and
that more thrombocytopenia and less nausea and vomiting            future studies demonstrated that in a clinical trial setting,
were reported with the gemcitabine and carboplatin                 gemcitabine and radiation can be given safely, and lead to high
combination.                                                       response rates. Because of the radiation-enhancing effects of

4 | Mornex & Girard
Annals of Oncology                                                                                                                                         review
gemcitabine and the severe toxicity seen in this initial trial,                               cancers—a report of 3 cases. Proc Am Soc Clin Oncol 2000; 19: 322a
caution needs to be used when combining these modalities.                                     (Abstr 1273).
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                                                                                              preferentially involves internal tissue and organs. Cancer 2004; 100:
acknowledgements                                                                              1793–1799.
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The authors wish to thank Scott Barker, PharmD, and Pete                                      etoposide-cisplatin (EC) in patients with inoperable stage IIIa/IIIb non-small cell
Fairfield, both of Eli Lilly and Company, for their assistance                                 lung cancer (NSCLC) with intermittent radiotherapy: a randomized phase II trial.
in the preparation of this manuscript, and Virginie Wautot for                                Proc Am Soc Clin Oncol 2001; 20: 270b (Abstr 2831).
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