Annals of Oncology Advance Access published June 9, 2006
Annals of Oncology
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 . shown activity in phase II trials in NSCLC as both a single agent
Chemotherapy has an obvious role in systemic control;  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 .
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 . 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 . 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 . Fields et al. evaluated
E-mail: email@example.com 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 . 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  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 
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
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 . 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 . The cutaneous reports were
gemcitabine given sequentially after primarily skin erythema and pruritus [15–18], while the
noncutaneous reactions included hepatic necrosis , optic
radiation neuritis, brainstem radio necrosis, lymphangitis , 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  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  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 , 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 .
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  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 . 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).
18. Friedlander PA, Bansal R, Schwartz L et al. Gemcitabine-related radiation recall
preferentially involves internal tissue and organs. Cancer 2004; 100:
19. Cicenas S, Pipiriene T, Burneckis A et al. Gemcitabine-cisplatin (GC) versus
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).
her excellent assistance for the manuscript submission. 20. Villanueva N, Esteban E, Fra J et al. Cisplatin plus gemcitabine with or without
vinorelbine as neoadjuvant therapy for radically treatable stage III non small cell
lung cancer (NSCLC). Preliminary results of a randomized study of the GON
(Grupo Oncologico del Norte de Espana). J Clin Oncol 2004; 22 (14S): 655
references (Abstr 7171).
1. Vokes EE, Choy H, Gandara D, Mattson K. Adjuvant and neoadjuvant treatments 21. Voznyi E, Dobrovolskaia N, Bychkov Y. Cisplatin + etoposide (EP) + subsequent
for NSCLC. Lung Cancer 2002; 38 (suppl 4): 29–35. radiotherapy vs cisplatin + gemcitabine + subsequent radiotherapy in
advanced non small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2002;
2. Schiller JH, Harrington D, Belani C et al. Comparison of four chemotherapy
21: 230b (Abstr 2740).
regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;
22. ´ ´
Blanco R, Sole J, Nogue M et al. Phase II multicentric study of concurrent
chemoradiation (CCR) with biweekly gemcitabine after induction chemotherapy
3. Fossella F, Pereira J, von Pawel J et al. Randomized, multinational, phase III
with cisplatin and gemcitabine in unresctable stage III non small cell lung cancer
study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin
(NSCLC). J Clin Oncol 2004; 22 (14S): 693 (Abstr 7322).
for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol
2003; 21: 3016–3024. 23. Argiris A, Liptay M, LaCombe M et al. A phase I/II trial of induction chemotherapy
with carboplatin and gemcitabine followed by concurrent vinorelbine and
4. Perng RP, Chen YM, Ming-Liu J et al. Gemcitabine versus the combination of
paclitaxel with chest radiation in patients with stage III non-small cell lung cancer.
cisplatin and etoposide in patients with inoperable non-small-cell lung cancer in
Lung Cancer 2004; 45: 243–253.
a phase II randomized study. J Clin Oncol 1997; 15: 2097–2102.
24. Perez ML, Fernandez OR, Cervantes GS, Tokunaga FJ. Gemcitabine plus
5. Zatloukal P, Petruzelka L, Zemanova M et al. Gemcitabine plus cisplatin vs.
carboplatin (GCb) followed by radiotherapy (RT) for treatment of locally advanced
gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer:
non small cell lung cancer (NSCLC): a pilot study. Proc Am Soc Clin Oncol 2003;
a phase III randomized trial. Lung Cancer 2003; 41: 321–331.
22: 707 (Abstr 2843).
6. Kosmidis P, Mylonakis N, Nicolaides C et al. Paclitaxel plus carboplatin versus
25. Blackstock AW, Socinski MA, Gu L et al. Initial pulmonary toxicity evaluation of
gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III
chemoradiotherapy (CRT) utilizing 74 Gy 3-dimensional (3-D) thoracic radiation
randomized trial. J Clin Oncol 2002; 20: 3578–3585.
in stage III non-small cell lung cancer (NSCLC): a Cancer and Leukemia Group
7. Le Chevalier T, Scagliotti G, Natale R et al. Efﬁcacy of gemcitabine plus
B (CALGB) randomized phase II trial. J Clin Oncol 2005; 23 (16S): 635s
platinum chemotherapy compared with other platinum containing regimens
in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.
26. Hamada E. A phase II nonrandomized trial of sequential chemoradiation
Lung Cancer 2005; 47: 69–80.
(gemcitabine/carboplatin plus thoracic radiation) in patients with unresectable
8. Lawrence TS, Eisbruch A, McGinn CJ et al. Radiosensitization by gemcitabine.
stage III non-small cell lung cancer (NSCLC). J Clin Oncol 2004; 22 (14S): 676
Oncology (Williston Park) 1999; 13 (10 suppl 5): 55–60.
9. Milas L, Fujii T, Hunter N et al. Enhancement of tumor radio response in vivo
27. Hirsh V, Duclos M, Del Vecchio P et al. Phase II trial with carboplatin/gemcitabine
by gemcitabine. Cancer Res 1999; 59: 107–114.
(Cb/G) induction chemotherapy (CT) followed by radiotherapy concomitantly with
10. Mason KA, Milas L, Hunter NR et al. Maximizing therapeutic gain with paclitaxel/gemcitabine (P/G) in stage III non small cell lung cancer (NSCLC):
gemcitabine and fractionated radiation. Int J Radiat Oncol Biol Phys 1999; 44: a preliminary report. J Clin Oncol 2005; 23 (16S): 650s (Abstr 7122).
28. Williams CC, Wagner H, Greenberg H et al. Phase II study of induction
11. Huang NJ, Hittelman WN. Transient inhibition of chromosome damage repair chemotherapy with gemcitabine and carboplatin (IndGC) followed by paclitaxel
after ionizing radiation by gemcitabine. Proc Am Assoc Cancer Res 1995; 36: and carboplatin with concurrent thoracic radiation (PCRT) for patients with
612 (Abstr 3643). unresectable stage III non-small-cell lung cancer (NSCLC): MCC-13240. J Clin
12. Fields MT, Eisbruch A, Normolle D, et al. Radiosensitization produced in vivo Oncol 2005; 23 (16S): 696s (Abstr 7307).
by once- vs. twice-weekly 2929-diﬂuoro-29-deoxycytidine (gemcitabine). Int J 29. Lee DH, Han JY, Cho KH et al. Phase II study of induction chemotherapy with
Radiat Oncol Biol Phys 2000; 47: 785–791. gemcitabine and vinorelbine followed by concurrent chemoradiotherapy with
13. Scalliet P, Goor C, Galdermans D et al. GemzarÒ (gemcitabine) with thoracic oral etoposide and cisplatin in patients with inoperable stage III non-small-cell
radiotherapy – a phase II pilot study in chemonaive patients with advanced non- lung cancer. Int J Radiat Oncol Biol Phys 2005; 63: 1037–1044.
small cell lung cancer. Proc Am Soc Clin Oncol 1998; 17: 499a (Abstr 1923). 30. Belani CP, Choy H, Bonomi P et al. Combined chemotherapy regimens of
14. Vokes EE, Herndon JE 2nd, Crawford J et al. Randomized phase II study of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer:
cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy a randomized phase II locally advanced multi-modality protocol. J Clin Oncol
followed by concomitant chemoradiotherapy for stage IIIb non-small-cell lung 2005; 23: 5883–5891.
cancer: cancer and leukemia group B study 9431. J Clin Oncol 2002; 20: 31. Curran WJ, Scott CB, Langer CJ et al. Long-term beneﬁt is observed in a phase
4191–4198. III comparison of sequential vs. concurrent chemoradiation for patients with
15. Jeter MD, Janne PA, Brooks S et al. Gemcitabine-induced radiation recall. unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003; 22:
Int J Radiat Oncol Biol Phys 2002; 53: 394–400. 621 (Abstr 2499).
16. Skarin A (ed). Side effects of chemotherapy. J Clin Oncol 2000; 18: 693–698. 32. Gandara DR, Chansky K, Albain KS et al. Consolidation docetaxel after concurrent
17. Wolff RA, Hirsch VJ, Pisters PW et al. Gemcitabine-induced hepatic necrosis after chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest
upper abdominal chemoradiation (chemoXRT) for pancreatic and biliary tract Oncology Group Study S9504. J Clin Oncol 2003; 21: 2004–2010.
doi:10.1093/annonc/mdl117 | 5