ARTICLE
Auteur(s) : Tommaso De Pas MD1, Giuseppe
Curigliano
MD1, Giulia Veronesi2, Gianpiero
Catalano
MD3, Chiara Catania MD1, Barbara
Jereczek-Fossa MD3,
Roberto Orecchia
MD3, Lorenzo Spaggiari MD2, Filippo
de Braud
MD1
1 Department of Medical Oncology
2 Division of Thoracic Surgery and
Radiotherapy
3 European Institute of Oncology, Via Ripamonti,
435, 20141 Milan, Italy
The combination of gemcitabine (2',2'-difluorodeoxycytidine) (GCB),
an analogue of deoxycytidine, and cisplatin (CDDP), has a well
established activity in non-small-cell lung cancer (NSCLC) [1-7].
After a four-week schedule proved to be burdened by severe
thrombocytopenia, leading to frequent omission of GCB
administration on day 15, many different schedules of GCB and CDDP
were tested in patients with advanced NSCLC in order to reduce
myelosuppression.
A three-week schedule of GCB + CDDP (GC) appeared to be
safe and active in patients with locally advanced or metastatic
NSCLC [5, 8-9], but to our knowledge no data in the induction
setting are available.
Patients with pN2-IIIa and IIIb mediastinoscopically-proven NSCLC
were enrolled into a prospective trial aimed to optimize a
three-fraction – per-day hyperfractionated-accelerated
radiotherapy (hfRT) in a multidisciplinary approach. Patients
received an induction chemotherapy followed by surgery (if staged
IIIa) and a three – fraction-per-day accelerated
radiotherapy. Chemotherapy initially consisted of 3 courses of
CDDP 100 mg/m2 d1 plus GCB
1000 mg/m2 dd1,8,15 repeated every
4 weeks and was later modified in CDDP
80 mg/m2 d1 plus GCB 1250 mg/m2
dd1,8 repeated every 3 weeks, because of unacceptable
myelosuppression.
The feasibility, the toxicity and the activity of this induction
chemotherapy are reported.
Patients and methods
Patient selection
Eligibility criteria for study entry included: age between 18
and 75 years, biopsy-proven stage-IIIA pN2/stage IIIb NSCLC,
World-Health-Organization (WHO) performance status score of
0 to 2, and an adequate baseline organ function defined as
absolute neutrophils (ANC) and platelets counts
≥ 1.5 × 103/μl and ≥
100 × 103/μl, respectively, as well as liver
and renal functions within normal limits. Patients who had previous
chemotherapy, radiotherapy, or presence of active infections were
excluded from the study. All patients gave written informed
consent, and the study was approved by the local Ethic
Committee.
Treatment plan
When the study started, treatment consisted of GCB
1000 mg/m2 administered as a 30-minute intravenous
infusion on days 1, 8, and 15 of a 28-day treatment cycle. On day
1, after GCB was given, CDDP 100 mg/m2 was infused
over 60 minutes. Treatment given on day 1 was preceded by
8 mg iv of dexamethasone and 8 mg iv of ondansetron for
the prophylaxis of nausea and vomiting, associated with adequate
hydration and electrolytes supplementation.
After the first 10 pts were treated with this schedule, the
protocol was amended and treatment scheduled in GCB
1250 mg/m2 administered as a 30-minute intravenous
infusion on days 1 and 8 and CDDP 80 mg/m2 on day 1
of a 21-day treatment cycle.
The doses of GCB and/or CDDP were adjusted to the nadir of ANC and
PLT, non hematological toxicity and to the outcomes of blood counts
and blood chemistry immediately before the infusion(s); clinical
toxicity, weekly blood count as well as serum creatinine and BUN
were recorded during treatment. Toxicity was evaluated according to
WHO criteria.
Treatment was repeated on day 28 (four-week schedule) or on day 21
(three-week schedule) if ANC and platelets were
≥ 1.5 × 103/μl and ≥
100 × 103/μl, respectively, and in presence
of < G2 non-hematological toxicity. Otherwise,
treatment was delayed for 1 week and, if these conditions were
not yet satisfied, discontinued.
Full dose of GCB was given on days 8 and 15 (four-week schedule)
if ANC and platelets were ≥ 1.5 × 103/μl and
≥ 100 × 103/μl, respectively,
with < G2 non-hematological toxicity (excluding
nausea/vomiting and alopecia). Chemotherapy was administered at 75%
of the planned dose in the event of G2 hematological toxicity
and/or if ANC and platelets were ≥
1.0 × 103/μl and ≥
75 × 103/μl, respectively, Otherwise,
administration of GCB was omitted.
Cisplatin was given at 75% of the planned dose in the presence of
G2 neurotoxicity or of G1 nephrotoxicity, and was withheld if
neurotoxicity exceeded G2 or if nephrotoxicity exceeded G1. Both
CDDP and GCB were administered at 75% of the planned dose in all
the next administrations in the event of febrile neutropenia (fever
≥ 38.5° with G4 neutropenia or febrile G3 neutropenia requiring
i.v. antibiotics or hospitalization), platelets <
25 × 103/μl or platelet
< 50 × 103/μl with bleeding.
Three cycles of chemotherapy were administered unless progressive
disease or intolerable toxicity were recorded.
Patient evaluation
Pretreatment evaluation included complete history and physical
examination, complete blood cell count, a full chemistry profile,
spirometry, bronchoscopy, computed tomography (CT) scan of the
brain, chest and upper abdomen, bone scan and ECG. Mediastinal node
involvement was confirmed by mediastinoscopy/tomy. During
treatment, a weekly complete blood cell count, creatinine and BUN
as well as a complete chemistry profile on the first day of each
cycle were performed.
All patients underwent tumor-response assessment after 2 and
3 cycles of treatment. WHO response criteria were used [10].
Computer tomography examinations were reviewed by the responsible
physicians (radiation-oncologist, surgeon and medical oncologist).
Repeated mediastinoscopy/tomy were not included in the
post-chemotherapy evaluation.
Three cycles were planned in both responders and in patients with
stable-disease, before surgery and/or three-time-daily accelerated
radiotherapy.
Dose intensity
Dose intensity (DI) (mg/m2/wk) was calculated by the
following formula: total milligrams of drug per body surface
areas/total days of therapy/7, where total days was the number of
days between day one of the first cycle and day 21 (three-week
schedule)/28 (four-week schedule) of the last one.
Results
Patient characteristics
From February 1998 to November 2000, 50 consecutive
patients were enrolled onto the study (table 1).
Table 1. Patients’
characteristics (n = 50)
|
Characteristic |
No of patients |
|
Median age (yrs) |
58 |
|
Range |
42-75 |
|
Male/Female |
38/12 |
|
Performance status (ECOG) |
|
|
0-1 |
45 |
|
2 |
5 |
|
Stage |
|
| IIIa
pN2/IIIb |
37/13 |
|
Histology |
|
|
Adenocarcinoma |
18 |
|
Large cell |
4 |
|
Squamous cell |
24 |
|
NAS |
4 |
The first 10 patients received CDDP
100 mg/m2 on day 1 and GCB
1000 mg/m2 on days 1, 8, and 15 of a 28-day
treatment cycle. Afterwards, because of hematological toxicity, the
protocol was amended and a treatment scheduled in GCB
1250 mg/m2 on days 1 and 8 and CDDP
80 mg/m2 on day 1 of a 21-day treatment cycle was
given to the next 40 pts enrolled.
All patients but one were assessable for chemotherapy-induced
toxicity and all for response to chemotherapy.
In all patients staged IIIa baseline CT scans proved a clinical N2
disease (largest diameter of the N2 nodes over 10 mm); N2
metastases were confirmed by mediastinoscopy/tomy in all cases.
Thirteen patients were staged IIIb. Ten patients had a
pathologically confirmed pN3 and 3 pts a T4 N0-2 disease;
no patient required Chamberlain procedure to assess pathological
N2; no patients with malignant pleural effusion were enrolled.
Toxicity
• Four-week schedule
A total of 29 four-week scheduled treatment cycles were
administered to 10 pts; all 26 cycles given to 9 pts
were evaluable for toxicity. We analyzed toxicity after the first
10 patients because of a perceived excessive toxicity.
Grade 3/4 hematological toxicity consisted of G4 and G3
thrombocytopenia, with recovery within a week, in 2 (7%)
cycles/1 pt and in 4 (14%) cycles/4 pts, respectively; it
was not associated with bleeding events. Moreover, G3 non-febrile
neutropenia, with recovery within a week, was observed in 4 (14%)
cycles/4 pts.
Non-hematological toxicity consisted of G2 nephrotoxicity in 3
(10%) cycles/3 pts.
Nausea and vomiting occurred frequently but never reached grade 3.
Flu-like symptoms were occasionally seen and never required
treatment modifications.
Overall, treatment-related toxicity caused a dose-reduction or
treatment omission on day 15 in 19 cycles
(65%)/9 pts (90%); moreover, G2 nephrotoxicity required
chemotherapy discontinuation after the 2nd cycle in
1 pt. Reasons for dose reduction - treatment omission are
listed in table 2.
Table 2. Four-week schedule:
reasons for dose-modifications/treatment omissions on day 15
* G2 nephrotoxicity required chemotherapy discontinuation
after the second cycle in 1 pt.
• Three-week schedule
After the protocol was amended, a total of
119 three-week-scheduled treatment cycles were administered to
40 pts. Thirty-nine pts were evaluable for treatment
compliance and 110 cycles were fully evaluable for
toxicity.
Grade 3/4 thrombocytopenia was registered in 2 (2%)
cycles/2 pts and in 2 (2%) cycles/1 pt, respectively; it
was not associated with bleeding events, with recovery within a
week.
Transient G3/4 neutropenia occurred in 3 (3%)
cycles/3 pts and in 1 (1%) cycle, respectively; overall,
2 episodes of febrile neutropenia were observed.
Non-hematological toxicity consisted of G3 vomiting in
1 cycle. Moreover, 1 pt experienced a transient
GCB-induced systemic capillary-leak syndrome, with complete symptom
recovery within 2 days after intravenous administration of
Furosemide and high-dose Dexamethasone.
As reported with the four-week schedule, flu-like symptoms were
occasionally seen and never required treatment modifications.
Overall, treatment-related toxicity caused a dose-reduction or
treatment omission in 10 cycles (10%)/7 pts (17%); no
patients required chemotherapy discontinuation. Reasons for dose
reduction - treatment omission are listed in table 3.
Table 3. Three-week
schedule: reasons for dose-modifications/treatment omissions
|
Day-8 GCB dose reduction/treatment omission (no of
cycles) |
Reasons for modifications
|
|
2 |
G4
thrombocytopenia |
|
3 |
G3
thrombocytopenia |
|
1 |
G1
thrombocytopenia |
|
2* |
G4
neutropenia |
|
1* |
G3
neutropenia |
|
1 |
Patient's compliance |
Total: 10/110 Cycles
7/40 pts |
|
* Febrile neutropenia occurred in 2 cycles.
• Radiation therapy
Acute RT toxicity (RTOG) was mainly related to esophageal
mucositis (grade 2 in 25 patients, grade 3 G3 in
4 patients). Concerning late toxicity, no grade
3 esophagitis occurred; on the opposite, one grade-3 lung
toxicity was diagnosed
• Dose-Intensity
Dose intensity has been calculated for each schedule of
administration. With the schedule CDDP 100 mg/m2 dd
1, 28 and GCB 1000 mg/m2 dd 1, 8, 15, 28, taking
into account dose reduction for each drug as well as any delay in
drug administration, the actual delivered dose intensities of both
CDDP and GCB, calculated to the start dose, were 86.5% of the
intended dose level, at all dose levels. Namely it was 90% for CDDP
and 82.7% for GCB. Cisplatin was administered within the 67% to
100% range of the intended dose in 100% of the courses. As a result
of omissions and dose reduction 9 out of the 10 pts
treated with this schedule did not received the intended dose of
GCB. Range of administration were included between 70% and 91.6% of
the intended dose. With the schedule CDDP 80 mg/m2
dd 1, 21 and GCB 1250 mg/m2 dd 1, 8, 21, the actual
delivered dose intensities of both drugs, calculated to the start
dose, were 99.55% of the intended dose level. Namely it was 99.7%
for CDDP and 99.5% for GCB. Cisplatin and GCB was administered
within the 91% to 100% and within 93.3% and 100% range of the
intended dose in 100% of the courses, respectively. As a result of
omissions and dose reductions 10 of the 110 evaluable courses
were not administered at the intended dose of GCB.
Response to induction therapy
All patients underwent tumor-response assessment after 2 and
3 cycles of treatment. All patients were evaluable for
response; all the CT scans of responding patients were reviewed.
Responses to chemotherapy are listed in table 4.
Table 4. Antitumor
activity
| Schedule |
No pts |
PR |
SD |
PD |
RR |
| 4-week |
10 |
6 |
3 |
1 |
60% |
| 3-week |
40 |
31 |
4 |
5 |
77% |
| All |
50 |
37 |
7 |
6 |
74%* |
* 95% CI: 60-85%.
Thirty-seven out of 50 patients (74%, 95% CI: 60-85%)
achieved a partial response, 7 had stable disease and
6 had disease progression. One nodal pathological complete
remission was obtained among the 24 pts that underwent
surgery.
Activity was seen with both the three-week and four-week
schedules, with 6 out of 10 and 31 out of 40 partial
responses and 1 and 5 tumor progressions, respectively.
All the 6 pts with progressive disease were staged IIIa and
none of them underwent surgery. Three suffered from local
progression while the sites of distant relapse in the
3 remaining patients were bone, pleura and Central Nervous
System.
All responses but one were obtained after the first 2 cycles.
Furthermore, all unresponsive patients but one showed a disease
progression at the first disease assessment.
Survival
At present, with a median follow-up of 13 mos, 2y survival
of all 50 pts and of the 24 pts staged IIIa that
underwent surgery is estimated as 37% (95%CI: 24-58%) and 47%
(95%CI:27-80%), respectively. Results are not mature to evaluate a
survival impact.
Discussion
A major randomized trial showed that survival was significantly
improved with continuous hyperfractionated accelerated radiotherapy
(CHART) when compared with conventional radiotherapy (RT) in
patients with non-small-cell lung cancer (NSCLC) localized to the
chest [11]. Taking into account that systemic chemotherapy (CT)
improves survival when added to RT for patients with stage-III
NSCLC [12-15], we started a prospective phase-II study with the aim
to optimize a multidisciplinary approach to treat stage-IIIa/IIIb
disease with a sequential combination of chemotherapy and a
three-fraction-per-day accelerated radiotherapy (hfRT).
Gemcitabine (GCB) plus cisplatin (CDDP) combination (GC) was
selected as induction CHT because of its confirmed antitumor
activity in patients with advanced NSCLC and its proved feasibility
and activity also in the induction setting [16].
Chemotherapy was scheduled s a 4-week regimen, consisting of
3 courses of CDDP 100 mg/m2 d1 plus GCB
1000 mg/m2 dd1,8,15, with CDDP administered after
GCB. An interim analysis of toxicity was performed after the first
10 pts completed induction chemotherapy. It resulted that the
treatment-related toxicity, mainly thrombocytopenia, required a
frequent dose omission or reduction (90% of patients, 65% of
cycles) of the GCB doses on day 15, G2 nephrotoxicity also causing
chemotherapy discontinuation in 1 pt. Grade
3/4 thrombocytopenia was the main hematological toxicity,
occurring in 21% of cycles.
Afterwards, the protocol was amended and the 40 pts
subsequently enrolled received 119 cycles of a treatment
scheduled in GCB 1250 mg/m2 on days 1 and 8 and
CDDP 80 mg/m2 on day 1 of a 21-day treatment
cycle.
Patient compliance to the three-week schedule was excellent, with
a favorable toxicity profile. Dose-reduction or treatment omission
were required in only 17% of patients/10% of cycles, with no
treatment discontinuation. Grade 3/4 thrombocytopenia was
observed in 4% of cycles, not associated with bleeding events and
with recovery within a week.
The actual delivered dose intensities of both CDDP and GCB
calculated to the start dose were 86.5% and 99.55% of the intended
dose level with the four-week and the three-week schedule,
respectively.
Our results sustained a better compliance for a three-week than a
four-week schedule of GC.
The high percentage of GCB day-15 omission required with the
28-day schedule is in line with observations from studies performed
both in patients with localized and with advanced NSCLC.
Many different four-week GC combinations tested in patients with
advanced NSCLC showed the omission of GCB on day15 to be a
limitation of the treatment, whether giving CDDP early in the cycle
[4], or fractionating CDDP on days 1 and 8 [17]. Although an
analysis of phase-II trials of four-week schedule showed that the
administration of CDDP on day 15 required a lower percentage
of GCB dose-omissions than early CDDP administration, omissions
occurred in up to 29% of patients in any case, being moreover
associated with a higher incidence of severe neutropenia. Also,
when a four-week schedule of GC was given by EORTC as induction
chemotherapy in patients with stage IIIa pN2 NSCLC, hematological
toxicity frequently caused dose omission (34%) or reduction (23%)
of the GCB doses on day 15, toxicity causing treatment
discontinuation in 15% of patients [16]. Of interest, a three-week
schedule was discussed by the authors as a possible way to reduce
toxicity.
On the other hand, a phase-II randomized trial showed a three-week
schedule of GC to be burdened by low toxicity, whether high
(100 mg/m2) or intermediate
(70 mg/m2) doses of CDDP were given. Namely, only
4% and 6% of GCB doses were reduced and omitted, respectively, when
CDDP was given at the dose of 70 mg/m2 [17]. A
21-day GC schedule was tested also by Cardenal in a phase-III study
[5], and provided a significantly higher response-rate and delay in
disease progression than an Etoposide-CDDP (EP) combination in
patients with advanced NSCLC. In this study G3/4 febrile
neutropenia was more pronounced in EP arm and
G3/4 thrombocytopenia in the GC arm.
In our study we obtained a high response rate, with
37 partial responses (overall response: 74%), 7 stable
diseases and 6 disease progressions. Although mediastinal
nodes were tumor-free in only 1 out of the 24 patients
who underwent surgery, the 2y survival of all the 50 pts and
of the 24 pts staged IIIa who underwent surgery was estimated
as 37% and 47% respectively, with a median follow-up of
13 mos.
The response rate of 74% was among the highest for induction
chemotherapy, and was obtained despite all patients had a
significant N2 disease at CT scan or a stage IIIb disease. Although
the design of the study and the limited number of patients do not
allow definitive conclusions, there was no suggestion of a
different activity between the four-week and the three-week
schedules, that achieved 6 out of 10 and 31 out of
40 partial responses and 1 and 5 tumor progressions,
respectively. In support of this observation, the clinical response
obtained in this trial is quit similar to that reported by the
EORTC Lung Cancer Cooperative Group (70% of 38 patients who
received the planned treatment), where only patients staged IIIa
pN2 were enrolled. Similar responses have been described in the
recent report of A. Depierre et al. [21]. This study was
powered to investigate if there was a difference from 45% to 60% in
2-year survival rates of patients with early-stage NSCLC treated
with an induction chemotherapy followed by surgery versus a control
group of patients receiving primary surgery. The observed results
52% to 59% was not significant. LThe response rates reported in
Depierre’s study among 179 patients treated with chemotherapy
were 11% pathological complete responses and 53% partial responses.
Although in the EORTC trial half of the 17 pts who underwent
surgery were reported having tumor-free mediastinal nodes after
induction chemotherapy [16], such a difference in pathological
response should be interpreted with caution, both because of the
low number of patients pathologically evaluated, and because of a
possible different selection in patients that underwent surgery
despite a disease stabilization after induction chemotherapy.
Namely, 1 pt with no-change was randomized in the EORTC trial
and 4 pts with no change were operated (2 pt: lobectomy
and 2 pts: pneumonectomy) in our study.
Moreover, it should be noted that the EORTC schedule was quite
similar to the schedule given to the first 10 pts treated in
our study, where only one nodal pathological complete remission was
obtained.
Because a GCB-related acute respiratory distress syndrome (RDS)
has being recognized [18-20], acute and late pulmonary toxicity
should be investigated as a possible limiting toxicity for an
induction GCB-containing CHT in patients expecting to undergo
sequential radiation to the lung.
In this trial the toxicity of the post-chemotherapy
three-fraction-per-day accelerated radiotherapy was mild, and never
required treatment discontinuation or interruption. Specifically,
grade 3-G4 toxicity according to RTOG scale was registered in
3 pts (grade 3 esophagitis); no patients suffered from
grade 2-4 lung toxicity, and no late clinical evidence of
worsening of pulmonary function occurred. The limitation of a
not-randomized trial notwithstanding, we suggest that GC
combination is highly active and should be considered for induction
in stage IIIa/IIIb NSCLC, and that a three-week should be preferred
to a four-week schedule because of its better toxicity profile.
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|
Day-15 GCB dose reduction/treatment omission (no of
cycles) |
Reasons for modifications
|
|
2 |
G4
thrombocytopenia |
|
4 |
G3
thrombocytopenia |
|
5 |
G2
thrombocytopenia |
|
2 |
G3
neutropenia |
|
2 |
G2
neutropenia (on day 1) |
|
1 |
G3
astenia |
|
3* |
G2
nephrotoxicity
(plus G2 vomiting in 1 cycle) |
|
Total: 19/29 Cycles
9/10 pts
|
|
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