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Feasibility of Administering Adjuvant Chemotherapy of Pemetrexed Followed by Pemetrexed/Oxaliplatin Immediately Post-VATS in Patients With Completely Resected NSCLC

Phase 2
18 Years
Open (Enrolling)
Non Small Cell Lung Cancer

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Trial Information

Feasibility of Administering Adjuvant Chemotherapy of Pemetrexed Followed by Pemetrexed/Oxaliplatin Immediately Post-VATS in Patients With Completely Resected NSCLC

Non-small cell lung cancer (NSCLC) accounts for the largest number of cancer deaths
annually, worldwide. (Ferlay et al, 2007) Of these, about 30% are early stage patients
(stage I and II). For this group of patients, radical surgery with mediastinal lymph node
dissection has been the mainstay of therapy with a reasonable curative option. However,
5-year survival rates for patients with pathologically staged IA-IIB disease are ranging
from 67% to 39%. (Mountain et al, 1997) Following surgery, distant recurrence is the most
common form of relapse and eventual cause of death. Assuming that these recurrences are due
to occult micrometastases at the time of surgery, trials on adjuvant systemic therapy have
been performed in an attempt to reduce the risk of recurrence and to improve survival.

In some of the recently published trials a clear benefit of adjuvant chemotherapy in early
stage NSCLC could not be achieved. (Tada et al, 2004; Scagliott et al, 2003; Waller et al,
2004) In marked contrast to these studies, three recent, big randomized trials on early
stage NSCLC patients with modern platin-based two-drug chemotherapy-regimens revealed a
significant advantage for overall or relapse free survival for chemotherapeutically treated
patients. (Arriagada et al, 2004; Winton et al, 2005; Douillard et al, 2006) The majority of
patients in the adjuvant treatment setting received a combination of cisplatin and
vinorelbine. A pooled analysis of five big randomized studies demonstrated that adjuvant
cisplatin-based chemotherapy significantly improves survival in patients with NSCLC (overall
HR of death 0.89, P=0.005) corresponding to a 5-year absolute benefit of 5.4% from
chemotherapy. (Pignon et al, 2008) However, toxicity and inadequate dose delivery have been
critical issues in all trials performed so far. Grade 3/4 toxicities are observed up to 73%
with rates of neutropenic fever up to 7%. Up to 77% of the patients had at least one dose
reduction or omission and 55% required one dose delay or more, most related to neutropenia.
(Pisters et al, 2005; Winton et al, 2005)

There are few data in the literature about how soon after surgery a patient begins adjuvant
chemotherapy, although most trials seem to start after a post-surgical interval of 4-6
weeks. A recent study reported that 26 patients, who underwent thoracoscopic (video-assisted
thoracic surgery, VATS) lobectomy, receiving chemotherapy, 73% completed a full course on
schedule and 85% received all intended cycles. (Nicastri et al, 2008) In another study,
complete resection was performed by thoracotomy in 43 patients and by thoracoscopy in 57
patients, compared with thoracotomy, patients undergoing thoracoscopic lobectomy had
significantly fewer delayed (18% versus 58%, P < 0.001) and reduced (26% versus 49%, P =
0.02) chemotherapy doses. A higher percentage of patients undergoing thoracoscopic resection
received 75% or more of their planned adjuvant regimen without delayed or reduced doses (61%
versus 40%, P = 0.03). There were no significant differences in time to initiation of
chemotherapy or toxicity. (Peterson et al, 2007) In comparison, the Cancer and Leukemia
Group B trial 9633 reported that 57% of patients received full-dose chemotherapy (Strauss et
al, 2008) and the Intergroup JBR.10 trial reported that 55% of patients had at least 1 dose
delay. (Winton et al, 2005) Approximately 34% of patients in the Adjuvant Lung Project Italy
series chemotherapy wing received all scheduled doses without adjustment or delay; 69%
completed their treatments with or without adjustments or delay.(Scagliotti et al, 2003) It
is conceivable that patients who undergo VATS may have a quicker recovery and in general
more strength to tolerate chemotherapy. There are theoretic survival benefits to starting
chemotherapy immediately after surgery because the body's tumor burden should be lowest, and
tumor growth fastest, at this time. Thus, chemotherapy administered immediately post-surgery
would be most effective, assuming that wound healing is adequate. (Nicastri et al, 2008)

Pemetrexed, a multi-target folate antimetabolite, shows clear activity in non-small cell
lung cancer. In a phase III study for patients with previously treated advanced non-small
cell lung cancer, the efficacy of single-agent pemetrexed, as determined by overall
survival, was similar to that of docetaxel. (Hanna et al, 2004) The combination of
oxaliplatin and pemetrexed has been of particular interest because it has demonstrated both
good efficacy and a tolerable side effect profile. Oxaliplatin is a
diaminocyclohexane-containing platinum compound that inhibits DNA replication and
transcription by forming DNA adducts. Its mechanism of action is similar to that of the
classic platinum drugs, but molecular pharmacology studies suggest that oxaliplatin
represents a distinct family of platinum compounds. It has a different cytotoxicity profile
from cisplatin and can be safely given in the outpatient setting without hydration therapy.
(Raymond et al, 1998) Moreover, oxaliplatin appears to interact synergistically with
pemetrexed. (Raymond et al, 2002) Phase I studies evaluated pemetrexed plus oxaliplatin in
patients with solid tumors, and showed the regimen was efficacious and well tolerated.
(Misset et al, 2004) The combination of oxaliplatin and pemetrexed was compared with
carboplatin and pemetrexed as first-line therapy for advanced NSCLC in a randomized phase II
study. Response rates were 27 and 33%, respectively, and not statistically different.
However, toxicity in the oxaliplatin/pemetrexed arm was quite low, this doublet can be
delivered easily and is well tolerated. Furthermore, it results in a 7.3% rate of grade 3/4
neutropenia only and the incidence of febrile neutropenia was 2.4%. Dose reductions occur
only in 2.6% cycles. Patients received 95.3% and 100% of the planned weekly mean doses of
pemetrexed and oxaliplatin, respectively. (Scagliotti et al, 2005)

Therefore, it seems reasonable to test a less toxic regimen also in early stages after
complete (R0) resection of the tumor, where reduced toxicities might improve the feasibility
of drug delivery, compliance and the convenience of treatment for the patient and hence
perhaps improve survival. The main purpose of this phase II trial is to evaluate the
clinical feasibility-in terms of patients without dose limiting toxicities or premature
treatment withdrawal or death-of administering adjuvant chemotherapy of pemetrexed followed
by pemetrexed/oxaliplatin immediately post-VATS in patients with completely resected NSCLC.

Inclusion Criteria:

- Patients with completely resected stage IB (> 4 cm), II, or IIIA non-squamous NSCLC
by VATS. Patient must be enrolled and begin therapy within 4 weeks from the date of
complete surgical resection.

- Fresh tissue must be available for genomics expression profiling.

- ECOG performance status of 0 or 1.

- No prior chemotherapy, radiation therapy, or biologic/targeted therapy within the
last 5 years. Prior therapy with low dose methotrexate or similar medications is
allowed if therapy used to treat non-malignant conditions.

- Age ≥ 18 years.

- No previous or concomitant malignancy in the past 5 years other than
curatively-treated carcinoma in situ of the cervix, or basal cell or squamous cell
carcinoma of the skin.

- No other serious medical or psychiatric illness.

- Signed informed consent.

- Required laboratory data within one week of enrollment:

- ANC or AGC ≥ 1500 per uL;

- Platelets ≥ 100,000 per uL;

- Total bilirubin ≤ 1.5 mg/dL;

- Creatinine < 2 mg/dL, creatinine clearance ≥ 45 mL/min;

- SGOT/SGPT ≤ 1.5× ULN.

- Females of child-bearing potential (not surgically sterilized and between menarche
and 1 year post menopause) must test negative for pregnancy within 7 days prior to or
at the time of enrollment based on a serum pregnancy test.

- Both sexually active males and females of reproductive potential must agree to use a
reliable method of birth control, as determined by the patient and their health care
team, during the study and for 3 months following the last dose of study drug.

Exclusion Criteria:

- Treatment within the last 30 days with a drug that has not received regulatory
approval for any indication at the time of study entry.

- Concurrent administration of any other anti-tumor therapy.

- Inability to comply with protocol or study procedures.

- Active infection requiring IV antibiotics, antifungal or antiviral agents, that in
the opinion of the investigator would compromise the patient's ability to tolerate

- Major surgery (other than definitive lung cancer surgery) within two weeks of study
or other serious concomitant systemic disorders that, in the opinion of the
investigator, would compromise the safety of the patient or compromise the patient's
ability to complete the study.

- Myocardial infarction having occurred less than 6 months before inclusion, any known
uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac
failure not controlled by medications.

- Contraindication to corticosteroids.

- Inability or unwillingness to take folic acid or vitamin B12 supplementation.

- Unwillingness to stop taking herbal supplements while on study.

- Presence of clinically significant third-space fluid collections (for example,
ascites or pleural effusions) that cannot be controlled by drainage or other
procedures prior to study entry and throughout study enrollment as the distribution
of pemetrexed in this fluid space is not fully understood.

- Inability to discontinue administration of aspirin at a dose > 1300 mg/day or other
long acting, non-steroidal anti-inflammatory agents for 2 days before, the day of,
and 2 days after the dose of pemetrexed (5 days prior for long-acting agents such as
piroxicam). Moderate dose ibuprofen may be continued.

- Female patients that are pregnant or breast-feeding.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the clinical feasibility rate (CFR) of 4 cycles of adjuvant chemotherapy with pemetrexed followed by pemetrexed/oxaliplatin in patients with NSCLC stage IB, IIA, IIB and IIIA after a postsurgical interval of 2-4 weeks.

Outcome Time Frame:

Every 21 days

Safety Issue:


Principal Investigator

Jianxing He, MD, FACS

Investigator Role:

Principal Investigator

Investigator Affiliation:

The First Affiliated Hospital of Guangzhou Medical University


China: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

June 2015

Related Keywords:

  • Non Small Cell Lung Cancer
  • Non small cell lung cancer
  • video assisted thoracic surgery
  • Adjuvant chemotherapy
  • Pemetrexed
  • Oxaliplatin
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms