(Chest. 2000;117:119S-122S.)
© 2000
American College of Chest Physicians
Adjuvant and Neoadjuvant Chemotherapy for Non-Small Cell Lung Cancer*
A Time for Reassessment?
Paul A. Bunn, Jr, MD;
James Mault, MD and
Karen Kelly, MD
*
From the Lung Cancer Program and Departments of Medicine (Drs. Bunn and Kelly) and Surgery (Dr. Mault), University of Colorado Cancer Center, Denver, CO.
Correspondence to: Paul A. Bunn, Jr, MD, University of Colorado Cancer Center, Box B-188, 4200 East 9th Ave, Denver, CO 80262; e-mail: paul.bunn{at}uchsc.edu
 |
Abstract
|
|---|
Surgical resection has limited success in curing non-small cell
lung cancer (NSCLC), particularly among patients with locally advanced
disease (stage IIIA). Combined modality regimens, utilizing surgery,
radiotherapy, and chemotherapy, have improved response rates, although
they have not been shown to significantly impact survival among
patients with completely resected stage I and II NSCLC. Future
improvements in NSCLC therapy, currently under investigation, are
likely to come from newer agents shown to be active in this disease and
from alternative schedules, such as neoadjuvant or concurrent combined
modality treatments. Neoadjuvant cisplatin-based chemotherapy has
already been shown to increase cure rates in stage IIIA NSCLC, from 10
to 15% to 25 to 30%. Newer active agents, such as paclitaxel,
vinorelbine, and gemcitabine, may be able to advance the cure
rate even further. Radiotherapy, which has been shown to decrease the
rate of local recurrence, may play a role as well.
Key Words: adjuvant therapy • cisplatin • lymph nodes • neoadjuvant therapy • non-small cell lung cancer • radiotherapy • recurrence
|
Introduction
|
|---|
Lung
cancer is the third most common cancer in the United States after
prostate and breast cancers, but it is the leading cause of cancer
death in both men and women.1
The low cure rate (14%)
accounts for the discrepancy between the incidence and mortality
ranking. The low cure rate can be attributed to lack of effective
screening and early detection measures, the propensity for early spread
of the cancer, and the inability of chemotherapy to cure advanced
systemic disease.
Less than 25% of non-small cell lung cancer (NSCLC) patients present
with stage I or II disease, which has a reasonable chance for cure with
surgical resection. Moreover, only about half of these resected
patients remain free of disease for 
5 years.2
The vast
majority of recurrences are in distant sites, suggesting that systemic
approaches will be required to improve the cure rate.3
Another problem in resected patients is the development of second
primary cancers,4
which needs to be addressed with
chemoprevention efforts. Fortunately, new therapeutic agents that
prolong survival with reduced toxicities in advanced-stage patients are
now available for study in early stage NSCLC patients in either
neoadjuvant or adjuvant settings,5
and new chemoprevention
agents are being evaluated. Combined modality approaches, novel classes
of agents, and new chemotherapeutic approaches provide a real
opportunity to improve the cure rate for patients with NSCLC.
|
Staging and Prognostic Features of NSCLC
|
|---|
The 1997 revised International Staging System should be used to
determine prognostic and therapeutic options for NSCLC
patients.2
The categories of the lung cancer staging
system, the approximate frequency of each stage at diagnosis, and
5-year survival rates following older therapies are summarized in Table 1
. Clearly, the involvement of regional lymph nodes worsens prognosis
more so than the extent of the primary tumor. The cure rate following
surgical therapy is considerably lower when any lymph nodes are
involved, and surgical cure is unlikely when there is clinically
detected mediastinal lymph node (N2) involvement.6
After stage, the next important prognostic features are performance
status, weight loss, and gender (female patients fare better than
male), in that order. Age does not appear to be a major independent
risk factor. While there are many articles suggesting that individual
biological or genetic markers are prognostically significant, no large
series with multivariate analysis proves such markers have independent
prognostic relevance. Thus, recent American Society of Clinical
Oncology guidelines do not include routine determination of such
markers.7
Because of the value of lymph node status as a prognostic marker,
complete staging has great importance. Neither chest CT nor MRI scans
are reliable determinants of pathologic mediastinal lymph node status.
Table 2 shows the frequency of pathologic involvement of mediastinal lymph
nodes based on the size of the nodes by CT scan.8
As
shown, markedly enlarged lymph nodes do not contain tumor in 33% of
cases, and completely normal nodes contain tumor 13% of the time.
Patients with normal-sized nodes and T2, T3, and central lesions are
found to have pathologic involvement in > 13% of cases. Thus, the
majority of NSCLC patients should have mediastinal lymph node biopsies
by bronchoscopy, mediastinoscopy, and/or mediastinotomy as part of
staging prior to therapy assignment. Select patients, such as those
with peripheral coin lesions (T1N0M0), may proceed to immediate
surgery.
Sites of Failure
Disease recurs in a large fraction of NSCLC patients, despite
complete surgical resection (Table 3
).3
Less than 25% of first recurrences are in regional
sites alone, regardless of the histology of the primary tumor. These
data imply that effective systemic treatment must be part of any
adjuvant or neoadjuvant therapy to have a major impact on survival.
|
Adjuvant Radiotherapy
|
|---|
Chest radiotherapy has been used as both preoperative and
postoperative adjuvant therapy without improving survival or overall
cure rates in multiple randomized trials and meta-analysis of these
trials.9
Preoperative radiotherapy with doses > 45 Gy
increases the operative morbidity and mortality and should not be used
alone or with chemotherapy.10
Postoperative chest radiotherapy produces a striking decrease in the
rate of regional recurrence (from 20 to < 5%).11
Because local recurrences may cause symptoms and morbidity, some
investigators believe routine use of radiotherapy is justified,
especially for patients with N2 disease, in which the local failure
rate is higher. Others prefer careful observation and periodic chest
radiographs, with radiotherapy reserved for cases of regional failure,
especially because a meta-analysis of all randomized trials showed a
worse survival in patients receiving postoperative
radiotherapy.12
|
Adjuvant Chemotherapy
|
|---|
The first chemotherapeutic agents widely studied in the
postoperative setting were alkylating agents, which have been studied
alone or in combination regimens. Unfortunately, these agents have
considerable toxicity, and in some randomized trials and meta-analysis
were associated with shortened survival.9
Thus, these
approaches cannot be justified.
In contrast, cisplatin-based chemotherapy was shown in meta-analysis of
all randomized trials to lengthen survival duration.9
Survival significantly improved in some of the individual randomized
trials, whereas in others it did not, but this is not surprising given
the small sample size in many of the trials and the limited magnitude
of the effect. Compliance with cisplatin-based therapy was quite poor
in many of the trials. In the meta-analysis, the hazard rate of death
was reduced by 13%,9
translating into a 5% absolute
improvement in 5-year survival rate; the number of patients studied was
small, and the survival differences were of borderline statistical
significance (p = 0.08).
Postoperative adjuvant cisplatin-based therapy has not been widely
adopted on the basis of these results. In a patient survey, Yellan and
Cella13
found that 95% of patients would elect to receive
adjuvant chemotherapy that offered a 5% improvement in survival. After
the results of the meta-analysis were published, < 1% of physicians
surveyed in the United Kingdom indicated they would offer the
postoperative adjuvant cisplatin-based chemotherapy to their patients,
despite the fact that 95% might elect to receive it.14
A number of additional larger adjuvant trials with postoperative
cisplatin-based therapy given alone or combined with chest radiotherapy
are in progress or were recently completed. There are no published
results of trials using chemotherapy regimens based on the newer
agents, such as paclitaxel, docetaxel, vinorelbine, or gemcitabine, in
patients with stage I-IIIA NSCLC. However, in advanced disease,
combinations with these agents are more effective than older
cisplatin-based regimens.5
Thus, results of adjuvant and
neoadjuvant trials with these new combinations are eagerly awaited. A
US and Canadian intergroup randomized trial designed to compare surgery
alone to surgery followed by chemotherapy with vinorelbine and
cisplatin is underway, and an intergroup neoadjuvant study comparing
preoperative carboplatin and paclitaxel followed by surgery to surgery
alone will begin soon.
Adjuvant Therapy With Combined Chemotherapy and Radiotherapy
Randomized trials designed to compare chemotherapy plus
radiotherapy to radiotherapy alone in patients with unresectable stage
III NSCLC showed that combined modality therapy with cisplatin-based
regimens significantly prolonged survival.9
When
chemotherapy and radiotherapy were given concurrently, there was a
significant decrease in local recurrence rates.15
Unfortunately, randomized trials and meta-analysis of these trials have
not found combined chemoradiotherapy to prolong survival in completely
resected stage I and II NSCLC patients,9
perhaps
reflecting the use of suboptimal cisplatin-based regimens. Results of
studies with more current cisplatin-based combined modality regimens
should be available within a few years. Studies in early stage NSCLC
using the newer agents combined with radiation given before or after
surgery should be conducted in the future.
|
Neoadjuvant Chemotherapy
|
|---|
There are no randomized trials of neoadjuvant "modern"
chemotherapy in stages I and II NSCLC, although there have been several
in stage IIIA NSCLC. The latter studies were based on phase II results
indicating increased survival compared with surgery alone. Many groups,
however, found survival of patients with N2 nodal involvement to be
very poor, with 5-year survival rates < 15%.6
A group
of investigators at Memorial Sloan-Kettering Cancer Center went on to
show that high response rates could be achieved in patients with
advanced NSCLC using mitomycin, vinblastine, and cisplatin
preoperatively to treat stage IIIA, N2 NSCLC patients, and survival
markedly improved compared with historical control
subjects.16
Other groups also have reported good results
with mitomycin, vinblastine, and cisplatin, although the regimen
produced excessive toxicity in some series.10
At least three randomized trials have been conducted to evaluate
neoadjuvant cisplatin-based chemotherapy based on these results (Table 4
).17
18
19
20
In all of the studies, survival improved among the
patients receiving cisplatin-based chemotherapy before and after
surgery. Although all three of the studies had small numbers of
patients, the survival results were statistically different in two of
the studies.17
18
19
Many investigators have interpreted
these studies to mean that surgery alone is inadequate in stage IIIA,
N2 NSCLC. Randomized trials are in progress to determine whether triple
modality regimens are superior to two modalities, and whether
chemotherapy plus surgery or chemotherapy plus radiotherapy are
preferred when two modalities are used.
The results of these trials also were used as an impetus for
neoadjuvant chemotherapy studies in stage I and II NSCLC, some using
the newer chemotherapy agents. For example, the multicenter Bimodality
Lung Oncology Team (BLOT) in the United States is evaluating the
two-drug combination of paclitaxel plus carboplatin given for two or
three cycles before surgery and for two or three cycles after surgery
(Fig 1 ).21
As of January 1999, 106 patients had been enrolled in
this trial. The objective response rate after two cycles was 59%, and
> 90% of patients have had a complete resection. Final results
should be available within a few years. This study will be followed by
a phase III intergroup randomized study comparing this approach to
surgery alone.
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1.. Ongoing phase II study of the BLOT is shown
(left).21
Because of the encouraging
results of this phase II study, an intergroup randomized study, shown
schematically (right), will begin soon. The chemotherapy
will consist of three cycles of paclitaxel plus carboplatin in the
experimental arm of this trial.
|
|
|
Conclusion
|
|---|
Surgery alone fails to cure the majority of resected NSCLC
patients because of systemic metastases that were undetected at the
time of surgery. Postoperative chest radiotherapy virtually eliminates
local-regional recurrences, but fails to increase and may even decrease
survival. Alkylating agent-based chemotherapy fails to improve survival
when used in an adjuvant setting. In contrast, cisplatin-based
postoperative chemotherapy improves the cure rate by 5% in resectable
NSCLC.
Neoadjuvant chemotherapeutic approaches have theoretical reasons for
being superior to postoperative adjuvant approaches. In stage IIIA
NSCLC, cisplatin-based chemotherapy improves the cure rate from 10 to
15% to as much as 40%. A preliminary study of paclitaxel and
carboplatin used as neoadjuvant therapy shows even more promising
results in stage IB and II NSCLC.
The new chemotherapy drugs, such as paclitaxel, vinorelbine, and
gemcitabine, improve survival in advanced NSCLC, compared to older
agents. These new therapies hold great promise to improve the cure rate
of early stage NSCLC patients in the future.
|
Footnotes
|
|---|
Abbreviations: BLOT = Bimodality Lung Oncology Team;
NSCLC = non-small cell lung cancer
|
References
|
|---|
-
Landis, SH, Murray, T, Bolden, S, et al (1998) Cancer statistics, 1998. CA Cancer J Clin 48,6-9[Abstract]
-
Mountain, CF (1997) Revisions in the international system for staging lung cancer. Chest 111,1710-1717[Abstract/Free Full Text]
-
Mountain, CF, McMurtrey, MJ, Frazier, OH (1980) Current results of surgical treatment for lung cancer. Cancer Bull 32,105-108
-
Thomas, P, Rubinstein, L (1990) The Lung Cancer Study Group: cancer recurrence after resection; T1N0 non-small cell lung cancer. Ann Thorac Surg 49,242-247[Abstract]
-
Bunn, P, Kelly, K (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 5,1087-1100
-
Mountain, CF, Dresler, CM (1997) Regional lymph node classification for lung cancer staging. Chest 111,1718-1723[Abstract/Free Full Text]
-
. The American Society of Clinical Oncology. (1997) Clinical practice guidelines for the treatment of unresectable non-small cell lung cancer. J Clin Oncol 15,2996-3018[Abstract]
-
Mcloud, TC, Bourgouin, PU, Greenberg, RW, et al (1992) Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 182,319-323[Abstract/Free Full Text]
-
. Non-small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311,899-909[Abstract/Free Full Text]
-
Wagner, H, Jr, Lad, T, Piantadosi, S (1994) Randomized phase II evaluation of preoperative radiation therapy and preoperative chemotherapy with mitomycin C, vinblastine, and cisplatin in patients with technically unresectable stage IIIA and IIIB non-small cell lung cancer. LCSG 881. Chest 106(suppl),348S-354S[Medline]
-
. The Lung Cancer Study Group. (1986) Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 315,1377-1381[Abstract]
-
Stewart, LA, Burdett, S, Souhami, RL (1999) Postoperative radiotherapy (PORT) in non-small cell lung cancer (NSCLC): a meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTS). MRC cancer trials office, Cambridge, UK. University College London Medical School, London, UK [abstract 1760]. Proc Am Soc Clin Oncol 17,457A
-
Yellan, SG, Cella, DF (1995) Someone to live for: social well being, parenthood states, and decision making in oncology. J Clin Oncol 13,1255-1264[Abstract]
-
Crook, A, Duffy, A, Girling, DJ (1997) Survey on the treatment of non-small cell lung cancer in England and Wales [abstract]. Lung Cancer 18(suppl1),9
-
Schaake-Koning, C, Van Den Bogaert, W, Dalesio, O, et al (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326,524-530[Abstract]
-
Martini, N, Kris, MG, Gralla, RJ (1988) The effects of pre-operative chemotherapy on the resectability of non-small cell lung carcinoma with mediastinal node metastases. Ann Thorac Surg 45,370-379[Abstract]
-
Rosell, R, Gomez-Cordina, J, Comps, R, et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330,153-158[Abstract/Free Full Text]
-
Roth, JA, Fossella, F, Kamoki, R, et al (1994) A randomized trial comparing preoperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 86,673-680[Abstract/Free Full Text]
-
Roth, JA, Atkinson, EN, Fossella, F, et al (1998) Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 21,1-6[CrossRef][ISI][Medline]
-
Pass, HI, Pogrebniak, HW, Steinberg, SM, et al (1992) Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 53,992-998[Abstract]
-
Pisters, R, Kris, M, Ginsberg, J, et al (1999) Induction paclitaxel & carboplatin (PC) in early stage non-small cell lung cancer (NSCLC): early results of a completed phase II trial [abstract 1800]. Proc Am Soc Clin Oncol 18,467A
This article has been cited by other articles:
|
|
|
|
 
A. Marra, L. Hillejan, G. Zaboura, T. Fujimoto, D. Greschuchna, and G. Stamatis
Pathologic N1 non-small cell lung cancer: Correlation between pattern of lymphatic spread and prognosis
J. Thorac. Cardiovasc. Surg.,
March 1, 2003;
125(3):
543 - 553.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
