(Chest. 2000;117:110S-118S.)
© 2000
American College of Chest Physicians
Postoperative Adjuvant Therapy for Patients With Resected Non-Small Cell Lung Cancer: Still Controversial After all These Years*
Henry Wagner, Jr, MD
*
From the H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL.
Correspondence to: Henry Wagner, Jr, MD, H. Lee Moffit Cancer Center and Research Institute, 12902 Magnolia Dr, Room 3157, Tampa, FL 33612-9497; e-mail: Decomarj{at}moffitt.usf.edu
 |
Abstract
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Patients with clinical stage I and II non-small cell lung cancer
(NSCLC) generally are considered candidates for surgical resection,
with cure rates as high as 80% reported for some subsets. Locoregional
and systemic adjuvant therapies have been evaluated in patients with
lymph node involvement or pathologic T3 status, although considerable
controversy regarding an appropriate standard of care continues to
exist. Several trials have evaluated postoperative radiation therapy,
the majority of which suggest that overall survival may be only
minimally improved with this adjuvant therapy, but local failure is
probably reduced. Trials evaluating the role of adjuvant chemotherapy
have been few, often enrolling small numbers of patients. Several
recent reviews summarizing the results of these trials suggest that,
although some adjuvant chemotherapy regimens may have biological
activity, results have not been consistent, and further study is
warranted for regimens that include newer chemotherapy agents. CNS
relapse is one of the most common sites of metastasis in NSCLC, and
prophylactic cranial irradiation (PCI) has been evaluated in a number
of trials to reduce the risk of local failure at this site. Data from
these trials strongly suggest that a prospective trial of PCI in
patients with NSCLC at high risk for isolated CNS relapse is warranted.
Future clinical trials evaluating new radiographic, immunologic, and
molecular technologies for early detection of second primary tumors
also should be considered, particularly in patients with resected
T1N0M0 lesions.
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Introduction
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Patients
with clinical stage I and II non-small cell lung cancer (NSCLC) have
classically been considered candidates for primary surgery. Surgical
treatment alone can cure a substantial portion of these patients, as
high as 80% of those with pathologic T1N0 squamous cell
carcinomas.1
Histologic involvement of hilar and/or
mediastinal lymph nodes or pathologic T3 status clearly indicates a
poorer prognosis, with increased risk of both local and systemic
recurrence, and has often been considered an indication for adjuvant
postoperative treatment. While effective adjuvant therapy is clearly
desirable in this setting, there has been considerable controversy as
to whether any currently available therapy given in the postoperative
setting is of sufficient clinical benefit to be considered an
appropriate standard of care. This article will review data of recent
trials, addressing the roles of both locoregional and systemic adjuvant
strategies and suggest strategies for future clinical investigations.
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Postoperative Adjuvant Therapy: General Considerations
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Postoperative adjuvant therapy may be defined as treatment
administered to patients who have undergone surgical removal of all
known disease, but who are considered at risk for recurrence. This
excludes those patients with incomplete resections, microscopically
positive margins, intraoperative tumor spill, and other situations
where there is known, albeit often microscopic and nonevaluable,
residual disease. In the true adjuvant setting, one is treating the
individual patient because of the statistical risk that he or she still
has disease despite an apparent complete resection. Such reasoning
entails the treatment of some individuals who are in fact already cured
and stand to gain nothing from adjuvant treatment.
The rationale for adjuvant therapy (using any modality) hinges on four
propositions:
- Many patients who have undergone "curative" resections
actually have remaining viable tumor cells, either locally,
systemically, or both.
- This residual microscopic tumor will, if no intervention is
taken, grow and, after an interval, lead to clinically detectable
disease.
- Treatment of clinically apparent recurrent disease is rarely
curative. Survival of most patients with recurrence is short and of
impaired quality.
- The effectiveness of most currently available anticancer
treatments, including radiation therapy and cytotoxic chemotherapy, is
inversely related to tumor burden. For any given level of treatment
intensity, small amounts of tumor are more likely to be eradicated than
larger ones.
The arguments have been validated by the development of effective
adjuvant therapy for patients with breast and colorectal cancer, but
the effectiveness of adjuvant therapy has remained controversial in
other common human tumors, such as squamous cell carcinomas of the head
and neck and NSCLC.
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Rates and Patterns of Failure Following Surgical Resection
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Several investigators and cooperative groups have published
careful studies of the follow-up of resected patients that allow us to
distinguish groups of patients at risk for local and/or systemic
failure following primary surgical resection. Several of these series
are summarized in Tables 1
,
2
. It can be seen that both local and distant relapse rates increase with
increasing T and N stages, and that distant failure is more common than
local failure (either alone or as a component) for all stage groups.
Patterns of failure vary to some degree with histologic type, with
adenocarcinomas and large cell undifferentiated carcinomas more likely
to spread distantly than squamous cell carcinomas. Local failure,
however, contributes a substantial portion of the overall failure risk
for patients with N2 nodal involvement.
Several more recent series have attempted to determine in further
detail the effect of the extent of nodal involvement on local control
and survival. Sawyer et al8
reported data on several
hundred patients resected at the Mayo Clinic. On univariate analysis,
they found that both the number of involved N2 nodal stations (single
vs multiple) and involved N2 nodes (single vs multiple) correlated with
4-year survival, although neither correlated significantly with local
control. On multivariate analysis, however, the extent of N2 nodal
involvement was no longer significantly correlated with either of these
outcomes, while the number of involved N1 nodes was highly predictive
of both local control and survival. Patients with involvement of only
inferior mediastinal nodes had better survival than those with inferior
and superior mediastinal involvement, although this did not predict for
local control. The authors noted that the lack of correlation of extent
of N2 involvement on multivariate analysis may have been due in part to
the fact that complete nodal dissections or extensive samplings were
not generally performed, with dissection terminated with the finding of
any degree of N2 involvement.
Andre et al8a
described 702 patients with resected N2
disease and found that two factors were highly predictive of survival.
These included whether N2 involvement was detected clinically by CT
scan in patients with minimal N2 disease (ie, in nodes < 1
cm), and the number of involved N2 levels (single vs multiple). They
did not report in detail on patterns of relapse, but noted that local
or regional relapses were seen in 26% of patients. CNS relapses were
observed frequently in patients with adenocarcinoma or in those who
received neoadjuvant chemotherapy (50% and 49%, respectively).
The significance of extracapsular extension (ECE) in lung cancer is not
well defined. In squamous cell carcinoma of the head and neck, ECE is
highly predictive for local recurrence, while it is not highly
predictive in adenocarcinoma of the breast.9
Unfortunately, the presence or absence of ECE is not routinely reported
by most pathologists, and even in the recent North American Intergroup
(INT 0115) trial, which required reporting of ECE, this information was
not consistently reported (H. Wagner, MD, and L. Martin; personal
communication; 1999). One surgical review indicated a poorer
prognosis for patients with ECE than intranodal disease, but this has
not been well studied in the context of adjuvant mediastinal
irradiation.10
11
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Postoperative Radiation Therapy
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Several older retrospective series claimed that postoperative
irradiation of mediastinal and hilar nodes improved survival in
patients with resected NSCLC, particularly if they had nodal
metastases.12
13
This issue has been investigated in
several prospective trials that, although methodologically flawed,
provide a consensus answer that overall survival is minimally (if at
all) improved, but local failure is probably reduced with such
treatment.
The North American Lung Cancer Study Group (LCSG) conducted a phase III
trial in which patients with resected squamous cell carcinoma of the
lung were randomized between observation and mediastinal irradiation
(50 Gy in 5 weeks).14
Entry was restricted to patients
with squamous histology because of the greater tendency of this
histology to fail locally rather than distantly, compared with
adenocarcinoma and large cell carcinoma. Even for patients with
squamous histology, however, distant failure was the most common path
of failure after an apparent complete resection (Tables 1
, 2)
. The
majority of patients had N1 disease, but smaller proportions had N2 or
T3N0 disease. The results of the trial were striking. Local failure as
a first site of relapse was seen in 20% of patients on the observation
arm, but in only 1% of those randomized to adjuvant nodal irradiation.
Survival, however, was not significantly improved in the study, either
overall or for any subgroup of patients. The LCSG and other trials of
adjuvant postoperative radiation have been criticized for their small
sample size, mixture of N1 and N2 patients, variable compliance with
the assigned treatment regimen, and incomplete patient follow-up by
relying on data on site of first failure. It should be remembered,
however, that these deficiencies did not prevent the demonstration of a
striking effect of radiation therapy (RT) on local control. What was
lacking was not the efficacy of the treatment modality in achieving
local control, but rather the sufficiency of local control alone for
long-term freedom from disease.
The Medical Research Council conducted a randomized comparison of
observation vs postoperative RT in 308 patients with resected
T1–2N1–2 disease.15
The dose was 40 Gy over 3 weeks, and
posterior blocks were allowed to limit the spinal cord dose to 35 Gy.
No overall survival difference was seen between the two arms, but there
was a suggestion of benefit for patients with N2 disease (3-year
survival of 21% in the control arm and 36% with RT). Local recurrence
was only moderately reduced, from 41 to 29%, with the RT technique
used in this study.
Dautzenberg et al16
recently reported the results of a
large multi-institution randomized trial of postoperative RT conducted
by the French Lung Cancer Study and Treatment Group (Groupe d’Etude et
de Traitement des Cancers Bronchiques). Patients with complete
resection were randomized to observation or postoperative RT to the
ipsilateral hilum, mediastinum, and supraclavicular areas. Dose was 40
Gy to the initial fields and an additional 20 Gy to the hilum,
bronchial stump, and mediastinum. Treatment was given with four
fractions of 2.5 Gy/wk or five fractions of 2.0 Gy/wk, according to
local institutional preference. Initially, the trial was limited to a
small number of centers and had rigorous requirements for treatment and
patient follow-up. Because of poor accrual, the study was opened to a
larger number of institutions and data collection requirements were
relaxed.
Thirty percent of entered patients were in stage I, 25% in stage II,
and 45% in stage III. Overall survival, which was the primary end
point of the trial, was significantly decreased for the patients
receiving postoperative RT (p = 0.002). There was no difference in
cancer-related deaths, but a significant excess of intercurrent deaths
was associated with RT (72 vs 24 in the control arm, p = 0.0001).
Furthermore, postoperative RT as delivered in this trial failed to
significantly improve local disease control, although the difference
approached significance for patients with N2 disease. When the excess
complications in the RT arm were examined, they were found to correlate
with the radiation fraction size but not with total dose.
In an editorial discussing this trial, Bonner17
pointed
out that its design predicted its outcome. The use of high radiation
doses, in some cases with larger than usual fractions, for a mixed
group of patients, many of whom were at low risk for local failure,
would not be likely to produce major clinical benefit.
Several other smaller trials have been reported, and their results are
summarized in Table 3
. A common theme of these earlier trials is that while postoperative
mediastinal radiation reduces the rate of local failure, this has not
translated to improved survival. Several factors, both biological and
technical, are likely to contribute to this observation. A survival
benefit for postoperative RT would most readily be seen in those
patients with frequent rates of local failure and relatively less
distant failure. As seen in Tables 1
, 2
, this would exclude N0 patients
and suggest that N2 patients, particularly those with squamous
histology, might show the greatest benefit. The availability of active
systemic adjuvant therapy would modify these considerations.
The technical component comes with the ability to appropriately
restrict the radiation dose to the appropriate targets and minimize
dose to the lungs and heart. This is critical for the limitation of
late treatment-related morbidity and mortality in these patients whose
smoking has already left them with considerable cardiopulmonary
compromise. Two groups have reported data suggesting that the
introduction of more modern treatment planning and delivery techniques
can reduce either observed morbidity and mortality26
or
reduce calculated normal tissue dose and complication
probability27
in patients receiving adjuvant mediastinal
postoperative RT. Such a reduction in the risk of complications might
well shift the therapeutic ratio in favor of postoperative RT, but this
currently remains a hypothesis to be tested.
In 1998, the Postoperative Radiation Therapy (PORT) Meta-Analysis
Trialists Group published a meta-analysis, based on individual data on
22,128 patients from nine randomized trials comparing observation to
postoperative RT in NSCLC.28
They found an overall
worsening of survival with radiotherapy, with a 21% relative increase
in the hazard ratio, which was highly significant (Fig 1
). However, when the hazard function was examined as a function either
of stage (I to III) or nodal status (N0 to N2), it was clear that the
excess risk of death was inversely correlated with stage and nodal
involvement, highest for stage I and N0 patients and no different from
unity for stage III or N2 patients (Fig 2
). They concluded that postoperative RT was detrimental to patients with
early-stage (I-II) completely resected NSCLC, but that its role in
patients with resected N2 disease remained unclear.
The design of this meta-analysis raises a number of cautions about its
interpretation. Techniques of staging, surgical resection (including
choice of lobectomy or pneumonectomy and extent of nodal
sampling), and radiation (including target volume, dose, fractionation,
time from surgery to start of RT, beam energy, and treatment planning
methodology) clearly differed considerably among the nine trials. Seven
of the nine trials included patients treated with cobalt 60
beams, which have poorer dose distributions than higher energy beams
from linear accelerators, and thus give more dose to surrounding normal
tissues. Only one trial used CT for planning, and seven allowed the use
of spinal cord blocks, which typically result in reduction of the dose
to the midline mediastinal structures such as pretracheal and
precarinal nodes. It is thus very questionable that the conclusions of
the trialists (significantly improved control [p = 0.005)] was
outweighed by excessive toxicity in N0 and N1 patients) would
necessarily hold for patients planned and treated using modern
radiotherapy techniques.
The Cancer and Leukemia Group B (CALGB) is currently conducting a
prospective trial of postoperative RT in patients with resected N2
NSCLC (CALGB 9734). All patients receive four cycles of adjuvant
carboplatin plus paclitaxel, and are then randomized to no further
therapy or to RT to the mediastinum (50 Gy in 25 fractions). While this
study addresses the important issue of the role of postoperative RT in
N2 patients, it has several possible methodologic problems. First,
based on current data, it is difficult to justify adjuvant chemotherapy
with this regimen as proven standard therapy. Second, there are few
data on the efficacy of delayed postoperative RT in improving local
control. Unless the chemotherapy is effective in at least suppressing
proliferation of residual microscopic mediastinal disease, the 12-week
delay in starting RT may reduce its efficacy, as has been reported in
other tumor sites, such as breast and head and neck. In this trial, it
will be necessary first to determine whether delayed mediastinal
irradiation improves local control, and then, only if it does, ask
further whether this impacts survival.
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Postoperative Chemotherapy
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The high rates of systemic failure following resection of NSCLC
have long made the development of effective systemic therapy a high
priority in lung cancer. Unfortunately, despite the great need for such
treatment and the frequency of lung cancer, clinical trials of
postoperative adjuvant chemotherapy have been few and often small,
particularly when compared to trials in other diseases, such as breast
cancer.
Several reviews have summarized the state of the art of adjuvant
chemotherapy in resected NSCLC, including both completed trials and
those currently underway.29
30
31
The authors have observed
that, while there have been hints of biological activity of adjuvant
postoperative chemotherapy, there has not been a consistent effect from
trial to trial, either for stage I patients or for those with nodal
metastases. Tables 4
and Table 5
summarize results of the larger trials. Because of this lack
of consensus, the NSCLC Meta-analysis Group conducted a
meta-analysis of all published randomized trials comparing observation
with adjuvant chemotherapy. Although there was no overall benefit seen,
the results were distinctly different by type of chemotherapy regimen.
Older alkylating agent-based regimens worsened survival by 5%,
whereas cisplatin-based regimens gave a 5-year survival improvement
of 5% (Table 6
). While there was considerable heterogeneity of stage, surgical
procedure, and planned as well as delivered chemotherapy, this result
suggested modestly active chemotherapy for metastatic disease could
improve survival in the adjuvant setting, as had been previously
demonstrated in breast and colorectal cancers. It was believed that
differences between the older and newer drug regimens likely reflected
both greater intrinsic activity of the newer drugs, as well as improved
ability to deliver adequate dose-time schedules because of aggressive
and effective supportive care (eg, better antiemetics,
improved management of neutropenia).
In the late 1980s, the clinical cooperative groups in the United States
and Canada planned and activated a large intergroup trial designed to
test the efficacy of postoperative chemotherapy in patients with
completely resected N1 and N2 NSCLC. After extensive discussion of
trial design, a two-arm comparison of postoperative RT with or without
concurrent chemotherapy (cisplatin and etoposide) was adopted. The use
of postoperative RT in both arms was designed to optimize local
control, potentially increasing the ability to detect an effect of
chemotherapy on systemic metastases. It was also believed that a
comparison of two treatment arms rather than treatment vs observation
would be more acceptable to both patients and physicians.
Four hundred eighty-eight patients were entered on this trial, and 368
were found to be fully eligible and evaluable. The difference between
these two numbers largely reflects the number of patients who did not
have adequate nodal sampling or dissection as specified by the
protocol. Specifically, patients were excluded if they had been
registered as N1 without having had adequate sampling of mediastinal
nodes.
The results of this trial, INT 0115 (E3590), were first presented at
the annual meeting of the American Society of Clinical Oncology in
1999.41
There was no difference in survival for the two
arms (Fig 3
). This conclusion held regardless of whether all 488 entered patients
or 368 eligible and evaluable patients were considered. Multivariate
analysis does not show a benefit of the chemotherapy used in this study
(four cycles of cisplatin and etoposide beginning concurrently with the
start of radiotherapy) for any clinical subset of patients. Concurrent
chemoradiation therapy also failed to improve local mediastinal
control, compared to radiotherapy alone. Overall, it was not possible
to show any benefit for adjuvant chemoradiation as delivered in this
study.
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Figure 3. INT 0115 trial: Survival in patients who
received postoperative radiation therapy (RT) with or without
chemotherapy (cisplatin and etoposide). Trt Arm = treatment arm;
Chemo = chemotherapy.
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While much of the variability in recent adjuvant trials is probably due
to the statistical noise inherent in small studies, there may also be
valid biological differences in molecular alterations of specific
tumors. In a trial where there was an overall benefit from adjuvant
tegafur, Takada et al42
demonstrated that there was also
significant improvement for patients with normal p53 function as
assessed by immunohistochemistry (Table 7
). Similarly, in the INT 0115 trial, Schiller et al43
examined the impact of p53 and ras mutations in predicting
effectiveness of adjuvant treatment with postoperative RT and
cisplatin/etoposide to postoperative RT without chemotherapy. They
found that p53 status did not correlate with impact of therapy, but
that recurrence was significantly reduced for patients with wild-type
but not mutant K-ras (Table 8 ). In the future, it may be that these and other predictive markers can
be used to select individualized adjuvant therapy in NSCLC, much as
estrogen and progesterone receptors and HER/2-neu status
have been useful in selecting adjuvant therapy of breast cancer.
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CNS Relapse and Its Prevention
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It has long been recognized that the CNS, chiefly the brain, is a
common metastatic site in NSCLC. This is particularly true for
adenocarcinoma and large cell undifferentiated carcinoma. In small cell
lung cancer (SCLC), where the risk of CNS metastases has long been
recognized, a number of trials and a recent meta-analysis have shown
that prophylactic brain irradiation (PCI) administered to patients in
complete remission following induction therapy can significantly reduce
the risk of brain metastases (by about 50%), as well as produce a
modest but significant improvement in overall survival (5.4% at 3
years).44
While the global risk for brain metastases, particularly isolated brain
metastases, was modest in a review of mostly early stage patients
treated on several LCSG trials,45
several recent trials,
which have used aggressive neoadjuvant therapy plus resection, have
shown much higher rates, ranging from 30 to 40% (Table 9
). This suggests that prophylactic management of brain relapse, if
effective and nontoxic, might improve quality of life and possibly
survival in NSCLC.
Stuschke et al48
recently reported a retrospective
comparison of patients on their neoadjuvant trial who did or did not
receive PCI. Patients had N2 disease and were treated with induction
cisplatin/etoposide for three cycles followed by concurrent accelerated
RT (45 Gy/30 fractions for 3 weeks) during the fourth
chemotherapy cycle. Responding patients then underwent resection.
Because of a high rate of CNS failure seen in the first 28 patients,
subsequent patients received PCI (30 Gy/15 fractions) at the same time
as chest irradiation. PCI reduced the rate of isolated brain relapse as
first site of failure from 30 ± 10% to 8 ± 6% at 4 years, and
decreased the overall incidence of brain metastases from 54 ± 10%
to 13 ± 6%. Both squamous and nonsquamous histology patients were
at risk for brain metastases without PCI and had reduction with PCI.
Several small randomized trials of PCI in patients with NSCLC have been
published (Table 10
). In these trials, the status of intrathoracic disease was not
specified and there was likely uncontrolled disease in the majority.
Although differences in brain relapse rate did not reach statistical
significance in any of these trials, all showed a trend to a lower rate
with PCI.
It has been noted for several decades that long-term survivors of SCLC,
particularly those who have received PCI, may have a variety of
neurologic abnormalities. The frequency of these has varied
tremendously from series to series, in part due to the end point being
reported (significant impairment in everyday activities, abnormalities
of detailed neuropsychiatric testing, or asymptomatic changes on CT
and/or MRI), as well as due to differences in radiation dose, schedule,
and timing relative to chemotherapy. In some series, the rate of
significant impairment has been substantial. The etiology of these
effects is poorly understood. Several studies have reported differences
in pre-PCI neurologic functioning between SCLC patients and age- and
gender-matched control subjects.52
53
More recent
randomized trials evaluating PCI in SCLC complete responders suggest
less neurologic impairment than observed in some earlier trials,
perhaps related to more carefully fractionated radiotherapy, shorter
overall duration of chemotherapy, and avoidance of concurrent
chemotherapy and PCI. However, the number of patients at risk for late
neurotoxicity in these recent trials is low, and further careful
follow-up is required.
These data strongly suggest that the time has come for a prospective
trial of PCI in patients with NSCLC at high risk for isolated CNS
relapse, most likely those with resected N2 disease
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Conclusion
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The role of adjuvant RT for patients with resected early stage
NSCLC remains ill-defined. Several prospective trials have indicated
that mediastinal RT can substantially decrease local relapse rates,
particularly for patients with squamous histology, but that this does
not lead to a measurable improvement in survival. The recent
meta-analysis as well as the large randomized trial reported by
Dautzenberg et al38
have suggested significant survival
detriment for adjuvant mediastinal RT, particularly for patients with
N0 or N1 disease. As discussed above, these series must be interpreted
carefully in light of the substantial heterogeneity in surgical and
radiotherapeutic technique. With excessively toxic RT applied to N0
patients who are at low risk of local recurrence, a survival detriment
is not surprising. It remains to be determined whether postoperative RT
given with modern treatment planning techniques is of benefit for
patients with N2 disease. The current CALGB trial may answer this
question. Unfortunately, no other prospective trials of postoperative
radiotherapy are presently underway.
While a modest survival gain might not have been detectable in the
small trials conducted to date, it is likely that the high frequency of
systemic disease in patients with positive nodes mandates effective
systemic as well as local adjuvant strategies. In patients with high
risk of local failure (multiple positive nodes, extracapsular disease,
known incomplete resection), it is reasonable to offer postoperative
RT. Whether combinations of adjuvant RT and chemotherapy will lead to
improved survival in these patients remains to be studied. While
adjuvant mediastinal irradiation has often been viewed as a routine and
standard technique, it can be associated with significant cardiac and
pulmonary toxicity, and care in treatment planning and delivery is
mandated as much here as in definitive treatment.
Despite the compelling rationale for adjuvant systemic therapy in
patients with resected node-positive NSCLC, it has been difficult to
identify an effective regimen with present agents. While a
meta-analysis of > 1,000 patients showed a survival benefit of about
5% using cisplatin-containing regimens, this was not confirmed in the
large INT 0115 trial examining postoperative RT with or without
cisplatin and etoposide. This and other discrepancies between published
series clearly point to the need for further prospective trials that
include a control arm with no postoperative adjuvant therapy. However,
recent data from several series indicating greater benefit for
preoperative chemotherapy make this the treatment sequence of choice in
patients who can be identified as high risk when treated with surgery
alone.
In patients with locally advanced NSCLC, the incidence of brain
metastases is high, and has increased as local and systemic therapies
have improved. With CNS failure approaching 50% in patients with
resected stage IIIA (N2) in several series, and the limited
effectiveness of treatment for established brain metastases, the
role of PCI in patients with locally advanced NSCLC who have
responded well to initial treatment (good response to chemotherapy
and/or radiotherapy, complete surgical resection) needs to be
investigated prospectively. Our experience with investigation of PCI in
SCLC suggests that these trials should be large enough to detect a
modest but clinically meaningful improvement in survival (on the order
of 5%), and should look carefully at both baseline and post-PCI
neurologic functioning.
Finally, it must be kept in mind that even those patients with the most
favorable NSCLC, those with resected T1N0M0 lesions, are at high risk
for developing second primary lung cancers, on the order of 2 to 3%/yr
for at least 10 years after initial resection.54
This
high-risk group represents an ideal cohort for the investigation of new
radiographic, immunologic, and molecular technologies for early
detection of second primary tumors.55
|
Footnotes
|
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Abbreviations: CALGB = Cancer and Leukemia Group B;
ECE = extracapsular extension; INT 0115 = North American
Intergroup; LCSG = Lung Cancer Study Group; NSCLC = non-small
cell lung cancer; PCI = prophylactic brain irradiation;
PORT = Postoperative Radiation Therapy; RT = radiation therapy;
SCLC = small cell lung cancer
|
References
|
|---|
-
Williams, DE, Pairolero, PC, Davis, CS, et al (1981) Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 82,70-76[Abstract]
-
Wagner, H, Bonomi, P (1995) Preoperative and postoperative therapy for non-small cell lung cancer. Roth, J Ruckdeschel, J Weisenburger, T eds. Thoracic oncology ,147-163 W.B. Saunders Philadelphia, PA.
-
Feld, R, Rubenstein, L, Weisenberger, T, et al (1984) Sites of recurrence in resected stage I non-small-ell lung cancer: a guide for future studies. J Clin Oncol 2,1352-1358[Abstract]
-
Pairolero, P, Williams, D, Bergstralh, M, et al (1984) Post-surgical stage I bronchogenic carcinoma: morbid implications of recurrent disease. Ann Thorac Surg 38,331-338[Abstract]
-
. for the Lung Cancer Study GroupThomas, P, Rubinstein, L (1990) Cancer recurrence after resection: T1N0 non-small cell lung cancer. Ann Thorac Surg 49,242-247[Abstract]
-
Martini, N, Flehinger, B, Nagasaki, F, et al (1983) Prognostic significance of N1 disease in carcinoma of the lung. J Thorac Cardiovasc Surg 86,646-653[Abstract]
-
Martini, N, Flehinger, B (1987) The role of surgery in N2 lung cancer. Surg Clin North Am 67,1037-1049[ISI][Medline]
-
Sawyer, T, Bonner, J, Gould, P, et al (1997) The impact of surgical adjuvant thoracic radiation therapy for patients with nonsmall cell lung carcinoma with ipsilateral mediastinal lymph node involvement. Cancer 80,1399-1408[CrossRef][ISI][Medline]
-
Andre, F, Gronenwald, D, Pignon, JP, et al (1999) Survival of patients with resected N2 Non-small cell lung cancer (NSCLC): heterogeneity of prognosis and evidences for a subclassification. Proc ASCO 18,1802
-
Van Houtte, P, Mornex, F, Rocmans, P (1998) Limites et perspectives de la radiotherapie postoperatoire dans le cancer bronchique. Cancer Radiother 2,252-259[Medline]
-
Emami, B, Kaiser, L, Simpson, J, et al (1997) Postoperative radiation therapy in non-small cell lung cancer. Am J Clin Oncol 20,441-448[CrossRef][ISI][Medline]
-
Larssen, S (1973) Pretreatment classification and staging of bronchogenic carcinoma. Scand J Thorac Cardiovasc Surg 10,1-47
-
Choi, N, Grillo, H, Gardiello, M, et al (1980) Basis of new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int J Radiat Oncol Biol Phys 6,31-35[ISI][Medline]
-
Green, N, Kurohara, S, George, F, et al (1975) Postresection irradiation for primary lung cancer. Radiology 116,405-407[Abstract]
-
. 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]
-
Stephens, R, Girling, D, Bleehen, N, et al (1996) The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1–2, N1–2, M0 disease. Br J Cancer 73,632-639
-
Dautzenberg, B, Arriagada, R, Chammard, A, et al (1999) A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Cancer 86,265-273[CrossRef][ISI][Medline]
-
Bonner, J (1999) The role of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma: seeking to optimize local control and survival while minimizing toxicity. Cancer 86,195-196[CrossRef][ISI][Medline]
-
Patterson, G, Ilves, R, Ginsberg, R, et al (1982) The value of adjuvant radiotherapy in pulmonary and chest wall resection for bronchogenic carcinoma. Ann Thorac Surg 34,692-697[Abstract]
-
Bangma, P (1971) Post-operative radiotherapy. Deely, T eds. Modern radiotherapy: carcinoma of the bronchus ,163-170 Appleton-Century-Crofts New York, NY.
-
Van Houtte, P, Rocmans, P, Smets, P, et al (1980) Postoperative radiation therapy in lung cancer: a controlled trial after resection of curative design. Int J Radiat Oncol Biol 6,983-986[ISI][Medline]
-
Israel L, Bonadonna G, Sylvester R, et al. Controlled study with adjuvant radiotherapy, chemotherapy, immunotherapy, and chemoimmunotherapy in operable squamous carcinoma of the lung. In: Muggia F, Rozencweig, eds. Lung cancer: progress in therapeutic research. New York, NY: Raven Press, 1979
-
Debevec, M, Bitenc, M, Vidmar, S, et al (1996) Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study, 1988–1992. Lung Cancer 14,99-107[CrossRef][ISI][Medline]
-
Mei, W, Xianzhi, G, Weibo, Y, et al (1994) Randomized clinical trial of post-operative irradiation after surgery for non-small cell lung carcinoma. Lung Cancer 10,388
-
Ricci, S, Milani, F, Gramaglia, A, et al (1991) Surgery vs. surgery + radiotherapy in T2N1–2 non-small cell lung carcinoma: an analysis of mean term data [abstract]. Lung Cancer 7,99
-
Lafitte, JJ, Ribet, ME, Prevost, BM, et al (1996) Postresection irradiation for T2N0M0 non-small cell carcinoma: a prospective, randomized study. Ann Thorac Surg 62,830-834[Abstract/Free Full Text]
-
Phlips, P, Rocmans, P, Vanderhoef, P, et al (1993) Postoperative radiotherapy after pneumonectomy: Impact of modern treatment facilities. Int J Radiat Oncol Biol Phys 27,525-529[ISI][Medline]
-
Schraube, P, von Kampen, M, Oetzel, D, et al (1995) The impact of 3-D radiotherapy planning after a pneumonectomy compared to a conventional treatment set-up. Radiother Oncol 37,65-70[CrossRef][ISI][Medline]
-
. PORT Meta-analysis Trialists Group (1998) Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 352,257-263[CrossRef][ISI][Medline]
-
Bonomi, P, Faber, L (1997) Postoperative and preoperative chemotherapy for non-small cell lung cancer. Cancer Control 4,297-306[Medline]
-
Giaccone, G, Manegold, C, Rossel, R, et al (1998) An update on European randomized studies in non-small cell lung cancer. Semin Oncol 4,11-17
-
Le Chevalier, T (1998) Adjuvant chemotherapy in non-small cell lung cancer. Semin Oncol 25,62-65[ISI][Medline]
-
Niiranen, A, Niitamo-Korhonen, S, Kouri, M, et al (1992) Adjuvant chemotherapy after radical surgery for non-small cell lung cancer: a randomized study. J Clin Oncol 10,1927-1932[Abstract]
-
Feld, R, Rubenstin, L, Thomas, P, et al (1993) Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small cell lung cancer. J Natl Cancer Inst 85,299-306[Abstract/Free Full Text]
-
. The Study Group of Adjuvant Chemotherapy for Lung Cancer (1995) A randomized trial of adjuvant postoperative chemotherapy in non-small cell lung cancer (the second cooperative study). Eur J Surg Oncol 21,69-77[CrossRef][Medline]
-
Wada, H, Hitomi, S, Teramatsu, T, et al (1996) Adjuvant chemotherapy after complete resection in non-small cell lung cancer. J Clin Oncol 14,1048-1054[Abstract/Free Full Text]
-
Holmes, E, Gail, M (1986) Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 4,710-715[Abstract/Free Full Text]
-
Figlin, R, Piantadosi, S (1994) A phase 3 randomized trial of immediate combination chemotherapy vs. delayed combination chemotherapy in patients with completely resected Stage II and III non-small cell carcinoma of the lung. Chest 106,310-312
-
Dautzenberg, B, Chastang, C, Arriagada, R, et al (1995) Adjuvant radiotherapy versus combined sequential chemotherapy followed by radiotherapy in the treatment of resected non-small cell lung carcinoma. Cancer 76,779-786[CrossRef][ISI][Medline]
-
Ohta, M, Tsuchiya, R, Shimoyama, M, et al (1993) Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: results of a randomized prospective study. J Thorac Cardiovasc Surg 106,703-708[Abstract]
-
Lad, T (1994) The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or involved highest sampled paratracheal node (Stage IIIA). Chest 106(suppl),302S-306S[Abstract/Free Full Text]
-
Keller, S, Adak, S, Wagner, H, et al (1999) Prospective randomized trial of postoperative adjuvant therapy in patients with completely resected Stages II and IIIA non-small cell lung cancer: an Intergroup trial (E3590) [abstract 1793]. Proc Am Soc Clin Oncol 18,465A
-
Takada, F, Yanagihara, K, Ohtake, Y, et al (1999) p53 status predicts the efficacy of postoperative oral administration of tegafur for completely resected non-small cell lung cancer. Jpn J Clin Oncol 90,432-438
-
Schiller, J, Adak, S, Feins, R, et al (1999) Prognostic significance of p53 and K-RAS mutations in primary resected non-small cell lung cancer: preliminary results from a prospective randomized trial of postoperative adjuvant therapy (Intergroup Trial 0115) [abstract 1789]. Proc Am Soc Clin Oncol 18,464A
-
Auperin, A, Arriagada, R, Pignon, J-P, et al (1999) Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N Engl J Med 341,476-484[Abstract/Free Full Text]
-
Figlin, R, Piantadosi, S, Feld, R, et al (1988) Intracranial recurrence of carcinoma after complete surgical resection of stage I, II and III non-small cell lung cancer. N Engl J Med 318,1300-1305[Abstract]
-
Law, A, Daly, B, Madsen, M, et al (1997) High incidence of isolated brain metastases (CNSMets) following complete response (CR) in advanced non-small cell lung cancer (NSCLC): a new challenge [abstract 248]. Lung Cancer 18,65
-
Eberhardt, W, Wilke, H, Stusschke, M, et al (1997) Preoperative chemotherapy and chemoradiotherapy based on hyperfractionated accelerated radiotherapy followed by surgery in locally advanced (LAD) inoperable NSCLC stages IIIA and IIIB: the value of PCI [abstract 249]. Lung Cancer 18,65
-
Stuschke, M, Eberhardt, W, Pottgen, C, et al (1999) Prophylactic cranial irradiation in locally advanced non-small cell lung cancer after multimodality treatment: long-term follow-up and investigation of late neuropsychologic effects. J Clin Oncol 17,2700-2709[Abstract/Free Full Text]
-
Cox, J, Petrovich, Z, Paig, C, et al (1978) Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung. Cancer 42,1135-1140[CrossRef][ISI][Medline]
-
Russell, A, Pajak, T, Selim, H, et al (1991) Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastases: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21,637-643[ISI][Medline]
-
Umsawadi, T, Valdivieso, M, Chen, T, et al (1984) Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol 2,253-259[Medline]
-
Komaki, R (1993) Neuropsychological functioning of patients with small cell lung cancer prior to and shortly following prophylactic cranial irradiation: evidence for pre-existing cognitive impairments [abstract 1084]. Proc Am Soc Clin Oncol 12,327
-
van Oosterhout, AG, van de Pol, M, ten Velde, GP, et al (1996) Neurologic disorders in 203 consecutive patients with small cell lung cancer: results of a longitudinal study. Cancer 77,1434-1441[CrossRef][ISI][Medline]
-
Martini, N, Bains, M, Burt, M, et al (1995) Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109,120-129[Abstract/Free Full Text]
-
Tockman, M, Erozan, Y, Gupta, P, et al (1994) The early detection of second primary lung cancers by sputum immunostaining. Chest 106(suppl),385S-390S
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Abstract
Introduction
