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The Role of Radiation, With or Without Chemotherapy, in the Management of NSCLC

The Role of Radiation, With or Without Chemotherapy, in the Management of NSCLC

ABSTRACT: Lung cancer is the leading cause of cancer death in the United States. Surgery is the treatment of choice for early stage patients. Despite radical surgery, patients with early stage lung cancer remain at risk for recurrence. The role of adjuvant therapy remains to be clearly defined. Locally advanced non–small-cell lung cancer is too extensive for surgical resection, yet does not show evidence of metastatic disease. Historically, these patients were treated with radiation alone. More recent studies have provided the rationale for combining radiation with chemotherapy for patients with good performance status who have locally advanced disease. For patients with marginally resectable tumors, treatment is often given preoperatively (neoadjuvant) as a means of shrinking the tumor to make it resectable. In patients with clearly unresectable disease, radiation with chemotherapy has been established as better than either modality alone. Palliative radiation alone can be used for patients who cannot tolerate this aggressive approach. The optimal sequencing, as well as the best chemotherapeutic agent to use, remains under investigation. Some of the newer agents showing promise in the treatment of non–small-cell lung cancer include paclitaxel (Taxol) and carboplatin (Paraplatin). Other agents that are currently under investigation include topotecan, gemcitabine, and vinorelbine (Navelbine). [ONCOLOGY 13(Suppl 5):93-100,1999]


Introduction

Lung cancer is the leading cause of cancer
death in the United States. In 1999, it is estimated that 171,600
people will be diagnosed with lung cancer, and 158,900 deaths will be
attributed to this disease.[1] It is important first to distinguish
small-cell lung cancer from non–small-cell cancer, because
small-cell lung cancer is managed primarily with chemotherapy. Non–small-cell
lung cancer, on the other hand, is managed primarily with local
modalities, such as surgery in early stage disease, and radiation,
with or without chemotherapy, in the locally advanced setting.

Because treatment is based on the stage of disease at presentation,
patients should be fully staged with a complete history, physical
examination, computed tomography (CT) scan, and laboratory studies.
Pathologic examinations by bronchoscopy, mediastinoscopy, or anterior
mediastinotomy are important steps in determining resectability.[2]
The American Joint Committee on Cancer and the Union Internationale
Contre le Cancer have adopted the revised staging of lung cancer.[3]
In the revised staging classification, T3, N0 has been moved from
stage IIIA to stage IIB to reflect its better prognosis.[4]

Role of Surgery

Surgery is the treatment of choice for patients with early stage lung
cancer (stages I and II). Some patients who are technically
resectable are medically inoperable due to poor cardiac or pulmonary
reserve; these patients should be treated with radiation alone with
curative intent. Retrospective studies have shown that such patients
can achieve a 5-year survival of 10% to 27%.[5,6] Controversy
surrounds the need for patients with poor pulmonary function and
small peripheral lesions to undergo elective mediastinal
irradiation.[7] We currently use smaller target volumes to deliver
higher doses to the primary tumor alone.

Patients with early stage non–small-cell lung cancer (T1-T2, N0)
who are resected generally do not require further adjuvant therapy.
Randomized studies evaluating postoperative radiation in N0 patients
have shown no benefit.[8] Randomized studies evaluating adjuvant
chemotherapy in stage I patients have also not shown a consistent
benefit. In a randomized study of 110 patients with T1-3, N0
non–small-cell lung cancer, the addition of adjuvant
chemotherapy (cyclophosphamide, doxorubicin, and cisplatin) showed a
slight benefit over surgery alone, with a 5-year survival of 67% vs
56% (P = .05). The randomization process, however, placed more
patients with advanced disease in the surgery-only arm.[9] Despite
radical surgery, patients with early stage non–small-cell lung
cancer are at risk for both distant and local recurrence and may be
considered for trials examining the role of adjuvant chemotherapy or
biologic agents, but there is currently no established role for
adjuvant therapy in this group.

Even among patients with more advanced disease, surgery remains the
treatment of choice for those who are resectable. The role of
adjuvant therapy (radiation alone, chemotherapy alone, or radiation
plus chemotherapy) in this group remains to be clearly defined. If
combined, the best sequencing of these three modalities is still unclear.

Role of Radiation Alone

The role of adjuvant radiation alone was examined in a randomized
study of 210 patients with stage II/III squamous cell carcinoma of
the lung. Following surgery, patients received 50 Gy in 25 fractions
or no further treatment. This study showed a significant decrease in
local recurrence (3% vs 41%, P < .05) in node-positive patients
but no difference in overall survival.[10] This lack of benefit may
have been due to the fact that more than two thirds of first failures
were systemic, not local, and therefore would not be expected to be
changed by adding radiation. It is hard to extrapolate these data to
the treatment of the average non–small-cell lung cancer patient,
because all patients on this study had squamous cell histology and
all were intraoperatively staged. Moreover, given the high incidence
of distant metastasis, it seems logical that concurrent chemotherapy
would be required to see a survival benefit. We are awaiting the
final results of the recently closed intergroup trial, which
randomized patients with resectable stage II/IIIA non–small-cell
lung cancer to postoperative radiation alone or radiation combined
with cisplatin and etoposide. Preliminary analysis does not show a
statistically significant survival advantage for chemoradiotherapy
over radiation alone.[11]

Locally advanced lung cancer is disease that is too extensive for
surgical resection, yet without any evidence of distant metastasis.
Previously, these patients were treated with radiation alone. In an
early study by the Radiation Therapy Oncology Group (RTOG), patients
were randomized to 40-Gy split-course radiation, or 40-, 50-, or
60-Gy continuous-course radiation. Patients who received 60 Gy had a
higher response rate, better local control, and improved 3-year
survival.[12] This study provided the basis for our current standard
of 60 Gy.

Radiation Plus Chemotherapy

Although radiation alone was previously considered the standard of
care for unresectable non–small-cell lung cancer, several
randomized studies[13-18] and meta-analyses[19-21] have provided the
rationale for the current American Society of Clinical Oncology
(ASCO) recommendations for combined-modality therapy using radiation
with chemotherapy for patients with good performance status who have
locally advanced disease.[22] The optimal sequencing of these
modalities, however, remains to be determined. Chemotherapy, with or
without radiation, may be used preoperatively (neoadjuvant) as a
means of shrinking marginally resectable disease, postoperatively to
decrease the risk of local and distant recurrence, or as primary
therapy for unresectable disease.

N2 disease can be divided into that which (1) is not visible by
preoperative CT scans and found only at the time of mediastinoscopy
or pathologic evaluation of resected specimens, (2) has multiple
levels of nodal involvement easily seen on preoperative staging
studies, or (3) has bulky mediastinal nodes. N2 disease not visible
by preoperative evaluation is best suited for postoperative
radiation, with or without chemotherapy, whereas nodal disease easily
seen by preoperative staging evaluation is best treated with
neoadjuvant, combined-modality therapy followed by surgery, when
possible. Bulky mediastinal disease may be best suited for primary
therapy with chemotherapy and radiation.

Neoadjuvant Combined-Modality Therapy

There have been several phase II studies suggesting the value of
neoadjuvant therapy. Early randomized studies have established that
radiation alone as neoadjuvant therapy is inadequate.[23] Radiation
can be added to neoadjuvant chemotherapy either concurrently or
sequentially. Advantages to concurrent chemotherapy and radiation
include the potential for synergy between the two modalities.
Sequential treatment, on the other hand, may be better tolerated, and
both modalities can be given to their fullest extent.

Southwest Oncology Group (SWOG) 8805 was a phase II trial that
enrolled 126 patients to receive induction chemotherapy with two
cycles of cisplatin and etoposide and concurrent radiation to 45 Gy,
followed by resection if response occurred or disease stabilized.
Objective response to induction therapy occurred in 59% of patients;
29% had stable disease. The 3-year survival rate was 26%.[24]

Encouraging phase II studies led to the development of phase III
studies examining the role of neoadjuvant chemotherapy (with or
without radiation) in patients with potentially resectable
non–small-cell lung cancer. Three randomized studies, summarized
in Table 1, showed significant
improvement in survival and distant recurrence favoring the induction
chemotherapy arm.[25-27]

In patients with unresectable non–small-cell lung cancer,
radiation alone was previously considered the standard of care.
Unfortunately, older series examining the role of radiation have not
always found a survival advantage. In a multi-institutional trial
randomizing patients with unresectable non–small-cell lung
cancer to chemotherapy alone (vindesine 3 mg/m²/week), standard
radiation (60 Gy), or radiation and vindesine, the median survival
and overall survival were comparable in all three arms.[28]

These poor results with radiation alone have led to the development
of combined-modality treatments using chemotherapy and radiation with
more effective systemic therapy, as well as agents that have the
potential for radiosensitization. Randomized studies evaluating
sequential chemotherapy and radiation in patients with unresectable
non–small-cell lung cancer are summarized in
Table 2
. Cancer and Leukemia Group B (CALGB) 8433 randomized
unresectable stage III patients to radiation alone or two cycles of
cisplatin/vinblastine followed by radiation. The radiation consisted
of 60 Gy in 2-Gy fractions. The response rate for the
combined-modality arm was 56%, vs 43% for patients receiving
radiation alone. The combined-modality arm had a significantly
improved median survival (13.8 vs 9.7 months, P = .0066) over
radiation alone.[13] The long-term follow-up shows that 5-year
survival remains superior for the combined-modality arm (17% vs
6%).[14] Although more toxicities were anticipated in the
combined-modality arm, the incidence of esophagitis and pneumonitis
was approximately the same in both arms. Severe infections, however,
occurred more frequently in patients receiving combined-modality
therapy (7% vs 3%).

A second randomized study of sequential chemotherapy and radiation,
RTOG 8808/Eastern Cooperative Oncology Group (ECOG) 4588, also showed
an improvement in median survival (13.8 vs 11.4 months, P = .03) for
combined-modality therapy over either standard fractionation
radiation alone or hyperfractionated radiation alone. The radiation
in the standard fractionation arm consisted of 60 Gy (2-Gy fractions,
5 days/week) over 6 weeks. The hyperfractionated regimen was 69.6 Gy
(1.2 Gy/fraction, twice daily) over 4 weeks. The combined-modality
arm received the same radiation as the standard fractionation arm but
treatment was preceded by induction chemotherapy, consisting of
cisplatin (100 mg/m²) on days 1 and 29 and 5 mg/m²
vinblastine every week for 5 weeks. Radiation began on day 50. The
1-year survival was statistically better for the combined-modality
arm (60%, P = .03) over radiation alone given as standard
fractionation (46%) or hyperfractionation (51%). The median survival
was also improved on the combined-modality arm (13.8 months) over
both arms receiving radiation alone.[15] In the 5-year update of this
study, the 5-year survival remains significantly improved for
induction chemotherapy followed by radiation (8%, P = .04) over
standard fractionation radiation (5%) or hyperfractionated radiation (6%).[29]

The third large randomized study of sequential chemotherapy and
radiation also showed an advantage to induction chemotherapy prior to
radiation. The radiation was 65 Gy, and the induction chemotherapy
included vindesine, cyclophosphamide, cisplatin, and lomustine. The
2-year survival was significantly improved on the combined-modality
arm (21% vs 14%, P = .08). There was also a significant improvement
in the rate of distant metastases in the patients receiving chemotherapy.[16]

In locally advanced lung cancer, as in the neoadjuvant setting,
concurrent chemotherapy and radiation has the added advantage of
providing synergy between the two treatment modalities.
Unfortunately, one can also anticipate an increase in toxicities. Table
3
summarizes randomized studies of concurrent chemotherapy and
radiation for locally advanced non–small-cell lung cancer. The
European Organization for Research and Treatment of Cancer (EORTC)
trial evaluating cisplatin and radiation with weekly low-dose
cisplatin (30 mg/m²/week) or radiotherapy with daily
very-low-dose cisplatin (6 mg/m²/day) showed a significant
improvement in 2-year survival (P = .009) with daily low-dose
cisplatin (26%) over radiation alone (13%). Patterns of failure
showed that this was primarily due to an improvement in local control
in patients who received combined-modality therapy.[17]

A second randomized study examined the value of concurrent
chemotherapy (carboplatin, etoposide) and hyperfractionated radiation
to hyperfractionated radiation alone. The median survival was
improved with combined-modality therapy (22 mo vs 14 mo, P = .021).
Interestingly, the two groups experienced similar incidence of acute
and late high-grade toxicity.[18]

Despite some controversy, several meta-analyses[20-21] have confirmed
the value of chemotherapy plus radiation over radiation alone. In one
meta-analysis using data from published reports, there was a 30%
reduction in mortality at 2 years (odds ratio = .70) with
platinum-based chemotherapy, compared to an 18% reduction in
mortality at 2 years (odds ratio = .82) for non–platinum-based
chemotherapy and radiation.[21] A separate meta-analysis using
individual patient data from 52 randomized clinical studies showed an
absolute survival benefit of 4% at 2 years with platinum-based
chemotherapy over radiation alone.[19] These results have prompted
ASCO, as well as the Ontario Lung Cancer Disease Site Group, to
recommend combined-modality therapy as standard of care for good
performance patients with locally advanced non–small-cell lung
cancer.[22,30] Palliative radiation alone can be used for patients
who cannot tolerate this aggressive approach.

A meta-analysis using data from 14 randomized trials and 2,589
patients found that the addition of chemotherapy to radiation reduced
the risk of death at 2 years (relative risk 0.87, confidence interval
0.81 to 0.94). This corresponded to a mean gain in life expectancy of
2 months.[20] Although there is a small benefit with the addition of
chemotherapy to radiation, this must be balanced against the
increased toxicity of combined-modality treatment. Therefore, the use
of combined-modality therapy remains under investigation for locally
advanced non–small-cell lung cancer.

A retrospective analysis using data on 461 patients from five
completed RTOG trials found that the overall response rate was
significantly worse in patients who had received sequential
chemotherapy and radiation over those who had received concurrent
chemotherapy plus either standard or hyperfractionated radiation. The
3-year survival was better in the concurrent chemotherapy and
hyperfractionated radiation arm compared to either sequential or
concurrent chemotherapy with standard radiation. Nonhematologic
toxicities were significantly worse in the concurrent chemotherapy
with hyperfractionated radiation arm compared to either sequential or
concurrent chemotherapy with standard radiation (Table
4
).[31]

A single study, reported thus far only in abstract form, has directly
compared sequential to concurrent chemotherapy plus radiation and
found concurrent therapy to be superior in terms of overall response
rate (84% vs 66%, P < .05) and median survival (16.5 vs 13.3
months, P = .05, log-rank).[32] However, the optimal sequencing of
radiation with chemotherapy for locally advanced non–small-cell
lung cancer is still under investigation. The recently closed trial,
RTOG 9410, which is summarized in Table
5
, should answer some of these questions.[33]

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