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Role of multimodality treatment for lung cancer

Seminars in Surgical Oncology 2000; 18:143–151
Role of Multimodality Treatment for
Lung Cancer
RAFAEL ROSELL, MD,1* AND ENRIQUETA FELIP, MD2
1Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
2Hospital Vall d’Hebron, Barcelona, Spain
Locally advanced non-small cell lung cancer (NSCLC) is, in fact, a systemic disease requir-
ing a multimodality approach for optimal treatment. The role of preoperative chemotherapy
has been established and is now an accepted treatment for resectable Stage IIIA NSCLC.
Several studies have addressed the feasibility and efficacy of preoperative chemotherapy
followed by surgery. All these induction chemotherapy trials have reported a high radio-
graphic response rate, high respectability rate and improved survival in completely resected
patients. The findings of three published randomized trials indicate that the survival rate of
Stage IIIA patients is better with induction chemotherapy plus surgical resection than with
resection alone. More recently, Phase II trials using concurrent chemoradiotherapy have
been tested with encouraging results. Chemo-therapy combined with thoracic radiotherapy
has emerged as a primary treatment option for locally advanced, unresectable NSCLC. Ran-
domized trials and subsequent meta-analyses have shown a clear survival benefit with plati-
num-based combination chemotherapy administered with thoracic radiation—as compared
to radiation alone—in treating inoperable Stage IIIA and IIIB lung cancer. Combined mo-
dality treatment in locally advanced NSCLC continues to evolve and is the subject of ongo-
ing research. Despite clinical advances, many aspects of the management of these patients
are yet to be fully clarified: Is surgical resection really necessary for Stage IIIA patients?
What is the value of altered-fractionation radiotherapy and three-dimensional conformal
radiation therapy? What is the optimal sequencing of radiotherapy and chemotherapy? In
this regard, new chemotherapeutic agents may provide additional benefits in the multimodality
approach, and it is for this reason that various studies are underway which have incorporated
new agents in the front line setting. Finally, a better understanding of the biology of tumors
could well help us to optimize treatments. In the future, molecular classification of NSCLC
may provide a useful tool when making therapy-related decisions. Semin. Surg. Oncol.
18:143–151, 2000.

KEY WORDS: lung neoplasms; non-small cell lung carcinoma; combined modality therapy;
neoplasm staging; neoplasm DNA; combined antineoplastic agents; adjuvant
chemotherapy; adjuvant radiotherapy; neoadjuvant therapy; radiation
dosage; dose fractionation; drug administration schedule; radiation dose-
response relationship; prognosis; p53 gene; clinical trials; survival rate

INTRODUCTION
able Stage III disease show a survival advantage for pa- Approximately 25% to 35% of non-small-cell lung can- tients receiving preoperative chemotherapy. Furthermore, cer (NSCLC) patients present with Stage III disease, de- in locally advanced unresectable Stage III patients with a fined as locally advanced tumor confined to the chest good performance status and minimal weight loss, com- without distant metastasis. The impact of surgery or radio- bined chemotherapy and thoracic radiation has emerged therapy alone in locally advanced NSCLC has been mini- mal, with published studies showing 5-year survival rate<10%. Combined modality therapy employing systemic *Correspondence to: Rafael Rosell, MD, Medical Oncology Service, and local approaches has achieved favorable results in pa- Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, tients with locally advanced NSCLC. Studies in resect- Barcelona, Spain. E-mail: rrosell@ns.hugtip.scs.es 2000 Wiley-Liss, Inc.
Rosell and Felip
INDUCTION CHEMOTHERAPY WITH OR
TABLE I. Phase II Preoperative Chemotherapy Studies
WITHOUT RADIOTHERAPY FOLLOWED BY
SURGERY IN RESECTABLE STAGE III NSCLC
Surgical resection alone in Stage IIIAN2 NSCLC is as- sociated with poor outcome [1–3]. There are selected sur- gical series for patients with N2 disease which suggest that 20% of patients are cured. It is important to stress that thesepatients are highly selected and do not represent the usual pCR, pathologic complete response; MSKCC, Memorial Sloan-KetteringCancer Center; CALBG, Cancer and Leukemia Study Group B.
patients with clinical N2 disease. What these series do in-dicate is that in patients with microscopic N2 disease, sur- free interval for the neoadjuvant chemotherapy group were gery and radiation can achieve a 20% cure rate. In those 28.7 months and 12.7 months, respectively, vs. 15.6 months patients with bulky ipsilateral mediastinal lymph nodes and 5.8 months for the control arm; the differences be- visible on a computed tomography (CT) imaging of the tween treatment groups, however, were not statistically chest, only 18% complete resection has been achieved with significant. The M.D. Anderson Cancer Center [10] and a 9% 3-year survival despite complete surgical removal our Spanish Lung Cancer Group (SLCG)[11] randomized [3]. By itself, thoracic radiotherapy provides local control trials are similar in design. Both studies show a statisti- and effective palliation of tumor-related symptoms but has cally significant improvement in survival for those patients minimal impact on the survival of these patients [4]. The who received pre-operative chemotherapy. These trials majority of patients with Stage IIIA NSCLC require have established induction chemotherapy followed by sur- multimodality therapy if they are to achieve a 5-year sur- gery as one reasonable means of treating Stage IIIA vival [5]. There are several reasons for using systemic NSCLC. The M.D. Anderson investigators have recently therapy prior to resection. First, preoperative chemotherapy updated the long-term follow-up of their patients [12]. The provides the earliest opportunity to treat any widespread increase in survival conferred by peri-operative chemo- micrometastatic subclinical disease. Second, the response therapy was maintained during the extended observation rate to chemotherapy in patients with locally advanced dis- period. The overall 3- and 5-year survival rates for the peri- ease is approximately twice as high as that in patients with operative chemotherapy group were 43% and 36%, respec- Stage IV disease. The use of chemotherapy at this point tively. The overall 3- and 5-year survival in our might enable resection of some lesions that initially were preresectional chemotherapy arm [13] was close to the 28% considered unresectable, and it provides the opportunity reported by the MSKCC group and agrees with the results to sterilize mediastinal lymph node metastases.
of the M.D. Anderson trial (Table II).
In the past 15 years, many Phase II trials have investi- Several Phase II trials have analyzed the use of preop- gated the use of pre-operative chemotherapy as part of the erative chemoradiotherapy as an induction protocol. Con- treatment plan for Stage IIIA patients. Preoperative che- current chemotherapy and radiation has the theoretical motherapy studies, as exemplified by the Memorial Sloan- advantage of synergy between modalities and minimal Kettering Cancer Center (MSKCC) [6] and Toronto [7] delay in the introduction of either [14]. This approach mitomycin, vinblastine, and cisplatin (MVP) trials, have emphasizes both the importance of local control as well as demonstrated what appear to be improved median survival distant metastatic control in the cure of patients with Stage time and prolonged 5-year survival as compared to his- III disease. The pre-operative dose of radiation is rarely torical controls. More recently, the Cancer and Leukemia greater than 45 Gy in order to avoid unacceptable surgical Group B (CALGB) tested pre- and postoperative chemo- morbidity. Median survival with induction chemo- therapy with two cycles of vinblastine/cisplatin before sur- radiotherapy ranges from 13 to 25 months. Survival at 5 gery and two more cycles of the same chemotherapy after years ranges from 18% to 37%. While this 5-year survival surgery [8]. The results from the MSKCC, Toronto, and rate may appear higher than the induction chemotherapy CALGB studies are remarkably similar. Each enrolled only strategy, much of the difference may be explained by more N2 patients. Response rate to induction chemotherapy stringent patient selection. In the Southwest Oncology ranged from 65% to 77%. Median survival ranged from Group (SWOG) study (protocol 8805) reported by Albain 15.5 months to 19 months, and 5-year survival was re- et al., Stage IIIA and IIIB NSCLC patients received two markably consistent at 17% to 19% (Table I).
cycles of pre-operative cisplatin/etoposide and concurrent There are three randomized Phase III trials indicating thoracic radiotherapy (45 Gy) [15]. This trimodality therapy that neoadjuvant therapy in Stage IIIA disease improves was feasible and achieved an encouraging 26% 3-year sur- survival. In 1992, Pass et al. published a small random- vival rate—and a recently reported 20% 6-year survival ized study of 27 patients with NSCLC and histologically rate—with no differences found between bulky IIIAN2 and confirmed N2 disease [9]. Median survival and disease- IIIB stages [16]. In this study, almost 50% of T4N0-1 pa- Multimodality Treatment for Lung Cancer
TABLE II. Radomized Trials of Induction Chemotherapy Plus Surgery as Compared to Surgery Alone in Stage IIIA Non-Small-Cell
Lung Cancer

EP, etoposide/cisplatin; MIC, mitomycin/ifosfamide/cisplatin; CEP, cyclophosphamide/etoposide/cisplatin tients with stable disease who were resected survived after can be used to evaluate the likelihood of new approaches achieving this aim. These include resection rate, tumor Recent trials have attempted novel fractionation schemes downstaging by elimination of mediastinal lymph node combined with concurrent cisplatin chemotherapy to fur- disease, and improvement in pathologic complete response ther enhance response rates and optimize resection rates rate. Several reports of induction chemotherapy or com- and local control. Choi et al. from the Massachusetts Gen- bined chemoradiation therapy have highlighted an im- eral Hospital employed preoperative twice-daily (BID) proved survival in patients with complete resection. In the radiation therapy and two cycles of concurrent cisplatin/ CALGB 8935 study, those patients who attained complete vinblastine/fluorouracil in Stage IIIAN2 and IIIB NSCLC resection had a 3-year survival rate of 46%, whereas this patients [17]. They reported 84% complete resection, 67% number fell to 25% for those with incomplete resection histopathologic tumor downstaging, and a 5-year survival and to 0% in unresectable tumors [8]. This point has also rate of 37%. Eberhardt et al. carried out an interesting study been confirmed in the MSKCC trial in which completely in which 94 Stage IIIA and IIIB patients received four resected patients had a 41% 3-year survival rate in con- cycles of preoperative cisplatin/etoposide: three cycles trast with 5% for the remainder [6]. In the Eberhardt et al.
before radiation therapy and a fourth cycle combined with study, complete resection was achieved in 53% of patients BID radiation (45 Gy, 1.5 Gy/F, BID in 3 weeks) [18].
included [18]. Patients with complete resection had a me- Complete resection was obtained in 53% of patients, 60% dian survival of 42 months, with 3-and 4-year survival rates of Stage IIIA and 45% of Stage IIIB groups. The median survival time and 4-year survival rates were 20 months Data from the Massachusetts General Hospital study and 31% for Stage IIIA, and 18 months and 26% for Stage point to the relevance of downstaging as a useful surro- IIIB patients, respectively. Recently, Thomas et al. exam- gate for 5-year survival [17]. Twenty-eight of the 42 pa- ined preoperative chemotherapy (two cycles of ifosfamide/ tients with mediastinoscopically-confirmed N2 disease carboplatin/etoposide) with subsequent chemoradiotherapy treated with preoperative chemotherapy and concomitant (carboplatin/vindesine with concurrent 45 Gy, 1.5 Gy/F, radiation therapy were downstaged. In those patients in BID) and then surgery in patients with Stages IIIA and whom N2 disease persisted, the risk of death was fivefold IIIB NSCLC [19]. Median survival (Stage IIIA, 25 months; greater than in downstaged patients. A favorable effect of Stage IIIB, 17 months) compares favorably with other stud- downstaging was also seen in the SWOG study (protocol ies in which Stage III patients received conventionally frac- 8805), in which the 3-year survival rate was 41% in pa- tionated preoperative chemoradiotherapy (Table III).
tients with mediastinal lymph nodes sterilized by treatment,but only 11% in those whose nodes were still positive at Predictors of Survival
The main goal of pre-operative therapy is to prolong Pre-operative chemotherapy studies suggest the impor- survival. However, there are useful surrogate markers that tance of attaining pathologic complete response as a use- TABLE III. Pre-operative Chemoradiotherapy Phase II Studies
Rosell and Felip
ful surrogate for long-term survival. In the MSKCC [6] Fleck et al. conducted a Phase III randomized clinical trial and Toronto [7] studies, impressive 5-year survival rates (presented only as an abstract) in which pre-operative con- (61% and 66%, respectively) have been observed in those current chemoradiotherapy was compared with pre-opera- patients who achieved pathologic complete response after tive chemotherapy alone in patients with Stage IIIAN2 and induction chemotherapy (14% of patients in the MSKCC IIIB NSCLC [21]. The pre-operative chemoradiotherapy con- study and 8% of patients in the Toronto). In our previous sisted of two cycles of cisplatin/fluorouracil and 30 Gy of SLCG neoadjuvant trial, pre-operative moderate-dose concurrent radiation with an additional 30 Gy postoperatively cisplatin (50 mg/m2) was employed in combination with for patients with residual disease. Patients in the pre-opera- ifosfamide and mitomycin (MIC), and only 3% of patients tive chemotherapy-alone arm received three cycles of achieved pathologic complete response [11]. In the CALGB cisplatin/mitomycin/vinblastine before surgery and three study, no pathologic complete response was found in any additional cycles of cisplatin/etoposide postoperatively for of the 46 resected tumors [8]. Using concomitant patients with residual disease. The pre-operative chemo- chemoradiation, pathologic complete response was ob- radiation arm resulted in a significantly improved response served in 9.5% of patients in the Choi study [17], and in rate, complete resection rate and rate of freedom from progres- 26% of patients in the Eberhardt study [18].
sion. The German Lung Cancer Cooperative Group has starteda prospective Phase III study that compares pre-operative che- UNCLARIFIED POINTS IN STAGE IIIA
motherapy followed by BID chemoradiation and then sur- NSCLC TREATMENT
gery with preoperative chemotherapy alone followed by The Role of Surgery in Stage IIIA Patients
surgery and then radiotherapy [22]. The trial will be contin- At present, surgery is an important part of multimodal ued until 350 patients have been randomized.
treatment in Stage IIIA NSCLC since it is still the main cura-tive therapeutic approach and remains an effective means to New Drugs in the Neoadjuvant Setting
help control local-regional tumor. Furthermore, in several Although impressive initial results are often achieved with studies of induction chemotherapy, complete resection has pre-operative chemotherapy or concomitant chemoradio- had a major impact on median and long-term survival. How- therapy, the majority of patients eventually relapse. Two- ever, there are ongoing trials studying whether surgery im- thirds of the relapses are systemic. Clearly, more effective proves long-term results in this population. In a randomized chemotherapy combinations should be sought to improve trial currently initiated in North America (Intergroup 0139 results [23]. In advanced or metastatic NSCLC, the Eastern trial), concurrent radiotherapy and cisplatin plus etoposide Cooperative Oncology Group (ECOG) study showed that induction is followed by randomization to surgery or con- paclitaxel/cisplatin was better than etoposide/cisplatin in tinuation of radiotherapy up to 61 Gy. Since March 1995, terms of response rate, time to progression and survival [24].
280 patients have been accrued, and the first interim analy- The SLCG has recently reported that, gemcitabine/cisplatin sis will be conducted when 250 have completed the speci- yielded a 41% objective response rate in 69 patients in con- fied period of follow-up. It appears from preliminary data trast with only 22% in 66 etoposide/cisplatin treated patients that compliance was good and treatment has been well tol- (P = 0.002) [25]. Differences also surfaced on time to pro- erated. The European Organization for Research and Treat- gression (6.9 months vs. 4.6 months, P < 0.001 by logrank ment of Cancer (EORTC) study 08941 compares the effect test). One focus for future research is to integrate new ac- of surgery vs. radiotherapy on the outcome of Stage IIIAN2 tive agents into the neoadjuvant setting. In Stage IIIAN2 patients who responded after three cycles of induction che- NSCLC, preliminary data from the EORTC group show a motherapy [20]. The choice of chemotherapy in this ongo- 77.5% objective response rate with gemcitabine/cisplatin ing study is being left to the investigator.
[26]. Betticher et al. analyzed preoperative docetaxel/cisplatin combination in Stage IIIAN2 NSCLC and reported Pre-operative Strategies
a 66% response rate with very low toxicity [27].
An optimal preoperative strategy is yet to be established.
If we compare results in patients receiving induction Uses of Molecular Markers to Select Patients
chemoradiotherapy with those receiving induction chemo- and Therapies
therapy alone, differences in the downgrading rates (60% Molecular recognition of micrometastases in the serum to 70% with pre-operative chemoradiation vs. 30% with tumor DNA of NSCLC patients may help to identify pa- chemotherapy alone) and differences in pathologic com- tients at highest risk of relapse. Rosell et al. investigated plete responses (up to 20% with pre-operative chemo- aberrant methylation, a mechanism of inactivating tumor radiation vs. less than 10% with chemotherapy alone) seem suppressor genes, in 22 patients with resected NSCLC not to correlate with differences in complete resection rates [28,29]. At least one of the following genes: p16, DAP (53% vs. 60%). Therefore, the addition of radiotherapy to kinase, GSTP1, or MGTMT was found in 68% of NSCLC pre-operative programs deserves further evaluation.
tumors. In 73% of positive primary tumors, the same ab- Multimodality Treatment for Lung Cancer
normal methylation pattern was also found in matched se- pared with 6% in the radiotherapy-alone arm [34]. Le rum samples. Since patients had been completely resected, Chevalier et al. also demonstrated a 2-month increase in this finding must indicate the presence of residual disease the median survival rate and a 7% improvement in the 2- or micrometastases. Knowledge about these genetic alter- year survival rate after combined chemoradiation in a large ations could have prognostic importance and may identify group of patients with unresectable squamous cell and large the patients who should receive the most aggressive sub- cell carcinomas [35]. The Intergroup trial conducted by sequent treatment. In order to plan future approaches the the Radiation Therapy Oncology Group (RTOG) and molecular blueprint of lung cancer should be identified.
ECOG found similar magnitudes of benefit [36] (Table IV).
Monzó et al. have identified beta-tubulin missense muta- In unresectable NSCLC patients, the investigators com- tions in 33% of NSCLC patients and none of the patients pared the following regimens: 1) radiotherapy (60 Gy); 2) with mutations had an objective response to paclitaxel treat- induction chemotherapy (vinblastine/cisplatin) followed by ment [30]. Tubulin mutations may be a novel mechanism radiotherapy (60 Gy); and 3) BID radiotherapy (69.9 Gy).
of resistance to anti-tubulin drugs in NSCLC and somatic They observed improved 1-year survival rates and median mutations of beta-tubulin could help in customizing treat- survival duration for the induction chemotherapy arm, re- ment. Future trials are planned to validate beta-tubulin as porting 60% and 13.8 months for combined therapy; 46% a prognostic marker of response in NSCLC.
and 11.4 months for radiotherapy alone; and 51% and 12.3months for the hyperfractionated radiotherapy arm. Al- Neoadjuvant Chemotherapy in Stage I-II NSCLC
though the preliminary analysis did not show any advan- One focus for research is the earlier stages of disease, in tage of hyperfractionated radiotherapy over the standard which induction chemotherapy may also have a role. Ini- fractionation radiotherapy, after a longer follow-up time, tial efforts have been made by the Bimodality Lung On- the data suggest that the hyperfractionated radiotherapy cology Team. In a multicenter, Phase II trial in 94 patients arm would have a better 3-year survival rate [37]. It should with T2N0, T1-2N1, and T3N0-1 NSCLC and a negative be pointed out that the CALGB trial and the confirmatory mediastinoscopy, treatment consisted of induction chemo- RTOG/ECOG trial accrued only a selected subset of therapy with paclitaxel/carboplatin for two cycles followed NSCLC patients with excellent performance status, mini- by surgery and then three additional cycles of chemo- mum weight loss, and no scalene or supraclavicular node therapy [31]. Major responses occurred in 56% and 84% involvement. Two meta-analyses that looked at all of the of patients were completely resected. No increased or un- randomized studies have confirmed the impact of chemo- expected toxicity or surgical morbidity have been observed.
therapy in the Stage III disease treatment setting [38,39].
In this study, only 38% of patients completed postopera- Although the degree of improvement was modest, it was tive chemotherapy. In a recently presented study, Depierre statistically significant and definitely altered the natural et al. suggested that neoadjuvant chemotherapy could im- history of this disease. However, local and distant failures prove survival in Stage I-II NSCLC [32]. The SLCG has still occurred in the majority of patients.
designed a Phase III trial of neoadjuvant chemotherapy Concomitant chemoradiotherapy offers an alternative vs. adjuvant (paclitaxel/carboplatin) vs. surgery alone for strategy for combined therapy. Conflicting data have been Stages I-II NSCLC patients. Sub-analyses of several ge- derived from randomized trials involving patients with netic abnormalities are to be performed in this trial.
COMBINED-MODALITY THERAPY IN
TABLE IV. Randomized Trials of Combined Modality Therapy
in Advanced Unresectable Non-Small Cell Lung Cancer

LOCALLY ADVANCED UNRESECTABLE NSCLC
Chemotherapy improves survival when added to radio- therapy for patients with unresectable Stage III NSCLC.
The first randomized trial to show a survival advantage of combined chemoradiation therapy was reported by the CALGB (protocol 8433) [33]. Response was observed in 56% of patients who received two cycles of vinblastine/ cisplatin given before 60 Gy of radiation and in 43% of patients who received radiation alone. The median survival duration for the combined chemoradiotherapy arm was 13.8 RTOG/ECOG trial included a comparative radiotherapy-only arm us- months as compared to 9.7 months for the standard radio- ing hyperfractionated radiotherapy (69.6 Gy delivered at 1.2 Gy per therapy arm (P = 0.007). Five-year survival rate was also fraction twice daily); 3-year survival for the hyperfractionated radio-therapy arm was 14% (P = 0.07 vs. standard radiotherapy).
longer in the combined chemoradiation therapy group (i.e., CT, chemotherapy; RT, radiotherapy; RTOG, Radiation Therapy On- 19% vs. 7%). Recently, Dillman et al. reported the 7-year cology Group; ECOG, Eastern Cooperative Oncology Group; CALBG, survival of the combined modality arm as 13% as com- Rosell and Felip
unresectable Stage III NSCLC. Several studies have failed cal trials. It appears that improvement in the patterns of to demonstrate a significant survival benefit with concomi- subsequent disease progression was different between se- tant chemoradiotherapy using single-agent cisplatin. Soresi quential and concurrent strategies. In the sequential-regi- et al. found no improvement in either median or progres- mens trials, a delay or decrease in the development of sion-free survival when weekly cisplatin (15 mg/m2) was subsequent distant metastases was noted in the combined added to radiation (50 Gy) in patients with unresectable modality treatment arm as compared with radiotherapy NSCLC [40]. Similarly, Trovo et al. observed no differ- alone, whereas enhanced control of intrathoracic tumor ences in patterns of relapse or median survival when a daily burden was noted using concurrent combined modality low dose of cisplatin (6 mg/m2) was added to radiotherapy therapy as compared with radiotherapy alone. In many (45 Gy) [41]. In a three-arm randomized trial conducted sequential-therapy regimens, chemotherapy doses are given by the EORTC, treatment included radiation alone (30 Gy at the maximum-tolerated doses, whereas most concurrent followed by a 3-week rest period and then 25 Gy), identi- regimens generally use reduced chemotherapy doses.
cal radiation plus cisplatin at 30 mg/m2/week during ra- Three major randomized trials have completed patient diation, or radiation plus cisplatin at 6 mg/m2/day [42].
accrual and compare concurrent chemotherapy and radia- Although overall response rates were similar for the three tion regimens to sequential regimens for good-performance arms, overall survival improved in the radiation plus status locally advanced NSCLC patients. These studies are cisplatin arms over radiation alone (P = 0.04), particularly the West Japan Lung Cancer Group trial [45,46], CALGB/ for radiation plus daily cisplatin as compared with radia- ECOG trial [47], and RTOG 9410. The Japanese trial dem- tion only (P < 0.009). This favorable impact on survival onstrated a survival advantage with a concurrent regimen has been observed despite relatively low response rates of of mitomycin/vindesine/cisplatin and split course radio- 12% to 14% to single-agent cisplatin in Phase III trials.
therapy over the same chemotherapy given before continu- Several studies have suggested that concurrent chemo- ous-course radiotherapy, with median survival times of 16.5 therapy with hyperfractionated radiotherapy could improve and 13.3 months, respectively (P = .03998) [45]. This ben- the survival outcome of patients with locally advanced in- efit was maintained at 5 years (15.8% vs. 8.9%, respec- operable NSCLC. Lee et al. reported the results of a Phase tively) [46]. Surprisingly, esophagitis rates were low in both II study in which 79 unresectable NSCLC patients were arms, perhaps owing to the split-course nature of the tho- treated with two cycles of oral etoposide and cisplatin and racic radiotherapy in the concurrent arm. The CALGB/ hyperfractionated radiotherapy (1.2 Gy BID, to 69.6 Gy) ECOG trial randomized unresectable Stage III NSCLC [43]. Toxicity was significant with a 53% grade 3 or 4 esoph- patients to receive either sequential vinblastine/cisplatin agitis, and 25% grade 3 or 4 lung toxicity. Median survival followed by radiation therapy or the same induction che- was 18.9 months (21.1 months for patients with weight loss motherapy with a weekly dose of carboplatin (100 mg/m2/ of ≤5%). The survival outcome from this regimen com- week) during the radiation portion of treatment [47]. The pares favorably with that of other chemoradiation trials [40– addition of the single agent carboplatin increased the com- 42]. Jeremic et al. evaluated the activity of hyperfractionated plete response rate from 10% to 18% and decreased local radiotherapy (1.2 Gy BID, to 69.6 Gy) as compared with progression within the boost volume from 53% to 43%.
the same radiation plus concomitant low dose of carboplatin/ However, this was not sufficient to have an impact on sur- etoposide administered daily to 131 patients with Stage III vival. The RTOG trial randomized 611 patients to one se- NSCLC [44]. In this study, the radiation plus concomitant quential arm or two concurrent arms, one of which used chemotherapy arm resulted in significantly better median twice-daily radiotherapy. Accrual was completed in July survival (22 months in the chemoradiotherapy arm vs. 14 1998, and survival results will be available in the year 2000.
months in the radiotherapy-alone arm) and better overallsurvival at 4 years (23% in the chemoradiotherapy arm vs.
The Role of Altered-Fractionation Radiotherapy
9% in the radiotherapy-alone arm). The 4-year local recur- Schedules and Three-Dimensional Conformal
rence-free survival rate was also significantly higher in the Radiotherapy
chemoradiotherapy arm than in the radiotherapy-alone arm Novel radiation fractionation regimens is an area of con- tinued investigation. The RTOG published a five-arm ran-domized trial of hyperfractionated radiotherapy in patients CONTROVERSIAL ASPECTS OF
with advanced, unresectable NSCLC [48]. Hyperfraction- UNRESECTABLE STAGE III
ated radiotherapy was given at a dose of 1.2 Gy in two NSCLC TREATMENT
fractions per day, to total doses of 60, 64.8, 69.6, 74.4, and Optimal Scheduling of Thoracic Radiotherapy
79.2 Gy. Results showed no survival differences among and Chemotherapy
the three highest total dose arms. Patients who received a Numerous sequences of chemotherapy and radiation total dose of 69.6 Gy had a median survival of 13 months, therapy have been, and continue to be, evaluated in clini- and a 2-year survival rate of 29%. These findings were Multimodality Treatment for Lung Cancer
significantly superior to results obtained with lower doses tients is expected to be completed by late 2000. An ongo- of hyperfractionated radiotherapy in this study. Continu- ing ECOG randomized Phase III study (2597) is compar- ous hyperfractionated accelerated radiotherapy (CHART) ing standard radiotherapy to a thrice-daily radiotherapy is another novel regimen in which multiple fractions per regimen preceded by two cycles of paclitaxel/carboplatin.
day are given in a short period of time. Saunders et al.
At present, the incorporation of new chemotherapeutic demonstrated a survival advantage with CHART (1.5 Gy agents is needed to improve local and distant disease con- 3 times per day, 12-days, to 54 Gy), vs. standard radio- therapy alone (60 Gy) in a trial of 563 locally advancedNSCLC patients treated without chemotherapy [49]. The CONCLUSIONS
role of such aggressive altered-fractionation radiotherapy Locally advanced NSCLC is a systemic disease requir- when combined with chemotherapy is the subject of on- ing a multimodality approach to its management. New chemotherapeutic agents should be integrated in the Stage Experience to date demonstrates that dose escalation in III disease treatment setting to further improve results.
locally advanced NSCLC has been accomplished safely Future strategies should also incorporate newer ways to using three-dimensional conformal radiotherapy, limiting administer radiation therapy. The optimum chemotherapy target volumes [50,51]. More follow-up and experience and radiotherapy integration schedule remains to be deter- will determine late toxicity, maximum dose, and efficacy mined. These combined-modality programs are now be- of dose escalation with three-dimensional conformal ra- ing included in early stage disease trials. In addition, our diation therapy. Strategies should be developed to integrate understanding of the molecular biology of lung cancer is this modality into the combined treatment of locally ad- increasing and it is to be hoped that this greater knowl- edge of genetic alterations will help to more accuratelyselect patients for therapies.
The Value of New Chemotherapeutic Agents in
p53 gene mutations still represent the molecular blue- Combined Modality Treatment
print in lung cancer. Intriguingly, p53 mutations have re- In the 1990s, several new chemotherapeutic agents have cently been correlated to response to neoadjuvant been shown to have promising activity against NSCLC.
chemotherapy in a Stage IIIA and IIIB NSCLC. This is the Although a number of randomized trials have been com- first study to prove such correlation, although these re- pleted comparing new agents or combinations with estab- sults should be taken with caution due to the rather small lished regimens, no randomized trial has yet been number of patients analyzed [57]. Moreover, Japanese in- completed that compares such a regimen and new agents vestigators are detecting micrometastatic cancer cells in in conjunction with thoracic radiotherapy for locally ad- bone marrow using cytokeratin (CK) 18. In addition, CK vanced NSCLC. Instead, a number of Phase II trials have 18 cells were detected in 50% of patients with p53 posi- been completed, and they demonstrate promising survival tive tumors, as opposed to only 1 out of 10 patients with- rates and acceptable toxicity. Belani et al. conducted a out p53 staining [58]. More translational research is Phase II trial to evaluate concurrent weekly paclitaxel 45 required in the field of neoadjuvant multimodality ap- mg/m2 and carboplatin 100 mg/m2 plus thoracic radiation in 38 patients with locally advanced, unresectable NSCLC The survival curves indicate that patients with T4 N0- [53]. The overall 1-year survival was 61%, and 39% of N1 have very good survival when complete resection is patients were alive after 3 years of follow-up. Choy et al.
attained following chemoradiotherapy. However, for those reported median survival rates of around 20 months with patients clinically staged with T4 N2 disease, the optimal regimens using concurrent paclitaxel/carboplatin, and tho- approach seems to be chemoradiation only. A great dispar- racic radiotherapy [54]. Recently, the CALGB completed ity of results is reported when surgical treatment is at- a randomized Phase II trial (9431) in which patients re- tempted in patients with T4 N0 (reviewed in Garrido et al.
ceived two cycles of induction gemcitabine/cisplatin, [59]). Various important questions concerning this matter paclitaxel/carboplatin, or vinorelbine/cisplatin, followed by have yet to be elucidated. For example, the concept of a dose-reduced concurrent chemotherapy/radiotherapy downstaging T4 disease potentially involves converting a regimen of the same agents [55]. Docetaxel/carboplatin probable pneumonectomy to a standard lobectomy after combination is also being analyzed in Stage III NSCLC neoadjuvant chemotherapy [60]. In an effort to clarify patients [56]. In addition to these trials, there is an ongo- which patients with unresectable Stage III can turn out to ing randomized Phase II trial comparing three combined- be operable, several investigators have proposed various modality regimens (sequential therapy, concurrent therapy, modifications of the current TNM classification system.
and combined sequential/concurrent therapy) using Grunenwald and Le Chevalier [61] have proposed to break paclitaxel/carboplatin in patients with locally advanced, down T4 disease into T41 including invasion of superior unresectable NSCLC. Accrual of the necessary 260 pa- vena cava, left atrium, carina, trachea and great vessels.
Rosell and Felip
Moreover, Ruckdeschel [62] has also proposed subclassi- current cisplatin/etoposide (PE) plus chest radiotherapy (RT) fol-lowed by surgery in bulky, stages IIIA(N2) and IIIB non-small cell fication of Stage IIIA N2 according to the small or huge lung cancer (NSCLC): 6-year outcomes from Southwest Oncology N2 involvement, as well as multi-station N2 disease. How- Group Study 8805 [Abstract]. Proc Am Soc Clin Oncol 1999;18: ever, we must concede that the role of surgery in locally 17. Choi NC, Carey RW, Daly W, et al: Potential impact on survival of advanced disease has not been completely elucidated and improved tumor downstaging and resection rate by preoperative we are awaiting the results of the above mentioned ongo- twice-daily radiation and concurrent chemotherapy in stage IIIA ing randomized trials (reviewed in Kubota [63] and non-small cell lung cancer. J Clin Oncol 1997;15:712–722.
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