These trials have used two different treatment strategies, induction chemotherapy alone or concurrent

chemoradiation before resection. The rationale for chemotherapy alone as induction treatment is that it

potentially allows the use of a more intense dose and the use of some drugs, such as mitomycin, that

cannot be administered in conjunction with radiation. Proponents of this approach also believe that

chemotherapy is as effective as induction treatment as is combined chemoradiation, and that separating

the two modalities allows irradiation to be used postoperatively, when a higher total dose can be given.

Proponents of concurrent preoperative chemoradiation believe that this approach provides adequate

systemic treatment of micrometastatic disease and more effective control of bulky primary and

mediastinal tumors.

Neoadjuvant Trials of Chemotherapy Alone before Resection

One of the best-known early trials to demonstrate the feasibility of combining induction chemotherapy

with subsequent pulmonary resection in patients with stage III NSCLC was developed by Martini et

al.133 at Memorial Sloan-Kettering Cancer Center. In 1984, this group initiated a trial of high-dose,

cisplatin-based (120 mg/m2) chemotherapy followed by resection for patients with clinical N2 disease.

Vindesine or vinblastine and subsequently mitomycin were added to form the so-called “MVP” regimen.

Postoperative radiation was given to patients who had persistent mediastinal nodal tumor at

thoracotomy, and all patients received two additional cycles of chemotherapy postoperatively. In 136

patients treated from 1984 to 1991, the major response rate to induction chemotherapy was 77%

(105/136), and the complete resection rate was 65% (89/136). A complete pathologic response was

noted in 19 patients (21%) at the time of resection. The overall survival at 5 years was 17% and the

median survival was 19 months; a distinct improvement over the historical survival for this group of

patients. Seven treatment-related deaths (5%) occurred in this study, five of which were postoperative.

A phase II trial, reported by the CALGB in 1995, of induction chemotherapy enrolled 74 patients,

treated with two cycles of cisplatin (100 mg/m2 on days 1 and 29) and vinblastine (5 mg/m2 per week)

without mitomycin followed by resection for patients with mediastinoscopy-proven stage IIIA N2

disease.134 In addition, two cycles of chemotherapy and 59.4 Gy of radiation were given

postoperatively. Sixty-three patients (85%) had either an objective response or stable disease after

induction therapy and underwent thoracotomy, with operative mortality rate of 3.2%. Twenty-three

patients (37% of thoracotomies, 31% of all patients) had a complete resection, with 3-year survival of

46%. The overall 3-year survival was 23%. The lower resectability rate in this trial than in the study

performed at Memorial Sloan-Kettering potentially reflected both the multi-institutional nature of this

trial and the use of a less intensive chemotherapy regimen (primarily because of the omission of

mitomycin). The overall long-term survival appeared similar for the two trials.

Trials of Induction Chemoradiation Followed by Resection

The second approach to combined-modality therapy and resection for stage III NSCLC has been to

combine chemotherapy and radiation preoperatively (Table 79-10). This strategy aims to control

micrometastatic disease while utilizing the synergism of concurrent radiation and chemotherapy to

reduce tumor bulk in the primary site and mediastinum.

The largest reported phase II neoadjuvant trial of concurrent chemotherapy and radiation was a multiinstitutional study performed by the Southwest Oncology Group.138 Both stage IIIA and stage IIIB

patients were entered, although notably, pathologic documentation of the initial tumor stage, usually by

mediastinoscopy, was required. The induction regimen included two cycles of cisplatin (50 mg/m2 on

days 1 and 8) and etoposide with 4,500 cGy of concurrent radiation in 25 fractions. All patients

underwent thoracotomy unless their disease progressed. The objective response rate to induction

therapy in the 126 eligible patients was 59%. The resectability rates were 85% for the IIIA N2 group

and 80% for the IIIB group. Nearly two-thirds of the patients had no viable tumor or only minimal

residual foci of tumor in their surgical specimens. The 3-year survival rate was 27% for the IIIA group

and 24% for the IIIB group, with median survival of 13 and 17 months, respectively. The best predictor

of survival after surgery was the absence of tumor in the mediastinal nodes at surgery (3-year survival

of 44%). The majority of recurrences were distant, and the brain was the single most common site. The

operative mortality rate was 6%, and the overall treatment-related mortality was 10%. An important

finding of SWOG 8805 was that survival was the same for patients with stage IIIB NSCLC by virtue of

T4 tumor status and patients with stage IIIA N2 disease. Patients with N3 disease had a poor overall

survival. Importantly, the long-term follow-up of this study showed that the survival rates at 3 years

were sustained at 6 years.142 Important differences between the Southwest Oncology Group trial and

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earlier neoadjuvant trials were the careful documentation of pretreatment stage, the use of a higher

dose of continuous radiation (4,500 cGy rather than 3,000 cGy of continuous or 4,000 cGy of splitcourse radiation), and the fully concurrent manner in which the chemotherapy and radiation were

administered.

A North America Intergroup clinical trial sought to determine whether neoadjuvant therapy including

resection is superior to nonsurgical treatment with chemotherapy and higher-dose radiation in patients

with stage IIIA NSCLC. In the Intergroup 0139/RTOG 9309 trial,43,140 patients with proven pN2, stage

IIIA NSCLC were randomized to receive neoadjuvant chemotherapy with concurrent thoracic RT (TRT)

followed by operation or continuation with definitive TRT.

Of 429 patients accrued over 92 months, 396 patients were considered eligible, and were treated with

cisplatin (50 mg/m2), on days 1 and 8, and etoposide (50 mg/m2), on days 1 to 5, every 3 weeks for 2

cycles, as well as 45 Gy TRT. Patients randomized to resection (n = 202) underwent operation 4 to 6

weeks later. Patients randomized to definitive radiation (n = 194) continued without break to a total of

61 Gy. Following operation or completion of TRT, consolidation with 2 cycles of cisplatin and etoposide

was given. Of note, less than two-thirds of patients undergoing operation received consolidation

treatment, compared with over 75% of patients receiving chemoradiation only. There was no mortality

in either group during induction chemoradiation. Mortality in the surgical treatment arm was 8%, with

14 of 16 deaths occurring in patients undergoing pneumonectomy.

RESULTS

Table 79-10 Results of Representative Neoadjuvant Trials for Stage III Non–Small

Cell Lung Cancer: Induction Chemoradiotherapy Followed by

Resection

The median follow-up for the study population was 23 months (range 1 to 125 months). Progressionfree survival (PFS) was improved from a median of 10.5 months to 12.8 months, and 5-year PFS from

11% to 22% with the addition of surgery. There appeared to be improved local control with the

addition of surgery, with local failure occurring in only 10% of surgically treated patients compared

with 22% in the nonsurgical group, although this was not statistically significant. However, no

statistically significant differences were seen in overall survival, with 5-year survival of 20% and 27%

for the chemoradiation alone and chemoradiation and surgery groups, respectively. This study indicated

that carefully selected patients with N2-positive stage IIIA NSCLC can be treated with multimodality

therapy including resection.

The role of surgery for patients whose tumors appear to require pneumonectomy remains

controversial as well. In the recently published German Lung Cancer Study Group trial, patients were

randomized to induction chemotherapy (cisplatin and etoposide) followed by chemoradiation

(concurrent carboplatin and vindesine) and then by resection, or induction chemotherapy followed by

surgery alone. Of 524 eligible patients, randomized and started on treatment, 296 underwent operation

and 272 were resectable. In an intention-to-treat analysis of randomized, eligible patients, no

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differences in progression-free or overall survival were observed between the treatment groups.

Patients receiving preoperative chemoradiation were more likely to achieve complete resection among

those with resectable tumors (98/131 vs. 84/141, p = 0.008), and were more likely to have evidence

for mediastinal downstaging and pathologic response, but again with no significant difference observed

in progression-free or overall survival. Of 104 patients who required pneumonectomy, including 39 on

the right, mortality was slightly greater among patients treated with preoperative chemoradiation (7/50

vs. 3/54), but this was not statistically significant.141 Parenchymal-preserving bronchoplastic techniques

also can be considered for those patients who might otherwise require pneumonectomy.143 Whether

such technically challenging approaches can be undertaken in the setting of recent radiation therapy

remains to be established.

Stimulated by the promising results of the Southwest Oncology Group 8805 trial for patients with T4

disease, Grunenwald et al.120 performed a phase II trial of similar design for stage IIIB T4 NSCLC. The

induction regimen consisted of cisplatin (100 mg/m2), 5-fluorouracil, and vinblastine with 45 Gy of

concurrent hyperfractionated (twice daily) radiation. Of 25 patients enrolled, 16 were subsequently

eligible for surgery, and 12 had complete resection. No induction treatment–related or operative deaths

occurred. This study confirmed that complete resection after induction therapy is feasible in a

significant number of stage IIIB T4 tumors, a subset of stage IIIB tumors previously considered

inoperable under any circumstances.

Current Status of Neoadjuvant Therapy and Resection

Clinical trials evaluating neoadjuvant therapy have demonstrated the feasibility of induction

chemotherapy and resection for the treatment of stage III NSCLC. Most studies showed improved rates

of resectability and survival in comparison with the historical experience for resection or radiation

alone. The optimal treatment approach to these locally advanced tumors has not yet been fully defined,

especially because neoadjuvant trials have varied with respect to eligibility criteria, inclusion of both

stage IIIA and stage IIIB tumors, accuracy of pretreatment staging, and type of induction regimens. The

response, resectability, and survival rates have not been uniformly reported. In some studies, instead of

reporting results as a percentage of the total number of patients entered into the study, the authors

reported resectability rates as a percentage of the patients with a radiographic response, and only the

survival rates of patients who underwent resection were emphasized.

The potential toxicity of neoadjuvant regimens should not be overlooked. Induction regimens

including high-dose cisplatin (≥100 mg/m2) or radiation doses of 4,000 to 4,500 cGy have been well

tolerated, but radiation doses of 5,500 cGy or higher have been associated with an excessive risk for

postoperative ARDS and bronchial stump leak. Good response rates have been achieved with

chemotherapeutic agents including paclitaxel, docetaxel, gemcitabine, and carboplatin, which are

tolerated better by patients. Determining the contribution of these agents in combined-modality therapy

will require further trials, especially as the major form of relapse continues to be distant metastatic

disease.

Future Directions

6 In addition to new chemotherapeutic agents, new radiation techniques, such as hyperfractionated or

accelerated schedules, also merit further exploration in neoadjuvant trials with concurrent

chemotherapy. Adelstein et al.,144 from the Cleveland Clinic, conducted a study in which 45 patients

with stage IIIA or IIIB NSCLC received induction cisplatin, paclitaxel and 30 Gy of accelerated

hyperfractionated radiation therapy (1.5-Gy fraction twice daily). Resection was then performed

approximately 4 weeks after induction. The overall response rate was 54%. Forty patients (89%)

proceeded to operation, and 32 patients (71%) underwent complete resection. Five complete pathologic

remissions were seen. Fourteen patients overall were downstaged. Patients received a consolidation

dose of chemotherapy and additional radiation to a total of 60 to 63 Gy. The 2-year relapse-free survival

rate was 47%, and the 2-year survival rate was 65%. No apparent therapy-related deaths occurred, but

the toxicity was high, with 89% of patients experiencing significant mucositis and 20% experiencing

esophagitis of grade 3 or worse. Three-dimensional conformal therapy permits higher radiation dosing

(>70 Gy) of the tumor while sparing surrounding normal lung to provide improved local control.145,146

7 The management of stage III NSCLC is complex and still evolving. Many trials indicate that

resectability and survival rates are probably improved with the use of combined-modality therapy than

with radiation or resection alone. Regimens incorporating high-dose cisplatin with or without moderatedose radiation have achieved the best results with acceptable levels of toxicity. Careful patient

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