Preoperative Chemotherapy/Radiation Therapy for Early Stage and Locally Advanced Non-Small Cell Lung Carcinoma

Brian E. Lally

Harvey I. Pass

Kathy S. Albain

Surgery remains the cornerstone of management for patients with non-small cell lung cancer (NSCLC). Unfortunately, at the time of initial diagnosis, approximately half of all patients have localized disease and less than a third are candidates for surgical exploration. Despite complete resection, 5-year survival rates are disappointing, ranging from 73% for T1N0 disease to 24% for patients with T1-3N2 based on the proposed International Association of the Study of Lung Cancer staging recommendations (Table 55.1).¹ The ability of a patient to undergo a surgical resection of their lung cancer is associated with an improved survival, but this is the result of many factors. Despite complete resection, many patients develop local and distant recurrence and die as a result of uncontrolled lung cancer.

Efforts at improving survival for patients with resectable NSCLC, as well as those with potentially resectable, more advanced local disease, examined the use of chemotherapy or radiation in the postoperative (adjuvant) or preoperative (neoadjuvant or induction) settings. Postoperative therapy is discussed in Chapter 53. This chapter will focus on the use of chemotherapy and/or radiation in the preoperative setting. In approaching this topic, the reader must understand that this is one of the most controversial topics in the management of potentially resectable NSCLC. Some of the more contentious inquiries include: (a) whether it is justified to consider induction therapy in patients who, at presentation, can have a definitive (R0) resection of all disease; (b) whether a surgical resection should ever be performed after combined modality treatment in stage IIIA/B disease; (c) what (if any) pretreatment patient characteristics help determine the optimal method of local control; (d) what prescription for the timing of the local and systemic therapy best maximizes treatment effect with a minimum of complications; and (e) what specific cytotoxic chemotherapy combinations should be used. For patients with locally advanced disease, the current standard of care is concurrent chemotherapy and radiotherapy (chemoRT), and the long-term survival results in reported randomized phase III trials are between 8% and 15%. The limitations of this approach include persistent local disease, which is reported to be as high as 83% after treatment with chemotherapy and full-dose RT, and very high distant failure rates, primarily in the brain. Moreover, persistence of local disease after completion of treatment portends an especially poor prognosis, not only as a result of the local effects of the uncontrolled tumor but also hypothetically as a potential source of metastatic seeding. Those advocating a surgical removal of residual disease hypothesize that this method for local control could render a proportion of these patients disease free.

The pros and cons of how to orchestrate chemotherapy, RT, and surgery for locally advanced lung cancer revolve around the optimization of dose intensity, toxicity, and efficacy. Patients have better tolerance of adjunctive therapies prior to thoracotomy, resulting in improved delivery of planned doses of chemotherapy and RT. The ability to actually monitor the sensitivity of the tumor to the therapy at a time when micrometastatic disease may be lowest, while also cytoreducing the local tumor burden (possibly leading to improved resectability and a potential for less pneumonectomies) are appealing hypotheses for an induction strategy. Arguments against a neoadjuvant approach revolve around the impact of the therapy on the presurgical, nutritional, and immunological status of the patient, possibly leading to a delay of definitive surgery, early tumor progression, technically challenging surgery (especially if RT is incorporated in the induction program) and poor postoperative healing.

The most significant argument against the use of preoperative chemotherapy may be that the benefit associated with chemotherapy use in NSCLC has been rather extensively demonstrated in the postoperative setting.²,³,⁴ This benefit appears to increase with more advanced disease. The investigations into adjuvant chemotherapy were based on a metaanalysis suggesting a potential benefit.⁵ With more trials of preoperative chemotherapy having been completed over time, similar analyses have recently been performed, with results suggesting a possible survival benefit.⁶,⁷,⁸ Given the heterogeneous populations that represent the patients with lung cancer clinically, some patients will benefit more from adjuvant therapy, whereas other patients may benefit more from induction therapy.

TABLE 55.1 Survival Rates for Early Stage NSCLC Based on Clinical and Pathologic Staging

		Overall Survival
		Clinical		Pathologic
Stage	TNM Classification	MST	5-Year	MST	5-Year
IA	T1a/bN0M0	60	50%	119	73%
IB	T2aN0M0	43	43%	81	58%
IIA	T2bN0M0 or T1/T2aN1M0	34	36%	49	46%
IIB	T2bN1M0 or T3/T4N0M0	18	25%	31	36%
IIIA	T1/2N2M0 or T3/T4N1/2M0	14	19%	22	24%
IIIB	T4N2M0 or TanyN3M0	10	7%	13	9%
Overall survival, expressed as median survival time (MST) and 5-year survival by clinical and pathologic stage using the proposed International Association of the Study of Lung Cancer recommendations.¹

INDUCTION THERAPY FOR LOCALLY ADVANCED LUNG CANCER (STAGES IIIA AND IIIB)

First-Generation Induction Trials

Radiation Therapy as the Sole Induction Modality The initial trials of preoperative RT from the 1950s to the early 1970s were conducted without the benefit of modern staging technologies⁹,¹⁰,¹¹,¹² and before effective cytotoxic chemotherapies for NSCLC existed. Pathologic complete responses (pCRs) were reported in up to 27% of patients, but operative morbidity rates rose with RT doses greater than 40 Gy. A large randomized study published in 1975, however, found no difference in overall survival (OS),¹² and a subsequent study from the Lung Cancer Study Group (LCSG 881)¹³ for patients with pathologic stage IIIA (N2) disease given 44 Gy before surgery had disappointing results, with only one pCr and a median survival of 12 months. The last randomized trial that used RT alone as induction treatment was Cancer and Leukemia Group B (CALGB 9134).¹⁴ This trial closed early because of poor accrual, and long-term results were not encouraging. Thus, based on more recent studies, RT is no longer recommended as the sole induction modality prior to surgery.

Early Phase II Studies of Induction Chemotherapy with or without Radiotherapy In the 1980s, a series of phase II induction trials of first-generation cisplatin-based chemotherapy were performed with or without sequential RT prior to surgery.¹⁵,¹⁶,¹⁷,¹⁸,¹⁹ These were small trials with staging heterogeneity, and broad variability in both the amount of low-versus high-volume disease and in the percentage of biopsy-proven N2 disease. Three trials employed the CAP regimen (cyclophosphamide, doxorubicin, and low-dose cisplatin), whereas two studies used cisplatin plus etoposide-based preoperative chemotherapy. The study designs and outcomes of these trials are outlined in Table 55.2.¹⁵,¹⁶,¹⁷,¹⁸,¹⁹ Response rates (RR) from the induction therapy were 39% to 82%, resection rates (percent of original number accrued) were 14% to 88%, and the survivals were highly variable. Staging and volume of tumor differences within these trials preclude conclusions about efficacy or comparisons across trials; however, these pivotal studies demonstrated the general safety of surgery after induction therapy and in some instances, provided intriguing survival data.

Therefore, larger, second-generation trials were designed that enrolled more restricted stage subsets, and required, in most instances, pathologic documentation of nodal disease. The following sections review the major categories of secondgeneration studies and long-term survival from selected trials.

Second-Generation Phase II Studies of Induction Chemotherapy as the Sole Induction Modality

Five phase II second-generation studies of induction therapy tested preoperative chemotherapy. These trials are described in Table 55.3.¹³,²⁰,²¹,²²,²³,²⁴,²⁵ Although all studies required pathologic documentation of N2 disease, tumors with a wide range of disease bulk were accrued. The LCSG 881 trial was a two-arm phase II randomized trial, in which one arm was assigned preoperative chemotherapy and the other received preoperative RT.¹³ The results were reported for the entire group of patients and not separately for each treatment arm. Four of the studies utilized preoperative vinblastine and cisplatin with or without mitomycin C (MVP, VP [etoposide + cisplatinum]), and the fifth trial tested continuous infusion cisplatin and 5-fluorouracil (5-FU) with leucovorin rescue. The RT was variably given (intraoperative, postoperative, or not at all), and information on why RT was either given or withheld was not provided in detail for some of the studies. Thus, lack of concordance on the disease bulk and RT utilization variables makes comparison of results among the studies difficult.

Resection rates (based on the entire denominator) were 51% to 68%. Postoperative mortality ranged from 0% to 18%. The causes of death were predominantly pulmonary or cardiopulmonary. Pulmonary complications attributable to mitomycin C in the Memorial Sloan-Kettering study, including the three lethal ones, all occurred after the cumulative dose of 24 mg/m². The studies that did not use mitomycin C had lower perioperative death rates. pCR rates ranged from 0% to 15%. Postoperative RT did not provide additional benefit in the Memorial Sloan-Kettering study (p = 0.24); however, the selection of patients receiving RT was based on unfavorable response to neoadjuvant chemotherapy, not by randomized assignment. In the Dana-Farber study, all mediastinal downstaging to N0 or N1 occurred in patients with low-volume disease. The CALGB study noted that persistent N2 disease following induction chemotherapy is unfavorable. Although there was no correlation between radiographic response to the induction regimen and pathological downstaging at the time of surgery, patients with a pCR in N2 nodes were felt to potentially benefit from surgical resection. Survival outcomes were highly variable, with median survival ranging from 12 to 21 months, because of differences in the study eligibility and design, as reviewed previously. In the Dana-Farber study and CALGB trial 8935, 15% and 41% of first relapses occurred in the brain, respectively.

TABLE 55.2 Early Phase II Studies of Induction Chemotherapy with or without Radiotherapy

Investigators	Volume	Treatment Program	Patients	Biopsy-Proven N2/N3 Disease (%)	Response Rate (%)	Resection Rate (% Original N)	Median	Long-Term Survival
Dana-Farber I¹⁵	T3 or low-volume stage III (N2)	CAP × 2 →RT →surgery → RT →CAP × 3	41	68	43	88	32	31%, 3 yrs
LCSG 831¹⁶	T3 or low-volume stage III (N2)	CAP × 3 with split RT → surgery	39	51	51	33	11	8%, 2 yrs
University of Chicago¹⁷	High-volume T3 or T4N2 or N3	VdEP × 2 →surgery →RT	21	100	70	14	8	34%, 1 yr
Dana- Farber II¹⁸	T1-3N2 (mixed low and high volume)	CAP × 4 + RT → surgery → RT	54	94	39	56	18	22%, 5 yrs
Perugia¹⁹	T1-3N2 (clinically high tumor volume)	EP × 2 − 3 →surgery → variable RT	42	0	82	72	24	24%, 3 yrs
Median survival in months.
A, doxorubicin; C, cyclophosphamide; E, etoposide; LCSG, Lung Cancer Study Group; P, cisplatin; RT, radiotherapy; Vd, vindesine.

TABLE 55.3 Second-Generation Phase II Studies of Induction Chemotherapy as the Sole Induction Modality

Investigators	N	Disease Burden	Treatment Schedule	Response Rate (%)^*	Complete Resection Rates (%)^*	Treatment-Related Mortality (%)^††	Operative Mortality (%)^*	pCR‡ Rates (%)	pCR† in Mediastinal Nodes (%)^*	Median Survival (mo)
LCSG 881¹³	26	High volume	MVP × 2 →surgery or 44 Gy →surgery	65	68	14.5	18	4	Not stated	12
Memorial²⁴	136	Mixed volume	MVP × 2 − 3 →surgery → radiotherapy for persistent N2	78	65	5	5	14	32	19
Toronto²⁰,²¹	65	Mixed volume	MVP × 2 →surgery → MVP × 2 for responders	68	53	12	5	5	Not stated	19
Dana-Farber²²	34	Mixed volume	PFL (continuous infusion) × 3 →surgery →radiotherapy	65	62	0	0	15	44	18
CALGB 8935²³,²⁵	74	High volume	VP × 2 →surgery →VP × 2 →radiotherapy	64^§§	62	2.7	3.2	0	12	15
^*Percent of all enrolled patient. ^††Pathological complete response. ^‡‡Percent of patients subjected to surgery. ^§§Includes stable disease.
CALGB, Cancer and Leukemia Group B; F, 5-fluorouracil; L, leucovorin; LCSG, Lung Cancer Study Group; M, mitomycin C; P, cisplatin; pCR, pathologic complete response; V, vinblastine.

TABLE 55.4 Second-Generation Phase II Studies of Induction Chemotherapy before Surgery

Investigators	N	Disease Burden	IIIA (N2) (%)	T3N0-1/T4 or N3 (%)	Treatment Schema	Response Rate (%)^*	Complete Resection Rate (%)^*	Treatment-Related Mortality (%)	Operative Mortality (%)^††	pCR (%)	pCR in N2 (%)	Median Survival (mo)
SWOG 8805²⁶	126	High volume	60	0/40	EP × 2 + 45 Gy → surgery →EP × 2 + 14 Gy if persistent N2/incomplete resection	59	71	10	8	15	38	15
LCSG 852³⁰	85	High volume	85	0/13	PF × 2 + 30 Gy → surgery	56	52	8	7	9	NS	13
Rush Presbyterian²⁷	85	Mixed volume	73	21/6	PF or PEF + 40 Gy (split course) →surgery	92^*	71	3.5	5	20	26	22
CALGB I²⁹	41	Mixed volume	80	20/0	PVF × 2 + 30 Gy → surgery →PVF × 1 + 30 Gy	64^‡‡	61	15	10	17	NS	16
Tufts²⁸	42	High volume	66	2/45	EP × 2 + 59.4 Gy → surgery →PE × 4 or carbo T × 4	69^*	79	0	0	21	59	30
^*Percent of original number. ^††Percent of patients subjected to surgery. ^‡‡Includes stable disease.
CALGB, Cancer and Leukemia Group B; Carbo, carboplatin; E, etoposide; F, 5-fluorouracil; Gy, gray; LCSG, Lung Cancer Study Group; NS, not stated; P, cisplatin; SWOG, Southwest Oncology Group; T, paclitaxel; V, vinblastine.

Second-Generation Phase II Studies of Induction Chemoradiotherapy before Surgery

Trial Designs and Results The other major category of second-generation induction studies utilized concurrent chemoRT induction therapy in which the RT began on day 1 of the chemotherapy. These phase II trials are described in Table 55.4.²⁶,²⁷,²⁸,²⁹,³⁰ The RT varied in schedule (continuous to split course) and in total dose (30 to 59 Gy, single fractionation). All induction chemotherapy was cisplatin-based, with the addition of either etoposide, 5-FU, vinblastine, or some combination of these drugs. The treatment prescribed after surgical resection was not uniform among these five studies. There was no therapy after surgery in the Rush-Presbyterian and LCSG 852 trials; two cycles of additional chemotherapy plus 14 Gy of RT were given in the Southwest Oncology Group (SWOG) 8805 study (if residual disease in chest or mediastinum); and one cycle of chemotherapy plus 30 Gy of RT was used in the CALGB trial (all patients). The Tufts investigators initially gave etoposide plus cisplatin postoperatively, but later in the trial allowed use of the carboplatin plus paclitaxel regimen.

Eligibility criteria for the five second-generation chemoRT induction trials were more varied than for the studies of induction chemotherapy alone. Biopsy documentation of N2 disease or T4 status was required only in the SWOG, LCSG, and CALGB trials, and the SWOG trial was unique in this regard because pathologic proof of N2, T3, or N3 disease was mandated. A broad range of stage subsets were included across trials, so that stage IIIA (N2) accounted for 47% to 87% of patients per trial. Two studies included T3N0 or T3N1 (21% and 20% in the Rush-Presbyterian and CALGB studies, respectively), whereas all patients with stage IIIA disease in the SWOG 8805, LCSG 852, and Tufts trials had N2 nodal involvement. The stage IIIB subsets of T4 and/or N3 were allowed in all trials except the CALGB study and accounted for 6% to 53% of patients per trial. The SWOG 8805 and Tufts trials were designed for bulky disease, whereas the others allowed a mix of minimal and bulky presentations.

Response or “response plus stable” (one study) rates were 56% to 92%, and 52% to 76% of the total number of patients accrued to each study had a complete resection at thoracotomy. Twenty-six of the thirty patients with stable disease as their “best” response to induction chemoRT underwent a complete resection of tumor in the SWOG 8805 trial.²⁶ The pCR rates were 16%, 21%, and 27% in the LCSG, SWOG, and Rush-Presbyterian trials, respectively.²⁶,²⁷,³⁰ An additional 37% had rare microscopic foci of tumor cells as the sole residual disease in the SWOG trial. It was demonstrated that postinduction assessment of nonresponse by computed tomography (CT) scan is often misleading because 46% of the 26 patients with resectable stable disease in the SWOG study had pCR or only rare microscopic foci.²⁶

The operative mortalities were predominantly pulmonary related, as observed in the induction chemotherapy trials. The cause of death often resembled the adult respiratory distress syndrome (ARDS) to be considered in more detail in the morbidity and mortality section of this chapter. The Tufts trial was unique in that postoperative ARDS was not observed, despite the high total dose of induction RT.²⁸ A rigid protocol to minimize fluids, transfusions, and the fraction of inspired oxygen (Fi02) was employed in this study. The Tufts trial also utilized a higher dose of preoperative RT, a prescription similar to those used for standard concurrent chemoRT without surgery. Thus, most of the allowable dose of RT was given upfront without a break. In the other trials, truncation of the RT occurred at around 45 to 50 Gy to plan for the surgery. Thus, patients with residual disease or unresectable disease could only receive full-dose RT via an interruption of several to many weeks, depending on time to recovery from surgery.

The median survival for the two studies that excluded T3N0-1 tumors and required pathologic staging were 15 and 13 months.²⁶,³⁰ In contrast, the other three trials included this better prognostic subset and did not require biopsy proof of the T and N substages. For these studies, the median survivals were 22, 16, and 20 months.²⁷,²⁸,²⁹ Patterns of first recurrence in the SWOG 8805 trial were 11% (locoregional only) and 61% (distant alone).²⁶ There was no difference in the sites of relapse between those patients with negative mediastinal nodes at the time of operation (but originally positive) versus those who had persistent involvement of the mediastinal nodes. A significant number of the distant first relapses (and in many cases, the only relapse or the sole cause of mortality) occurred in the brain.²⁶ The LCSG investigators noted that in patients who had complete resection, 28% of first recurrence sites were in the brain, in contrast to only 7% in patients who did not undergo surgery. In patients who experienced a recurrence in the brain, in almost one third that was the sole site of recurrence. Similar findings were noted by the SWOG 8805 study. The CALGB protocol called for prophylactic cranial irradiation (PCI) in patients with nonsquamous histologies who completed all the treatment, but about one third of eligible patients did not receive it. None of 13 patients who received PCI developed brain metastases, compared to 1 out of 7 who were eligible but did not receive it. The Tufts investigators also reported a very high rate of isolated brain metastases, all of which occurred within the first 32 months of follow-up.²⁸

The Stage IIIB Subgroup in Second-Generation (and Subsequent) Studies of Chemoradiotherapy Induction Trials From a subset of these second-generation chemoRT trials, data are available regarding the role of induction therapy followed by surgery in selected stage IIIB subsets. The LCSG 852 trial and the Rush-Presbyterian study included 13% “minimal T4” and 6% “selected T4” lesions (clinically staged), respectively.²⁷,³⁰ Separate survival data for this subset were not provided. Of note, two groups of investigators had reported equivalence in outcome of clinical stage IIIA and IIIB disease in combined modality trials with no surgery.³¹,³² However, these authors suggested that the clinical T4N0 subset may have a better outcome than the other subsets and perhaps should be removed from the IIIB category, just as the T3N0 subset had been reassigned to stage IIB instead of its former designation of IIIA.³³ Based on this observation in chemoRTalone trials, the SWOG 8805 study was designed prospectively to include a sufficient sample of the stage IIIB subgroup to allow independent assessment of outcome.

The SWOG 8805 trial was unique among the other chemoRT trials in that it included stage IIIB disease. Pathologic documentation of T4 or N3 disease was required and outcome was analyzed separately for this subset.²⁶,³⁴ The Tufts investigators also reported outcome separately for the IIIB group, but the staging requirements were radiographic rather than pathologic.²⁸ The resection rates in these two studies for stage IIIA(N2) were 76% and 76%, and 63% and 50% for stage IIIB, respectively.

The median, 2- and 3-year survivals were identical for the IIIA (N2) versus the IIIB group in the SWOG 8805 study (27%, 24%).²⁶ This phenomenon was not seen in the Tufts trial where the 3-year survivals were 73% and 32% for the clinical IIIA (N2) and IIIB subsets, respectively, possibly because of the aforementioned staging requirements leading to inaccuracies. Of note, in the SWOG 8805 study, the T4N0-1 subset had an outcome identical to the T1N2 substage and
achieved a 2-year survival of 64%. This substage variable was the only independent predictor of favorable outcome from the time of registration to the study in a multivariate analysis.²⁶ Exploratory survival analyses were conducted within the N3 subset of the SWOG trial, of which 27 patients were accrued. The 2-year survival for the contralateral nodal N3 subgroup was zero, whereas it was 35% for the supraclavicular N3 subset. However, the resection rate in this latter group was only 39%. An update of SWOG 8805 provided 6-year survival statistics: IIIA (N2), 20%; T4N0-1, 49%; and N2 or N3, 18%.³⁵

A follow-up trial to SWOG 8805 for pathologic stage IIIB disease was conducted by the SWOG (SWOG 9019). Identical induction chemoRT was utilized as in SWOG 8805, but no surgery was given; instead, the RT was continued without a break to 61 Gy and two additional cycles of EP were given.³⁶ The OS in this study was identical to that observed for the stage IIIB group in SWOG 8805. This suggested that in an identically staged patient population, chemoRT with definitive-dose RT may achieve the same benefit as surgical resection after induction chemoRT (and lower RT total dose). However, in the SWOG 9019 trial (chemoRT alone), the 2-year survival was only 33% for the T4N0-1 subset, compared to 64% in 2-year and 49% in 6-year survival in the surgical study, SWOG 8805.³⁵,³⁶ This historical comparison of these two consecutive trials in pathologically staged IIIB disease suggests that surgery for stage IIIB tumors might be beneficial only in the select substage of T4N0-1.

Based on these results, the Spanish Lung Cancer Group performed a phase II trial of induction chemotherapy with a cisplatin-based triplet follow by surgery for stage IIIA N2 and selected stage IIIB (T4N0-1).³⁷ A total of 136 patients were entered onto the study; the clinical RR in 129 assessable patients was 56%. Completely resected stage IIIA and IIIB patients (68.9% of those eligible for surgery) had an impressive median survival time of 48.5 months, with a 5-year survival rate of 41.4%. For completely resected stage IIIB patients, median survival time was 60.6 months, and 5-year survival rate was 53.2%. In the absence of mediastinal lymph nodes, median survival time for these patients was not reached, and 5-year survival rate was 57%. Still, a prospective randomized study is needed to validate these findings.

Additional studies have commented on the role of induction therapy for stage IIIB disease. Grunenwald et al.³⁸ prospectively studied 40 patients with stage IIIB disease, of whom 30 had T4 disease and 18, N3. Five patients had T4N0 tumors and one had T4N1. All patients underwent pretreatment surgical staging. Induction treatment consisted of 5-FU, cisplatin, and vinblastine for two cycles. A total of 42 Gy of external RT was given split in two 21 Gy courses, 1.5 Gy bid, with 10 days of rest between the courses. Patients who responded to the induction regimen underwent thoracotomy. A clinical response was obtained in 73% of patients and in 60% resection was performed. The resection was complete in all but one patient who underwent thoracotomy. Four patients (10%) had complete pathological response and 30% had complete mediastinal clearance. There were five treatment-related deaths and seven additional patients suffered serious morbidity. Median survival was 15 months and 5-year OS was 19%. Thirty percent of overall patient number had locoregional relapse and 50% had distant relapse. Pathological mediastinal nodal downstaging was the only significant favorable prognostic factor in a multivariate analysis (5-year survival 42% for postinduction N0/N1 vs. 12 % for postinduction N2/N3 for resected patients). All long-term survivors had persistent viable tumor cells in the primary tumor but six of seven were postinduction N0-1.

Pitz et al.³⁹ treated patients with stage IIIB NSCLC with neoadjuvant gemcitabine and cisplatin without RT, followed by surgery in responding patients. There was an RR of 66%, resection rate of 44%, and perioperative mortality of 2.4%. Median survival for all patients was 15.1 months and 3-year survival was 15%. The investigators found no difference in outcome between T4N0 and N2/N3 subsets. However, only patients with a response after induction chemotherapy were considered for surgical resection.

These trials highlight that the T4N0/N1 substage as a group does particularly well with trimodality therapy.

Second-Generation Induction Trials: Long-Term Survival and Predictors of Outcome

Mature Survival Data Long-term survival data were reported in several of the trials of induction chemotherapy and induction chemoRT (Table 55.5). Several of the trials suggest that a plateau emerges on the tails of the survival curves, as 5- to 7-year survival of 17% to 34% were reported. Despite differences in methodology and patient populations, the longterm outcomes were encouraging and provided support for subsequent phase III trials.

Factors that Predict Favorable Outcome The seven phase II trials of induction chemotherapy or chemoRT depicted in Table 55.5 also analyzed predictors of long-term survival. Favorable outcome predictors included postinduction pCR, complete resection, T3N0 or T3N1 disease, T4N0 or N1 disease, and pathologic clearance of initial N2 or N3 involvement (nodal downstaging). The significance of these predictive factors varied across trials, but all factors were not uniformly assessed in each study. Nevertheless, in most trials, a factor related to the efficacy of the induction therapy was important. It was suggested that the inclusion of RT in the induction removes the possible importance of pCR as a predictor observed in chemotherapy-only induction programs. However, the Memorial Sloan-Kettering Cancer Center trial of MVP alone did not report statistical significance to pCR.²⁴,⁴⁰ Response to induction therapy was not an important predictive factor in some trials, most likely because of the mandate in those studies to resect disease even if “stable” was the best response.²⁶ This observation underscores the inability of standard CT scanning to detect those patients with major postinduction responses.

The SWOG 8805 trial analysis showed that nodal downstaging was an independent favorable prognostic impact of intermediate (2- to 3-year) survival is of interest, and was the
only significant factor in a multivariate model that included complete resection rate, pCR, and multiple other factors.²⁶ This variable was also the most important univariate discriminant of 6-year survival, although complete resection emerged as a long-term survival predictor as well.³⁵ The survivals 3 and 6 years after thoracotomy for patients with uninvolved nodes at surgery were 41% and 33%, respectively, versus only 11% and 11% if there was persistent mediastinal disease. Unfortunately, the prognostic impact of nodal downstaging was not assessed in multivariate models for any other study with second-generation therapy.

TABLE 55.5 Long-Term Survival in Selected Second-Generation Phase II Induction Trials in NSCLC

Investigators	Disease Burden	Included T3N0 or N1?	Biopsy Proof of N2 Status Required?	Selected Stage IIIB Included?	Long-Term Survival
Memorial²⁴	Mixed volume	No	Yes	No	28%, 3 yrs; 17%, 5 yrs
Toronto²⁰,²¹	Mixed volume	No	Yes	No	26%, 3 yrs
SWOG 8805²⁶	High volume	No	Yes	Yes	27%, 3 yrs; 20%, 6 yrs, stage IIIA (N2); 24%, 3 yrs; 22%, 6 yrs, stage IIIB
CALGB II²²	High volume	Yes	No	No	28%, 3 yrs; 22%, 7(+) yrs
CALGB 8935²⁵	High volume	No	Yes	No	23%, 3 yrs
Rush-Presbyterian²⁷	Mixed volume	Yes	No	Yes	40%, 3 yrs
Tuft²⁸	High volume	Yes	No	Yes	37%, 5 yrs
CALGB, Cancer and Leukemia Group B; NSCLC, non-small cell lung cancer; SWOG, Southwest Oncology Group.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Tags: Principles and Practice of Lung Cancer: The Official Reference Text of The IASLC

Aug 25, 2016 | Posted by drzezo in CARDIOLOGY | Comments Off

Thoracic Key

Fastest Thoracic Insight Engine

Preoperative Chemotherapy/Radiation Therapy for Early Stage and Locally Advanced Non-Small Cell Lung Carcinoma

Related

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree

Thoracic Key

Fastest Thoracic Insight Engine

Preoperative Chemotherapy/Radiation Therapy for Early Stage and Locally Advanced Non-Small Cell Lung Carcinoma

Share this:

Related

Related posts:

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree