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J Thorac Cardiovasc Surg 2003;126:17-25
© 2003 The American Association for Thoracic Surgery

General thoracic surgery

Value of accelerated multimodality therapy in stage IIIA and IIIB non–small cell lung cancer

^a From the Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
^b the Transplant Center, Division of Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio, USA,
^c Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
^d Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
^e Department of Biostatistics and Epidemiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.

Received for publication May 9, 2002; accepted for publication January 14, 2003.

^* Address for reprints: Malcolm M. DeCamp, MD, The Cleveland Clinic Foundation, 9500 Euclid Avenue/Desk F25, Cleveland, OH 44195, USA
decampm{at}ccf.org

	Abstract

Top Abstract Patients and methods Results Discussion Appendix 1 References

 
OBJECTIVES: This study was undertaken to assess accelerated multimodality therapy in patients with IIIA and IIIB non–small cell lung cancer in terms of toxicity, feasibility, response, survival, and recurrence (value) and to identify predictors of pathologic response and improved survival.

METHODS: Between October 1994 and September 2000, a total of 105 patients with stage pIIIA (n = 78) or pIIIB (n = 27) non–small cell lung cancer were enrolled in a study of accelerated multimodality therapy, consisting of hyperfractionated radiotherapy with concurrent chemotherapy (paclitaxel and cisplatin) followed by resection and postoperative chemoradiation. Multivariable correlates of pathologic response and survival were assessed.

RESULTS: Toxic effects related to induction therapy necessitated hospitalization in 40% of patients (n = 42); treatment-related mortality was 9% (n = 9). With respect to feasibility, 100% of patients completed induction therapy, 93% (n = 98) of cancers were operable, 79% (n = 83) of cancers were curatively resectable, and 77% (n = 81) of patients completed all therapy. Sterilization of mediastinal nodes was similar (P = .6) for pN2 (35%) and pN3 (30%) disease. Median, 2-year, and 5-year survivals were 27 months, 53%, and 32%, respectively. Locoregional recurrence, distant recurrence, and both were seen in 6% (n = 6), 45% (n = 47), and 3% (n = 3) of patients, respectively. Pathologic response was not predictable. Nodal status predicted incrementally decreasing survival for patients with cancers downstaged to ypN0 or ypN1 (n = 35) versus ypN2 (n = 44) versus ypN3 (n = 20; P < .001). In addition, advancing age, squamous histologic type, and higher pT predicted poorer survival.

CONCLUSIONS: Accelerated multimodality therapy is equally valuable in IIIA and IIIB non–small cell lung cancers. Despite unpredictable response to induction therapy, younger patients and those with nonsquamous histologic type, sterilization of mediastinal lymph nodes, and lower pT benefit most. A ypN2 stage reduces but does not preclude long-term survival.

For the past decade, the approach to therapy for both stage IIIA and stage IIIB non–small cell lung cancer (NSCLC) at The Cleveland Clinic Foundation has differed from that of previous clinical trials.^1-3 An accelerated multimodality protocol was implemented^4,5 with the aims of improving feasibility, pathologic response, and survival and of reducing tumor recurrence with acceptable toxicity (value). Accelerated multimodality therapy consists of induction chemotherapy and concurrent hyperfractionated radiotherapy,^6,7 resection with unilateral lymphadenectomy, and accelerated adjuvant chemotherapy with concurrent hyperfractionated radiotherapy. Objectives of this study were to assess accelerated multimodality therapy in patients with stage IIIA and IIIB NSCLC in terms of toxicity, feasibility, tumor response, survival, and tumor recurrence (value) and to identify predictors of pathologic response and improved survival within this group.

	Patients and methods

Top Abstract Patients and methods Results Discussion Appendix 1 References

 
Patients
Between October 1994 and September 2000, a total of 105 patients (58% male, mean age 57 ± 10 years) with IIIA (n = 78) or IIIB (n = 27) NSCLC were enrolled in the study of accelerated multimodality therapy (Table 1). Only 7 (7%) had cT4 disease (involvement of superior vena cava [n = 2] and mediastinum [n = 5]; surgical staging for these patients indicated pN0 disease in 3 cases, pN2 in 3, and N3 in 1. Of the 105 patients, 102 (97%) had stage III disease because of mediastinal nodal involvement.

The study was approved by The Cleveland Clinic Foundation’s Institutional Review Board and was reviewed annually. Written informed consent was obtained from each patient before therapy began.

Treatment
Accelerated induction therapy
Induction therapy consisted of a 12-day course of concurrent chemoradiotherapy, as previously reported elsewhere (Figure 1). ⁵ A 4-day continuous infusion of cisplatin (20 mg · m^-2 · d^-1) and a 24-hour infusion of paclitaxel (175 mg · m^-2) given on day 1 were administered to inpatients. Concurrent accelerated fractionation radiation therapy consisting of twice daily 1.5-Gy fractions given at least 6 hours apart were administered Monday through Friday during the first 2 weeks of treatment.

View larger version (10K): [in this window] [in a new window]   Figure 1. Treatment schema for accelerated hyperfractionated chemoradiotherapy followed by resection and adjuvant, consolidative chemoradiation for patients with stage IIIA and stage IIIB NSCLC. Cisplatin dose was 20 mg · m-2 · d-1 for 4 days and paclitaxel dose was 175 mg · m-2 as 24-hour infusion. CDDP, Cisplatin; BID RT, twice-daily radiotherapy at 1.5 Gy per fraction.

Resection
Resection consisted of lobectomy, bilobectomy, or pneumonectomy with complete unilateral mediastinal lymphadenectomy.

Accelerated adjuvant therapy
Within 6 to 8 weeks of resection, patients underwent a 2-week course of accelerated concurrent chemoradiotherapy similar to induction therapy (Figure 1). There were no chemotherapy dose reductions. Total adjuvant radiotherapy dose was between 30 and 33 Gy. Total spinal cord dose was <45 Gy with lateral and oblique fields; posterior spinal cord blocks were not used.

Assessment
Value of accelerated multimodality therapy was assessed in relation to its risks and benefits.

Toxicity
Toxicity of induction and toxicity of adjuvant therapy were assessed by symptoms, signs, hospitalization, and related mortality. Surgical morbidity and mortality were included as components of toxicity.

Feasibility
Feasibility was assessed by ability of patients to complete induction therapy, operability, curative resectability, and ability to complete adjuvant therapy.

Tumor response
Tumor response was defined as downstaging of cT or pN. Complete response was defined as ypT0N0.⁸ Partial response was defined as reduction in cT or pN without a reciprocal increase in the other (progressive disease). For patients with pN3 disease, nonresponse was defined as ypN2.

Survival and tumor recurrence
Survival and tumor recurrence were assessed by patient follow-up. Patients were followed up every 3 months with clinical examination and chest radiographs. Additional testing was directed by clinical findings. Survivals from the time of commencement of induction therapy and after surgery were assessed by both the Kaplan-Meier method and a parametric method that resolves the number phases of instantaneous risk of death (hazard function).⁹ Recurrence was classified as locoregional (tumor within the ipsilateral thorax), distant (tumor outside the ipsilateral thorax), or both. The common closing date was October 17, 2001. Median follow-up was 18 months (range 2-79 months).

Data analysis
Descriptive statistics included mean ± SD and median and quartiles for continuous variables, with frequencies and percentages for categorical variables.

Predictors of pathologic response
Factors predictive of pathologic response were sought by multivariable logistic regression analysis with a stepwise selection procedure for which retention in the final model required P < .05. Factors considered potential predictors of pathologic response were age, gender, race, pretreatment T, pretreatment N, pretreatment stage, cell type, and clinical response.

Predictors of survival
The strategy to identify predictors of survival proceeded in two steps with multiphase hazard function methodology.⁹ At both steps we incorporated demographic characteristics, tumor histologic type, operative resection (pneumonectomy vs lobectomy), and date of therapy. Details are given in Appendix 1.

First, we focused on individual components of final pathologic TNM classification (ypTNM) and on the differences between pretreatment cT, pN, and ypTNM. We then added the variable pretreatment stage IIIB to test whether initial stage influenced survival beyond TNM classification. Second, we added to the previous the postresection stage grouping and pathologic response to treatment (complete, partial, none, or progressive disease). Then we again added the variable for pretreatment stage IIIB. The equation from this second multivariable analysis was solved for various combinations of risk factor values that illustrate the constellation of characteristics leading to good and to poor survival, as described by Kirklin and Barratt-Boyes.¹⁰

	Results

Top Abstract Patients and methods Results Discussion Appendix 1 References

 
Value of therapy
Toxicity
During induction therapy, most patients experienced nausea, vomiting, mucositis or dysphagia, and neutropenia (Table 2), although grade III or IV symptoms were infrequent. Forty-two patients (40%) required hospitalization for febrile neutropenia. There were no toxicity-related deaths from induction therapy. Although toxicity was common, it was manageable.

There were 2 toxicity-related deaths during adjuvant therapy, 1 from necrotizing pneumonia with subsequent bronchopleural fistula and 1 from postemetic esophageal perforation. One patient had a nonfatal myocardial infarction related to occult coronary artery disease. Other toxic effects were similar to those of induction therapy (Table 2).

Feasibility
All patients completed induction therapy in 12 days (100%). Ninety-eight patients (93%) were operative candidates. Among the 7 inoperable cases, 4 patients had locoregional progression, 2 had new distant metastatic disease, and 1 was considered medically unfit for surgery.

Eighty-three patients (79%) underwent curative resection. Of 15 patients who did not undergo curative resection, 6 had incomplete resection, 2 had residual N3 disease, 2 had intrapulmonary metastatic disease, and 5 had extensive involvement of the superior vena cava (n = 3), descending aorta (n = 1), or muscular chest wall (n = 1). Curative resections included pneumonectomy (n = 36), bilobectomy (n = 5), and lobectomy (n = 42).

Of the 91 operative survivors, 84 (92%) commenced adjuvant therapy. Among the 7 who did not receive adjuvant therapy, 2 had protracted postoperative courses and 5 had disease progression. Among the 84 patients who began adjuvant therapy, 2 did not complete therapy because of toxicity, 1 died, and 1 had disease progression. One additional toxicity-related death occurred soon after adjuvant therapy was completed. Thus 81 of the 105 enrolled patients (77%) completed and survived accelerated multimodality therapy.

Tumor response
There were no clinically determined complete responses, probably because of the brief interval between induction therapy and reassessment. Sixty-two percent of patients had a measurable partial response, defined as a more than 50% reduction in the sum of the crossed diameters of measurable tumor. Thirty-one percent had stable disease, and 6% had progression. Pathologic examination of the resected tissue demonstrated a complete response in 12 patients (11%), a partial response in 43 (41%), stable disease in 33 (31%), and progressive disease in 17 (16%).

Overall, 35 patients had sterilization of mediastinal lymph nodes (downstaged; Table 3). This response occurred in similar proportions of patients with IIIA (n = 27/78, 35%) and IIIB (n = 8/27, 30%) disease (P = .6). Postresection tumor classifications are listed in Appendix Table 1.

View larger version (17K): [in this window] [in a new window]   Figure 2. Postoperative survival after accelerated chemoradiotherapy. A, Survival. Each circle represents death positioned on vertical axis according to Kaplan-Meier estimator. These are accompanied by vertical bars representing asymmetric 68% confidence limits (equivalent to ±1 SE). Numbers in parentheses represent survivors at that interval. Smooth curve is parametric estimate of survival enclosed within dashed asymmetric 68% confidence bands. B, Hazard. Instantaneous risk of death (hazard function) is represented by solid curve enclosed within dashed 68% confidence limits. Although early risk is high, this hazard is of short duration, resulting in few early deaths.

Predictors of pathologic response
No pretherapy patient, staging, or tumor factor was predictive of pathologic response.

Predictors of survival
The most important predictor of survival was pathologic stage (P < .001; Figure 3). Patients with disease downstaged to ypN0 (pathologic stages 0, I) or ypN1 (pathologic stage II) had 55% ± 10% 5-year survival, whereas patients with persistent stage IIIB disease were unlikely to survive 2 years (18% ± 9%). A statistically distinctive and novel intermediate cohort in this study was the group with residual stage IIIA, ypN2 disease. These patients had a median survival of 27 months, with 31% ± 9% 5-year survival.

View larger version (20K): [in this window] [in a new window]   Figure 3. Survival by pathologic stage. Both Kaplan-Meier (symbols) and parametric (curves) survival estimates are depicted as in Figure 2, A. Parametric estimates are truncated when remaining survivors are few. Patients with pathologic stage 0 to II had survival superior to those with residual N2 disease (stage IIIA), who in turn had longer survival than did nonresponders (stage IIIB, P < .001).

A young patient with either large cell cancer or adenocarcinoma whose tumor was sterilized (downstaged) with induction therapy had excellent survival (Figure 4), regardless of whether the clinical stage was IIIA or IIIB before treatment. However, an older patient with squamous carcinoma that did not respond to treatment and continued in pathologic stage IIIB had limited survival (Figure 4).

View larger version (22K): [in this window] [in a new window]   Figure 4. Good risk and poor risk patients. Shown at upper portion of graph is 45-year-old patient whose adenocarcinoma was sterilized by accelerated chemoradiotherapy. For comparison, we present same patient profile except with squamous cell carcinoma. Survival at bottom of graph is for 65-year-old patient who did not respond to therapy and was found to have T4 tumor at surgery. Two curves represent squamous and nonsquamous tumor histologic types.

	Discussion

Top Abstract Patients and methods Results Discussion Appendix 1 References

Toxicity (risk)
Induction therapy followed by surgery was toxic, but toxicity was manageable and not fatal. Despite toxicity, surgery was not delayed, and surgical mortality was comparable to that with other protocols. Morbidity occurred in nearly every third patient, but more than half were atrial arrhythmias. Thus although morbidities were multiple, they seemed not to be excessive. Toxicity of adjuvant therapy was similar to that of induction therapy, but in this final phase of therapy, toxicity-related deaths did occur. The overall observed treatment-related mortality of 9% compares favorably with the 10% reported by the multicenter Southwest Oncology Group (SWOG), which followed a more standard protocol of induction chemoradiation and resection.¹

Feasibility
Induction therapy followed by resection was feasible. Resectability in 79% of cases is superior to rates reported after induction chemotherapy alone in stage IIIA N2 NSCLC^11-13 and similar to the rate reported by SWOG after neoadjuvant chemoradiotherapy for both stage IIIA and stage IIIB disease.¹ This accelerated strategy was feasible even though most cases of IIIB disease were pN3, unlike with SWOG 8805.

An advantage of accelerated multimodality therapy is superior patient compliance and less attrition as a result of accumulated toxic effects, increasing feasibility. Seventy-seven percent of patients completed all prescribed treatment, whereas only 45% of patients enrolled in Cancer and Leukemia Group B 8935 completed the prescribed therapy.¹¹ Although a similar proportion of patients in SWOG 8805 (78%) completed induction therapy, adjuvant therapy was prescribed and given to only 37 (29%) of 126 trial participants.¹

Response
Clinical response to accelerated induction therapy was similar to the response to three cycles of induction chemotherapy alone¹⁴ or to two cycles of concurrent chemoradiotherapy.^1,15 The 12-day induction protocol had pathologic response (complete and partial) and nodal downstaging similar to those of other concurrent regimens lasting 33 days¹⁵ and 36 days.¹

Survival
Accelerated multimodality therapy produced a median survival 1 year longer than that seen in SWOG 8805, a phase II trial that also enrolled patients with both stage IIIA and IIIB disease.¹ Long-term survival (>5 years) was seen in 30% of patients, whereas it was 26% at 3 years in SWOG 8805.¹

Recurrence
Local control was excellent, with only 9% of patients having cancer recurrence in the ipsilateral thorax, compared with a 30% local recurrence rate reported by Grunenwald and colleagues¹⁵ in patients with IIIB disease and a 20% rate in SWOG 8805.¹Distant metastases remain the most common and discouraging problem. Nearly half of the patients had systemic recurrence, usually in the brain, a common finding with multimodality treatment of stage IIIA and IIIB disease.^1,2,11-15

Predictors
Pathologic downstaging was the most important predictor of improved survival. Approximately a third of patients had their disease downstaged to N0 or N1, with a 5-year survival of almost 55%. This is similar to survival among patients with newly diagnosed stage IB or stage IIA NSCLC.¹⁶ Mediastinal nodal sterilization provided equivalent survival regardless of whether the disease was initially N2 or N3.

Persistent mediastinal nodal metastasis has been reported as a reliable predictor of death,^1,2,15 with 18% 3-year survival. These results question the benefit of resection in the absence of nodal downstaging.

In contrast, this report establishes an important middle ground. Patients with residual N2 disease (ypN2 status) after accelerated induction therapy had a median survival of 27 months, with 31% 5-year survival. One possible explanation for this near doubling of survival despite persistent N2 disease is the accelerated time frame. Indeed, some patients with microscopic residual nodal disease at the time of resection might in fact have had sterilization if several more weeks had elapsed before removal. This is reflected in a lower percentage of apparent pathologic downstaging in our study (33%) than the 67% and 53% rates reported after standard induction therapy for N2 disease.^1,2 However, the rate is similar to that observed after induction therapy for stage IIIB cancers.^14,15

Strengths and limitations
In this analysis we have highlighted the value of accelerated multimodality therapy for stage III NSCLC. It is difficult to know whether the enhanced overall survival is related to limited toxicity, increased feasibility, or better pathologic response. Hazard function analysis allowed treatment-related death to be distinguished from cancer-related death.⁹ In Figure 2, B, the area under the early, steep portion of the curve is the risk of toxicity-related death. Its height is governed by the toxicity of treatment (concurrent chemoradiation and surgery), and its width reflects duration of therapy. Accelerated therapy results in a brief period of treatment-related death risk. After completion of treatment, a steady-state risk of death reflects the ongoing and unremitting effects of residual or recurrent cancer.

Enhanced feasibility and response with manageable toxicity and prolonged survival are arguably the central strengths of accelerated multimodality therapy for both stage IIIA and stage IIIB NSCLC. These depend on dedicated multidisciplinary care and come with some unexpected costs, especially those related to unscheduled hospital readmission. The demonstrated feasibility of delivering all components of prescribed therapy is a testament to the expertise of our multimodality team and the increased stamina of selected patients who are treated rapidly. Experience and clinical volume translate into better outcomes in many realms of surgery.¹⁷ Requirements of experienced medical and radiation oncologists and general thoracic surgeons may limit the application of accelerated multimodality therapy to large-volume centers.

Clinical inferences
Accelerated multimodality therapy is equally valuable in stage IIIA and stage IIIB disease, but pathologic response cannot be predicted. Patients with N2 and N3 disease respond similarly. Improved survival is seen in younger patients and those with nonsquamous histologic type, sterilization of mediastinal lymph nodes, and lower ypT. Persistent ypN2 disease reduces the probability of long-term survival but does not preclude it.

	Appendix 1

Top Abstract Patients and methods Results Discussion Appendix 1 References

 
Predictors of survival
Two aspects of identifying predictors of survival were unconventional, although, as has been pointed out to the readership of this Journal, they are rapidly becoming mainstream in statistical circles in one form or another: (1) careful consideration of the scaling of continuous and ordinal variables and (2) variable selection on the basis of random sampling (bootstrap bagging¹⁸).

For scaling, continuous and ordinal variables were assessed univariably by decile risk analysis to suggest a set of transformations of scale that may be required to ensure good calibration to survival. Then 1000 bootstrap data sets were constructed and analyzed by stepwise forward selection with a criterion for retention of variables in the models of P = .1. The 1000 models were then subjected to analyses of correlated variables to quantify frequency of occurrence of each cluster of variables. The most frequently occurring member of a cluster appearing in at least 50% of the bootstrap analyses was selected for the final multivariable equation. The 50% rule equally balances false-positive and false-negative identification of risk factors. For each continuous and ordinal variable selected by the 50% rule, the scaling that most frequently was observed in these 1000 models was selected as the transformation incorporated into the final model.

Tabular results of multivariable analyses include an expression of frequency of bootstrap occurrences (reliability of identification of risk factors). Regression coefficients rather than hazard ratios are presented because of the nonproportional nature of the multiphase hazard method and because of the transformations of scale required for continuous and ordinal variables.

	Acknowledgments

 
We thank Diane Baisden for database management, Barbara Chonko and Tess Knerik for editorial assistance, and Brian Kohlbacher for graphics expertise.

	References

Top Abstract Patients and methods Results Discussion Appendix 1 References

 

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11. Sugarbaker DJ, Herndon J, Kohman LJ, Krasna MJ, Green MR. Results of cancer and leukemia group B protocol 8935.A multiinstitutional phase II trimodality trial for stage IIIA (N2)non-small-cell lung cancer. Cancer and Leukemia Group B ThoracicSurgery Group. J Thorac CardiovascSurg. 1995;109:473–483[Abstract/Free Full Text]
    
12. Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB Jr, Lee JS, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–680[Abstract/Free Full Text]
    
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Malcolm M. DeCamp Thomas W. Rice Sudish C. Murthy Eugene H. Blackstone Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DeCamp, M. M. Articles by Blackstone, E. H. Search for Related Content PubMed PubMed Citation Articles by DeCamp, M. M. Articles by Blackstone, E. H. Related Collections Lung - cancer