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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 952-958

Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival


1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
2 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
3 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA

Date of Web Publication25-Jul-2016

Correspondence Address:
Salma K Jabbour
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08901
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.177214

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 > Abstract 


Background: We seek to investigate whether carboplatin-based induction chemotherapy before modern day concurrent chemoradiotherapy (CCRT) improves survival in patients with bulky, locally advanced nonsmall cell lung cancer (NSCLC).
Materials and Methods: This analysis included 105 patients with Stage II and III NSCLC treated with definitive CCRT from 2003 to 2013. All patients underwent definitive treatment with weekly platinum-based doublet chemotherapy delivered concurrently with 60–66 Gy of thoracic radiotherapy. Thirty patients who received induction chemotherapy before CCRT had T4 disease, N3 disease, or gross tumor volume (GTV) of >150 cm 3. These patients were compared to those with unresectable disease who received CCRT alone without induction chemotherapy. Statistical analysis included univariate and multivariate methods.
Results: Mean follow-up time was 15.6 months. Patients treated with carboplatin based induction chemotherapy demonstrated prolonged overall survival (28.2 vs. 14.2 months, P = 0.04), progression free survival (12.6 vs. 9.0 months, P = 0.02), and distant metastasis free survival (15.8 vs. 10.1months, P = 0.05) compared to those who received CCRT alone without induction chemotherapy. Univariate analysis revealed older age, larger GTV, and squamous pathology as negative prognostic factors. When controlling for these factors, Cox regression analysis indicated a trend toward significantly improved overall survival in the induction cohort (P = 0.10).
Conclusion: In patients with large tumors or bulky nodal NSCLC, carboplatin-based induction chemotherapy may be an important addition to definitive CCRT in the modern era. Our findings strongly support further investigation induction chemotherapy in this population.

Keywords: Chemoradiation, induction chemotherapy, nonsmall cell lung cancer


How to cite this article:
Ahmed I, Ferro A, Baby R, Malhotra J, Cohler A, Langenfeld J, Aisner J, Zou W, Jabbour SK. Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival. J Can Res Ther 2016;12:952-8

How to cite this URL:
Ahmed I, Ferro A, Baby R, Malhotra J, Cohler A, Langenfeld J, Aisner J, Zou W, Jabbour SK. Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival. J Can Res Ther [serial online] 2016 [cited 2019 Dec 9];12:952-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/952/177214




 > Introduction Top


As the leading cause of cancer worldwide, lung cancer has remained difficult to provide long-term disease control.[1] Approximately, 85% of patients with this highly fatal diagnosis have nonsmall cell lung cancer (NSCLC). With relatively recent developments in our therapeutic approach, patients with NSCLC face a slightly improved prognosis, in large measure from concurrent chemoradiation therapy (CCRT); nonetheless survival rates remain poor, with 2-year survival at just 50%.[2] Approximately, half of all patients diagnosed with NSCLC present with either Stage II or Stage III disease.[3] For these patients, distant failure rates tend to be high despite locoregional response. A 2008 outcomes analysis of Stage III NSCLC patients, treated with definitive CCRT, reported locoregional progression in 8% of patients but distant failure in 58%.[4] In 2010, another study reported 30% local failure and 35% distant failure in Stage III and oligometastatic Stage IV patients treated with definitive CCRT.[5] For patients with high metastatic potential, systemic treatment with induction chemotherapy before CCRT could be crucial for early treatment of distant micrometastatic disease.

For patients with inoperable locally advanced disease, CCRT therapy has served as the mainstay of treatment nearly three decades.[6],[7] Induction chemotherapy improves survival when added to definitive radiation therapy (RT) alone.[8] However, once CCRT was established as the standard of care for locally advanced, unresectable NSCLC, median survival for these patients rose to approximately 17 months.[6], 7, [9],[10],[11],[12] Multiple studies have evaluated the role of induction chemotherapy with CCRT, including the CALGB 39801 and LAMP studies.[11],[13] Although many oncologists have interpreted these studies to show no benefit with the addition of induction chemotherapy to CCRT, there are multiple issues that confound the interpretation of these studies in the modern day. These older induction chemotherapy trials occurred before positron emission tomography/computed tomography (PET/CT) staging or three-dimensional (3D) RT planning became routine practice and before dose-volume histogram (DVH) criteria for lung toxicity were uniformly employed.

The LAMP trial enrolled patients from 1998 to 2001, and CALGB 39801 enrolled from 1998 to 2002 before 3D radiation treatment planning was routine.[11],[13] At that time, DVH criteria for lung toxicity were not uniformly employed to reduce rates of radiation pneumonitis.[14] CALGB 39801 allowed 2D conformal planning, while the LAMP trial does not detail specific RT techniques used in the study.[11],[13] When evaluating the survival curves from these studies, it is apparent that there is a significant rate of morbidity during months 2–6 when high-grade radiation pneumonitis is seen.[15] Given the poor survival rates possibly due to outdated radiation techniques and resultant toxicity, it is likely that the possible survival benefit afforded by induction chemotherapy would have been outweighed by possible treatment toxicities. Likewise, the lack of routine PET/CT staging could also have resulted in less accurate staging and inadvertent inclusion of patients with occult Stage IV disease, resulting in poorer survival rates.

Notwithstanding controversial results in earlier studies, full dose induction chemotherapy may indeed improve tumor control. This may be accomplished by radiosensitization of intrathoracic disease, reduction of nodal bulk, and destruction of micrometastases warranting further investigation of its potential benefits to treatment, as well as subpopulations most likely to benefit.[16] In this study, we postulated that induction chemotherapy could potentially provide a benefit for large volume disease, extensive mediastinal lymphadenopathy, or T4 disease in a more modern population uniformly staged with PET scan and treated with modern RT.


 > Materials and Methods Top


Our Institutional Review Board-approved, single-institution retrospective cohort analysis included patients with locally-advanced, inoperable NSCLC who were treated definitively with carboplatin-based doublet chemotherapy and thoracic RT to 60–66 Gy between 1999 and 2013. Patient privacy was maintained in accordance with Health Insurance Portability and Accountability act regulations.

All study participants had an initial consultation that involved a history and physical exam. Histologic or cytologic diagnosis confirming adenocarcinoma, squamous cell carcinoma, poorly differentiated NSCLC, and/or NSCLC not otherwise specified was required for initiation of therapy. Thus, all patients included had confirmed NSCLC. Thoracic CT and PET/CT scans were utilized for clinical staging, and patients were staged according to the AJCC tumor node metastasis (TNM) Cancer Staging Manual, 6th edition.[17] Only those patients with surgically unresectable Stage IIA to Stage IIIB NSCLC were included in the review. All patients received CCRT with curative intent, and patients undergoing induction chemotherapy received a carboplatin-based regimen. Exclusion criteria were prior surgery or stereotactic body RT for NSCLC, small cell or neuroendocrine histology, Stage I or Stage IV disease, induction chemotherapy without carboplatin, and definitive therapy with RT only due to intolerance of concurrent chemotherapy.

At this institution, induction chemotherapy is typically prescribed for patients with extensive primary tumors or bulky nodal disease to assess chemosensitivity. Select patients with poor performance status may also receive induction chemotherapy before proceeding to CCRT. A 2006 Japanese study defined large primary tumors as any tumor with gross tumor volume (GTV) >52 cm 3 while a 2010 Italian paper defined it as any tumor with GTV > 100 cm 3.[18],[19] Additionally, N2 disease is considered the bulky nodal disease in literature.[19] All patients who underwent induction chemotherapy at our institution due to tumor bulk presented with T4 disease, N3 disease, or GTV > 135 cm 3. [Table 1] lists T and N stage, GTV and additional rationale for induction therapy – if applicable – for each patient in the induction cohort. Those who received induction chemotherapy were assessed for tumor response. If thoracic CT showed stable disease or local progression after induction therapy, the patient proceeded to CCRT. If there was evidence of distant progression on CT, the patient would receive chemotherapy alone and was excluded from this study.
Table 1: All patients who received induction CT prior to CCRT

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The primary variable of interest in this study was treatment with induction chemotherapy before CCRT. The typical induction chemotherapy regimen involved two cycles of intravenous (IV) infusional delivery of a carboplatin-based doublet, and sometimes triplet, therapy. The most common induction regimen was paclitaxel (200 mg/m 2/week), and carboplatin (area under the curve [AUC] =6) given for two cycles of 3 weeks each.

Definitive chemotherapy was administered weekly with daily RT to a total dose of 60–66 Gy. Specifically, the definitive chemotherapy regimen consisted of IV infusional drug delivery on days 1, 8, 15, 22, 29, 36, and 43 of RT. The typical chemotherapy regimen included paclitaxel (45–60 mg/m 2/week) plus carboplatin (AUC = 2/week). On days when the patient was treated with RT and chemotherapy, RT was delivered following the administration of chemotherapy. Thirteen elderly/infirm patients received a single-agent as the concurrent chemotherapy.[20],[21]

During RT, each patient was placed in a supine position with arms up to allow accurate reproducibility of the target lesion among treatment sessions, and a large rigid pillow or mold was utilized for each patient to allow for immobilization. RT was delivered to the involved field using 3D conformal or intensity-modulated technique. The prechemotherapy tumor volume was included to a dose of 40–45 Gy followed by a boost to postchemotherapy tumor volumes. RT was delivered through anteroposterior fields first to 40 Gy in 1.8 or 2 Gy/fraction/day. This was followed by oblique fields to avoid the spinal cord for an additional 20–26 Gy, for a total RT dose of typically 60–66 Gy. If patients presented with involved bilateral mediastinal lymph nodes, then intensity modulated RT was employed either from the onset of RT or for the boost/off-cord component of their RT. The analytic anisotropic algorithm was employed with tissue inhomogeneity corrections, with 6 MV or 15 MV photons used to deliver the RT. The radiation dose for the spinal cord was <50 Gy. The mean lung dose was <20 Gy and V5 <60–70% and V20 <37%.

Follow-up chest CT was performed 6–8 weeks after the completion of CCRT and then every 3 months for the 1 year and every 6 months for 2 years, then yearly thereafter. These CT scans were evaluated by radiology, medical oncology, and radiation oncology.

Study endpoints and statistical analysis

Overall survival (OS) was the primary endpoint in this study. Other endpoints of interest included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). All four parameters were quantified using the difference between the date of NSCLC diagnosis and date of last follow-up and/or recurrence or death. Survival analysis was performed comparing patients undergoing induction followed by CCRT (“induction”) with patients receiving only CCRT (“concurrent”).

The computer software program R (version 2.15.1) was used for all statistical analyses (The R Project for Statistical Computing, http://www.r-project.org/). Survival curves were produced using the Kaplan–Meier method, and cohorts were compared using log-rank testing. Chi-squared or Fisher's exact tests were employed when appropriate with a P =0.05 or less indicating significance. A P value between 0.05 and 0.10 was considered to represent a trend toward significance. Cox regression was used in univariate analysis of all potential confounders. All variables found to significantly influence OS were included in multivariate analysis.


 > Results Top


Patient characteristics

Of 204 patients treated for lung cancer at our institution since 1999, we identified 105 patients who met the inclusion criteria of this study. This population had a median follow-up period of 15.6 months and a median age of 65.5 years. Most patients (72.4%) exhibited an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 before treatment. All patients received definitive RT to a median of 62 Gy [Table 2] and [Table 3].
Table 2: Baseline patient characteristics

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Table 3: Clinicopathologic features and treatment characteristics

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Study cohorts consisted of: (a) induction, (n = 30, 28.6%) and (b) concurrent (n = 75, 71.4%) chemotherapy. The two cohorts were identical in regards to patient characteristics, clinicopathologic features, and treatment. T and N-stage distribution was similar among cohorts. No significant differences existed between cohorts with respect to age, gender, smoking status, ethnicity, and presence of the following comorbidities chronic obstructive pulmonary disease, hyperlipidemia, and congestive heart failure. Disease characteristics were also similar among cohorts, including tumor pathology, TNM stage, and stage group. Concurrent chemotherapy regimen and total dose of RT were also similarly distributed between cohorts [Table 2] and [Table 3].

Survival analysis

Carboplatin-based induction chemotherapy before CCRT significantly improved survival in patients with bulky, inoperable, and locally-advanced NSCLC when compared with lower volume, noninduction treated cases. One and two-year survival for the study population were 63.8% and 28.6%. In our population, the induction cohort demonstrated a median OS of 28.2 months, whereas the concurrent cohort exhibited an OS of 14.2 months (P = 0.04) [Figure 1]. Overall 1- and 2-year survival rates were 76.7% and 53.3% in the induction cohort while they were 60.0% and 18.7% in the concurrent group. Univariate testing exposed older age (P = 0.01), greater tumor volume (P = 0.03), and squamous cell pathology (P = 0.02) as negative prognostic factors in OS. Subsequent multivariate analysis accounting for these factors demonstrated a persistent survival benefit with induction chemotherapy trending toward significance (hazard ratio = 0.6 [0.33–1.10], P = 0.10). Older age remained a strong negative predictor of OS (P = 0.02).
Figure 1: Kaplan–Meier overall survival curve, red = induction (n = 30), black = concurrent (n = 75)

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Induction chemotherapy with carboplatin also affected disease progression. Patients who underwent induction chemotherapy experienced longer periods without recurrence, with a median PFS of 12.6 months, versus 9.0 months in patients who did not undergo induction therapy (P = 0.02) [Figure 2]. LRRFS rates were similar in the induction and concurrent cohorts (16.7 vs. 12.6 months, respectively, P = 0.21) [Figure 3], but DMFS was significantly improved in the induction cohort (15.8 vs. 10.1 months, P = 0.05) [Figure 4]. At 1-year, 56% of concurrent patients had failed distantly, versus 43.3% of induction patients.
Figure 2: Kaplan–Meier progression-free survival curve, red = induction (n = 30), black = concurrent (n = 75), PFS = Progression-free survival

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Figure 3: Kaplan–Meier locoregional recurrence-free survival curve, red = induction (n = 30), black = concurrent (n = 75), LRRFS = Locoregional failure-free survival

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Figure 4: Kaplan–Meier distant metastasis-free survival curve, red = induction (n = 30), black = concurrent (n = 75), DMFS = Distant metastasis-free survival

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 > Discussion Top


Induction chemotherapy may, in fact, play a role in the optimal treatment of locally advanced, inoperable NSCLC. In this study, we sought to define the potential survival benefit associated with carboplatin-based induction chemotherapy administered before definitive CCRT using modern techniques. We hypothesized that patients with particularly bulky primary or nodal disease might derive the most benefit from induction therapy although the ideal subset of patients for this therapy is currently unknown. Patients at this institution who underwent induction chemotherapy before CCRT had T4, N3, or large GTV tumors and demonstrated significantly longer OS, PFS, and DMFS than patients who underwent CCRT alone. Indeed, prior studies investigating the value of induction chemotherapy for locally-advanced NSCLC do exist, including some prospective Phase II and III trials.[2],[3],[13],[22],[23] However, all previous studies either found no benefit associated with induction chemotherapy before CCRT or alternatively they reported relatively lengthy survival rates with induction therapy but were designed without control arms. Trials such as LAMP or CALGB 39801, on which oncologists currently base practice decisions, were conducted without consistent use of PET staging, with outdated radiation planning techniques and lack of modern knowledge of DVH constraints, likely contributing to increased rates of lung toxicity and poorer survival. Our study included patients treated with modern RT techniques and PET staging. We demonstrate a survival benefit for patients with bulky disease treated with induction chemotherapy followed by CCRT, as compared with CCRT alone, and may alter outcomes for patients treated in the modern day.

A 2005 Phase II noncomparative trial by Belani et al. analyzed survival and toxicity outcomes associated with three different regimens of thoracic radiotherapy delivery: sequential chemotherapy followed by thoracic radiothererapy (SCRT), induction chemotherapy with CCRT, and CCRT with consolidation chemotherapy.[13] Median OS rates for the respective arms were 13.0, 12.7, and 16.3 months suggesting no benefit with induction chemotherapy. However, accrual was discontinued early for the induction arm after a discouraging preliminary analysis, no boundary definitions were published for discontinuation, and the accrual goal for statistical accuracy was not met.

In 2002, Vokes et al. conducted a Phase II trial examining survival and toxicity outcomes associated with three different induction chemotherapy regimens followed by CCRT for Stage IIIB NSCLC (CALGB 9431).[22] This study reported an overall median OS of 17.0 months, and an OS as high as 18.3 months for one arm, at a time when the expected OS was 13–14 months with SCRT and 16–17 months CCRT.[9],[10] These encouraging results led to the conception of CALGB 39801, a randomized Phase III trial published in 2007 comparing survival and toxicity in Stage III NSCLC patients undergoing either definitive CCRT or induction chemotherapy followed by CCRT.[11] However, the survival difference between the two arms was not statistically significant (P = 0.30), with relatively shortened OS of 14 months in the induction cohort and 12 months in the noninduction cohort.

A more recent study than the LAMP and CALGB studies was the SWOG S0023 trial by Kelly et al., which showed a median survival of 27 months with the incorporation of routine PET staging and DVH criteria for organs at risk.[24] In this study, patients underwent CCRT followed by three cycles of adjuvant chemotherapy. Additionally, the 2007 Phase II HeCOG trial, induction therapy with gemcitabine/paclitaxel followed by CCRT yielded a median survival of 20.8 months, about 24% better than the standard at the time.[2] Those who exhibited a tumor response, or at least stable disease postinduction, had a median survival of 31.4 months–141% of the then expected survival. In this study, all were treated with more modern 3D conformal RT. Furthermore, a 2013 phase II trial of induction chemotherapy followed by CCRT in 49 patients reported a median survival of 21.8 months.[16]

Our results suggest that when combined with modern day RT and planning techniques, induction chemotherapy before CCRT may indeed benefit particular cases, perhaps those with more extensive primary tumors or bulky nodal NSCLC. All patients who underwent induction chemotherapy at our institution due to tumor bulk presented with T4 disease, N3 disease, or GTV >135 cm 3. In contrast, CALGB 39801 excluded patients with scalene, supraclavicular, or contralateral hilar lymph node involvement.[11] Patients with pleural effusions, tumors invading the vertebral body, or ECOG score greater than 1 were also excluded from CALGB 39801. Seemingly, our study included patients with greater disease burden and slightly poorer median performance status. Nevertheless, the median OS of our study population was 15.6 months, with an OS of 14.2 months in the noninduction cohort and an OS of 20.0 months for the induction cohort, which in fact consisted of bulkier NSCLC cases. N3 nodal status was detected in 53.3% of induction patients, more than double the proportion of N3 disease (24.0%) in the concurrent cohort [Table 2]. Theoretically, equalization of disease bulk among cohorts could possibly reveal more prominent improvements in survival benefit and distant control associated with induction chemotherapy. This would need to be addressed in future studies.

In this investigation, carboplatin-based induction chemotherapy reduced distant metastasis in patients, in addition to prolonging survival. Due to its systemic nature, chemotherapy is thought to eliminate micrometastatic disease and potentially reduce rates of distant failure. Hence, we hypothesized that distant failure would be further reduced in our induction cohort. At 1 year, 56% of concurrent patients had failed distantly, versus 43.3% of induction patients. Although the distant recurrence rates are not necessarily low in our population, it is significantly lower in our induction group. Addition of induction chemotherapy to standard definitive CCRT could potentially improve distant control in patients, a parameter which has yet to be optimized.

We also expected a greater difference in OS between cohorts in the multivariable analysis. Although univariate calculations showed a significant prolongation in OS in the induction cohort, multivariate analysis offered only a trend toward significance (P = 0.10). As this was a retrospective cohort study, it is possible that sources of bias (selection bias, information bias) and unknown confounders in this analysis affected the statistical significance of our results. In addition, though our cohort censuses followed a 1:2 ratio (induction: concurrent), our overall subject pool, and especially the induction cohort, were relatively small in number. Nonetheless, the stark difference in 2-year survival rates – 53.3% in induction cohort versus 18.7% in concurrent cohort – suggests that carboplatin-based induction chemotherapy provides a survival benefit most apparent in the long-term. With comparable rates of locoregional control between the two cohorts, it is possible that distant control contributes to the major survival benefit with induction chemotherapy.


 > Conclusion Top


Our retrospective cohort study found a significant survival benefit associated with carboplatin-based induction chemotherapy in patients with bulky Stage II and III inoperable NSCLC. Specifically, we observed a significant benefit in OS, PFS, and DMFS. Considering statistically significant results in this small, retrospective study, further investigation with larger, more homogeneous populations, and prospective study design using modern RT techniques is warranted. Patients would greatly benefit with clarification of an ideal target population for induction chemotherapy.

Financial support and sponsorship

Dr. Salma K. Jabbour has received an honorarium from Abbott Laboratories. Dr. Joseph Aisner has received ongoing funding from the National Cancer Institute and serves as a board member for Bristol Myers Squibb. For the remaining authors none were declared.

Conflicts of interest

There are no conflicts of interest.

 
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