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Implications of Delayed Initiation of Radiotherapy: Accelerated Repopulation after Induction Chemotherapy for Stage III Non-small Cell Lung Cancer

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Implications of Delayed Initiation of Radiotherapy

Accelerated Repopulation after Induction Chemotherapy for Stage III

Non-small Cell Lung Cancer

Chien P. Chen, MD, PhD,* Vivian K. Weinberg, PhD,† Thierry M. Jahan, MD,‡

David M. Jablons, MD,§ and Sue S. Yom, MD, PhD*

Introduction: For patients with stage III non-small cell lung cancer treated with induction chemotherapy (ICT), delayed initiation of subsequent radiotherapy (RT) may allow for repopulation in the interval between treatment modalities and during the early phase of RT. We quantified the impact of postinduction RT timing by evaluating the pace of tumor regrowth.

Methods: Institutionally approved retrospective review identified 21 analyzable patients with stage III non-small cell lung cancer who had platinum-based ICT followed by RT⫹/⫺ chemotherapy from 2002 to 2009. Radiographic response was determined by RECIST criteria and the volume of the single largest tumor mass on the pre-ICT, post-ICT, and RT-planning computed tomography scans. Results: After ICT, the median percent volume change from pre-ICT baseline was⫺41% (range ⫺86 to ⫹86%). By the RT-planning computed tomography scan, the median percent volume change from the post-ICT timepoint was⫹40% (range ⫺11 to ⫹311%) and the median volume change was⫹20 ml (range ⫺4 to 102 ml); these changes were significant (p⫽ 0.0002). Similar results were seen for tumor diameter. A correlation was observed between the amount of delay and degree of regrowth for percent volume (p⫽ 0.0006) and percent diameter change (p⫽ 0.003). A delay greater than 21 days produced greater increases in percent volume change (p⫽ 0.002) and percent diameter (p⫽ 0.055) than lesser delays.

Conclusions: After ICT, tumor regrowth can occur within a few weeks. Radiation treatment planning should begin as soon as pos-sible after the administration of ICT to maximize the benefits of cytoreduction.

Key Words: Stage III lung cancer, Induction chemotherapy, Radi-ation, Repopulation.

(J Thorac Oncol. 2011;6: 1857–1864)

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or patients with stage III non-small cell lung cancer (NSCLC), optimal treatment may include concurrent chemoradiation (CRT) or preoperative chemotherapy or CRT followed by an attempt at definitive surgical resection. For certain stage III cases, induction chemotherapy (ICT) has been theorized to provide the potential benefits of enhancing resectability, testing chemosensitivity to a particular systemic regimen, or reducing the tumor volume that must be treated with high doses of radiation and thus reducing radiation-related toxicity.

Early small randomized trials suggested a role for perioperative ICT for stage III patients.1–3A secondary

anal-ysis of RTOG 8804/8808 showed that for locally advanced NSCLC treated with radiotherapy or chemoradiotherapy, ICT was associated with a trend toward a survival benefit,4

espe-cially for patients with nonsquamous histology. In a recent phase II protocol of patients with stage III NSCLC, neoad-juvant chemotherapy followed by chemoradiotherapy and definitive surgery for stage IIIA bulky and selected IIIB patients has so far demonstrated promising results.5,6 In the

early-stage NATCH trial, subgroup analyses showed that patients with the highest stage disease included in the trial, either stage II or T3N1, achieved nonsignificant but nominal improvement in 5-year overall survival with neoadjuvant chemotherapy compared with either surgery alone or surgery with adjuvant chemotherapy, and more patients in the preop-erative chemotherapy arm received all three cycles.7

It is important to note that randomized studies have indicated that superior survival is achieved with concurrent CRT rather than sequential chemotherapy and radiotherapy in locoregionally advanced lung cancer.8 –12 For eligible

pa-tients, upfront concurrent CRT should be considered first as the accepted standard of care. However, the greater toxicity

*Department of Radiation Oncology, School of Medicine; †Biostatistics Core, Helen Diller Family Comprehensive Cancer; ‡Department of Thoracic Medical Oncology, School of Medicine; and §Department of Thoracic Surgery, School of Medicine, University of California, San Francisco, California.

Disclosure: The authors declare no conflicts of interest.

Address for correspondence: Sue S. Yom, MD, PhD, Department of Radi-ation Oncology, University of California, San Francisco, 1600 Di-visadero Street, Suite H1031, San Francisco, CA 94115. E-mail: yoms@radonc.ucsf.edu

Previously presented, in part, at the 52nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, in San Diego, CA, October 31 to November 1, 2010.

The data and conclusions in this article have not been published in any other format.

Primary data collection and initial analysis were performed by two authors (C.P.C. and S.S.Y.). Final analysis and figures were reviewed by biosta-tistician (V.K.W.). All authors participated in the conceptualization, review of analyses, and approval of the final manuscript.

Copyright © 2011 by the International Association for the Study of Lung Cancer

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experienced during concurrent CRT may not make it the most tolerable or most strategic choice for all patients.

Thus, particularly for patients who have an initially marginal performance status, ICT may be used to decrease the burden of locoregional disease to enable subsequent definitive treatment or to identify patients harboring subclin-ical distant metastasis for whom the toxicity of intensified local treatment may not be justified. However, especially in this population with marginal performance status, the prompt initiation of subsequent definitive treatment may be delayed because of various reasons, including recovery from post-ICT toxicities, difficulty tolerating restaging procedures after ICT, and logistical delays in the scheduling and start of radiother-apy treatment. Unfortunately, post-ICT delays in initiating subsequent therapy may result in accelerated tumor re-growth.13 Regrowth of tumor and loss of the cytoreductive

advantages achieved from ICT may result in a greater pro-pensity for treatment failure.14 A shorter overall treatment

package time is known to improve local control and survival after radiotherapy in patients with lung cancer, especially if cellular repopulation results in a local failure.15,16

For patients with stage III NSCLC who are considered radiotherapy (RT) candidates after ICT, delays in RT initia-tion may allow for accelerated repopulainitia-tion in the interval between modalities and during the early phase of RT. The purpose of this study is to quantify the impact resulting from delays in planning postinduction RT, as measured in terms of tumor regrowth, in the setting of contemporary ICT regimens.

MATERIALS AND METHODS Patient Population

Patients with locally advanced NSCLC who received ICT and underwent computed tomography (CT) simulation in preparation for thoracic RT given at the University of Cali-fornia, San Francisco, between 2002 and 2009 were identified for this retrospective investigation. These patients were eli-gible for analysis if they received ICT before thoracic RT, underwent three-dimensional CT-based simulation before RT, and did not have surgical tumor resection after ICT or before RT. Patients typically received ICT with the initial intent of reducing tumor bulk to allow for a surgical resection or to allow for safer radiotherapy delivery.

Thirty-one patients met initial criteria for inclusion, but 10 patients were excluded due to inadequately documented clinical and radiographic data from the postinduction and preradiotherapy periods. An institutional waiver of informed consent (study 10-03691) was granted for retrospective re-view of the medical records of these patients.

For the 21 patients included in this study, a staging diagnostic CT scan with and without contrast was performed before ICT was started, and a restaging diagnostic CT was obtained after the last cycle of ICT. Subsequently, a radio-therapy-planning CT was performed. All CT scans had a slice thickness of no more than 3 to 5 mm.

Treatment Regimens

All but one patient received platinum-based ICT. The most common regimen was carboplatin-paclitaxel for three

cycles. Other chemotherapy regimens included platinum-dou-blets such as carboplatin-navelbine for three cycles, carbopla-tin-gemcitabine for three cycles, and cisplatinum-etoposide for two cycles. One patient received one cycle of single-agent vinorelbine but because of toxicity was switched to single-agent gemcitabine for four cycles. For those who were treated with concurrent chemoradiotherapy after ICT, most patients received a concurrent taxane, carboplatin-paclitaxel, or cis-platinum-etoposide chemotherapy.

All patients except one received post-ICT thoracic RT for curative intent. Fourteen (67%) patients received concur-rent chemoradiotherapy after ICT, with the concurconcur-rent che-motherapy regimens as described. Seven (33%) patients re-ceived radiotherapy alone after ICT. The median prescribed radiation dose was 6300 cGy (range 1400 –7400 cGy), and the mean prescribed dose was 5478 cGy.

Determination of Radiographic Response For the purpose of this study, radiographic response was determined by measuring the single largest tumor mass both by largest diameter, per RECIST criteria, and volumetri-cally.17 The delineation of the radiographically identified

tumor mass and the calculation of the volume of the tumor mass were performed on CT scans using ADAC Pinnacle 8.0d (Madison, WI). Measurements were taken from the pre-ICT, post-ICT, and RT-planning CT scans using the standard lung level and window settings. Measurements were performed by one observer (C.P.C.) and supervised for con-sistency of procedures by a radiation oncologist experienced in thoracic target delineation (S.S.Y.). Assuming a constant growth rate, doubling time (DT) was estimated using the Schwartz formula18:

DT⫽ (t2⫺ t1) ln 2/ln (VRT-planning/Vpostinduction)

whereby (t2⫺ t1) represents the interval between the

post-ICT CT and the RT-planning CT. Statistical Analysis

Descriptive statistics were calculated to summarize patient and tumor characteristics. Nonparametric tests were performed to evaluate change in measurements because of the sample size and the possibility of non-normality. To analyze the change in tumor volume and tumor diameter, the Wil-coxon matched pairs test was applied. Spearman’s correlation coefficients were calculated to explore the relationship be-tween the interval bebe-tween the postinduction restaging CT and the planning CT scan with the percent change in tumor volume and with the percent change in tumor diameter. The Mann-Whitney U test was used to compare the distributions of the percent change in the tumor volume and in the tumor diameter for patients with delays of less than 21 days versus 21 days or longer in starting RT. All statistical calculations were carried out using Statistica version 6.0 (StatSoft, Inc., Tulsa, OK). Significance was defined as a probability value less than 0.05, and no adjustments were made for multiple testing.

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RESULTS Patient Demographics

Patient and tumor characteristics are summarized in Table 1. The median age was 66 years, and the median Karnofsky Performance Status score was 80. There were 15 (71%) stage IIIA and 6 (29%) stage IIIB patients. Clinical T stages were 14% T1, 29% T2, 19% T3, and 38% T4 tumors. Nodal stages were 14% N0, 10% N1, 62% N2, and 14% N3. Various histologies were represented (52% squamous, 43% adenocarcinoma, and 5% large cell).

Tumor Changes

Table 2 summarizes the median, minimum, maximum, mean, and standard deviation for tumor volume and tumor diameter measurements. The median pre-ICT tumor volume and diameter were 80 ml (range 11.5– 626 ml) and 5.7 cm (range 2.7–11.0 cm), respectively. The median post-ICT tumor volume and diameter were 48.9 ml (range 6.1–392.2 ml) and 4.1 cm (range 1.2–10.4 cm), respectively. Thus, generally, a substantial cytoreductive response was seen in response to ICT resulting in a median decrease of⫺19.8 ml (range ⫺253.6–60.6 ml) in volume and ⫺1.0 cm (range ⫺4.8–1.5 cm) in diameter. Sixteen patients experienced a decrease in both tumor volume and diameter. However, with a median interval between modalities of 21 days (range⫺3 to 176 days), the median tumor volume and diameter as derived from the RT-planning CT regrew to 59.8 ml (range 6.8 – 450 ml) and 5.7 cm (range 2.1–10.1 cm), respectively. The median change in volume was 20 ml (range⫺4 to 102 ml) with a median change in diameter of 0.5 cm (range ⫺0.3 to 2.1 cm).

Transitions from one therapeutic modality to another are prone to delays for a variety of reasons. In our series, delays in initiation of subsequent local therapy were caused by logistical/scheduling constraints in 14 of 21 cases, but there were also more complex issues such as planned surgical intervention followed by a patient’s refusal of surgery (5/21 cases) and post-ICT-related toxicities or complications (2/21 cases). Figure 1 serves as an illustrative example of how delays in initiation of subsequent local therapy can lead to significant tumor repopulation after ICT. Figure 1A shows the CT scan obtained before initiation of ICT given for a large right-sided NSCLC tumor. Figure 1B shows the CT obtained after ICT, demonstrating a notable radiographic response. However, after a delay of 45 days, in Figure 1C, the tumor size has increased, recovering 64% of the post-ICT volume and 37% of the post-ICT tumor diameter as determined per RECIST criteria.

To quantify the tumor response in terms of volume and diameter from pre-ICT to post-ICT timepoints and the sub-sequent tumor regrowth from post-ICT to the timepoint of the RT-planning CT, we calculated the percent tumor volume and diameter changes observed for these two intervals. Figure

TABLE 1. Patient and Tumor Characteristics

Gender

Male 11 (52%)

Female 10 (47%)

Age, median (range), yr 66 (52–86) KPS, median (range) 80 (70–100) Stage (IIIA 15, IIIB 6), n (%)

T1 3 (14) T2 6 (29) T3 4 (19) T4 8 (38) N0 3 (14) N1 2 (10) N2 13 (62) N3 3 (14) M0 21 (100) Histology, n (%)

Squamous cell carcinoma 11 (52) Adenocarcinoma 9 (43) Large-cell carcinoma 1 (5) Location of primary lung tumor, n (%)

RUL 6 (29)

RML 3 (14)

RLL 4 (19)

LUL 5 (24)

LLL 3 (14)

KPS, Karnofsky Performance Status; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.

TABLE 2. Preinduction, Postinduction, and RT-Planning CT Tumor Size

Delay Time (d) Preinduction Tumor Volume (ml) Postinduction Tumor Volume (ml) RT-Planning CT Tumor Volume (ml) Preinduction Tumor Diameter (cm) Postinduction Tumor Diameter (cm) RT-Planning CT Tumor Diameter (cm) Median 21.0 80.0 48.9 59.8 5.7 4.1 5.7 Minimum ⫺3.0 11.5 6.1 6.8 2.7 1.2 2.1 Maximum 176.0 626.2 392.2 450.0 11.0 10.4 10.1 Mean 31.8 117.7 77.0 102.2 6.0 4.7 5.5 SD 37.9 141.6 94.6 115.9 2.3 2.4 2.3

Delay time: time between postinduction chemotherapy CT scan and radiotherapy planning CT. Preinduction tumor volume: tumor volume of largest lesion (T⬘) on preinduction chemotherapy CT scan. Postinduction tumor volume: tumor volume of T⬘ on postinduction chemotherapy CT scan. RT-planning CT tumor volume: tumor volume of T⬘ on postinduction chemotherapy CT scan. Preinduction tumor diameter: tumor diameter based on RECIST criteria of largest lesion (T⬘) on preinduction chemotherapy CT scan. Postinduction tumor diameter: tumor diameter based on RECIST criteria of T⬘ on postinduction chemotherapy CT scan. RT-planning CT tumor diameter: tumor diameter based on RECIST criteria of T⬘ on postinduction chemotherapy CT scan.

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2A presents the percent change in tumor volume post-ICT and at RT-planning for each patient. Sixteen (76%) patients had a reduction in tumor volume after ICT, whereas five (24%) had stability or tumor progression. However, from the time of the postinduction CT to the time of the RT-planning CT, 14 (87.5%) of the 16 patients who had shown a radiographic response exhibited tumor regrowth, whereas 2 had disease stability or a slight further decrease in tumor volume. Of the five patients who had stability or tumor progression after ICT, all five experienced tumor growth from the time of the post-ICT restaging CT to the RT-planning CT (range 19 – 57% regrowth). Similar trends were seen using the metric of percent diameter change as illustrated in Figure 2B.

Figure 3 summarizes the median percent change with ranges in the volume and diameter for these same intervals: time from pre- to post-ICT RT scan and time from post-ICT RT scan to RT-planning CT. The median percent change in the tumor volume for these two intervals were⫺41% (range ⫺86 to 86%) and 40% (range ⫺11 to 311%), respectively. Similarly, the median percent change in the tumor diameter

were ⫺17% (range ⫺63 to 27%) and 14% (range ⫺3 to 172%). The Wilcoxon matched pairs test resulted in statisti-cally significant differences in the tumor volume changes from the pre-ICT to post-ICT CT scans (p⫽ 0.003) and from the post-ICT to RT-planning CT scans (p⫽ 0.0002). Similar trends for tumor diameter changes were observed (p⫽ 0.001 and 0.0002, respectively).

Tumor Change in Relation to Delay Time To determine if tumor growth was related to an increased interval time between the end of ICT and the start of RT, Spearman correlation coefficients were calcu-lated. Both the percent change in volume and percent change in diameter were significantly correlated with the interval delay (days) with correlation coefficients of 0.69 (p ⫽ 0.0006) and 0.62 (p ⫽ 0.003) for volumetric and diameter changes, respectively.

Using the median duration between post-ICT and the RT-planning CT, the study cohort was dichotomized with 12 patients having a durationⱕ21 days and 9 patients having a

FIGURE 1. Tumor response and regrowth during interval between postinduction chemotherapy restaging CT scan and RT-plan-ning CT. A, Preinduction chemotherapy CT of a large right-sided NSCLC tumor. B, Postinduction chemotherapy CT showing partial response to ICT. C, RT-planning CT, obtained 45 days after postinduction chemotherapy restaging CT, illustrates tumor regrowth. CT, computed tomography; RT, radiotherapy; NSCLC, non-small cell lung cancer; ICT, induction chemotherapy.

FIGURE 2. Percent change in tumor volume and tumor diameter. A, Tumor volume changes for each patient during two time intervals. Light gray bars represent the percent volume change from pre-ICT to post-ICT. Dark gray bars are the percent volume changes from post-ICT to the time of the RT-planning CT. B, The second figure summarizes percent change in diameter for each patient during these two time intervals. ICT, induction chemotherapy; RT, radiotherapy; CT, computed tomography.

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duration⬎21 days. Figure 4 illustrates that for patients with a delay duration ofⱕ21 days, there was a smaller percentage tumor growth versus that seen in patients having more than 21 days of delay between the postinduction CT to the RT-planning CT (median change in percent volume: 24 ml versus 34 ml and median change in percent diameter: 10 cm versus 35 cm). This cutpoint was found to result in a statistically significant difference in the percent change in the tumor volume and of borderline significance for the percent change

in the tumor diameter (p⫽ 0.002 for volume change and p ⫽ 0.055 for RECIST criteria). Figure 5 further illustrates the relationship between delay in radiotherapy initiation and tumor regrowth as a series of scatter plots.

Tumor Volume Doubling Time

To assess how fast the tumor volume increased from post-ICT CT to the RT-planning CT, tumor volume DT were calculated. All except two patients experienced a regrowth in tumor volume, and the percent decrease in volume for these two patients was 3 and 11%. The overall median DT was 44 days (range 18 – 668 days). The median tumor volume dou-bling times for adenocarcinomas and squamous cell carci-noma were 49 and 44 days, respectively. Given that the median DTs were found to be on the order of weeks, it is of no surprise that statistically significant tumor regrowth oc-curred in a short interval after ICT, even for patients who had a delay of 21 days between treatment modalities.

Tumor Response Based on Chemotherapy Regimen

The various ICT regimens used in this study are sum-marized in Table 3. For all induction regimens, the median tumor change seemed to be a shrinkage of the tumor ranging from a volume change of⫺20 to ⫺42% and largest diameter change of ⫺6 to ⫺44%. However, with median delays ranging from 15 to 27 days, the tumor grew with a median tumor volume change ranging from 12 to 45% and with a median largest diameter change ranging from 9 to 17%. No chemotherapy regimen seemed to be superior than another in regards to the amount of tumor regrowth.

DISCUSSION

Delays during transition periods from one treatment modality to another are known to lead to accelerated tumor repopulation. In this study, we found that there was a statis-tically significant regrowth even during what might be con-sidered a relatively short transition interval of about 3 weeks. Of note, this was true regardless of the ICT regimen, although a caveat preventing more specific conclusions is the relatively small sample size for each of the different regimens of chemotherapy. In regards to tumor volume doubling time, our results are consistent with findings found in previous stud-ies.13The median doubling time of 44 days is shorter than

that seen for untreated lung cancers, which is often greater than 100 days,19and this difference could suggest accelerated

repopulation in our cohort postinduction. We thus recom-mend that for patients treated with ICT, the logistical process of transition to RT treatment planning begin as soon as possible after administration of the last planned chemother-apy cycle to maximize the reduction in tumor burden. Within the limits of medical tolerability, these results might also be considered in future studies examining post-ICT tumor re-population for patients being considered for surgery.

One consideration raised by this study is that treatment delays due to transitions between modalities may mask po-tential survival benefits that could be achieved from combi-natorial approaches incorporating ICT. Meta-analyses of che-motherapy have shown a 4 to 7% improvement in 2-year

FIGURE 3. Median percent change in tumor volume and tumor diameter from pre-ICT to post-ICT CT scans and from post-ICT to RT-planning CT scans. ICT, induction chemo-therapy; CT, computed tomography; RT, radiotherapy.

FIGURE 4. Percent volume changes dichotomized by the delay of the start of RT. Percent volume change, grouped according to interval delay ofⱕ21 days or ⬎21 days be-tween postinduction chemotherapy CT scan and radiother-apy planning CT. A significant difference was observed (p⫽ 0.002). RT, radiotherapy; CT, computed tomography.

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survival when chemotherapy is added either neoadjuvantly or concurrently with radiotherapy,20,21 and more particularly,

upfront concurrent chemoradiotherapy offers superior sur-vival compared with sequential CRT approaches in locally advanced NSCLC.10,12,22,23However, in the sequential arms

of these studies, radiotherapy was started in a time period ranging from 2 to 4 weeks after the completion of the ICT. As shown in our study, patients who experienced a delay of 21 days or less between the completion of chemotherapy and their radiotherapy-planning CT experienced less tumor re-growth than those with an interval greater than 21 days. Even minor delays in initiating locally directed treatment after ICT might contribute to the inefficiency of the rendered treatments and mute the cytoreductive benefits of ICT. Generally speak-ing, the overall treatment package time has been shown to be critical for outcomes in NSCLC and in other malignant conditions such as head and neck cancer.24

Most of the studies comparing sequential versus con-current chemoradiotherapy regimens have used conventional daily radiotherapy regimens. However, altered-fractionation

radiotherapy may offer an alternative means of compensation for the timing of radiotherapy initiation after ICT. In early studies, continuous, hyperfractionated, accelerated radiother-apy (CHART) decreased the overall treatment time to 12 consecutive days and improved outcomes when compared with conventional radiotherapy regimens that required 6 weeks of treatment.25However, these trials raised concern for

increased pulmonary toxicity when CHART occurred within 4 weeks after chemotherapy. Hence, subsequent trials incor-porating ICT and CHART used a gap of at least 4 to 6 weeks.26 Although limited because of poor accrual, small

randomized trials have indicated that even with delays of 4 to 6 weeks between the completion of chemotherapy and initi-ation of CHART, stage III patients treated with ICT followed by CHART can achieve a median survival of greater than 20 months.26Accelerated radiotherapy schedules could

compen-sate for the detrimental effects of an extended treatment package time.

One limitation of our study was the small sample size. The analysis was limited by the relatively small number of

FIGURE 5. Scatter plots illustrating the relationship of days between postinduction CT and planning RT scan to (A) percent volume regrowth and (B) percent diameter change by RECIST criteria. Regression line is provided with R2coefficient of

deter-mination to estimate proportion of variability accounted for by the model (superior fit when tumor changes are plotted by RECIST criteria). CT, computed tomography; RT, radiotherapy.

TABLE 3. Summary of Induction Chemotherapy Regimens Used in this Study

Chemotherapy Cycles n Pre-ICT to Post-ICT (% Vol of Initial) Post-ICT to RT CT (% Vol of Post-ICT) Pre-ICT to Post-ICT (% RECIST of Initial) Post-ICT to RT CT

(% RECIST Post-ICT) Delay (d)

Platinum doublet w/ Taxanes 2–4 9 ⫺41.3 (⫺80.2 to 86.4) 32.3 (⫺10.6 to 92.8) ⫺30.0 (⫺50.23 to 24.0) 10.7 (⫺2.9 to 41.2) 21 (8 to 53) Gemcitabine 2–6 5 ⫺38.8 (⫺86.2 to ⫺34.9) 40.1 (⫺2.6 to 133.9) ⫺43.9 (⫺63.4 to ⫺13.5) 14.1 (1.0 to 172.1) 15 (⫺3 to 176) Etoposide 2 2 ⫺20.9 (⫺42.8 to 1.03) 45.3 (39.6 to 51.0) ⫺6.0 (⫺16.5 to 4.5) 17.2 (9.1 to 25.2) 22 (21 to 23) Othera 3–6 4 ⫺42.2 (⫺71.5 to 50.8) 42.6 (7.6 to 310.6) ⫺19.1 (⫺43.1 to 27.0) 15.5 (5.1 to 103.0) 27 (2 to 49) Other chemob 5 1 ⫺20.4 11.9 ⫺13.0 9.0 21 Pecent change in tumor size represented as median percent change with range indicated within parentheses.

aPlatinum doublet with either pemetrexed or navelbine; combination involving sequential platinum doublets such as carbo-paclitaxel 2c followed by carbo-gemcitabine or such

as carbo-gemcitabine 3c followed by docetaxel 3c.

bVinorelbine 1c followed by single agent gemcitabine 4c.

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patients treated in this manner at our institution. We restricted our inclusion criteria to only this group of patients to keep the analysis as clear as possible. A second limitation of our study was that only the largest single tumor mass was measured, such that a mixed response or aggregate response of all tumor burden was not analyzed. The post-ICT responses of minor areas of tumor involvement were not considered reasonable to analyze or as clinically relevant as the response of the dominant tumor mass. Therefore, we chose to focus on the largest area of clearly measurable disease that could be identified readily across all the scans. Although we did not differentiate between primary or nodal disease progression, we found that in only two cases was the dominant mass not the primary lung tumor. The majority of the patients were analyzed based on the response of bulky primary disease, which we believe is a very relevant clinical end point.

However, a strength of our study’s measurement pro-cedures was the use of both a volumetric measurement and RECIST criteria; both were found to change dramatically in relation to radiotherapy delay. For a well-demarcated spher-ical tumor, changes in tumor size per RECIST criteria and volumetric assessments are well correlated.27 However,

be-cause NSCLC tumors are often spiculated and asymmetric, a volumetric approach may be more suitable to assess the response of irregularly shaped tumors.28Although RECIST is

a standard means of assessing response to systemic therapy, it may not be sensitive enough to detect significant but eccentric responses.

Another limitation of our study was the lack of integration of functional imaging assessments. It was not the standard of care during the time period covered by this study to obtain positron emission tomography (PET) or PET-CT scans for patients at each stage of their multimo-dality therapy. It does remain unclear whether RECIST, or any volumetric assessment, is superior to the prognostic and therapeutic information obtained from other types of imaging, especially in the era of PET and magnetic reso-nance imaging.29 –31

Finally, an area which will require further exploration is quantification of the impact of radiographically determined response on overall disease outcomes. Some studies indicate that response to ICT does correlate with outcomes,32–36 but

other studies suggest that an early response to ICT has no impact on survival.37This question was beyond the scope of

our analysis but could be an interesting analysis to apply to larger, better-controlled datasets. Certainly, from the perspec-tive of radiation oncology, capitalizing on the radiographic response to ICT in planning radiotherapy target volumes should have some impact on reducing treatment-related tox-icities such as pneumonitis or esophagitis; whether this would be significantly affected by minimization of the delay in transitioning to radiotherapy also remains an issue to be defined more clearly in the future.

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