Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma

Abstract

Introduction

Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicities. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) to previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D).

Methods

We analyzed 209 patients who underwent P/D and adjuvant RT (n[CONV]=131, n[IMPRINT]=78) for MPM between 1974 and 2015. The primary endpoint was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing ri sks analysis was performed for local failure-free (LFFS) and progression-free survival (PFS). Univariate (UVA) and multivariate analysis (MVA) was performed with relevant clinical and treatment factors.

Results

The median age was 64 years, 80% were male. Patients receiving IMPRINT had significantly higher rates of epithelial histology, advanced pStage and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 vs 12.3 months, p=0.001). Higher Karnofsky performance score (KPS), epithelioid histology, macroscopically complete resection (MCR), and use of chemotherapy/IMPRINT were found to be significant factors for longer OS upon MVA. No significant predictive factors were identified for local failure or progression. Fewer patients developed grade ≥2 esophagitis after IMPRINT compared to CONV (23% vs 47%).

Conclusions

Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicities in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events.

Introduction

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy affecting the pleura and commonly associated with previous asbestos exposure. While some advances have been made in the various therapeutic approaches including lung-sparing surgical technique, chemotherapy drug types and doses and radiation therapy techniques, their impact on patient outcomes in a multimodality context remains unclear.

For patients with favorable histology and resectable disease, cytoreductive surgery with the goal of a macroscopically complete resection (MCR) has been the centerpiece of multimodality management at our institution. The debate about the optimal surgical procedure in MPM is ongoing. When compared retrospectively, patients undergoing lung-sparing techniques with complete resection (P/D and extended P/D (EPD)) as opposed to patients having an extrapleural pneumonectomy (EPP) were found to have at least equivalent overall survival with less postoperative morbidity and mortality than after EPP. ^1-5 This observation has led to a shift in surgical approach from predominantly EPPs to a more frequent use of lung-sparing approaches such as P/D and EPD. To exclude confounding by surgical approach, this study includes only patients who underwent lung-sparing surgery. We used the International Association of the Study of Lung Cancer (IASLC) Mesothelioma Domain and the International Mesothelioma Interest Group (IMIG) definitions of P/D in this study.⁶

Platinum/pemetrexed chemotherapy has been established as the standard of care for systemic therapy in patients with MPM, since it was shown to significantly improve overall survival compared to platinum chemotherapy alone in a phase III trial (12.1 vs 9.3 months) (Vogelzang et al.) and confirmed by a similar study using ralitrexed (van Meerbeeck et al.).^{7, 8} Typically four cycles are administered in the setting of multimodality therapy, delivered either as neoadjuvant or adjuvant therapy.

Adjuvant hemithoracic radiation therapy has been explored as part of multimodality treatment to reduce the risk of local and regional failure, especially after lung-sparing surgery given the high risk of microscopic residual disease. While 2D combined photon/electron conventional RT had historically been the standard technique available at the time, the development of intensity-modulated pleural radiation therapy (IMPRINT) in the past decade has made a more precise application of hemithoracic RT possible, reducing areas of dose uncertainty and doses to underlying organs at risk, in particular the lungs, but also the heart, liver, stomach, kidneys and bowels. ^9-18

In a recent prospective phase II trial we demonstrated the safety of hemithoracic IMPRINT after chemotherapy and P/D for patients with MPM.¹⁹

In this study, we analyzed our institutional database to compare outcomes and toxicities of patients with MPM treated with lung-sparing surgery followed by either adjuvant conventional RT or IMPRINT.

Methods and Materials

Study design and patients

For this study, data of patients with MPM treated at our institution between 1974 and 2015 were collected from the institutional database. Patients were included if they had lung-sparing surgery as well as adjuvant radiation therapy (RT).

Tumor information, treatment details and follow-up data were retrieved from the patients' medical records. Toxicity was scored per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Given the uncertainty about categorizing radiation pneumonitis we defined grade 2 pneumonitis as patients requiring systemic prednisone, and grade 3 pneumonitis as patients requiring continuous oxygen or need for hospitalization.

Treatment characteristics

All patients underwent one of three lung-sparing types of surgical procedure, namely extended pleurectomy/decortication (EPD), pleurectomy/decortication (P/D), or partial pleurectomy (PP). Only 15 patients (11%) in the CONV group received chemotherapy, but 90% of patients in the IMPRINT group were treated with neoadjuvant or adjuvant chemotherapy. With the exeption of two cases, all patients in the IMPRINT group received a platinum/pemetrexed doublet.

The technique of conventional RT performed at our institution has been previously described by Kutcher et al.²⁰ and Gupta et al.²¹ Patients were immobilized with their arms raised above their head in supine position. The field borders were the top of T1 superiorly, the bottom of L2/base of diaphragm inferiorly, the ribcage including the skin laterally and the contralateral border of the vertebral bodies medially. A 1.5 to 2.0cm margin was added medially if mediastinal nodes were involved. Patients were simulated using fluoroscopy or CT, and the planning target volume (PTV) was defined as the pleura and diaphragm with a 1cm margin. Blocks were placed anteriorly and posteriorly over abdomen and lung, and - starting at 1980 cGy - over the heart in the case of left-sided tumors. There was a 15% scatter under the blocks from the photon fields, therefore a supplemental daily electron dose of 153 cGy was prescribed. The spinal cord was excluded from the treatment field for the final 2 fractions to avoid overdosing. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using linear accelerators.

Since 2004 we have developed a hemithoracic pleural IMRT technique for MPM patients that was previously described.^{15, 16, 19} Patients were immobilized with their arms raised above their head in supine position. The initial PTV was defined using the planning CT scan and encompassed the hemithoracic pleura and chest wall reaching from the thoracic inlet until the insertion of the diaphragm at the L1/L2 vertebral body. A PET-CT scan and respiratory correlated 4D-CT scan (available since 2008) were used to further refine the target volume. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using Varian linear accelerators with a dynamic multileaf collimator.

Statistical methods and design

The primary endpoint of the analysis was overall survival (OS). Local failure free survival (LFFS) and progression free survival (PFS) were determined as well. All endpoints were measured beginning at the start of radiation therapy until the date of event (death, local failure or progression, respectively) or until the last follow-up date. The Kaplan-Meier method was used for calculating overall survival rates, Cox proportional hazards regression model was used for OS analysis, and a Fine and Gray competing risks analysis was performed for LFFS and PFS. Univariate analysis (UVA) was performed for the following factors: age at diagnosis, sex, Karnofsky performance score (KPS), histology, laterality of tumor, clinical and pathological stage, macroscopically complete resection (MCR), chemotherapy, RT technique and RT dose. Factors with a p-value ≤ 0.15 were considered candidates for stepwise multivariate analysis (MVA) to evaluate the association of RT technique with each endpoint. Forward and backward selection procedures were implemented to confirm results. Incidence of significant (≥ grade 2) toxicities were compared between RT techniques using Fisher's exact test. These results were adjusted for multiple comparisons using the Bonferroni method. Statistical analysis was conducted with the software SAS version 9.4 (SAS Institute Inc. Cary, NC), and R version 3.1.2 package cmprsk.

Results

Patient characteristics

We analyzed 209 patients with MPM who met the inclusion criteria. The median age of patients was 64 (range: 34 to 84), male to female ratio was 4:1 and median KPS was 80 (range: 60 to 100). 131 patients (63%) received conventional external beam radiation therapy (CONV) and 78 (37%) intensity-modulated pleural radiation therapy (IMPRINT). All patients treated since March 2005 received IMPRINT. Eighty-five patients (41%) received chemotherapy (70 IMPRINT and 15 CONV patients). Significant differences between the CONV and IMPRINT group were noted in age (> 64 years: 45% and 65% respectively, p=0.006), KPS (>80: 31% and 50% respectively, p=0.008), histology (epithelioid: 59% and 86% respectively, p<0.0001) and stage (pathological stage III and IV (advanced): 49% and 76% respectively, p=0.0001). Chemotherapy was administered significantly more often in the IMPRINT group (90% vs. 11%, p<0.0001) and IMPRINT was also associated with higher total prescription radiation doses (total dose >4500cGy: 65% vs 11%, p<0.0001). Detailed patient characteristics are shown in Table 1.

Table 1. Distributions of patient and clinical characteristics.

Factor	Total (N=209)	CONV (N=131, 63%)	IMPRINT (N=78, 37%)
Age at diagnosis1
≤64	99 (47)	72 (55)	27 (35)
>64	110 (53)	59 (45)	51 (65)
Sex
Male	168 (80)	108 (82)	60 (77)
Female	41 (20)	23 (18)	18 (23)
KPS1
≤80	130 (62)	91 (69)	39 (50)
> 80	79 (38)	40 (31)	39 (50)
Histology
Epithelioid	144 (69)	77 (59)	67 (86)
Non-epithelioid	65 (31)	54 (41)	11 (14)
Laterality
Right	120 (57)	74 (56)	46 (59)
Left	89 (43)	57 (44)	32 (41)
Clinical stage
Early stage	114 (55)	79 (60)	35 (45)
Advanced stage	95 (45)	52 (40)	43 (55)
Macroscopically complete resection (MCR)
No	102 (49)	66 50%)	34 (44%)
Yes	107 (51)	65 (50%)	44 (52%)
Pathological stage
Early	86 (41)	67 (51)	19 (24)
Advanced	123 (59)	64 (49)	43 (55)
Chemotherapy
No	124 (59)	116 (89)	8 (10)
Yes	85 (41)	15 (11)	70 (90)
Dose (cGy)1
≤4500	143 (68)	116 (89)	27 (35)
>4500	66 (32)	15 (11)	51 (65)

¹Cutoffs were based on median value.

Note: values displayed as n (%)

Survival

The median follow-up among survivors was 21.4 months (range 1.2 to 95.1 months) from the start of RT. Median overall survival (OS) was 20.2 months (95% Confidence Interval [CI] 13.5 – 28.2 months) in the IMPRINT cohort compared to 12.3 months (95% CI 10.0 – 15.3 months) in the CONV cohort [Figure 1]. One- and 2-year survival rates were higher for patients receiving IMPRINT (69% and 42% versus 50% and 20% for CONV).

Figure 1. Kaplan-Meier Overall Survival Curves Stratified by RT technique.

Factors associated with higher OS on UVA were KPS > 80% (vs ≤ 80%, HR 0.62, 95% CI 0.45-0.85, p=0.003), epithelioid histology (vs. non-epithelioid, HR 0.55, 95%CI 0.40-0.75, p=0.0002), MCR (vs. non-MCR, HR 0.72, 95% CI 0.53-0.97, p=0.03), IMPRINT (vs. CONV, HR 0.58, 95% CI 0.42-0.81, p=0.001) and a total RT dose >4500 cGy (HR 0.70, 95% CI 0.50-0.96, p=0.03). On MVA, KPS > 80% (p=0.01), epithelioid histology (p=0.003), MCR (p=0.01) and IMPRINT (p=0.02) were significantly associated with longer OS. [Table 2]

Table 2. Analysis of overall survival for all patients.

Factor	Univariate Analysis		Stepwise Multivariate Analysis Final Model
	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at diagnosis
≤64	1.00
>64	1.06 (0.79 – 1.42)	0.70
Sex
Male	1.00
Female	0.76 (0.51 – 1.11)	0.15
KPS
≤80	1.00		1.00
> 80	0.62 (0.45 – 0.85)	0.003	0.66 (0.47 – 0.91)	0.01
Histology
Epithelioid	0.55 (0.40 – 0.75)		0.61 (0.44 – 0.85)
Non-epithelioid	1.00	0.0002	1.00	0.003
Laterality
Right	1.00
Left	1.03 (0.76 – 1.38)	0.86
Clinical stage
Early stage	1.00
Advanced stage	0.95 (0.70 – 1.27)	0.71
Macroscopically complete resection (MCR)
No	1.00		1.00
Yes	0.72 (0.53 – 0.97)	0.03	0.71 (0.53 – 0.96)	0.03
Pathological stage
Early	1.00
Advanced	0.94 (0.70 – 1.27)	0.71
Chemotherapy
No	1.00
Yes	0.63 (0.46 – 0.86)	0.004
Radiation technique
Conventional photon/electron	1.00		1.00
IMRT	0.58 (0.42 – 0.81)	0.001	0.66 (0.47 – 0.92)	0.02
Dose (cGy)
≤4500	1.00
>4500	0.70 (0.50 – 0.96)	0.03

Although chemotherapy was associated with improved survival in the UVA (vs. no chemotherapy, HR 0.63, 95%CI 0.46-0.86, p=0.004), it did not enter into the stepwise Cox proportional hazards MVA final model as it was highly correlated with RT technique. Seventy patients (90%) receiving IMPRINT also underwent chemotherapy, while only 15 patients (11%) in the CONV cohort received chemotherapy (p<0.001 by Fisher's exact test). As IMPRINT entered into the MVA model, chemotherapy did not contribute significantly to the prognosis of OS, and thus did not enter into the MVA final model. The results from the MVA final models using stepwise, forward and backward selection procedures were identical. Further analysis showed that when RT technique was removed as a candidate of the stepwise MVA, KPS > 80% (p=0.009), epithelioid histology (p=0.002), MCR (p=0.02), and chemotherapy (p=0.02) remained associated with longer OS.

Local Failure

There were 116 cases of local failure (LF) (56% of all patients), 72 patients died without LF and 21 patients were censored at last follow-up. The 1-and 2-year cumulative incidences of local failure were 42% and 60% for IMPRINT versus 34% and 47% for CONV. There was no significant difference in cumulative incidence of LF between the two groups (p=0.08 by Gary's test). There were no factors significantly associated with higher rates of local control either in uni- or multivariate analysis.

Progression-Free Survival

145 patients (69%) progressed, 48 died without progression of disease and 16 were censored at last follow-up. The 1- and 2-year cumulative incidences of disease progression were 53% and 72% for IMPRINT and 47% and 69% for CONV. There was no significant difference in cumulative incidence of progression between the groups (p=0.07 by Gray's test). Only one factor, left sided MPM (vs. right sided), approached a significant level of association with progression of disease (HR =1.38 (95% CI of 1.00-1.41), p=0.05). Stepwise MVA showed left-sided disease (HR 1.36, 95% 0.99 – 1.87, p=0.06) and female gender (HR 1.37, 95%CI 0.99 – 1.91, p=0.06) were marginally significant for a higher risk of progression.

Toxicities

Patients undergoing IMPRINT were found to have significantly higher rates of grade 2+ fatigue (47% vs 16%, p<0.0001) and cough (18% vs 2%, p<0.0001) while the CONV cohort showed more cases of grade 2+ esophagitis (23% vs 47%, p=0.0007). After adjusting for multiple comparisons using the Bonferroni method, all p-values remained at p<0.006. There was no significant difference seen in the rates of grade grade 2+ radiation pneumonitis (26% in the IMRINT vs. 35% in the CONV cohort, p=0.17), nausea (both 24%, p=1.0), vomiting (6% vs 8%, p=1.0), dyspnea (27% vs 24%, p=0.62) and dermatitis (13% vs 15%, p=0.69). There were 4 possibly toxicity-related deaths in the CONV group (two of which were grade 5 radiation pneumonitis) and 2 in the IMPRINT group (one grade 4 and one grade 5 radiation pneumonitis).

Discussion

Multimodality treatment is commonly the preferred treatment approach for patients with resectable MPM. However, the optimal combination of multimodality therapies remains unclear. At our institution we have a longstanding history of conducting prospective and retrospective studies on the multimodality management of patients with MPM. Here we present a complete series of patients treated with multimodality treatment on a lung-sparing surgical backbone of P/D. To our knowledge it represents the largest series of lung-sparing surgery and adjuvant radiation therapy performed by a high-volume institution with significant experience in this complex disease. Patients were treated with adjuvant RT using conventional techniques in the early years and an IMRT technique in the last decade. In these 209 patients with MPM that underwent lung-sparing multimodality treatment we found promising overall survival outcomes in patients that received platinum/pemetrexed-based chemotherapy and adjuvant IMPRINT compared to CONV. We also found that higher KPS and epithelioid histology was associated with longer OS, which is in line with previously reported results.^{22, 23}

A few aspects should be considered in addition to the inherent limitations of a retrospective analysis. Our study includes patients treated over 40 years. During this period of time, many aspects of radiation oncology but also in the fields of medical and surgical oncology have significantly changed. In addition to technical advances in the treatment of MPM, platinum/pemetrexed chemotherapy has, over the past decade, emerged as standard first-line therapy for inoperable MPM^{8, 24} and has become an essential part of our multi-modality treatment approach. This explains the large discrepancy between the groups regarding the inclusion of chemotherapy in the multimodality treatment (90% in IMPRINT group and only 11% in CONV group). Given the observed effect size of our modern trimodality treatment approach we believe that the use of trimodality therapy including both modern platinum/pemetrexed chemotherapy and IMPRINT compared to surgery and conventional RT alone likely prolongs overall survival. While the IMPRINT group had some more favorable patient characteristics, such as higher KPS, more epithelioid histologies, and more chemotherapy administered, it also contained several unfavorable patient characteristics, including older age and more advanced pathologic stage, that would likely counteract the favorable characteristics.

Our analysis did not identify significant contributors associated with higher incidences of progression or local failures on MVA. While left-sided MPM and female gender were marginally significant on MVA of progression, caution is advised not to overinterpret these findings given the 95% confidence interval of 1.00 - 1.41 for left-sided MPM on UVA. While one could argue the lack of improved local control within the IMPRINT group means that it is unlikely that radiation has a role in improved survival, it is important to note that patients are followed much more closely and with more precise imaging modalities such as CT and PET/CT imaging, in the era of platinum/pemetrexed chemotherapy and IMPRINT. This development of more accurate imaging has likely increased the likelihood of early recurrence detection and shortened the time for the detection of local and distant failure which may explain the apparent lack of difference in local failures and PFS. However, in patients with MPM disease progression is so strongly correlated with OS that it is fair to hypothesize that the observed OS benefit is due to improved disease control.

Our toxicity analysis showed higher rates of grade 2+ cough and fatigue in the IMPRINT group but, more significantly, a lower rate of grade 2+ esophagitis compared to the CONV group. Additionally, while not statistically significant, pneumonitis rates were lower in IMPRINT group as well. As this is a retrospective study, evaluation of toxicity rates overall remains subject to inaccuracy especially for patients treated before electronic medical records were available. The higher rates of cough and fatigue may be attributed to the fact that the documentation of toxicities has become more standardized, electronic medical record systems have been established and toxicities have been more carefully recorded in the past decade. However, the observed significant decrease grade 2+ esophagitis and numerical albeit not statistically significant decrease in grade 2+ pneumonitis suggests that the use of IMPRINT may lead to less severe side effects. Grading of radiation pneumonitis remains somewhat subjective, for instance with different thresholds for initiating systemic prednisone for grade 2 pneumonitis. Clinically, we feel that we observe less frequent and less severe radiation pneumonitis with the use of IMPRINT. We may need an even larger patient cohort to show a statistically significant decrease in pneumonitis compared to the CONV group. In general, however, IMRT has been shown in mesothelioma and multiple other disease sites to be associated with decreased radiation dose to organs at risk, leading to a decrease in toxicities.^25-27 It is fair to assume that improved dosimetric control and less radiation to organs at risk with IMPRINT is associated with less toxicity.

To conclude, we have found that IMPRINT in the context of modern chemotherapy and lung-sparing surgery as a part of modern trimodality treatment in MPM is associated with improved outcomes such as higher overall survival and lower rates of severe toxicity compared to lung-sparing surgery and conventional RT alone.

Table 3. Analysis of grade 2+ toxicity by RT technique.

Grade 2+ Toxicity	RT Technique				p-value
	Conventional photon/electron		IMPRINT
	N	%	N	%
Nausea					1.00
No	100	76	59	76
Yes	31	24	19	24
Vomiting					1.00
No	121	92	73	94
Yes	10	8	5	6
Esophagitis					0.0007
No	70	53	60	77
Yes	61	47	18	23
Cough					<0.0001
No	129	98	64	82
Yes	2	2	14	18
Dyspnea					0.62
No	100	76	57	73
Yes	31	24	21	27
Fatigue					<0.0001
No	110	84	41	53
Yes	21	16	37	47
Dermatitis					0.69
No	111	85	68	87
Yes	20	15	10	13
Pneumonitis					0.17
No	85	65	58	74
Yes	46	35	20	26