Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

Charlotte De Bondt; Ioannis Psallidas; Paul E. Y. Van Schil; Jan P. van Meerbeeck

Disclosures

Transl Lung Cancer Res. 2018;7(5) 

In This Article

PICO 1: Is Multimodality Treatment Better Than CT Alone?

Primary Endpoint: Survival

Two groups have analyzed the pooled mesothelioma data in the National Cancer Database (NCDB), wherein MPM patients' records are collected. Both report that almost half of the patient population received no mesothelioma specific treatment. Saddoughi et al. found that the 3 percent of MPM patients who underwent multimodality treatment between 2004–2013 performed better than those treated with CT alone (median overall survival 19.9 vs. 11.3 months, respectively).[15] Nelson et al. confirmed the use of multimodality treatment in only 8% of seemingly ideal trimodality treatment patients (under 70 years old, stage I through III, epithelioid histology).[16]

Although some reports are in favor of a multimodal approach when it comes to the treatment of MPM, others have shown similar or even better overall survival treating patients with CT alone. The explanation for this lies in the morbidity and mortality associated with EPP.

Hillerdal et al. treated a series of patients with MPM with a combination of carboplatin, liposomal doxorubicin and gemcitabine. They found an overall median survival of 13 months. Epithelioid subtypes reached a median survival of 17 months and even 21 months in good performance status patients, comparable with the outcome of patients treated with neoadjuvant CT and EPP, suggesting that treatment with CT alone is equally effective in similarly selected MPM patients.[17]

Sharkey et al. retrospectively analyzed their database in order to establish the ideal timing for CT in patients treated with EPP and to identify which MPM patients benefit most from (neo)adjuvant CT. Their results showed a median survival from time of diagnosis of 23.3 months in the adjuvant CT group and 23.9 months in the neo-adjuvant group. A scenario wherein no CT was given until disease progression, performed similarly with a median survival of 20.3 months. Those patients with non-epithelioid histology and nodal involvement performed better with true adjuvant CT than when it was delayed (overall survival 15.6 vs. 8.2 months and progression free survival 14.9 vs. 6.0 months respectively).[18]

The Mesothelioma and Radical Surgery (MARS) trial, which randomized eligible patients after 3 cycles of induction CT to either EPP or postoperative radiotherapy (PORT) versus 3 more cycles of CT without attempt at resection or RT, concluded that the likelihood of a benefit of EPP on the overall survival and quality of life endpoints was small. This futility analysis caused the premature closure of the trial and affected standard practice worldwide.[19] Median survival of the EPP group (14.4 months) was low compared to 19.5 months in the no EPP group, but also lower than in other similarly designed historical EPP trials. The start date of the time-to-event analysis—after induction CT—is the most likely explanation for this comparably low outcome, as in other trials this was calculated from the time CT was started.

Additionally, overall survival reported in the CT arm of the MARS trial is significantly better than that reported in certain multimodality treatment series. Bille et al. included 25 patients in a prospective study examining the effects of trimodality treatment and reported a median survival of only 12.8 months.[20]

Although intertrial comparisons are hazardous, these results do not strengthen the role of surgery in the treatment of MPM, especially when considering the time patients undergoing a multimodality treatment spend hospitalized after surgery or due to complications of treatment.

The MARS group is currently assessing the feasibility of a study comparing CT alone versus CT and eP/D. Patients will be randomized to either eP/D or no surgery after completing 3 cycles of CT.[21]

The addition of RT to surgery has also been studied, with variable results. The SAKK 17/04 trial, a prospective randomized trial, assessed whether adding PORT to a combination of neo-adjuvant CT (cisplatin-pemetrexed) and EPP resulted in a better locoregional relapse-free survival.[22] Although they showed a significantly longer local relapse free survival in the RT arm (9.4 vs. 7.6 months), the authors were unable to make a convincing case for the addition of PORT to CT and surgery when it comes to median survival seeing as it was similar to the no-RT arm, namely 19.3 vs. 20.8 months respectively. The addition of PORT also comes at a price, as there was a radiation related death in the SAKK PORT arm, as opposed to no treatment related mortality in the SAKK no PORT arm.

These findings were similar to those published by a Japanese group performing a feasibility study with a comparable trimodality protocol (CT-EPP-RT) in mesothelioma patients. Median survival in this patient population was 19.9 months and although they met the primary endpoints of achieving a macroscopic complete resection and maintaining an acceptable treatment related mortality, they concluded that the risk-benefit ratio was unsatisfactory. Progression free survival time was 11 months in those wherein a macroscopic complete resection was achieved.[23]

It would be premature however to exclude RT from the treatment of MPM altogether based on these results alone. It is plausible that more rigorous patient selection and fine-tuning of the techniques could result in better outcomes and less toxicity. The SAKK trial included patients with extensive disease (proven N2 status) and non-epithelioid type mesotheliomas, both of which are negative prognostic features usually serving as exclusion criteria in this type of trial. The RT regimen in both trials also consisted of hemithoracic RT, which is associated with a high radiation dose and hence high toxicity. EPP was the surgical procedure of choice in both trials, which has a high mortality and is prone to complications. In this light, the results of the JMIG1101 trial, a prospective feasibility study of induction CT followed by P/D will be of particular interest.

A recent systematic review of randomized controlled trials of multimodality treatment in MPM (namely MARS and SAKK trials), concluded that based on this data there is not enough evidence to support standardized implementation of a combined modality treatment, especially given the morbidity and cost associated with these treatment protocols.[24]

In conclusion, the current evidence in favor of a combined modality approach is weak and likely subject to different biases. Nevertheless, the rationale is challenging and the best survival data reported were obtained in series combining local and systemic modalities.

Other Endpoints

Marulli et al. did a retrospective analysis of mesothelioma patients who received neo-adjuvant CT and found that it improved their pulmonary lung function tests and exercise capacity.[25] Not only should this affect quality of life, this could also prime patients before surgery, possibly resulting in lower surgery-associated morbidity.

Maintaining a satisfactory physical condition is essential for completing these demanding treatment schedules. Exactly how challenging these therapies are, is revealed in the number of patients completing the treatment protocols, or the time it takes to reach completion versus an optimal preset timeline. In the EORTC 08031 study, a prospective feasibility study assessing multimodality treatment (CT-EPP-PORT) in the treatment of early stage MPM, only 42% of enrolled patients were able to complete the treatment within the preset time frame.[26] In the aforementioned SAKK trial, only 36% of patients were able to or agreed to proceed on to RT after undergoing neo-adjuvant CT and EPP.[22] So, attrition is high and compliance to treatment becomes an important endpoint. Omitting to report this attrition is common in retrospective series and is the cause for the commonly encountered immortality bias in combined mortality series.

Toxicity is systematically underreported thus minimalizing the morbidity associated with multimodality treatment schedules. Toxic or treatment-related deaths are most often the result of complications brought on by surgery or radiation. In the SMART trial (IMRT followed by EPP and CT), de Perrot et al. report that 24 out of 62 patients developed a grade 3 or higher toxicity. This number does not account 6 patients with multiple grade 3 or higher toxicities, summing up to 31 the overall number of single serious adverse events in this patient group.[27] In their series, Federico et al. had to reduce the radiation dosage after two patients died due to radiation related cardiopulmonary complications.[28] Even after this dose reduction, the grade 3–4 toxicity incidence remained high at 66.7% of patients. Note that this is again the percentage of patients developing one or more grade 3–4 toxicities, not the number of single serious adverse events.

On occasion, adverse events are reported per treatment modality (e.g., CT related toxicity) instead of an overall number of adverse events.[22,23,29] This too can lead to an underestimation of the morbidity inflicted by the entire treatment regimen.

Table 3 shows the toxic deaths reported in the prospective multimodality treatment trials. As these are mostly complications of local treatment, improvements should be made in these areas in order to reduce mortality.

Unfortunately, neither resection nor RT currently results in adequate locoregional disease control. Cao et al. pooled the results of all major trimodality treatment trials and found disease relapse to occur most often locally, with an incidence ranging between 4–41%.[32]

In conclusion, a combined modality approach leads to accumulated toxicity and mortality which is the main reason for the failure of CMT to show an unequivocal benefit in outcome. Any approach reducing the latter might well result in an improved survival and adoption of CMT.

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