Malignant pleural effusion research provides insights to improve surgical study design

Malignant pleural effusion (MPE) remains a significant health care problem affecting approximately 150,000 U.S. patients each year.1 Despite being relatively common, MPE investigations have been encumbered by disease and treatment diversity, as well as difficulties proposing research to terminally ill patients with compromised quality of life.

Traditionally, patients are managed by inpatient applications of sclerosants like talc by video-assisted thoracic surgery or chest tube to accelerate pleurodesis. Gaining popularity are the small pleural catheters (usually tunneled) that are placed in the outpatient setting and that can control symptoms by protracted drainage. Recently, the results of an Alliance/Cancer and Leukemia Group B (CALGB) trial were published to help address which of these options might be better.2

Patients who received a tunneled catheter were more likely to be alive with maintenance of effusion control at 30 days. Also, effusion control correlated well with improved quality of life scores. While randomization and consistency of the data supported the conclusions, the fact that the final analysis was of a much smaller sample size and a simpler endpoint than planned was a major limitation. Larger trials have shown that tunneled catheters are not inferior to talc pleurodesis.3

Lessons for future study

By reviewing the challenges impeding this trial, important lessons for the future study of MPE are evident. First, patient preference for one of the treatments was a considerable barrier to enrollment. This limitation should have been obvious given that one treatment required several days of inpatient care, whereas the other could be done on an outpatient basis but lasted longer and required considerable self-care or caregiver involvement. Potential volunteers preferred inpatient or outpatient therapies in about equal proportion (this preference ratio is discussed in more detail later in this article). Furthermore, practitioner biases aligned with those patient preferences, or dominant approaches in certain regions may have existed.

The second important lesson gleaned from this study revealed that investigator review of the patient history and chest imaging often failed to exclude poor candidates for this pleurodesis research based on high 30-day mortality or trapped lungs. The complex organ system failures occurring in end-stage cancer may require a multiple parameter algorithm to reduce the chance of unexpected mortality. For the problem of detecting trapped lungs, the use of pleural manometry during thoracentesis has been established as a useful guide at certain centers.4

Given that these challenges were not subtle, it is curious that many cooperative group trials are released to a broad network of sites with little or no small-scale piloting to detect obvious flaws in eligibility or patient/practitioner equipoise. This is especially the case with surgical trials where the innovation questions frequently relate to different levels of invasiveness.

This research also underscores the need for something other than traditional randomized trials to compare treatments with different levels of patient acceptance. While this need has been a problem for surgeons wishing to compare minimally invasive operations with traditional open procedures, emerging less-toxic chemotherapy or radiation treatments will likely pose similar problems for medical or radiation oncologists.

To address this issue, the randomized double-consent design of Zelen (which has been used in cooperative group trials) provides hypothesis testing as valid as traditional studies.5 The accrual targets are larger, but almost all patients can participate, even if they reject the allocated arm, because the design takes this rejection into account. Such an amendment was actually proposed for this Alliance/CALGB trial because a critical Zelen design variable (the 50 percent preference ratio mentioned previously) was known.

Conclusion

Our research shows that tunneled pleural catheters are reliable methods to control MPE and may be optimal if full lung expansion is uncertain. This experience also suggested that a phased data gathering approach to better launch complex surgical trials and the selective use of alternative trial designs would enhance such future endeavors.


References

  1. Hunt BM, Farivar AS, Vallières E, Louie BE, Aye RW, Flores EE, Gorden JA. Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions. Ann Thorac Surg. April 17, 2012. [E-pub ahead of print.]
  2. Demmy TL, Gu L, Burkhalter JE, Toloza EM, D’Amico TA, Sutherland S, Wang X, Archer L, Veit LJ, Kohman L. The Cancer and Leukemia Group B. Optimal management of malignant pleural effusions (results of CALGB 30102). J Natl Compr Canc Netw. 2012;10(8):975-982.
  3. Davies HE, Mishra EK, Kahan BC, Wrightson JM, Stanton AE, Guhan A, Davies CW, Grayez J, Harrison R, Prasad A, Crosthwaite N, Lee YC, Davies RJ, Miller RF, Rahman NM. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: The TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389.
  4. Huggins JT, Sahn SA, Heidecker J, Ravenel JG, Doelken P. Characteristics of trapped lung: Pleural fluid analysis, manometry, and air-contrast chest CT. Chest. 2007;131(1):206-213.
  5. Zelen M. Randomized consent designs for clinical trials: An update. Stat Med. 1990;9(6):645-656.

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