Minimally Invasive Surgery for Resection of Diaphragm Metastases in Ovarian Cancer

Revised Ms #JMIG-D-18-00881

Accepted Manuscript

Minimally Invasive Surgery for Resection of Diaphragm Metastases in Ovarian Cancer Javier F. Magrina MD , Tatiana Cuesta Guardiola MD , Paul M. Magtibay III , Heidi E. Kosiorek , Paul M. Magtibay MD PII: DOI: Reference:

S1553-4650(18)31403-1 https://doi.org/10.1016/j.jmig.2018.12.003 JMIG 3701

To appear in:

The Journal of Minimally Invasive Gynecology

Received date: Revised date: Accepted date:

17 October 2018 3 December 2018 4 December 2018

Please cite this article as: Javier F. Magrina MD , Tatiana Cuesta Guardiola MD , Paul M. Magtibay III , Heidi E. Kosiorek , Paul M. Magtibay MD , Minimally Invasive Surgery for Resection of Diaphragm Metastases in Ovarian Cancer, The Journal of Minimally Invasive Gynecology (2018), doi: https://doi.org/10.1016/j.jmig.2018.12.003

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[Category: Original Article] Revised Ms #JMIG-D-18-00881 Minimally Invasive Surgery for Resection of Diaphragm Metastases in Ovarian Cancer

Tatiana Cuesta Guardiola, MD Paul M. Magtibay III Heidi E. Kosiorek

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Paul M. Magtibay, MD

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Javier F. Magrina, MD

Author Affiliations: Department of Surgical Gynecology (Drs Magrina, Cuesta Guardiola, and P. M. Magtibay, and Mr P. Magtibay III), Mayo Clinic Hospital, Phoenix, Arizona, and Biostatistics (Heidi Kosiorek), Mayo Clinic, Scottsdale, Arizona.

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Reprints: Javier F. Magrina, MD, Department of Medical and Surgical Gynecology,

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Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054 ([email protected]). Acknowledgment

Role of the Funding Source

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No external financial support was provided for any portion of this study.

Conflict of Interest

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None of the authors have a conflict of interest.

Running title: Resection of Diaphragm Metastasis

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Publisher: To expedite proof approval, send proof via email to [email protected]. ©2018 Mayo Foundation for Medical Education and Research

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Précis Minimally invasive surgery for resection of diaphragm metastases is feasible and safe in selected patients. The pulmonary complication rate is low; the recurrence rate

Abstract

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is similar to other abdominal sites.

Study Objective: To estimate pulmonary complications and diaphragm recurrence after

ovarian cancer (EOC). Design: Retrospective analysis. Design Classification: III.

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resection of diaphragm metastases by minimally invasive surgery (MIS) for epithelial

Setting: Mayo Clinic in Scottsdale, Arizona, from January 1, 2004, through January 31,

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2014.

Patients and Interventions: Selected cohort of 29 patients undergoing diaphragm

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resection by MIS (robotics, n=21; laparoscopy, n=8) for EOC. To assess for pulmonary complications most likely due to diaphragm resection, patients were excluded if they had

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preoperative pleural effusion or pulmonary disease or had undergone additional upper abdominal procedures.

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Measurements and Main Results: The mean age (SD) of the patients was 58.7 (14.9) years and the mean (SD) BMI was 24.2 (3.4). The mean size (SD) of diaphragm

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metastases was 56.7 (range, 2-145) mm. Full-thickness resection was performed in 6 patients; 23 had peritoneal resection. Complete resection was achieved in all patients with no conversions to laparotomy. Two patients (6.9%) had pulmonary complications (pleural effusion). Six patients (20.7%) had diaphragm recurrence; 10 patients (34.5%) had recurrence at other abdominal sites.

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Conclusions: Resection of diaphragm metastases by MIS appears to be feasible and safe for selected patients, with similar recurrence as other abdominal sites.

Abbreviations EOC, epithelial ovarian cancer

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Keywords: diaphragm resection; laparoscopy; ovarian cancer; robotics

FIGO, International Federation of Gynecology and Obstetrics

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MIS, minimally invasive surgery

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Introduction Diaphragm metastases are observed in more than 50% of patients with advanced epithelial ovarian cancer (EOC).1-3 Complete resection, when associated with

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complete resection of metastases elsewhere, has been shown to improve survival compared with unresected or residual diaphragm disease.4-6

Resection of diaphragm metastases is usually performed through a

laparotomy that extends to the xiphoid because of the presence of extensive disease

elsewhere.7-10 In selected patients resection can be performed with minimally invasive

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surgery (MIS), either laparoscopically or robotically. MIS is feasible, safe, and preferable to laparotomy for selected patients undergoing primary11 or secondary12,13 cytoreduction for EOC.

The objective of the present study was to evaluate pulmonary complications

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and recurrence of metastases in the diaphragm after excision of diaphragm metastases

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with MIS in selected patients undergoing cytoreductive surgery for EOC. Methods

Operative reports were reviewed for all patients undergoing cytoreductive

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surgery with diaphragm resection for EOC at Mayo Clinic in Scottsdale, Arizona, from January 1, 2004, through January 31, 2014. To analyze pulmonary complications most

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likely due only to diaphragm resection, patients were excluded if they had preoperative pleural effusion or pulmonary disease or if other upper abdominal metastases were

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resected, because these factors may contribute to pulmonary complications. 14 Exclusion of patients with upper abdominal metastases at other sites allowed for evaluation of diaphragm recurrence most likely related to previous diaphragm disease. The study was approved by the Mayo Clinic Institutional Review Board. In total, 29 patients were reviewed. Diaphragm resection was performed in the context of primary cytoreduction in 9 patients (31.0%), interval cytoreduction in 2

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(6.9%), and secondary cytoreduction in 18 (62.1). The 2 patients with interval debulking had received 3 courses of carboplatin-paclitaxel, while the 18 patients with secondary debulking had received 6 courses of carboplatin-paclitaxel after primary debulking. The

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surgical technique of peritoneal excision or full-thickness resection is not different than when performed by laparotomy. Abstracted data were age, body mass index, type and grade of tumor, International Federation of Gynecology and Obstetrics (FIGO) stage, type of surgical approach, size of metastases (defined as the largest dimension of the resected lesion), lesion location, lesion number (single or multiple), depth of resection

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(peritoneal [Figure 1] or full thickness [Figure 2]), operating time (from skin incision to skin closure), blood loss (difference between suction and irrigation fluids), intraoperative lung re-expansion (Figure 3), chest tube insertion, length of hospital stay, pulmonary complications, and diaphragm recurrence. Patients were selected on the basis of

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preoperative clinical and computed tomographic findings (Figure 4) and primary laparoscopic exploration for evaluating the feasibility of complete resection of all disease.

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Commonly, the patients lacked peritoneal nodular metastases and had metastatic disease in the abdomen and pelvis affecting 2 or more areas amenable to complete resection. The

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choice of laparoscopic or robotic resection was the surgeon’s decision, although the bias was for robotics. All patients underwent postoperative computed tomographic imaging of

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the abdomen and pelvis and received intravenous chemotherapy following primary, interval, and secondary debulking. Diaphragm recurrences were diagnosed on follow-up

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computed tomography or positron emission tomography or at a subsequent operation. Statistical Analysis Quantitative data were summarized as median and range; categorical data, as

frequency and percentage of sample. Group comparisons for quantitative variables were conducted with the nonparametric Wilcoxon rank sum test when 2 surgical groups were compared and with the Kruskal-Wallis test when more than 2 groups were compared. The

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Pearson 2 test was used for group comparisons with categorical variables. The significance level was P.05. Statistical analyses were performed with SAS Studio 3.4 software (SAS Institute Inc).

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Results Patient demographic characteristics, tumor data, and FIGO staging are

summarized in Table 1. Surgical approach (laparoscopic or robotic), depth of resection, diaphragm data (location, number, and size of metastases), perioperative outcomes,

residual diaphragm disease, and recurrence are summarized in Table 2. The mean size of

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diaphragm metastases was 56.7 mm (range, 2-145 mm); most were multiple and on the right diaphragm. Operating time, blood loss, and hospital stay included procedures in addition to diaphragm resection to resect other sites of disease, since diaphragm resection times were not measured independently. No patient had intraoperative complications

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related to diaphragm resection, and no procedures were converted to laparotomy. Pulmonary complications and metastatic recurrence in the diaphragm are

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summarized in Table 3. The only 2 patients (6.9%) with pulmonary complications (pleural effusion) had peritoneal resection. The effusions resolved spontaneously and

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were not clinically significant. The rate of metastatic recurrence in the diaphragm was lower in the peritoneal resection group and was similar to the rate of recurrence at other

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abdominal sites; the median time to recurrence was 2 years (range, 1-6 years). The size of diaphragm metastases was similar in patients with and without pulmonary complications

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and in patients with and without diaphragm recurrence. Intraoperative lung re-expansion was used in 4 of 6 patients who had full-thickness resection. None of the patients required chest tubes. Discussion The study findings suggest that, with careful patient selection and appropriate surgical expertise, complete resection of diaphragm metastases is feasible and safe. The

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low number of patients over a period of 10 years reflects the infrequency of the procedure and prevents the formation of definite conclusions, but the results provide insights into the outcomes of resection of diaphragm metastases by MIS. A comparison with

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laparotomy patients was difficult because of differences in extent of disease and magnitude of resections even when not considering patients with pleural effusion, pulmonary comorbidities, and upper abdominal procedures.

Patients who may be candidates for MIS have metastatic disease affecting 2 or more areas in the abdomen and pelvis and no or minimal peritoneal nodular

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metastases. At surgery, the robotic system is not prepared until laparoscopic exploration confirms that all sites of disease, including those in the diaphragm, can be completely removed with MIS.

Diaphragm resection times were not measured separately for the patients in

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our study. A console time of 80 minutes was reported in a case report of robotic excision of a single, ventral diaphragm recurrence.15 We could not find published diaphragm

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resection times for laparotomy in the referenced studies. Among our patients, the pulmonary complication rate was low (6.9%) and

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was likely related to the exclusion of patients with the factors described above that may contribute to pulmonary morbidity unrelated to diaphragm resection.14 None of our

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patients had pneumothorax, which has been reported for 2% to 14% of laparotomy patients,3,7,16 possibly because of the use of intraoperative lung re-expansion in 4 of the 6

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patients who underwent full-thickness resection (Figure 3). Intraoperative lung reexpansion has been shown to reduce pneumothorax.7,17 An endoscopic approach would be expected to decrease the risk of pneumothorax because of the ingress of carbon dioxide at a low pressure into the pleural cavity instead of room air (containing 70% nitrogen) at the barometric pressure at sea level of 760 mm Hg. The mean size of metastases did not appear to affect pulmonary complications because it was similar for

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patients with and without complications (32.0 mm and 58.6 mm, respectively) (P=.32) (Table 3). Patients have a lower rate of pulmonary complications with peritoneal

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diaphragm resection (19.5%-46.6%) compared with full-thickness resection by laparotomy (33.0%-72.7%), so peritoneal resection is preferable if all the metastatic lesion can be excised.17-19 In the present study, pulmonary complications occurred only in patients who underwent peritoneal resection, likely because they were in higher number. Recurrence in the diaphragm was diagnosed in 6 patients (20.7%), and

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recurrence at other abdominal sites in 10 patients (34.5%), indicating that control of diaphragm disease was acceptable compared with other sites. The mean size of the diaphragm metastases did not seem to affect diaphragm recurrence because it was similar for patients with and without recurrence (56.8 mm and 56.7 mm, respectively) (P=.73)

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(Table 3).

The present study has several drawbacks in addition to its retrospective

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nature and low number of patients. Other than surgeon’s choice, no specific criteria were used to determine whether patients underwent laparoscopic or robotic surgery, although

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the bias was for robotics. Procedures in addition to hysterectomy, adnexectomy, and omentectomy were not accounted for because they were not in the upper abdomen. The

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morphologic features of the diaphragm metastases were not documented, and plaquelike

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lesions have been associated with a higher risk of recurrence. 3 It appears reasonable to conclude that resection of diaphragm metastases

should not necessarily indicate the need for laparotomy and that MIS is feasible and safe in selected patients if all disease can be completely resected. Complete resection is directly related to careful patient selection through preoperative evaluation and laparoscopic exploration and consideration of surgical expertise.

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References 1.

Fanfani F, Fagotti A, Gallotta V, et al. Upper abdominal surgery in advanced and recurrent ovarian cancer: role of diaphragmatic surgery. Gynecol Oncol.

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2010;116(3):497-501. Nougaret S, Addley HC, Colombo PE, et al. Ovarian carcinomatosis: how the radiologist can help plan the surgical approach. Radiographics. 2012;32(6):17751800; discussion 1800-1773. 3.

Tsolakidis D, Amant F, Van Gorp T, Leunen K, Neven P, Vergote I.

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Diaphragmatic surgery during primary debulking in 89 patients with stage IIIB-IV epithelial ovarian cancer. Gynecol Oncol. 2010;116(3):489-496. 4.

Aletti GD, Dowdy SC, Gostout BS, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006;107(1):77-85. Rodriguez N, Miller A, Richard SD, et al. Upper abdominal procedures in

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advanced stage ovarian or primary peritoneal carcinoma patients with minimal or

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no gross residual disease: an analysis of Gynecologic Oncology Group (GOG) 182. Gynecol Oncol. 2013;130(3):487-492. Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete

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cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a

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meta-analysis. Gynecol Oncol. 2013;130(3):493-498.

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Bashir S, Gerardi MA, Giuntoli RL, 2nd, Montes TP, Bristow RE. Surgical technique of diaphragm full-thickness resection and trans-diaphragmatic decompression of pneumothorax during cytoreductive surgery for ovarian cancer. Gynecol Oncol. 2010;119(2):255-258. Dowdy SC, Loewen RT, Aletti G, Feitoza SS, Cliby W. Assessment of outcomes and morbidity following diaphragmatic peritonectomy for women with ovarian carcinoma. Gynecol Oncol. 2008;109(2):303-307.

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Einenkel J, Ott R, Handzel R, Braumann UD, Horn LC. Characteristics and management of diaphragm involvement in patients with primary advanced-stage ovarian, fallopian tube, or peritoneal cancer. Int J Gynecol Cancer.

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2009;19(7):1288-1297. Grimm C, Harter P, Heitz F, du Bois A. The sandwich technique of diaphragmatic stripping or full-thickness resection for advanced ovarian cancer: how to keep it short and simple. Int J Gynecol Cancer. 2015;25(1):131-134. 11.

Magrina JF, Zanagnolo V, Noble BN, Kho RM, Magtibay P. Robotic approach

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for ovarian cancer: perioperative and survival results and comparison with laparoscopy and laparotomy. Gynecol Oncol. 2011;121(1):100-105. 12.

Escobar PF, Levinson KL, Magrina J, et al. Feasibility and perioperative outcomes of robotic-assisted surgery in the management of recurrent ovarian

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cancer: a multi-institutional study. Gynecol Oncol. 2014;134(2):253-256. Magrina JF, Cetta RL, Chang YH, Guevara G, Magtibay PM. Analysis of

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secondary cytoreduction for recurrent ovarian cancer by robotics, laparoscopy and laparotomy. Gynecol Oncol. 2013;129(2):336-340. Chereau E, Rouzier R, Gouy S, et al. Morbidity of diaphragmatic surgery for

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advanced ovarian cancer: retrospective study of 148 cases. Eur J Surg Oncol.

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2011;37(2):175-180.

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Holloway RW, Brudie LA, Rakowski JA, Ahmad S. Robotic-assisted resection of liver and diaphragm recurrent ovarian carcinoma: description of technique. Gynecol Oncol. 2011;120(3):419-422. Devolder K, Amant F, Neven P, van Gorp T, Leunen K, Vergote I. Role of diaphragmatic surgery in 69 patients with ovarian carcinoma. Int J Gynecol Cancer. 2008;18(2):363-368.

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17.

Terauchi F, Okamoto A, Wada Y, et al. Incidental events of diaphragmatic surgery in 82 patients with advanced ovarian, primary peritoneal and fallopian tubal cancer. Oncol Lett. 2010;1(5):861-864. Pathiraja PN, Garruto-Campanile R, Tozzi R. Diaphragmatic peritonectomy

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versus full thickness diaphragmatic resection and pleurectomy during cytoreduction in patients with ovarian cancer. Int J Surg Oncol. 2013;2013:876150. 19.

Zapardiel I, Peiretti M, Zanagnolo V, et al. Diaphragmatic surgery during primary

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cytoreduction for advanced ovarian cancer: peritoneal stripping versus

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diaphragmatic resection. Int J Gynecol Cancer. 2011;21(9):1698-1703.

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Legends

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Figure 1. A, Peritoneal resection of superficial metastases in the left diaphragm. B,

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Peritoneal defect after completion of resection.

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Figure 2. A, Right diaphragm with multiple metastases, superficial and invasive. B, Fullthickness resection of invasive nodular metastasis after completion of peritoneal

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resection.

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Figure 3. Closure of the right diaphragm with intraoperative lung re-expansion.

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Figure 4. Computed tomographic image of isolated recurrence in the right dorsal

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diaphragm with superficial liver involvement.

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Table 1. Demographic and Tumor Data for 29 Patients With Diaphragm Metastases Feature

Value

Age at surgery, y 58.7 (14.9)

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Mean (SD) Median (range)

61.0 (30.0-86.0)

BMI Mean (SD)

24.5 (3.4)

Median (range)

24.2 (18.3-29.5)

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Histology, No. (%) Serous

24 (82.7)

Endometrioid

2 (6.9) 1 (3.4)

Other Tumor grade, No. (%)

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I

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II III

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Clear cell

2 (6.9)

6 (20.7) 6 (20.7) 17 (58.6)

FIGO stage, No. (%)

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IIIC IV

28 (96.6) 1 (3.4)

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); FIGO, International Federation of Gynecology and Obstetrics.

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Table 2. Perioperative Data for 29 Patients With Diaphragm Metastases Feature

Value

Laparoscopic

8 (27.6)

Robotic

21 (72.4)

Type of resection, No. (%) 23 (79.3)

Full thickness

6 (20.7)

Diaphragm metastases, No. (%) Single

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Peritoneal

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Surgical procedure, No. (%)

10 (34.5)

Multiple

19 (65.5)

Side, No. (%)

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Left

Bilateral Size, mm

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Mean (SD)

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Right

Median (range)

2 (6.9)

17 (58.6) 10 (34.5)

56.7 (40.8) 46.0 (2.0-145.0)

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Operating room time, min Mean (SD)

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Median (range)

238.2 (102.6) 212.0 (75.0-505.0)

Blood loss, mL Mean (SD) Median (range)

236.4 (393.4) 100.0 (25.0-1,600.0)

Length of hospital stay, d Mean (SD)

3.1 (3.2)

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Median (range)

2.0 (1.0-12.0)

Pneumothorax

0 (0.0)

Pleural effusion

2 (6.9)

Other

0 (0.0)

Residual disease in diaphragm, No. (%) None

29 (100)

Recurrence of disease, No. (%) 6 (20.7)

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Diaphragm

10 (34.5)

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Other

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Pulmonary complications, No. (%)

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Table 3. Pulmonary Complications and Diaphragm Recurrence by Depth of Resection and Size of Metastases 1. Depth of resection

Pulmonary complications

0 (0.0%)

Diaphragm recurrence

2 (33.3%)

B. Peritoneal (n=23) 2 (8.7%)

Diaphragm recurrence

4 (17.4%)

2. Size of diaphragm metastases

Yes

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A. Pulmonary complications

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Pulmonary complications

n

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(n=2)

Size, mm

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A. Full thickness (n=6)

No

Total

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(n=27)

(n=29)

Value .32a

2

27

29

32.0 (32.5)

58.6 (41.3)

56.7 (40.8)

Median

32.0

46.0

46.0

Range

9.0-55.0

2.0-145.0

2.0-145.0

Yes

No

Total

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(n=6)

(n=23)

(n=29)

Value

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Mean (SD)

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B. Diaphragm recurrence

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Size, mm n Mean (SD)

6

23

29

56.8 (34.7)

56.7 (43.0)

56.7 (40.8)

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Median

50.5

Range

46.0

2.0-145.0

2.0-145.0

Kruskal-Wallis test.

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a

10.0-115.0

40.0