Effect of Pre-Operative Internal Obturator Muscle Mass Index in MRI on Biochemical Recurrence of Prostate Cancer Patients After Radical Prostatectomy: A Multi-Center Study

doi:10.21203/rs.3.rs-111912/v1

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Effect of Pre-Operative Internal Obturator Muscle Mass Index in MRI on Biochemical Recurrence of Prostate Cancer Patients After Radical Prostatectomy: A Multi-Center Study

https://doi.org/10.21203/rs.3.rs-111912/v1

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Purpose: Recent reports show that the pre-operative or post-operative skeletal mass index (sarcopenia) affects survival rates for various cancers; however, the link between prostate cancer survival and sarcopenia is unclear. Therefore, this study examined the effect of the pre-operative internal obturator muscle (IOM) mass index on biochemical recurrence (BCR) of prostate cancer (PCa) patients who underwent radical prostatectomy.

Methods: In total, 222 patients, who underwent open or robot-assisted radical prostatectomy at seven centers in 2011 and were followed up for 5 years, were enrolled. BCR was examined in the context of pre-operative IOM mass index and BMI.

Results: The mean age of the patients was 67.82 ± 6.23 years, and the mean pre-operative prostate-specific antigen (PSA) level was 11.61 ± 13.22 ng/ml. There was no significant difference in baseline characteristics between the low and high IOM mass index groups (p > 0.05). Age, pre-op PSA level, ECE, and T-stage were not associated with BCR (p = 0.049, p < 0.001, p = 0.001, p = 0.004, respectively). BMI, prostate volume, Gleason score, resection margin, N-stage, M-stage and IOM mass index was not associated with BCR (p > 0.05).

Conclusions: Pre-operative IOM mass index was not associated with BCR; however, long-term follow-up is necessary to evaluate cancer-specific and overall survival of PCa patients.

Urology & Nephrology

Prostatic neoplasms

Sarcopenia

Internal obturator muscle

Recurrence

Prostate cancer (PCa) is the most common cancer in men worldwide.¹ The incidence of PCa in Asia is among the lowest in the world.¹ However, the incidence in the Republic (Rep.) of Korea is increasing rapidly.² PCa mortality rates have fallen in high-resource countries, but have increased or remain stable in low-resource countries.¹ PCa-associated mortality in the Rep. of Korea is increasing along with incidence.²

Sarcopenia is a condition characterized by progressive and generalized loss of muscle mass and strength.³ Sarcopenia predicts drug toxicity and time-to-tumor progression in patients undergoing chemotherapy.⁴ The impact of sarcopenia in cancer patients has been studied, and data suggest that sarcopenia is independently associated with post-operative outcome following resection of colorectal cancer, hepatocellular carcinoma, pancreatic cancer, and bladder cancer.^5–8 In addition, sarcopenia is a prognostic marker for disease recurrence and mortality in patients with urologic cancers.^8–11

Radical prostatectomy (RP) is the gold standard treatment for localized PCa. RP is often the treatment of choice for younger and less morbid patients. A previous report suggests that sarcopenia is associated with non-cancer-related death in PCa patients undergoing radiotherapy.¹² Conversely, Mason et al. report that sarcopenia is not independently associated with perioperative complications or oncologic outcomes after RP.¹³ Therefore, there is a lack of evidence supporting an association between sarcopenia and oncologic outcomes in PCa. Generally, sarcopenia, skeletal mass index (SMI) was defined as the cross-sectional area of the rectus abdominis; internal, external, and transverse obliques; psoas; quadratus lumborum; and erector spinae muscles from L3 down. Most surgeon performed MRI imaging work-up for prostatectomy. So, internal obturator muscle (IOM) is the only measurable muscle in the pelvis MRI axial cut. However, there was no study between pre-operative IOM mass index and oncologic outcomes in PCa. Therefore, we investigated the effect of pre-operative IOM mass index on biochemical recurrence (BCR) in Korean patients after radical RP.

Study population and data collection

In total, 222 PCa patients, who underwent open or robot-assisted RP at seven academic centers in 2011 and were followed up for 5 years, were enrolled. All patients had histologically confirmed primary adenocarcinoma of the prostate, and all had undergone pre-operative MRI within 3 months of surgery. Patients were excluded if they had previously received androgen deprivation therapy (ADT) or radiotherapy (RT). In addition, patients undergoing testosterone replacement therapy or taking medications that affect muscle mass were excluded.

Clinical and pathologic data included age, height, body weight, prostate-specific antigen (PSA) levels, prostate volume, pathologic T-, N-, and M-stage, receipt of adjuvant RT or ADT, and follow-up duration. BCR after RP was defined as a post-operative PSA level > 0.2 ng/mL. Patients undergoing adjuvant ADT or RT after RP were excluded in the BCR group. IOM mass index was measured by dividing the mean internal obturator muscle area (calculated from CT or MRI) by height (squared). All internal obturator muscle area measurements were performed by a single radiologist (Cho, BS, Fig. 1). All methods used for sample collection and analyses were approved by the Ethics Committee of Chungbuk National University Hospital, and all subjects provided written informed consent (IRB approval number: 2018-02-021).

Statistical analysis

IOM mass index was divided into two groups according to a median cut-off value. BMI was divided to three groups according to Korean BMI criteria.¹⁴ The baseline characteristics of the patients with a low IOM mass index and a high IOM mass index were compared using an independent t-test and the Chi-square test as appropriate. Comparisons of clinical and pathological parameters according to BMI were made using ANOVA and the Chi-square test as appropriate. The association between BCR and pre-operative IOM mass index or BMI values were examined using a Cox proportional hazards model and a Kaplan–Meier survival analysis. Statistical analyses were performed using the Statistical Package for Social Sciences, version 25 software (SPSS, Inc., Chicago, IL, USA). A p-value < 0.05 was considered statistically significant.

Baseline characteristics of the study population according to IOM mass index

The baseline characteristics of all the patients are shown in Table 1. The mean age was 67.82 ± 6.23 years, and the mean pre-operative PSA level was 11.61 ± 13.22 ng/mL. There was no significant difference in baseline characteristics between the low IOM mass index and high IOM mass index groups (p > 0.05).

Table 1

Baseline characteristics of all patients and according to the Internal obturator muscle (IOM) mass Index
Parameters	Overall	According to the IOM mass index
		Low IOM	High IOM	p-value
Number	222	111	111
Age (years)	67.82 ± 6.23	68.55 ± 6.11	67.10 ± 6.29	0.083
IOM (mm²/cm²)	11.23 ± 2.22
BMI (kg/m²)	24.46 ± 2.86	24.17 ± 2.86	24.74 ± 2.85	0.136
Pre-op PSA (ng/mL)	11.61 ± 13.22	11.12 ± 12.29	12.11 ± 14.12	0.579
Prostate volume (cc)	34.58 ± 14.13	35.56 ± 15.68	33.57 ± 12.33	0.313
Type of operation				0.200
RRP	163 (73.4)	77 (69.4)	86 (77.5)
LRP	1 (0.5)	0	1 (0.9)
RARP	58 (26.1)	34 (30.6)	24 (21.6)
Gleason score				0.441
≤6	59 (26.6)	24 (21.6)	35 (26.6)
7	145 (65.3)	78 (70.3)	67 (65.3)
8	8 (3.6)	4 (3.6)	4 (3.6)
9	10 (4.5)	5 (4.5)	5 (4.5)
T-stage				0.717
T2a	28 (12.6)	14 (12.6)	14 (12.6)
T2b	38 (17.1)	19 (17.1)	19 (17.1)
T2c	119 (53.6)	56 (50.5)	63 (56.8)
T3a	21 (9.5)	13 (11.7)	8 (7.2)
T3b	16 (7.2)	9 (8.1)	7 (6.3)
N-stage				0.155
0	267 (97.1)	111 (100)	109 (98.2)
1	8 (2.9)	0 (0.0)	2 (1.8)
cM stage				0.316
0	221 (99.5)	110 (99.1)	111 (100)
1	1 (0.5)	1 (0.9)	0 (0.0)
BCR				0.871
0	173 (77.9)	87 (78.4)	86 (77.5)
1	49 (22.1)	24 (21.6)	25 (22.5)
BMI: body mass index; pre-op PSA: pre-operative prostate-specific antigen; RRP: radical retropubic prostatectomy; LRP: laparoscopic radical prostatectomy; RARP: robot-assisted radical prostatectomy; BCR: biochemical recurrence.

Comparison of clinical and pathological parameters according to BMI

As shown in Table 2, there was no significant difference in clinical and pathological parameters according to BMI (p > 0.05).

Table 2

Comparison of clinical and pathological parameters according to body mass index
Parameter	≤ Normal	Overweight	Obese	p-value
Number	63	73	86
Age (years)	68.57 ± 6.06	68.07 ± 6.85	67.07 ± 5.76	0.321
IOM (mm²/cm²)	10.84 ± 2.18	11.13 ± 2.02	11.59 ± 2.37	0.115
BMI (kg/m²)	21.11 ± 1.45	24.06 ± 0.51	27.25 ± 1.79	< 0.001
Pre-op PSA (ng/mL)	13.97 ± 17.97	11.01 ± 10.93	10.40 ± 10.57	0.237
Prostate volume (cc)	32.54 ± 12.95	33.01 ± 14.39	37.54 ± 14.42	0.062
Type of operation				0.291
RRP	48 (76.2)	58 (79.5)	57 (66.3)
LRP	0 (0.0)	0 (0.0)	1 (1.2)
RARP	15 (23.8)	15 (20.5)	28 (32.6)
Gleason score				0.165
≤6	14 (22.2)	20 (27.4)	25 (29.1)
7	43 (68.3)	49 (67.1)	53 (61.6)
8	5 (7.9)	1 (1.4)	2 (2.3)
9	1 (1.6)	3 (4.1)	6 (7.0)
T-stage				0.220
T2a	7 (11.1)	14 (19.2)	7 (8.1)
T2b	7 (11.1)	13 (17.8)	18 (20.9)
T2c	37 (58.7)	37 (50.7)	45 (52.3)
T3a	5 (7.9)	5 (6.8)	11 (12.8)
T3b	7 (11.1)	4 (5.5)	5 (5.8)
N-stage				0.524
0	62 (98.4)	72 (98.6)	86 (100)
1	1 (1.6)	1 (1.4)	0 (0.0)
cM stage				0.282
0	62 (98.4)	73 (100)	86 (100.0)
1	1 (1.6)	0 (0.0)	0 (0.0)
BCR				0.521
0	46 (73.0)	59 (80.8)	68 (79.1)
1	17 (27.0)	14 (19.2)	18 (20.9)
IOM: Internal obturator muscle mass index; BMI: body mass index; pre-op PSA: pre-operative prostate-specific antigen; RRP: radical retropubic prostatectomy; LRP: laparoscopic radical prostatectomy; RARP: robot-assisted radical prostatectomy; BCR: biochemical recurrence

Cox proportional hazards model analysis of biochemical recurrence

Age, pre-op PSA, ECE, and T-stage was associated with BCR (p = 0.049, p < 0.001, p = 0.001, p = 0.004, respectively). However, there was no association between BCR and BMI, prostate volume, Gleason score, resection margin, N-stage, or M-stage (p > 0.05; Table 3). In particular, IOM mass index was not associated with BCR (p > 0.05; Fig. 2).

Table 3

Cox proportional hazards model analysis of biochemical recurrence
Parameter	HR	95% CI	p-value
Age (years)	0.945	0.892–1.000	0.049
IOM (mm²/cm²) (low vs. high)	0.891	0.462–1.719	0.731
BMI (kg/m²)			0.142
≤ Normal	-
Overweight	0.880	0.379–2.042
Obesity	0.455	0.195–1.063
Pre-op PSA (ng/ml)	1.064	1.045–1.083	< 0.001
Prostate volume (cc)	1.016	0.990–1.042	0.226
Gleason score			0.364
≤6	-
7	1.263	0.478–3.340
8	1.473	0.317–6.844
9	3.064	0.798–11.760
ECE (No vs. Yes)	5.551	2.011–15.322	0.001
Resection margin (- vs. +)	1.040	0.479–2.262	0.920
T-stage			0.004
T2a	-
T2b	13.260	2.218–79.262
T2c	3.157	0.609–16.373
T3a	1.564	0.177–13.785
T3b	4.830	0.700–33.326
N-stage (no involvement vs. LN involvement)	0.300	0.028–3.202	0.319
M-stage (no meta vs. meta)	0.000	0.000–	0.985
IOM: internal obturator muscle mass index; BMI: body mass index; pre-op PSA: pre-operative prostate-specific antigen; ECE: extracapsular extension; LN: lymph node.

The results of the present study suggest that IOM mass index is not associated with BCR after RP in Korean men. The present study is the first to show no significant association between IOM mass index and BCR in men with RP. Thus, IOM mass index may not be a prognostic marker for BCR in Korean men with localized PCa undergoing RP.

Previous studies suggest that high BMI is associated with increased risk of PCa.^{15, 16} A meta-analysis by Bergstrom et al. reports a 6% increase in the risk of PCa in overweight men and a 12% increase in obese men compared with men of normal weight.¹⁶ Maclnnis et al. reported a weak positive association between BMI and risk of PCa; BMI was associated with moderate increase in the risk of advanced PCa.¹⁵

The relationship between BMI and BCR after RP remains controversial. Freedland et al. reported that obesity among men treated with RP was associated with high-grade tumors, a trend toward increased risk of a positive surgical margin, and high BCR.¹⁷ Magheli et al. reported that high BMI is associated with adverse pathological findings and is a strong independent predictor of BCR after RP.¹⁸ Asmar et al. reported that both obesity and hypertension are associated with an increased risk of BCR after RP, independent of age at the time of diagnosis or tumor pathological features.¹⁹ By contrast, Tomaszewski et al. reported that obesity is not associated with adverse pathologic features, positive surgical margin, or BCR.²⁰ They suggested that their data provide evidence that obese men undergoing RP are not more likely to suffer PCa progression. In addition, Siddiqui et al. reported that obese patients appeared to have worse pathologic features at the time of prostatectomy; however, BMI did not appear to be an independent predictor of recurrence or survival after prostatectomy.²¹ The present study found no association between BMI and BCR. Therefore, we believe that the relationship between BMI and BCR after RP remains unclear.

Sarcopenia is a process associated with normal aging; however, it is exacerbated by the hypercatabolic state and inflammatory responses caused by malignancy.²² A systematic review by Joglekar et al. investigated the impact of sarcopenia on outcome following surgical resection of cancer and reported that sarcopenia is an independent prognostic factor for both complications and survival following surgical resection.²³ Sarcopenia is a more objective and comprehensive pre-operative risk factor that predicts all-cause survival for bladder cancer after radical cystectomy (RC).^{9, 24} With respect to PCa, several reports link sarcopenia and survival ^{12, 25}. Thus, sarcopenia could be used to predict non-cancer-related death in men with PCa after RT ¹² and may be a poor prognostic factor for CRPC treated with chemotherapy.²⁵ However, the association between sarcopenia and survival after RP is very unclear. Long-term follow-up studies are necessary to identify (or not) any association between sarcopenia or IOM mass index and survival.

We recognize that this study has several limitations. First, we only measured internal obturator muscle mass, but not SMI. In general, SMI was defined as the cross-sectional area of the rectus abdominis; internal, external, and transverse obliques; psoas; quadratus lumborum; and erector spinae muscles from L3 down. However, because this was a multi-institutional study, different authors have different protocols for pre-operative CT and MRI. Therefore, we selected only the internal obturator muscle area in the pelvis in the MRI, because of internal obturator muscle is the oncly measurable muscle in the pelvis MRI axial cut. So, we couldn't compared IOM mass with general SMI. Second, many patients who underwent RP at these institutions were excluded from the analysis due to differences in CT or MRI protocols. In some institutions, radiologists were not able to measure the internal obturator muscle at the same levels. Third, the follow-up period was too short to get an accurate picture of survival. In this case we did not examine cancer-specific or overall survival; studies may need follow-up data spanning more than 15 years to get an accurate picture of the association between IOM mass index and the survival of PCa patients.

Pre-operative IOM mass index was not associated with BCR; however, long-term (> 15 years) follow-up is necessary to better answer this still controversial question.

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

This study was supported by research fund from The Hannam Urological Association, 2018 and the International Science and Business Belt Program funded by the Ministry of Science, ICT & Future Planning (2017K000490).

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You are reading this latest preprint version

Effect of Pre-Operative Internal Obturator Muscle Mass Index in MRI on Biochemical Recurrence of Prostate Cancer Patients After Radical Prostatectomy: A Multi-Center Study

Status:

Version 1

Abstract

Figures

Introduction

Material And Methods

Study population and data collection

Statistical analysis

Results

Baseline characteristics of the study population according to IOM mass index

Comparison of clinical and pathological parameters according to BMI

Cox proportional hazards model analysis of biochemical recurrence

Discussion

Conclusions

Declarations

Conflicts of interest

Acknowledgements

References

Status:

Version 1