Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: a multicenter study

doi:10.21203/rs.3.rs-1840215/v1

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Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: a multicenter study

https://doi.org/10.21203/rs.3.rs-1840215/v1

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Aim

To compare survival outcomes, response rates, and adverse events (AEs) in proton pump inhibitor (PPI) user and non-user patients with metastatic colorectal cancer (mCRC) treated with regorafenib.

Methods

We included 272 patients with mCRC treated with regorafenib in this study. Patients were divided into two categories according to their status of PPI use. The primary endpoint was overall survival (OS). The secondary endpoints were time to treatment failure (TTF), response rates, and safety. To exclude immortal time bias in survival analyses, we compared PPI non-user patients and all patients.

Results

There were 141 and 131 patients in the PPI non-user and user groups. Baseline characteristics were similar in each group. Pantoprazole was the most used PPI. At the median 35.2 (95% Confidence Interval (CI): 32.6-37.9) months follow-up, the median OS was similar in PPI non-user and all patients (6.9 months (95% CI: 5.3-8.5) and 7.7 months (95% CI:6.6-8.8), p = 0.913). TTF was also similar in PPI non-user and all patients (3.3 months (95% CI:2.7-3.9) and 3.5 months (95% CI:3.0-4.0), p = 0.661). In multivariable analysis, no statistically significant difference was observed between PPI user and non-user groups in OS and TTF (Hazard Ratio (HR):0.99, 95% CI:0.77-1.28, p =0.963 for OS; HR:0.93, 0.77-1.20, p=0.598 for TTF). The objective response rates (ORR) were similar in the PPI non-user and user groups (19.8% and 16.8%, p=0.455). The rates of any grade AEs were also similar in each group.

Conclusion

This study showed that PPI was not associated with worse survival outcomes and safety profile in patients with mCRC treated with regorafenib.

drug-drug interactions

acid suppression

regorafenib

Regorafenib is one of the oral multi-target tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic colorectal cancer (mCRC), hepatocellular cancer (HCC), and gastrointestinal stromal tumor (GIST). [1, 6, 12] For all TKIs, drug-drug interactions due to their oral route administration are substantial for their effectiveness. In addition, the bioavailability of oral TKIs may change with drugs affecting gastric pH.[3] In this regard, one of the main concerns about the bioavailability of TKIs was the combined use of these agents with acid suppression therapies, such as proton pump inhibitors (PPIs) and anti-acids.[16, 19]

PPIs are usually prescribed to cancer patients for various reasons, such as treating dyspeptic symptoms, gastric bleeding prophylaxis, and preventing gastric damage from chemotherapy and radiotherapy.[9, 13] However, acid suppression with PPIs may affect the solubility and bioavailability of TKIs.[4, 10, 15] Indeed, the proportion of ionized forms of TKIs changes as per gastric pH. Usually, they need an acid environment for more ionization that can be absorbed easier than the non-ionized form.[10, 15]

However, there were conflicting results regarding the effect of PPIs and TKIs combinations on the clinical outcomes. For instance, in a study that assessed the impact of combined use of pazopanib and PPIs on survival outcomes and adverse events (AEs) profile, no difference was observed between the PPI user and non-user groups.[8] Conversely, a study including patients with HCC treated with TKIs showed increased mortality in the PPI user group. To date, one study evaluated the effect of esomeprazole on the bioavailability of regorafenib and concluded that the bioavailability of regorafenib was similar in PPI non-user and user groups. However, this study did not compare the survival outcomes between the groups.[2] Unfortunately, there is no data on whether regorafenib combined with PPI affects survival and safety outcomes in patients with mCRC.

This study aimed to assess the effect of PPIs on the survival outcomes, response rates, and AEs profile in patients with mCRC treated with regorafenib.

The local ethical committee approved this study in compliance with the “Declaration of Helsinki” and local guidelines.

Patients Cohort and Data Extraction

Patients with mCRC treated with regorafenib from eight cancer centers in Turkey between January 2015 and December 2021 were included in this multicenter retrospective cohort study. Patients were divided into groups according to their status of PPI use as PPI non-user and user groups. Demographic and clinical data were extracted from the electronic medical record systems and patients’ files. Patients who were prescribed PPI at any time after initiation of regorafenib were categorized in the PPI user group.

Endpoints

The primary endpoint was overall survival (OS), calculated from the initiation of regorafenib to the exitus. The secondary endpoints were time to treatment failure (TTF), calculated from the initiation of regorafenib to discontinuation for any reason, response rates, and safety. Response rates were assessed according to “Response evaluation criteria in solid tumors” (RECIST) 1.1. “Common Terminology Criteria for Adverse Events” (CTCAE version 4.03) was used to evaluate AEs.

Statistical Analysis

For descriptive analyses, median with interquartile range (IQR) for normally distributed continuous variables, mean ± standard deviation for non-normally distributed continuous variables, and percentages for categorical variables were used. Mann-Whitney U and independent samples t-tests were used to compare two groups for non-normally and normally distributed continuous variables. Chi-square or Fisher’s exact test was used to compare categorical variables. Kaplan-Meier estimates were used to calculate OS and PFS. To exclude immortal time bias, we compared PPI non-user patients with all patients. A log-rank test was used to compare survival curves. Cox’s proportional hazard regression model was constructed by using variables with a p-value of less than 0.2 in univariable analysis. A p-value of less than 0.05 was considered statistically significant. SPSS 27.0 for Mac (IBM Corp., Armonk, NY) and RStudio were used for all statistical analyses.

Baseline Characteristics

A total of 272 patients were included in this study. There were 141 and 131 patients in the PPI non-user and user groups, respectively. The median age at starting regorafenib was 61 (IQR:52-67) and 57 (IQR:48-65) in the PPI non-user and user groups. Most patients had an Eastern Cooperative Oncology Group (ECOG) 0 or 1 performance status and had left-sided colon or rectum tumors in each group. A full dose of regorafenib was started in approximately half of the patients, and dose reduction was required in about one out of four patients in the PPI non-user and user groups. Most patients received regorafenib in the third line in each group. All baseline characteristics were similar in the PPI non-user and user groups (Table 1).

Table 1. Baseline Characteristics

		PPI Non-user		PPI User		p
		n=141	*(%)*	n=131	*(%)*	p
Age at Starting Regorafenib years median (IQR)		61 (52-67)		57 (48-65)		0.101
Sex						0.063
	Male	77	(54.6)	86	(65.6)
	Female	64	(45.4)	45	(34.4)
ECOG Performance Status						0.805
	0-1	102	(72.3)	93	(71.0)
	2	39	(27.7)	38	(29.0)
Tumor Location						0.389
	Right Colon	24	(17.0)	25	(19.1)
	Left Colon	50	(35.5)	53	(40.5)
	Rectum	63	(44.7)	47	(35.9)
	Missing	4	(2.8)	6	(4.6)
Histological Subtype						0.085
	Non-mucinous	121	(85.8)	121	(92.4)
	Mucinous	20	(14.2)	10	(7.6)
KRAS or NRAS or BRAF Status						0.609
	Mutant Type	73	(51.8)	67	(51.1)
	Wilde Type	51	(36.2)	43	(32.8)
	Missing	17	(12.0)	21	(16.0)
First Site of Metastasis						0.195
	Liver	66	(46.8)	70	(53.4)
	Lung	19	(13.5)	12	(9.2)
	Peritoneal	13	(9.2)	9	(6.8)
	Intraabdominal Lymph Node	9	(6.4)	4	(3.1)
	Other	3	(2.1)	0	(0)
	Multiple	31	(22.0)	36	(27.5)
PPI Subtypes		N/A				N/A
	Pantoprazole			53	(40.5)
	Esomeprazole			28	(21.4)
	Lansoprazole			19	(14.5)
	Rabeprazole			3	(2.3)
Initial Dose of Regorafenib						0.574
	80 mg	29	(20.6)	23	(17.6)
	120 mg	45	(31.8)	51	(38.9)
	160 mg	60	(42.6)	57	(43.5)
	Missing	7	(5.0)	0	(0)
Presence of Dose Reduction						0.142
	No	93	(66.0)	102	(77.9)
	Yes	40	(28.3)	29	(22.1)
	Missing	8	(5.7)	0	(0.0)
Treatment Line of Regorafenib						0.106
	3	71	(50.4)	82	(62.6)
	4	60	(42.6)	40	(30.5)
	5-6	10	(7.0)	9	(6.9)
*Abbreviations: ECOG: Eastern Cooperative Oncology Group, IQR=Interquartile Range, N/A=Not applicable, PPI=Proton Pump Inhibitor*

Survival Outcomes and Response Rates

At the median 35.2 (95% Confidence Interval (CI): 32.6-37.9) months follow-up, the median OS was similar in PPI non-user and all patients (6.9 months (95% CI: 5.3-8.5) and 7.7 months (95% CI:6.6-8.8), p = 0.913). TTF was also similar in PPI non-user and all patients (3.3 months (95% CI:2.7-3.9) and 3.5 months (95% CI:3.0-4.0), p = 0.661). Kaplan-Meier estimates for OS and TTF are shown in Figures 1 and 2. In multivariable analysis, no statistically significant difference was observed between PPI user and non-user groups in OS and TTF (Hazard Ratio (HR):0.99, 95% CI:0.77-1.28, p =0.963 for OS; HR:0.93, 0.77-1.20, p = 0.598 for TTF), after adjusting for confounding variables (i.e., ECOG performance score for OS and initial dose of regorafenib for OS and TTF).

The objective response rates (ORR) were similar in the PPI non-user and user groups (19.8% and 16.8%, p=0.455). The best responses with regorafenib in each group are shown in Table 2.

Table 2. Best Response with Regorafenib

	PPI Non-user (n=141) (%)	PPI User (n=131) (%)	P
Complete Remission (CR)	1 (0.7)	0 (0)	0.243
Partial Remission (PR)	27 (19.1)	22 (16.8)
Stable Disease (SD)	46 (32.6)	35 (26.7)
Progressive Disease (PD)	40 (28.4)	51 (38.9)
Objective Response Rate (CR+PR)	28 (19.8)	22 (16.8)	0.455
Disease Control Rate (CR+PR+SD)	74 (52.4)	57 (43.5)	0.066
*Abbreviations: PPI=Proton Pump Inhibitor*

Safety

The rates of any AEs were similar in PPI non-user and user groups (37.6% vs. 38.9%, p=0.820 for grade 1-2, 21.3% vs. 22.1%, p=0.863). All subtypes of AEs were also similar in each group. All AEs are shown in Table 3.

Table 3. Adverse Events

	PPI Non-user n=141 (%)		PPI User n=131 (%)		p
	Grade 1-2	Grade ≥ 3	Grade 1-2	Grade ≥ 3	Grade 1-2	Grade ≥ 3
Any	53 (37.6)	30 (21.3)	51 (38.9)	29 (22.1)	0.820	0.863
Hand-Foot Syndrome	35 (24.8)	5 (3.5)	33 (25.2)	6 (4.6)	0.944	0.665
Fatigue	45 (31.9)	18 (12.8)	52 (39.7)	13 (9.9)	0.181	0.461
Hypertension	15 (10.6)	7 (5.0)	14 (10.7)	9 (6.9)	0.990	0.505
Diarrhea	24 (17.0)	3 (2.1)	22 (16.8)	2 (1.5)	0.960	1.000
Skin Rash	26 (18.4)	2 (1.4)	21 (16.0)	3 (2.3)	0.599	0.674
*Abbreviations: PPI=Proton Pump Inhibitor*

To the best of our knowledge, this was the first study that assessed the effect of PPI use on the survival and safety outcomes in patients with mCRC treated with regorafenib. This study revealed no impact of PPIs on the survival outcomes, response rates, and safety profile of regorafenib in those patients.

In a study assessing the bioavailability of regorafenib combined with omeprazole, de Man et al. showed no impact of esomeprazole on the bioavailability of regorafenib. This study also established that neither concomitant use nor 3-hour interval time between esomeprazole and regorafenib did not affect the bioavailability of regorafenib.[2] Our results were consistent with this bioavailability study. However, it should be noticed that the study of de Man et al. did not evaluate the survival outcomes.

Abdominal symptoms and dyspepsia are common in advanced cancer patients, and the rate of PPI use in those patients is high.[5] In addition to symptom control, PPIs protect gastric damage from steroids, radiation, and chemotherapeutics.[9] However, the results for interaction between the PPIs and TKIs are usually extrapolated from the studies, including patients with non-CRC treated with regorafenib. In this regard, a study by Wu et al. compared the PPI non-user and user groups in patients with HCC treated with TKIs, such as sorafenib, regorafenib, lenvatinib, and cabozantinib. This study showed that the mortality rate was higher in the PPI user group than in the PPI non-user group.[17] Of note, this study was critical as it demonstrated the effect of TKIs and PPIs interaction on the survival outcomes. However, we did not show the impact of PPIs on the survival outcomes of regorafenib. Patients receiving various TKIs and PPIs were included in the study of Wu et al. It might explain the difference between the results.[17]

It is well known that PPIs may cause diarrhea.[11] Several mechanisms, such as microscopic colitis and Clostridium difficile infection, may play a role in PPI-related diarrhea.[7, 14] However, the rate of patients who reported diarrhea among PPI non-user and PPI user groups were similar in our study. Furthermore, the rates of all AEs were similar in PPI non-user and user groups.

A study by Xie et al. concluded that chronic PPI use increases mortality in the general population.[18] However, our results did not confirm this data. Indeed, our patients did not receive PPIs for the time required to see the chronic effects of those drugs.

Our study has several limitations, mainly based on its retrospective nature. We did not have data regarding anti-acids received without a prescription. Furthermore, we did not know the PPI indications of included patients. We did not assess the duration of PPI use and patients’ daily receiving time. It should be noted that the interval time of regorafenib and PPI receiving may affect the bioavailability of regorafenib. Of note, we compared PPI non-user patients with all patients to exclude immortal time bias. It was a substantial strength of our study.

In conclusion, concomitant use of PPIs was not associated with worse survival outcomes and safety profile in patients with mCRC treated with regorafenib. Although it is hard to suggest that PPIs are entirely safe in those patients with the results of this retrospective study, they can be used in special conditions where they must be used.

AEs: Adverse Events

CI: Confidence Interval

CTCAE: Common Terminology Criteria for Adverse Events

ECOG: Eastern Cooperative Oncology Group

GIST: Gastrointestinal Stromal Tumor

HCC: Hepatocellular Cancer

IQR: Interquartile Range

mCRC: Metastatic Colorectal Cancer

ORR: Objective Response Rates

OS: Overall Survival

PPI(s): Proton Pump Inhibitor(s)

RECIST: Response Evaluation Criteria in Solid Tumors

TKIs: Tyrosine Kinase Inhibitors

TTF: Time to Treatment Failure

Funding

No funding was received for this study.

Conflicts of Interest

All authors disclose no financial interests or conflicts of interest.

Authors’ Contributions

Emre Yekedüz: Conceptualization, Data curation, Methodology, Visualization, Formal analysis, Writing – original draft. Mehmet Fatih Özbay: Data curation, Writing – review and editing. Dilek Çağlayan: Data curation, Writing – review and editing. Atila Yıldırım: Data curation, Writing – review and editing. Cihan Erol: Data curation, Writing – review and editing. Hasan Çağrı Yıldırım: Data curation, Writing – review and editing. Sezai Tunç: Data curation, Writing – review and editing. Neslihan Özyurt: Data curation, Writing – review and editing. Feyyaz Özdemir: Writing – review and editing, Supervision. Mehmet Ali Nahit Şendur: Writing – review and editing, Supervision. Abdurrahman Işıkdoğan: Writing – review and editing, Supervision. Saadettin Kılıçkap: Writing – review and editing, Supervision. Yüksel Ürün: Methodology, Writing – review and editing, Supervision. Şuayib Yalçın: Writing – review and editing, Supervision. Mehmet Artaç: Writing – review and editing, Supervision. Hasan Şenol Coşkun: Writing – review and editing, Supervision. Güngör Utkan: Conceptualization, Methodology, Data curation, Writing – review and editing, Supervision

Ethics Approval

This study was approved by the Ankara University Faculty of Medicine Human Research Ethics Committee, approval number İ9-601-21.

Consent to Participate

Waiver of informed consent was obtained from the Research Ethics Board due to the minimal risk to study subjects as well as the retrospective nature of this study.

Consent for Publication

Not applicable

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Acknowledgment

Not applicable

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No competing interests reported.

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Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: a multicenter study

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