Bisphosphonates as potential adjuvants for patients with cancers of the digestive system

Table 1 Summary of selected clinical studies of bisphosphonates in digestive cancers

Study Design	Cancer type	Population	Therapy	Main Findings
Prospective studies
Phase I pilot	Esophagus, gastric	Advanced disease	IMAB362 + ZA +/- IL-2	Ongoing
(NCT01671774)		Claudin 18.2 expression+
Phase I	Pancreas	n = 23 with resectable disease	ZA once pre-op, and twice post-op	Median/1 yr/2 yr OS:
				18 mo/86%/33%
				Median/1 yr/2 yr PFS:
				12 mo/27%/9%
				No improvement
Phase II	HCC	Advanced disease	Sorafenib + ZA	Ongoing
(NCT01259193)
Observational studies
Restricted open cohort study[15]	Colorectal	Region: Denmark 30505 postmenopausal female BP users matched 1:4 BP non-users	Alendronate	Alendronate associated with decreased incidence (HR = 0.69, 95%CI: 0.6-0.79), risk of death (HR = 0.62, 95%CI: 0.52-0.72) and longer survival (HR = 0.82, 95%CI: 0.7-0.97, P < 0.05)1
Systematic review and meta-analysis[16]	Colorectal	Country: various	Alendronate, pamidronate, etidronate, ibandronate, risedronate, ZA	Significant decrease in cancer incidence (HR = 0.83, 95%CI: 0.76-0.90)
		20001 cancer cases
		392106 patients total
Case control[17]	Colorectal	Country: Israel	Any oral BP (95% alendronate)	BP use > 1 yr associated with significant decrease in cancer risk (RR = 0.5, 95%CI:I 0.35-0.71)2
		Postmenopausal women
		933 cancer cases matched 1:1 with controls without cancer
Case control[46]	Esophagus, gastric	Country: United Kingdom	Any BP except pamidronate and ibandronate	Esophagus cancer risk significantly higher in female BP users than non-users (OR = 1.43, 95%CI: 1.18-1.72)3
		8636 cancer cases matched 1:4 with controls without cancer		Higher risk with alendronate
				No difference in gastric cancer risk
Nested case control[47]	Esophagus, gastric, colorectal	Country: United Kingdom	Any oral BP
		15613 cancer cases matched 1:5 with controls without cancer		Rx for BP associated with significant increase in risk of esophagus (RR = 1.3, 95%CI: 1.02-1.66, P = 0.02) but not gastric or colorectal cancer4
Matched cohort[48]	Esophagus, gastric	Country: Denmark		Highest risk: ≥ 10 Rx, ≥ 3 yr
		History of fracture	Any oral BP	85 cancer cases total
		13678 cases who filled BP Rx matched 1:2 with controls who did not fill BP Rx	(alendronate > etidronate > ibandronate, risedronate, clodronate)	BP use associated with significantly decreased risk of esophagus cancer (HR = 0.35, 95%CI: 0.14-0.85, P = 0.02)5 No effect on gastric cancer risk
Matched cohort[49]	Esophagus, gastric	Country: United Kingdom	Any oral BP	207 cancer cases total
		41826 cases Rx BP matched 1:1 with controls not Rx BP		No increase in risk of esophagus or gastric cancer. Risk not affected by NBP vs non-NBP, duration of use, history of GERD6
Nested matched case control[50]	Esophagus	Country: United States	Etidronate, tiludronate,	< 2% of cases and controls filled Rx for BP
		History of Barrett’s esophagus	alendronate, ibandronate, risedronate	Non-significant association between BP
		116 with cancer matched 1:6 with controls without cancer		use and esophagus cancer risk (incidence density ratio 0.92, 95%CI: 0.21-4.15)7
Nested case control using 2 datasets[51]	Esophagus, gastric, colorectal	Country: United Kingdom 55952 cancer cases matched 1:5 with controls without cancer	Alendronate, etidronate, ibandronate, risedronate	BP use not associated with risk of esophagus or colorectal cancer Short but not long term alendronate associated with increased risk of gastric cancer (OR = 1.91, 95%CI: 1.34-2.72, P < 0.001) in one dataset8
Case control[52]	Esophagus	Country: Taiwan	Alendronate, risedronate,	No relationship between BP use and esophagus cancer risk
		16204 cancer cases matched 1:4 with controls without cancer	clodronate, etidronate	Inverse relationship between esophagus cancer risk and BP duration and frequency of use
Meta-analysis observational data[53]	Esophagus	Country: various 3778 cancer cases 173612 BP users 483797 BP non-users	Ibandronate, etidronate, clodronate, zoledronate, pamidronate, alendronate	No association between BP use and esophagus cancer risk
Cohort study[55]	Esophagus, gastric	Country: United States 1.64 million patients > 68 yr old with history of osteoporosis and/or BP use	Any oral BP	No association between BP use and esophagogastric cancer risk9
		2308 cancer cases
		624840 BP users
Meta-analysis of observational data[56]	Esophagus, gastric, colorectal	Country: various 16662 cancer cases	Any oral BP	No significant association between BP use and overall digestive cancer risk
		79379 controls without cancer
Meta-analysis of observational data[61]	Colorectal	Country: various 63363 cancer cases 200047 BP users	Any oral BP	No significant change or borderline significant decrease in risk of colorectal cancer
		1038526 BP non-users
Case series[70]	HCC	Country: Italy n = 15 patients with bone	ZA	Decreased pain score and analgesic requirements
		metastases, heavily pre-treated		Median OS 10 mo
Retrospective cohort study[73]	HCC	Country: Japan n = 31 patients with bone metastases treated with radiation, 12 also received ZA	ZA	Significant decrease in 6-mo time to pain progression of radiated (0% vs 34%, P = 0.045) and non-irradiated (20% vs 66%, P = 0.005) bone metastases Significant decrease in 3-mo radiographic progression rate of non-irradiated bone metastases (29% vs 91%, P = 0.009)

¹Adjusted for age, colon cancer risk factors, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs (NSAIDs)/prednisolone/acetyl-salicylic acid (ASA) use in the past 12 mo;

²Controlled for alcohol consumption, body mass index;

³Adjusted for smoking, alcohol intake, dyspepsia, proton pump inhibitor (PPI) use, BMI, H. pylori status; ⁴Adjusted for smoking status, alcohol intake, BMI;

⁵Adjusted for Charlson index, concomitant medications;

⁶Adjusted for smoking, alcohol consumption, BMI, use of HRT/NSAIDs/PPI/H2-receptor antagonists, history of Barrett’s esophagus, gastroesophageal reflux disease (GERD);

⁷Adjusted for race, noncancer disease comorbidity index, use of PPI/NSAIDsPPI, H2-receptor antagonist;

⁸Adjusted for BMI, smoking status, alcohol consumption, ethnicity, history of osteoporosis, use of systemic corticosteroids, acid suppressive therapy, anti-inflammatory drugs, vitamin D use, comorbidities (rheumatoid arthritis, diabetes), gastrointestinal disease;

⁹Adjusted for age, gender, race, Medicare Part D low-income subsidy, comorbidities (Barrett’s esophagus, gastroesophageal disease, alcohol abuse, smoking status and/or chronic obstructive pulmonary disease, obesity, acid-suppressive therapy, bone density testing, diagnosis of fragility fracture, receipt of institutional care, NSAID use. OS: Overall survival; PFS: Progression-free survival; ZA: Zoledronic acid; HCC: Hepatocellular carcinoma.