Abstract
Background:
We aimed to determine whether hypomagnesemia predicts osteoradionecrosis development in patients with squamous cell carcinoma of the oropharynx and oral cavity who received platinum-based concurrent chemoradiation with or without induction therapy.
Methods:
We reviewed data from patients with head and neck cancers who had undergone chemoradiation with weekly cisplatin/carboplatin between January 1, 2010 and December 31, 2014 at our institution. Pathologic features, laboratory test results, disease stage, and social histories were recorded. The association between hypomagnesemia and osteoradionecrosis was analyzed controlling for known confounding factors.
Results:
Hypomagnesemia during cancer treatment was associated with osteoradionecrosis development (HR = 2.72, P = .037) independent of total radiation dose (HR = 1.07, P = .260) and smoking history (HR = 2.05, P = .056) among the patients who received platinum-based induction chemotherapy followed by concurrent chemoradiation.
Conclusions:
Hypomagnesemia was predictive of the development of osteoradionecrosis in patients with cancers of the oropharynx and oral cavity receiving platinum-based induction followed by concurrent chemoradiation.
Keywords: chemoradiation, head and neck cancer, hypomagnesemia, osteoradionecrosis, platinum-based
1 |. INTRODUCTION
Osteoradionecrosis (ORN) represents a significant and pernicious sequela of radiation therapy (RT) in patients with head and neck cancer (HNC) and is associated with severe symptom burden reducing quality of life in sufferers.1 It is defined a disorder characterized by necrosis occurring in the maxilla or mandible.2 Radiation dose, poor oral hygiene, dental extractions, and mandibulectomy are prominent risk factors for ORN development.3,4 The underlying pathogenesis of ORN is not completely understood. The most reported cause is radiation arteritis that leads to the development of a hypovascular and hypoxic environment and subsequently nonhealing bones. In addition, patients receiving platinum-based concurrent chemoradiation have a higher incidence of ORN than those receiving RT alone.5,6 Platinum agents, with their radiomimetic properties, have been proposed as a contributor to the pathogenesis of ORN.7 The direct impact of chemotherapy regimens as a modifier of RT-attributable mandibular injury remains unclear. However, evidence of skeletal abnormality and nontraumatic osteonecrosis has been reported in testicular cancer survivors who received a platinum-based regimen.8,9
Hypomagnesemia is one well-known side effect of platinum compounds, which are standard agents used in induction chemotherapy and in concurrent chemoradiation for patients with HNC.10 Magnesium disturbance might be the key mechanism of ORN development. Structurally, magnesium is the second most prevalent mineral to calcium in bone tissue. It is involved in calcium metabolism and plays an essential role in the absorption, synthesis, and activation of vitamin D.11 In addition, magnesium modulates parathyroid hormone (PTH) secretion both directly and indirectly through influencing calcium-regulated mechanisms.11 Furthermore, in human observational studies, low dietary magnesium intake was linked to bone density abnormalities and risk of fracture.12
Considering the known relationship of magnesium to bone health, hypomagnesemia represents an attractive and readily modifiable mechanistic rationale for increased incidence of ORN among patients who received chemotherapy with cisplatin/carboplatin than those treated with radiation alone. However, this connection has not been directly examined.
In order to ascertain whether magnesium-depleted states were associated with increased probability of mandibular injury, we sought to determine the relative incidence of ORN in patients with cisplatin/carboplatin-associated hypomagnesemia who received concurrent chemoradiation in our institutional database.
2 |. METHODS
2.1 |. Approval and consent
The current retrospective study and waivers of informed consent were approved by The University of Texas M. D. Anderson Cancer Center Institutional Review Board in accordance with an assurance filed with, and approved by, the Department of Health and Human Services.
2.2 |. Patient selection
Using the Tumor Registry database at M. D. Anderson, as well as databases for pathology, RT, and pharmacy, we identified patients with HNC who underwent chemoradiation with weekly cisplatin or carboplatin between January 1, 2010 and December 31, 2014. For our analysis, we selected data from patients who (a) were aged 18 years or older, (b) had pathologically confirmed squamous cell carcinoma of the oral cavity or oropharynx, and (c) received concurrent chemoradiation that included at least five cycles of weekly cisplatin or carboplatin at M. D. Anderson with at least 30 fractions of RT. Patients who had a chemoradiation course longer than 3 months (due to interruptions) were excluded from the analysis.
2.3 |. Data collection
Patient demographic data, including age, sex, vital status, and date of death or date of last follow-up, were obtained from the Tumor Registry. Data regarding cancer stage (TNM classification according to the eighth edition of the American Joint Committee on Cancer [AJCC]), human papillomavirus status, social history for smoking and alcohol, laboratory test results, and pharmacy dispensing records (chemotherapy administration) were obtained from the M. D. Anderson electronic medical records (Epic) and institutional Data Warehouse. Radiation prescription dose (defined as prescription to the target volume in the record-and-verify system) was extracted as alphanumeric data from the Radiation Oncology Data Bank.
As a standard practice in our institution, all patients with HNCs undergo evaluation by Dental Oncology consult before RT and are followed during and after RT. A diagnosis of ORN was determined through text abstraction from the electronic medical records if patients were observed to meet one or more of the following criteria (a) established ORN documented in Dental Oncology notes, (b) exposed mandible bone described in Dental Oncology notes, or (c) findings from CT or MRI consistent with ORN.
Nonsmoker refers to patients who had a smoking history of less than 5 pack-year (PY) at the time of cancer diagnosis. A positive alcohol use includes any current and past alcohol consumption. Baseline was defined as the period from 30 days before to the day the first dose of chemotherapy was administered, and treatment course was defined as the period from 1 day after the first dose of chemotherapy was administered to 7 days after the last dose of chemotherapy was administered.
Hypomagnesemia was defined as serum magnesium level <1.6 mg/dL. Grade 1 hypomagnesemia was defined as a serum magnesium level <1.6 to 1.2 mg/dL; grade 2 as <1.2 to 0.9 mg/dL; grade 3 as <0.9 to 0.7 mg/dL; and grade 4 as <0.7 mg/dL (based on National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0).2 Frequency of hypomagnesemia was the number of occurrences of hypomagnesemia.
2.4 |. Statistical analysis
The primary outcome was the development of ORN during a 5-year follow-up period starting from the first day of RT. Descriptive statistics (frequencies, medians, means, and SDs) were used to summarize study variables. The Student t test and the Mann-Whitney rank-sum test were used to assess significant differences in continuous variables where appropriate and the chi-square test was used to assess differences in categorical variables between the induction chemotherapy and no induction chemotherapy groups. We analyzed the occurrence of ORN using a competing risk model, with death as a competing event in the sense that the occurrence of a death modifies the chances for the occurrence of ORN. Cumulative incidence functions, which measure the subdistribution of failure from ORN, were estimated for hypomagnesemia and no hypomagnesemia groups. The hazard ratio (HR) estimate and its 95% confidence interval (95% CI) in competing risks were derived from univariate and multivariable proportional subdistribution hazards models. For all analyses, a 2-tailed P value <.05 was considered statistically significant. All statistical analyses were performed using R software (version 3.6.1; The R Foundation, http://www.r-project.org) with package cmprsk (version 2.2–7).
3 |. RESULTS
3.1 |. Patient selection
The patient selection process is illustrated in Figure 1. The final cohort included 562 patient cases with squamous cell carcinoma of the oral cavity or oropharynx who received concurrent chemoradiation with or without prior induction chemotherapy.
FIGURE 1.
Patient selection flowchart. RT, radiation treatment. *Indicates cancer sites other than oropharynx or oral cavity were removed. †Indicates radiation treatments not completed as prescribed or lasting more than 3 months because of interruption
3.2 |. Patient characteristics
Table 1 details patient sociodemographic and clinical characteristics. The median age was 59 years. Two-hundred and four patients had induction chemotherapy prior to concurrent chemoradiation and 358 had primary concurrent chemoradiation without any induction chemotherapy. The most common cancer site was the oropharynx (78.6%). Most patients had stage IV cancer based on the AJCC 7th Edition (85.4%).
TABLE 1.
Demographics and clinical characteristics (n = 562)
| Characteristic | No. (%) |
|---|---|
| Median age (IQR) | 59 years (52–65 years) |
| Sex | |
| Female | 106 (18.9) |
| Male | 456 (81.1) |
| Median baseline BMI (IQR) | 28.3 kg/m2 (24.7–32.3 kg/m2) |
| Cancer site | |
| Oral cavity | 120 (21.4) |
| Oropharynx | 442 (78.6) |
| Cancer stage | |
| Stage I, II, or III | 82 (14.6) |
| Stage IV | 480 (85.4) |
| HPV status | |
| Negative | 81 (14.4) |
| Positive | 237 (42.2) |
| Unknown | 244 (43.4) |
| Alcohol use, current | |
| No | 229 (40.7) |
| Yes | 333 (59.3) |
| Smoking, former or current | |
| No | 286 (50.9) |
| Yes | 276 (49.1) |
| Induction therapy | |
| No | 358 (63.7) |
| Yes | 204 (36.3) |
| Cisplatin cumulative dose (mg) | 430 (353, 553) |
| Carboplatin cumulative dose (mg) | 1564 (1080, 2178) |
Abbreviations: BMI, body mass index; HPV, human papillomavirus; IQR, interquartile range.
Table 2 shows the clinical characteristics of patients who did and did not receive induction chemotherapy. Patients who had undergone prior induction chemotherapy had significantly more frequent and more severe hypomagnesemia during the treatment course compared with patients who did not receive induction chemotherapy. The induction group had significantly higher percentage of smokers. The alcohol history was not significantly different between the groups. Slightly over 50% of patients in the induction chemotherapy group had undergone dental extraction before RT, which was significantly higher than in the no induction chemotherapy group (29.1%, P < .001). Over one third of the patients in the induction group had an induction regimen containing cetuximab, while only one patient in the no induction group had chemoradiation that included cetuximab. The median RT dose was significantly higher in the induction chemotherapy group (P = .032), with 78% receiving a total RT dose of 70 to 72 Gy (data not shown). ORN occurred in 19.6% of the patients in the induction chemotherapy group, compared with 17.6% in the no induction chemotherapy group; however, this difference was not statistically significant.
TABLE 2.
Clinical characteristics of patients who did and did not receive induction chemotherapy
| No. (%) | |||
|---|---|---|---|
| Characteristic | No induction chemotherapy | Induction chemotherapy | P |
| Total | 358 | 204 | |
| Tumor (T classification) | <.001 | ||
| TO or Txa | 0 (0.0) | 2 (1.0) | |
| T1 | 60 (16.8) | 19 (9.3) | |
| T2 | 146 (40.8) | 44 (21.6) | |
| T3 | 83 (23.2) | 64 (31.4) | |
| T4 | 69 (19.3) | 75 (36.8) | |
| Dental extraction | <.001 | ||
| No | 254 (70.9) | 101 (49.5) | |
| Yes | 104 (29.1) | 103 (50.5) | |
| Alcohol use | .188 | ||
| No | 138 (38.5) | 91 (44.6) | |
| Yes | 220 (61.5) | 113 (55.4) | |
| Smokingb | .070 | ||
| No | 193 (53.9) | 93 (45.6) | |
| Yes | 165 (46.1) | 111 (54.4) | |
| Hypomagnesemia during treatment course | <.001 | ||
| No | 224 (62.6) | 64 (31.4) | |
| Yes | 134 (37.4) | 140 (68.6) | |
| Hypomagnesemia grading | <.001 | ||
| No hypomagnesemia | 224 (62.6) | 64 (31.4) | |
| Grade 1 | 123 (34.4) | 127 (62.3) | |
| Grade 2 and more | 11 (3.1) | 13 (6.4) | |
| Frequency of hypomagnesemia (IQR) | 0 (0, 1) | 2 (0, 6) | <.001 |
| Median radiation dose (IQR) | 70 Gy (66–70 Gy) | 70 Gy (70–70 Gy) | .032 |
| Surgeryc | .198 | ||
| No | 309 (86.3) | 167 (81.9) | |
| Yes | 49 (13.7) | 37 (18.1) | |
| ORN | .632 | ||
| No | 295 (82.4) | 164 (80.4) | |
| Yes | 63 (17.6) | 40 (19.6) | |
| Cisplatin cumulative dose (mg) | 415 (348, 498) | 498 (360, 756) | <.001 |
| Carboplatin cumulative dose (mg) | 1129 (762, 1498) | 1943 (1479, 3003) | <.001 |
| Use of cetuximab | <.001 | ||
| No | 357 (99.7) | 127 (62.3) | |
| Yes | 1 (0.3) | 77 (37.7) | |
| Use of PPI | .028 | ||
| No | 302 (84.4) | 156 (76.5) | |
| Yes | 56 (15.6) | 48 (23.5) | |
| Use of diuretics | .027 | ||
| No | 353 (98.6) | 194 (95.1) | |
| Yes | 5 (1.4) | 10 (4.9) | |
Note: The values marked in bold italics indicate statistical significance (P < .05).
Abbreviations: IQR, interquartile range; ORN, osteoradionecrosis.
Tx refers no primary tumor.
Nonsmoker or smoked less than 5 pack-year.
Head and neck surgery before radiation excluding biopsy and tonsillectomy.
There were three main induction chemotherapy regimens observed in the current study: (a) docetaxel and cisplatin (n = 104, 51%), the majority was with fluorouracil (n = 82) and some received cetuximab or erlotinib with or without fluorouracil; (b) paclitaxel and carboplatin (n = 65, 32%) with (n = 57) or without cetuximab; and (c) carboplatin and docetaxel (n = 30, 15%), with some receiving fluorouracil, cetuximab, or erlotinib.
3.3 |. Competing risk regression of clinical factors and ORN
In the univariate competing risk regression analysis (Table 3), presence of hypomagnesemia during the treatment course and a positive smoking history were associated with increased incidence of ORN during the 5-year follow-up period among patients who had undergone prior induction chemotherapy (Table 3 and Figure 2), but not in the no induction group (Table 3 and Figure S1). T4 classification was significantly associated ORN development in the no induction chemotherapy group and remained a significant predictor in the multivariate analysis (Table 4). We selected RT dose and smoking status in the multivariate analysis based on the findings of the univariate analysis. The association between the occurrence of hypomagnesemia and incidence of ORN development in the induction chemotherapy group remained significant after adjusting for other factors (HR 2.72, 95% CI [1.06–6.97], P = .037) and remained nonsignificant in the no induction chemotherapy group (P = .810). Although not statistically significant, higher HR was also observed for radiation dose (HR 1.07, 95% CI [0.95–1.20], P = .260) in the induction chemotherapy group.
TABLE 3.
Univariate competing risk regression analysis of clinical factors and osteoradionecrosis
| Induction chemotherapy | No induction chemotherapy | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P | HR (95% CI) | P |
| Hypomagnesemia during treatment course | ||||
| No | Reference | |||
| Yes | 2.98 (1.15–7.68) | .024 | 0.94 (0.54–1.62) | .82 |
| Radiation dose | 1.09 (0.97–1.22) | .15 | 0.99 (0.92–1.06) | .70 |
| Dental extraction | ||||
| No | Reference | |||
| Yes | 1.20 (0.62–2.32) | .59 | 1.29 (0.85–1.95) | .24 |
| Tumor (T classification) | ||||
| Txa, T0 or T1 | ||||
| T2 | 1.66 (0.35–7.84) | .52 | 1.65 (0.63–4.35) | .31 |
| T3 | 1.55 (0.34–7.10) | .57 | 2.15 (0.79–5.85) | .13 |
| T4 | 2.57 (0.60 10.95) | .20 | 2.74 (1.00–7.46) | .049 |
| Alcohol use | ||||
| No | Reference | |||
| Yes | 1.34 (0.67–2.65) | .41 | 1.00 (0.58–1.71) | 1.00 |
| Smoking | ||||
| No | Reference | |||
| Yes | 2.15 (1.03–4.48) | .041 | 1.14 (0.68–1.93) | .62 |
Note: The values marked in bold italics indicate statistical significance (P < .05).
Abbreviations: CI, confidence interval; HR, hazard ratio.
Tx refers no primary tumor.
FIGURE 2.
Competing risk analysis for osteoradionecrosis stratified by the occurrence of hypomagnesemia
TABLE 4.
Multivariable competing risk regression analysis of clinical factors and osteoradionecrosis
| Induction chemotherapy | No induction chemotherapy | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P | HR (95% CI) | P |
| Hypomagnesemia during treatment course | ||||
| No | Reference | |||
| Yes | 2.72 (1.06–6.97) | .037 | 0.93 (0.54–1.62) | .81 |
| Radiation dose | 1.07 (0.95–1.20) | .260 | 0.98 (0.91–1.06) | .66 |
| Smoking | ||||
| No | Reference | |||
| Yes | 2.05 (0.98–4.29) | .056 | 1.17 (0.67–2.05) | .58 |
| Tumor (T classification)a | ||||
| Tx, T0 or T1 | Reference | |||
| T2 | 1.74 (0.66–4.59) | .260 | ||
| T3 | 2.38 (0.85–6.68) | .099 | ||
| T4 | 2.78 (1.01–7.64) | .047 | ||
Note: The values marked in bold italics indicate statistical significance (P < .05).
Abbreviations: CI, confidence interval; HR, hazard ratio.
In no induction group only.
4 |. DISCUSSION
Our results demonstrated a statistically significant association between hypomagnesemia and ORN development in patients with squamous cell carcinoma of the oropharynx and oral cavity who received platinum-based induction/concurrent chemoradiation. The significance remained outstanding after being adjusted for known confounding factors of smoking status and total RT dose. We believe this observed association has mechanistic and clinical relevance, and, based on our observational findings, warrants further investigation.
Chemoradiation is known to increase the risk for ORN compared with radiation alone13; however, the mechanism is unclear. Platinum agents cause additional physiological disruption, renal cell injury, and magnesium wasting.10 If magnesium intake does not adequately compensate for the renal wasting, hypomagnesemia occurs. Magnesium is an essential mineral in more than 300 enzymatic reactions that are imperative for normal human physiology, and it plays a pivotal role in bone health.11 Many human epidemiologic studies have suggested a considerable link between dietary magnesium deficiency and bone disorders. Low magnesium intake was found to be associated with low bone mineral density of the hip and whole body among more than 73 000 postmenopausal women who enrolled in the Women’s Health Initiative Observational Study.14 In a long-term (median follow-up of 25.6 years) prospective cohort study, low serum magnesium was strongly and independently associated with an increased risk of fractures among 2245 middle-aged white men.15 The association observed herein of hypomagnesemia with development of a bone disorder (ORN) in our study is consistent with these previous findings.
There are several potential mechanisms for magnesium deficiency to disrupt bone homeostasis. First, magnesium is a structural component of the bone. It also plays a multifaceted role in calcium metabolism11: (a) magnesium directly affects calcium absorption through the magnesium-dependent calcium absorption channel; (b) magnesium is a key element in the processes of absorption, synthesis, and activation of vitamin D; and (c) magnesium regulates PTH secretion. Dietary magnesium restriction has been shown to lead to significantly reduced serum levels of 1,25(OH)2-vitamin D and PTH in both animal and human experiments.16,17 Furthermore, hypomagnesemia may increase bone loss by decreasing bone formation and increasing bone absorption.11 In a magnesium-depleted rat model, bone pathologic analysis showed decreased osteoblasts and increased osteoclasts.18 Hypomagnesemia induced by platinum-based treatment may further impair bone healing that is compromised by RT-induced vasculitis. This may explain why platinum-based concurrent chemoradiation is associated with a higher risk of ORN than RT alone. Several studies have shown that magnesium administration corrected low serum PTH levels17,19 and end-organ resistance to PTH associated with magnesium depletion.20 The finding that hypomagnesemia is associated with ORN in our study and the current understanding of magnesium in bone health suggest that prevention of hypomagnesemia may help reduce the risk of ORN in patients with HNC receiving platinum-based therapy. Prospective studies are warranted to examine the benefit of prevention and correction of hypomagnesemia in mitigating ORN development in patients with HNCs.
In the current study, the association of hypomagnesemia with ORN development was significant only in patients who received induction chemotherapy prior to concurrent chemoradiation. The main culprit was likely that induction chemotherapy resulted in a higher total dose of platinum, which could lead to more severe and longer-lasting renal side effects and hypomagnesemia.10 In a prospective observation of 18 children who received cisplatin, ifosfamide, and methotrexate for osteosarcoma, hypomagnesemia was seen in four children years after receiving chemotherapy.21 A systematic review of long-term effects of childhood cancer treatments revealed a prevalence of hypomagnesemia of 7% to 29% among those who received cisplatin or carboplatin.22 The variation was likely a result of different treatment protocols. Hypomagnesemia detected in the patients who receive induction chemotherapy might be more prolonged and severe than that in patients who do not receive induction chemotherapy because of the higher cumulative dosage of platinum used with induction chemotherapy. This may explain the association of hypomagnesemia with ORN in the induction chemotherapy group in the current study. The use of cetuximab, PPI, or diuretics, which could contribute to hypomagnesemia, was higher in the induction group. Cetuximab interferes with renal magnesium reabsorption through reversible epidermal growth factor receptor inhibition and likely results in transient hypomagnesemia.23,24 The chronic use of PPI and/or diuretics, on the other hand, can cause a long-lasting state of magnesium deficiency. However, our study was not able to examine the relationship between duration of hypomagnesemia and ORN development owing to lack of long-term laboratory data. Further studies are needed to examine the correlation between duration of hypomagnesemia and ORN development. Finally, the current study observed higher incidence of ORN than some of the previous reports.23–25 We think the difference is resulted from that the ORN definition in the current study included all imaging indications of this bone abnormality regardless of clinical manifestation, many of them may recover and not develop into clinically evident ORN. This hypothesis requires to be confirmed with a prospective study.
Our study has limitations owing to its retrospective nature. First, the magnesium levels reported were usually measured within 24 to 48 hours of chemotherapy infusion; thus, the true occurrence and severity of hypomagnesemia might have been underrepresented in our study. Also, long-term serum magnesium data were not available and the association between duration of hypomagnesemia and ORN development thus could not be analyzed. In addition, because magnesium supplementation and nutritional magnesium intake in the study patients were not known to us, we cannot draw any conclusions about the impact of magnesium replacement on ORN development. Our chemotherapy data included only regimen received. We were not able to report planned treatment due to lack of data. In addition, outpatient pharmacy data, especially pharmacy information outside of our institution, was not sufficient to allow us to accurately compare the use of PPI or diuretics between the induction and no induction groups. The RT dose in our study was total dosage prescribed to the tumor (60–72 Gy), with 78% of the patients in the induction group receiving 70 to 72 Gy. The RT dose effect on ORN was not evident in our patients who uniformly received high dose to the tumor. However, we did not assess specific dose-volume parameters to the mandible for this study.26,27 Furthermore, direct prospective screening for ORN did not consistently occur during the same time frames relative to chemotherapy administrations. Considering the reversibility of ORN, the true occurrence of ORN could have been underdetected in post-treatment surveillance. Finally, the limited availability of data also restricted our analysis from including all confounding factors. Given the findings of this initial series, we intend to further examine the mechanistic underpinnings of the observed relationship between serum magnesium and bony injury through assessment of accruing institutional prospective observational radiotherapy dose-response28 cohorts (https://clinicaltrials.gov/ct2/show/NCT04265430) as a future expansion of the current effort.
5 |. CONCLUSION
Hypomagnesemia may be a candidate for predictive factor for ORN development in patients with squamous cell carcinoma of the oropharynx and oral cavity treated with platinum-based induction chemotherapy followed by platinum-based concurrent chemoradiation. Future efforts to ascertain the mechanistic relationship between hypomagnesemia of therapy and subsequent mandibular and orodental sequelae are warranted, as well as confirmation in other observational cohorts. Considering the essential role of magnesium in normal bone health, a prospective study is necessary to investigate the impact of prevention and correction of hypomagnesemia on mitigating ORN development in these patients.
Supplementary Material
ACKNOWLEDGMENTS
The authors thank Erica Goodoff, ELS, for editorial support. Stephen Y. Lai, Clifton D. Fuller, and Abdallah S. R. Mohamed received funding support from the National Institutes of Health (NIH) (1R01DE025248-01) and National Institute for Dental and Craniofacial Research (R56DE025248-01). The University of Texas M. D. Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant (P30 CA016672).
Funding information
National Institute for Dental and Craniofacial Research, Grant/Award Number: R56DE025248-01; National Institutes of Health (NIH), Grant/Award Numbers: P30 CA016672, 1R01DE025248-01
Footnotes
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of this article.
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