Hypercalcemia of Malignancy: Time to Pull the Brakes

Abstract

Hypercalcemia of malignancy (HOM) is usually seen in advanced stage and carries a poor prognosis. Survival outcomes are dismal and most of the patients are unable to receive subsequent definite anti-cancer therapy. There is lack of any retrospective or prospective data regarding hypercalcemia of malignancy in Indian population. We aim to describe survival outcomes in hypercalcemia associated with solid organ malignancies. Forty-five patients diagnosed with HOM associated with solid organ malignancies were included in the study. Patients were followed up till death. Clinical features and survival outcomes were noted. Squamous cell carcinoma of head and neck region and lung comprised most of the cases associated with HOM. Most of the patients presented with poor performance status. Median overall survival (OS) was 20 days (2–78 days). Median OS was 35 days (9–58 days) in those who received definite anti-cancer therapy. Four-week mortality rate was estimated as 59.5%, while this increased to 75.7% within 6 weeks from the diagnosis of hypercalcemia. Survival outcomes are poor after the diagnosis of hypercalcemia in cancer patients. Best supportive care including hospice care should be strongly considered at this point of time instead of definite systemic anti-cancer therapy.

Introduction

Hypercalcemia is seen in up to 40% of patients with malignancy during the course of illness and as an extreme event [1, 2]. This estimate is capricious as reported from different series and retrospective data; reason being the stage of presentation of disease, use of bisphosphonates, and the type of malignancy. Hypercalcemia of malignancy (HOM) is usually seen in the advanced stage of malignancy and portends a grave prognosis. Malignancy is usually evident itself clinically by the time it causes hypercalcemia. Most common malignancies associated with hypercalcemia include lung cancer, myeloma, renal cell carcinoma and carcinoma of the breast. HOM, although not a frequently seen entity, tends to occur more with squamous cell carcinoma as compared with other histologies [3, 4]. Complications associated with HOM include metabolic encephalopathy, dehydration due to volume loss and acute kidney injury (AKI). Almost half of the patients diagnosed with HOM succumb to their illness within 1 month of diagnosis and the next 25% within 3 months. Although bisphosphonate and anti-receptor activator of nuclear factor κ-B ligand (RANKL) therapy effectively restore normocalcemia, the effect is short lived and the prognosis remains poor. In the light of available evidence, it becomes necessary to consider best supportive care as the only therapeutic option rather than considering definite anti-tumour therapy. This approach appears more reasonable in resource-constrained setting like India.

To the best of our knowledge, no study has evaluated the outcome of HOM in Indian population. We therefore pursued to evaluate HOM and the survival outcomes related with various clinic-pathological parameters at a cancer research centre in North India.

Methods

A total of 45 patients diagnosed with HOM associated with biopsy-proven solid tumours, age 18 years and above were included in this prospective follow-up study. Considering HOM as an uncommon event and as a single centre study, we expected enrolment of 60 patients. However, slower accrual and strict eligibility criteria led to enrolment of only 45 patients during the study period of 30 months (June 2016 to November 2018). Patients were considered ineligible if they had a diagnosis of haematological malignancy, primary hyperparathyroidism, hyperthyroidism or hypothyroidism, end-stage renal disease or decompensated liver or heart disease. Paediatric patients were excluded from the study. Informed consent was taken from next of kin. Diagnosis of HOM was established on two consecutive values of corrected serum calcium above or 10.5 mg/dL along with a low or borderline normal value of serum intact parathyroid hormone (PTH) levels, normal serum vitamin D levels, and a normal thyroid function test. Other biochemical tests included liver and renal function tests and estimation of serum vitamin D levels. Eastern Cooperative Oncology Group (ECOG) PS, stage of the disease, presenting symptoms, presence or absence of bony metastases, and presence of AKI were noted at the time of diagnosis. Improvement in symptoms and improvement in PS were noted at follow-up. All patients were followed up till the time of death. Hypercalcemia was defined as corrected serum calcium level > 10.5 mg/dL. Common terminology criteria for adverse events (CTCAE) version 4.0 was utilized for grading of hypercalcemia (corrected serum calcium of > ULN–11.5 mg/dL = grade 1; > 11.5–12.5 mg/dL = grade 2; > 12.5–13.5 mg/dL = grade 3; > 13.5 mg/dL = grade 4) [5]. The Kidney Disease: Improving Global Outcomes (KDIGO) definition was used for AKI [6]. Overall survival (OS) was defined as date of first documentation of hypercalcemia event until death. Descriptive statistics was used for interpretation of data. Log-rank test was used for univariable analysis.

Results

The study group comprised of 45 patients (Table 1). Mean age of the group was 61.02 years (35–86). There were 26 male and 19 female patients. All patients presented to us with stage 4 disease except one who had stage 3 disease. Most of the patients had poor PS at the time of diagnosis of HOM. ECOG PS 4 was noted in 31 (68.9%) patients, PS 3 in 11 (24.4%), PS 2 in 2 (4.4%) and PS 1 in 1 (2.2%) patient. Most common symptoms associated with hypercalcemia were generalized weakness in 44 (97%) patients, hypercalcemic encephalopathy in 33 (73.3%) patients and vomiting in 18 (40%) patients. Mean corrected serum calcium was 13.38 mg/dL (10.9–17.98 mg/dL). As per CTCAE version 4.0, grade 1 (mild) hypercalcemia was detected in 7 (15.6%) and grade 2 (moderate) hypercalcemia in another 7 (15.6%) patients. Grade 3 (severe) and grade 4 (life threatening) hypercalcemia were detected in 9 (20%) and 22 (48.8%) patients, respectively.

Table 1.

Patients’ characteristics

Characteristics (n = 45)	No (range)
Mean age (years)	61.02 (35–86)
Male	26
Female	19
Stage
1	0
2	0
3	1
4	44
ECOG(PS)
1	1
2	2
3	11
4	31
Histology (squamous)	21
Lung	8
Head and neck	11
Ureter	1
CUP	1
Histology (non-squamous)	24
Breast	9
Lung	4
Gall bladder	3
Liver	1
Kidney	2
CUP	2
Ureter	1
Sarcoma	1
Urinary bladder	1
Bony metastases	23
Mean serum calcium (mg/dL)	13.38 (10.9–17.98)
Hypercalcemia (grade)
1 (mild)	7
2 (moderate)	7
3 (severe)	9
4 (life threatening)	22
Acute kidney injury	19
Treatment naïve	14
Median OS (days), n = 37	20 (2–78)
Treatment post diagnosis	9
Median OS (who received chemotherapy post diagnosis)	35(9–58)
Improvement in symptoms post treatment	29
Improvement in PS post treatment	6
In hospital death	28
Mortality within 4 weeks, n = 37	22
Mortality within 6 weeks, n = 37	28

ECOG Eastern Cooperative Oncology Group, PS performance status, CUP cancer of unknown primary, OS overall survival

Histological diagnosis of squamous cell carcinoma was established in 21 (46.7%) patients. These included 11 cases of head and neck primary site, 8 cases of carcinoma lung, and 1 each of carcinoma ureter and cancer of unknown primary (CUP). Non-squamous histology was identified in 24 (53.3%) patients and comprised of 9 cases of carcinoma of the breast, 4 carcinoma of the lung, 3 carcinoma of the gall bladder, 2 each of carcinoma of the kidney and CUP and 1 each of hepatocellular carcinoma, synovial sarcoma, adenocarcinoma of the ureter, and urothelial carcinoma of the bladder. AKI was diagnosed in 19 (42.2%) patients at the time of presentation. Bony metastases were seen in 23 (51.1%) patients likely contributing towards local osteolytic hypercalcemia. Fourteen (31.1%) patients were naïve for any definite anti-cancer therapy at the time of presentation.

Patients were treated as per the standard treatment guidelines. In addition to hydration therapy, 40 patients were administered bisphosphonate therapy as a standard treatment for hypercalcemia. Calcitonin and steroids were added as an adjunct if needed. Improvement in symptoms was noted in 29 (64.4%) patients; however, only 6 (13.3%) patients had improvement in PS. Only 9 (20%) patients were able to receive definite anti-cancer therapy after clinical improvement.

Survival data were available for 37 patients. Median OS was 20 days (2–78 days). Median OS was 35 days (9–58 days) in those who received definite anti-cancer therapy. Four-week mortality rate was estimated as 59.5% (22 patients), while this increased to 75.7% (28 patients) within 6 weeks from the diagnosis of HOM.

Median OS was numerically higher in those with an absence of bony disease, lower grades of hypercalcemia, squamous histology, absence of AKI, naïve for anti-cancer therapy at presentation and who received subsequent definite anti-cancer therapy. In the univariable analysis, no statistical difference was observed between presence and absence of bony metastases, AKI, severity grades of hypercalcemia, squamous and non-squamous histology. Longer OS was observed for patients who received subsequent anti-cancer therapy (41 vs 19 days; p = 0.04) (Table 2).

Table 2.

Univariable analysis

Factor	Median OS days (range)	p value
Bony metastases
Present	17 (4–78)	0.97
Absent	27 (2–58)
Hypercalcemia (grade)
1, 2 (mild–moderate)	25 (6–58)	0.52
3, 4 (severe–life threatening)	19 (2–78)
Histology
Squamous	28 (2–78)	0.16
Non-squamous	14 (2–55)
Acute kidney injury
Present	13 (2–52)	0.12
Absent	29 (4–78)
Treatment naive
Yes	26 (6–58)	0.77
No	18 (2–78)
Subsequent chemotherapy received
Yes	41 (9–58)	0.04
No	19 (2–78)

Discussion

This is the first study from India depicting the outcome of patients with HOM. Median OS in our study is 20 days ranging from 2 to 78 days. Only 20% of patients were able to receive subsequent chemotherapy in our study. In a retrospective analysis of 306 patients of malignancy-related hypercalcemia admitted at Instituto do Cancer do Estado de Sao Paulo, median OS was 40 days [7]. In this study, subsequent chemotherapy was administered to 32% of patients. Another retrospective database of 136 patients in aerodigestive cancers analysed by Penel et al. demonstrated the median OS as 35 days [8]. Ralston et al. reported median OS as 30 days in their study of cancer-associated hypercalcemia. In their study, 20% of the patients was able to receive subsequent anti-cancer therapy. Median OS was 135 days for the patients who received chemotherapy after an episode of hypercalcemia [9].

Similar results were seen in a retrospective cohort study of Cripe et al. among gynecologic oncologic patients. Median OS in their study was 38 days [10].

It is generally believed that hypercalcemia is a manifestation of advanced stage of malignancy, and patients succumb as a result of direct effects of cancer-like target organ failure, cachexia and sepsis. All these factors contribute towards poor PS. In our study, 93% of patients had poor ECOG PS of either 3 or 4. Poor PS was noted in 79% of patients with hypercalcemia at the time of presentation in the study of Ramos Reo et al. [7]. Most common histology associated with hypercalcemia in our study was squamous cell carcinoma (SCC) (46.7%). Head and neck cancers constituted the majority. Similar results have been demonstrated in previous studies where SCC has been the most common histology with head and neck cancers and lung cancer being the predominant site [7, 9].

Some important conclusions can be drawn from our study. Most of the patients with HOM at presentation have poor PS and majority of them have already received definite anti-cancer therapy in the past. Correction of hypercalcemia led to improvement of PS in only 6 (13.3%) patients in our study. Median OS remains poor even in those patients who receive subsequent anti-cancer therapy. Almost 75% of patients died within 6 weeks of diagnosis of HOM. Our results expose the poor prognostic nature of hypercalcemia, and oncologists must consider applying brakes on further definite anti-cancer therapy for these patients. Symptomatic improvement is often seen with vigorous hydration, bisphosphonate therapy and calcitonin. Best supportive care including a hospice transfer should be considered thereafter discussion with patient’s relatives. This seems more valid in a resource-constrained setting like India. It should be noted that decision for only best supportive care should be taken after considering all clinical and treatment-related factors. Subsequent chemotherapy should be offered only to young, treatment naive patients with a good PS.

Our study has few limitations. It was a single institution based study. Although HOM is not encountered frequently, we could enrol only 45 patients. Results of our study cannot be generalized to patients of paediatric age group and haematological malignancies as these were excluded from the study.

Authors Contributions

All authors contributed to final manuscript. DS, LA and MW were involved in the study design and protocol. DS, RS and LA contributed to data collection and manuscript writing. Data analysis and proof reading was done by DS and PPN.

Compliance with Ethical Standards

Conflict of Interests

The authors declare that they have no conflict of interests.