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Symptomatic hypercalcaemia in lung cancer
Respiratory Medicine (I 991) 85, 223-227
Symptomatic hypercalcaemia in lung cancer J. H. CAMPBELL*~, S. RALSTONt, I. T. BOYLEt AND S. W. BANHAM*
*Departmentfor Respiratory Medicine and t University Department of Medicine, Glasgow Royal Infirmary, Glasgow G31 2ES, U.K.
We report our experience of the presentation and management of symptomatic hypercalcaemia in advanced lung cancer. Between 1981 and 1987, 55 patients required urgent admission due to rapid clinical deterioration accompanied by significant hypercalcaemia (> 2.75 mmol 1- i). Forty patients (72%) had squamous cell cancer, five small cell, three large cell, two adenocarcinoma and five unclassified. Thirty-five had evidence of bony metastases. Symptoms were categorized for each patient on the basis of being either potentially attributable to hypercalcaemia or not. All patients were rehydrated but specific treatment schedules over the period varied [1981-1985: steroids, calcitonin, mithramycin; 1985-1987: aminohydroxypropylidene bisphosphonate (APD)]. Treatment resulted in a significant reduction in the prevalence of all systems except for pain and nausea/ vomiting; the greatest effect being seen on central nervous system and renal tract symptoms (75 and 80% reduction respectively; P < 0"005 pre- versus post-treatment). Overall, 45 patients (82%) had a biochemical response; serum calcium fell from 3-28+0.33mmoll -t (mean + sE) to a nadir of 2.54 + 0.36 mmol I-~ (P < 0.001). Twenty-five (49%) patients were discharged home. We conclude that despite the poor life expectancy of this group of patients (median survival 42 days) treatment of hypercalcaemia is worthwhile as it results in a significant symptomatic improvement.
Introduction
Hypercalcaemia is a common metabolic complication of lung cancer (1,2). Despite recent major advances in unravelling the pathogenesis of humoral hypercalcaemia of malignancy (3,4) there is still no universally effective therapy, and the perceived poor long-term prognosis of this group of patients has led many clinicians to adopt a negative approach to their management (5). Most published series on hypercalcaemia include patients with a wide range of underlying malignancies. Such pooled data, whilst valuable in stressing the common aspects of presentation and management, may mask other more disease-specific problems. These factors prompted us to review our experience in the management of symptomatic hypercalcaemia in lung cancer. Patients and Methods
Between 1981 and 1987 all hypercalcaemic patients in our hospital were identified by day to day scrutiny of the computerized biochemical records. Those that fulfilled the following criteria were included in this Received 16 August 1990 and accepted in revised form 4 December 1990. ++Towhom correspondence should be addressed at: Department of Respiratory Medicine, Royal Infirmary, 16 Alexandra Parade, Glasgow G31 2ES. 0954-6111/91/030223 + 05 $03.00/0
review: (i) adjusted serum calcium > 2.75 mmol 1-i; (ii) histologically proven lung cancer either at the time of presentation or later; (iii) symptoms which could possibly be attributed to hypercalcaemia. Asymptomatic hypercalcaemic patients and those moribund (patients thought by the attending physician to have a life expectancy of less than 48 h at the time of presentation) were not actively treated and are excluded from this study. Biochemical measurements were made on fasting blood samples using an autoanalyser and serum total calcium values were adjusted for albumin concentration using a nomogram (6). In patients with bone pain, the presence of metastatic bone disease was determined by plain X-rays and standard radionuclide bone scans. All patients were interviewed before and after treatment and their symptoms recorded. These were categorized at the time of presentation into five groups: (1) central nervous system (CNS) - confusion or coma; (2) gastrointestinal-anorexia, nausea, vomiting and constipation; (3) renal-polyuria, polydipsia; (4) general- malaise; and (5) p a i n - usually due to bone or visceral involvement by tumour. The therapeutic antihypercalcaemic regimes used over the 6-year period varied (Table 1). Mithramycin was given as an infusion of 25 mcg K g - J in 500 ml of dextrose and repeated after 2 days if the serum calcium © 1991 Bailli~re Tindall
224
J. H. Campbell et al. Table l Antihypercalcaemicdrug regimes. All patients were initially rehydrated with intravenous 0.9% saline over 48 h
Number of patients
Drug regime Steroids/calcitonin
8
Dose 40 mg prednisolone orally per day + 100 i.u. calcitonin 8-hourly
Mithramycin
I0
25 gg kg ~i.v.
Aminohydroxypropylidene bisphosphonate (APD)
32
5-45 mg i.v.
APD/calcitonin
3
15 mg APD daily, 400 i.u. calcitonin 8-hourly (each for 6 days)
Steroids only
2
40 mg prednisolone orally per day
Table 2 Baseline characteristics
Serum calcium at presentation mean+so: mmol I-~ Serum albumin g dl-i mean _+SD Number with inoperable disease Histology: Squamous Small cell Large cell Adenocarcinoma Unclassified
Table3 Symptoms
3.28 _ 0.33 29"0 + 6-7 51 (92.7%) 40 5 3 2 5
(72.7%) (9. 1%) (5-5%) (3"6%) (9.1%)
remained above 2.90 mmol 1- ~. Aminohydroxypropylidene bisphosphonate (APD) was given as an infusion of varying dosage in 250 ml of saline over4 h. Many of the patients included in this study had participated in previous studies the details of which have been reported elsewhere (7,8). The length of survival was defined as the time in days between the patients' first presentation with symptomatic hypercalcaemia requiring treatment and the date of death. Statistical tests used in analysis were the Chisquared test (with Yates correction) and the paired t-test. Results Fifty-five patients were studied, 42 male, with a mean age of 65 years (range 40-81). Baseline patient details are shown in Table 2. Twenty-eight patients (51%) were hypercalcaemic at the time that the diagnosis of lung cancer was made. In five, symptoms attributable to hypercalcaemia were the only symptoms at presentation but no patient had
Patients interviewed Malaise/fatigue Anorexia Confusion/mental changes Polyuria/polydipsia Constipation Pain Nausea/vomiting
Number
%
55 31 30 25 25 21 20 14
I00 56.3 54.5 45.4 45.4 38.2 36-4 25.4
symptomatic hypercalcaemia and occult lung cancer (i.e. normal chest X-ray). The mean time from diagnosis of lung cancer to development of hypercalcaemia, in those in whom it was not present at outset, was I I months with a range of 1-53 months. Thirty-six patients (65%) had a raised alkaline phosphatase, 24 of whom had evidence of bony matastases and seven patients had bony metastases with serum alkaline phosphatase within the normal range. Ten patients 0 8 % ) underwent thoracotomy and resection of the primary tumour: six of these developed hypercalcaemia post-operatively, one within l year, four within 2 years and one by 4 years. As might be predicted, non-specific symptoms such as malaise and fatigue were the commonest complaints at presentation reflecting the general state of these patients as well as the severity of hypercalcaemia (Table 3). However, CNS and renal tract symptoms increased significantly with increasing severity of hypercalcaemia-CNS: symptoms in 67% of patients with serum calcium > 3 . 4 m m o l l - I cf. 32% with serum calcium < 3.4 mmol i-~; renal tract: symptoms in 56% of patients with serum calcium > 3.4 mmol lel. 36% serum calcium < 3-4 mmol l - t.
Symptomatic hypercalcaemia in lung cancer
225
60 5O
~ 40 •.~ 3O
E
~
¢11~
0
ao
g
f l l FlJ f l i
I0
Q.
flJ
f l l
III
I
0 Z ~.)
c
o
.-
. _
~_
.=E o
r_l
Symptoms
o Z
Fig. 1. Prevalence of individual symptoms before ([]) and after ([]) antihypercalcaemic therapy.
5 E E E ._~ 4
B
B
3
I
I
Pre-treatment Post-treatment Fig. 2. Serum calcium values pre- and post-treatment, (O O) APD: P<0-001;(i l ) steroids + calcitonin: P<0-005; (& A) mithramycin: P<0.001. Values are mean + so.
Treatment resulted in a significant reduction in the prevalence of all symptoms except for pain and nausea/vomiting (Fig. 1). The greatest effect being seen on CNS and renal tract symptoms. Following antihypercalcaemic therapy the mean serum calcium fell from 3.28+0.33 m m o l l -~ (mean_SE) to a nadir of
2-54 + 0-36. All three therapeutic regimes studied produced a significant fall in serum calcium (Fig. 2), and differences between the groups were not significant. Side-effects of mithramycin were observed: nausea and vomiting in two patients (20%), mild transient thrombocytopaenia in one and transient rises in serum aminotransferase in five. Transient pyrexia occurred in four patients (13%) treated with APD, and local thrombophlebitis occurred at the infusion site in two. Five patients (45%) found the frequent calcitonin injections uncomfortable. The outcome in all 55 patients is summarized in Fig. 3. Forty-five (82%) patients having an initial biochemical response that was maintained up to the terminal stages (within 72 h of death) in 28. Relapse was defined as a rise in serum calcium to within 0"05 mmol 1-t of the original level accompanied by recurrence of symptoms. Only three of the 17 patients in this group were re-treated as the majority were terminally ill. Ten patients failed to respond, three of whom died within a week of starting therapy (two of pneumonia and one of PTE). Twenty-five patients (49%) were discharged home. This related to the control of hypercalcaemia, in that 79% of patients whose post-treatment calcium was less than 2 . 8 m m o l l -~ were discharged home compared with none of those whose calcium remained greater than 3-4 mmol 1-l. The life expectancy of the group was very poor with a median survival of 42 days (range 0-1450) and did not differ significantly between treatment groups. The
226
J. H. Campbell et al.
Responders 45 (82%) /
/ " ~
.~, Response maintained28 Terminallyill, treatment 14 /nofurtheractive.. Retreated 3 Symptomatic relapse17140%) ~ ,
55
"•k
. ~ Rapidlydeteriorated N°n-resp°nders/'~. from underTyingcancer7 IO (18%)
"%k Diedfrom concurrent illness withinone weekof treatment 3
Fig. 3. Diagrammatic representation of patient outcome.
main predictor of a longer term survival (greater than 6 months) was the use of specific anticancer treatment: of the four patients who survived for more than 6 months, three had received such therapy (one chemotherapy, one radiotherapy and one surgery). The only long-term survivor (still alive and normocalcaemic after 4 years) was a man with squamous cell cancer who underwent a curative resection. Discussion
Symptomatic hypercalcaemia is generally considered to occur in the advanced stages of cancer when there is an extensive tumour burden. Overall, our findings support this view for lung cancer and in this setting the symptoms of hypercalcaemia present a significant additional burden for which we now have effective treatment. Furthermore, almost half of our patients were hypercaicaemic at presentation and in five patients it was the symptoms attributable to hypercalcaemia rather than the tumour that directly led the patient to seek medical advice. None of our group had a normal chest X-ray, so occult lung cancer would appear to be an extremely uncommon cause of symptomatic hypercalcaemia. Squamous cell cancer was the commonest cell type (73%) but in contrast to the perceived wisdom a significant number of our group (9%) had small cell c a n c e r - a cell type not conventionally associated with hypercalcaemia. As the diagnosis was based on samples obtained at fibreoptic bronchoscopy these tumours could represent mixed tumour type but the presentation and course of their illness were typical of small cell lung cancer. All of the small cell patients had extensive bony metastases supporting the view that metastatic disease is the likely mechanism o f hypercalcaemia in this subset. Despite recent advances in understanding the mechanism of hypercaicaemia in lung cancer, the overall prognosis of this group of patients remains very poor,
half of our group dying within 2 months of the first episode of symptomatic hypercalcaemia. The outlook was particularly bleak for patients admitted during subsequent episodes. In keeping with previous studies, the main predictor of long-term survival was the availability of specific anticancer therapy. Nonetheless, we feel that a nihilistic approach to these patients is not justified as specific antihypercalcaemic therapy resulted in considerable palliation of symptoms with few associated side effects. We were particularly impressed by the improvement in CNS and renal tract symptoms, and symptom palliation was thought to have made a significant contribution to getting patients back into their home environment. All three treatment regimes (mithramycin, steroids plus calcitonin and APD) were effective in lowering serum calcium in the short-term. This initial response was sufficient to maintain 50% of the group normocalcaemic until the very terminal stages of their disease. Only three patients were actively re-treated as the vast majority were terminally ill by the time of relapse. What conclusions can we draw from this review? Symptomatic hypercalcaemia in the context of lung cancer can occur at any stage of the disease but is usually associated with an extensive tumour burden. It is not confined to the squamous cell type occurring in a significant proportion of small cell cancer patients. Even if curative treatment aimed at the underlying cancer is not feasible, specific antihypercalcaemic therapy is very effective in the short-term control of hypercalcaemia and offers good symptom palliation. The resultant clinical improvement justifies the use of such treatment even in patients with advanced lung cancer. References
I. Bender RA, Hanswn H. Hypercalcaemia in bronchogenic carcinoma. Ann Intern Med 1974; 80: 205-208.
S y m p t o m a t i c h y p e r c a l c a e m i a in lung cancer
2. Azzopardi JG, Freeman E, Poole G. Endocrine and metabolic disorders in bronchial carcinoma. Br M e d J 1970; 4: 528-529. 3. Sura LJ, Winslow GA, Wetterhall REH et al. A parathyroid hormone-related protein implicated in malignant hypercalcaemia: cloning and expression. Science 1987; 237: 839-836. 4. Mundy GR. Hypercalcaemia of malignancy revisited. J Clin hn,est 1988; 82: 1-6. 5. Fiskin RA, Heath DA, Bold AM. Hypercalcaemia-A hospital survey. Q J Med 1980; 196:405-418. 6. Gardner MD, Dryburgh F J, Fyffe JA, Jenkins AS. Predictive value of derived calcium figures based on the measure-
227
ment of ionised calcium. Ann Clin Biochem 1981; 18: 106-109. Ralston SH, Gardner MD, Dryburgh FJ, Jenkins AS, Cowan RA, Boyle IT. Comparison of aminohydroxypropylidene bispbosphonate, mithramycin and corticosteroid/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 1985; ii: 907-910. 8. Ralston SH, Alzaid AA, Gallacher SJ, Gardner MD, Cowan RA, Boyle IT. Clinical experience with aminohydroxypropylidene bisphosphonate (APD) in the management of cancer-associated hypercalcaemia. Q J Med 1988; 258: 825-834.
Symptomatic hypercalcaemia in lung cancer J. H. CAMPBELL*~, S. RALSTONt, I. T. BOYLEt AND S. W. BANHAM*
*Departmentfor Respiratory Medicine and t University Department of Medicine, Glasgow Royal Infirmary, Glasgow G31 2ES, U.K.
We report our experience of the presentation and management of symptomatic hypercalcaemia in advanced lung cancer. Between 1981 and 1987, 55 patients required urgent admission due to rapid clinical deterioration accompanied by significant hypercalcaemia (> 2.75 mmol 1- i). Forty patients (72%) had squamous cell cancer, five small cell, three large cell, two adenocarcinoma and five unclassified. Thirty-five had evidence of bony metastases. Symptoms were categorized for each patient on the basis of being either potentially attributable to hypercalcaemia or not. All patients were rehydrated but specific treatment schedules over the period varied [1981-1985: steroids, calcitonin, mithramycin; 1985-1987: aminohydroxypropylidene bisphosphonate (APD)]. Treatment resulted in a significant reduction in the prevalence of all systems except for pain and nausea/ vomiting; the greatest effect being seen on central nervous system and renal tract symptoms (75 and 80% reduction respectively; P < 0"005 pre- versus post-treatment). Overall, 45 patients (82%) had a biochemical response; serum calcium fell from 3-28+0.33mmoll -t (mean + sE) to a nadir of 2.54 + 0.36 mmol I-~ (P < 0.001). Twenty-five (49%) patients were discharged home. We conclude that despite the poor life expectancy of this group of patients (median survival 42 days) treatment of hypercalcaemia is worthwhile as it results in a significant symptomatic improvement.
Introduction
Hypercalcaemia is a common metabolic complication of lung cancer (1,2). Despite recent major advances in unravelling the pathogenesis of humoral hypercalcaemia of malignancy (3,4) there is still no universally effective therapy, and the perceived poor long-term prognosis of this group of patients has led many clinicians to adopt a negative approach to their management (5). Most published series on hypercalcaemia include patients with a wide range of underlying malignancies. Such pooled data, whilst valuable in stressing the common aspects of presentation and management, may mask other more disease-specific problems. These factors prompted us to review our experience in the management of symptomatic hypercalcaemia in lung cancer. Patients and Methods
Between 1981 and 1987 all hypercalcaemic patients in our hospital were identified by day to day scrutiny of the computerized biochemical records. Those that fulfilled the following criteria were included in this Received 16 August 1990 and accepted in revised form 4 December 1990. ++Towhom correspondence should be addressed at: Department of Respiratory Medicine, Royal Infirmary, 16 Alexandra Parade, Glasgow G31 2ES. 0954-6111/91/030223 + 05 $03.00/0
review: (i) adjusted serum calcium > 2.75 mmol 1-i; (ii) histologically proven lung cancer either at the time of presentation or later; (iii) symptoms which could possibly be attributed to hypercalcaemia. Asymptomatic hypercalcaemic patients and those moribund (patients thought by the attending physician to have a life expectancy of less than 48 h at the time of presentation) were not actively treated and are excluded from this study. Biochemical measurements were made on fasting blood samples using an autoanalyser and serum total calcium values were adjusted for albumin concentration using a nomogram (6). In patients with bone pain, the presence of metastatic bone disease was determined by plain X-rays and standard radionuclide bone scans. All patients were interviewed before and after treatment and their symptoms recorded. These were categorized at the time of presentation into five groups: (1) central nervous system (CNS) - confusion or coma; (2) gastrointestinal-anorexia, nausea, vomiting and constipation; (3) renal-polyuria, polydipsia; (4) general- malaise; and (5) p a i n - usually due to bone or visceral involvement by tumour. The therapeutic antihypercalcaemic regimes used over the 6-year period varied (Table 1). Mithramycin was given as an infusion of 25 mcg K g - J in 500 ml of dextrose and repeated after 2 days if the serum calcium © 1991 Bailli~re Tindall
224
J. H. Campbell et al. Table l Antihypercalcaemicdrug regimes. All patients were initially rehydrated with intravenous 0.9% saline over 48 h
Number of patients
Drug regime Steroids/calcitonin
8
Dose 40 mg prednisolone orally per day + 100 i.u. calcitonin 8-hourly
Mithramycin
I0
25 gg kg ~i.v.
Aminohydroxypropylidene bisphosphonate (APD)
32
5-45 mg i.v.
APD/calcitonin
3
15 mg APD daily, 400 i.u. calcitonin 8-hourly (each for 6 days)
Steroids only
2
40 mg prednisolone orally per day
Table 2 Baseline characteristics
Serum calcium at presentation mean+so: mmol I-~ Serum albumin g dl-i mean _+SD Number with inoperable disease Histology: Squamous Small cell Large cell Adenocarcinoma Unclassified
Table3 Symptoms
3.28 _ 0.33 29"0 + 6-7 51 (92.7%) 40 5 3 2 5
(72.7%) (9. 1%) (5-5%) (3"6%) (9.1%)
remained above 2.90 mmol 1- ~. Aminohydroxypropylidene bisphosphonate (APD) was given as an infusion of varying dosage in 250 ml of saline over4 h. Many of the patients included in this study had participated in previous studies the details of which have been reported elsewhere (7,8). The length of survival was defined as the time in days between the patients' first presentation with symptomatic hypercalcaemia requiring treatment and the date of death. Statistical tests used in analysis were the Chisquared test (with Yates correction) and the paired t-test. Results Fifty-five patients were studied, 42 male, with a mean age of 65 years (range 40-81). Baseline patient details are shown in Table 2. Twenty-eight patients (51%) were hypercalcaemic at the time that the diagnosis of lung cancer was made. In five, symptoms attributable to hypercalcaemia were the only symptoms at presentation but no patient had
Patients interviewed Malaise/fatigue Anorexia Confusion/mental changes Polyuria/polydipsia Constipation Pain Nausea/vomiting
Number
%
55 31 30 25 25 21 20 14
I00 56.3 54.5 45.4 45.4 38.2 36-4 25.4
symptomatic hypercalcaemia and occult lung cancer (i.e. normal chest X-ray). The mean time from diagnosis of lung cancer to development of hypercalcaemia, in those in whom it was not present at outset, was I I months with a range of 1-53 months. Thirty-six patients (65%) had a raised alkaline phosphatase, 24 of whom had evidence of bony matastases and seven patients had bony metastases with serum alkaline phosphatase within the normal range. Ten patients 0 8 % ) underwent thoracotomy and resection of the primary tumour: six of these developed hypercalcaemia post-operatively, one within l year, four within 2 years and one by 4 years. As might be predicted, non-specific symptoms such as malaise and fatigue were the commonest complaints at presentation reflecting the general state of these patients as well as the severity of hypercalcaemia (Table 3). However, CNS and renal tract symptoms increased significantly with increasing severity of hypercalcaemia-CNS: symptoms in 67% of patients with serum calcium > 3 . 4 m m o l l - I cf. 32% with serum calcium < 3.4 mmol i-~; renal tract: symptoms in 56% of patients with serum calcium > 3.4 mmol lel. 36% serum calcium < 3-4 mmol l - t.
Symptomatic hypercalcaemia in lung cancer
225
60 5O
~ 40 •.~ 3O
E
~
¢11~
0
ao
g
f l l FlJ f l i
I0
Q.
flJ
f l l
III
I
0 Z ~.)
c
o
.-
. _
~_
.=E o
r_l
Symptoms
o Z
Fig. 1. Prevalence of individual symptoms before ([]) and after ([]) antihypercalcaemic therapy.
5 E E E ._~ 4
B
B
3
I
I
Pre-treatment Post-treatment Fig. 2. Serum calcium values pre- and post-treatment, (O O) APD: P<0-001;(i l ) steroids + calcitonin: P<0-005; (& A) mithramycin: P<0.001. Values are mean + so.
Treatment resulted in a significant reduction in the prevalence of all symptoms except for pain and nausea/vomiting (Fig. 1). The greatest effect being seen on CNS and renal tract symptoms. Following antihypercalcaemic therapy the mean serum calcium fell from 3.28+0.33 m m o l l -~ (mean_SE) to a nadir of
2-54 + 0-36. All three therapeutic regimes studied produced a significant fall in serum calcium (Fig. 2), and differences between the groups were not significant. Side-effects of mithramycin were observed: nausea and vomiting in two patients (20%), mild transient thrombocytopaenia in one and transient rises in serum aminotransferase in five. Transient pyrexia occurred in four patients (13%) treated with APD, and local thrombophlebitis occurred at the infusion site in two. Five patients (45%) found the frequent calcitonin injections uncomfortable. The outcome in all 55 patients is summarized in Fig. 3. Forty-five (82%) patients having an initial biochemical response that was maintained up to the terminal stages (within 72 h of death) in 28. Relapse was defined as a rise in serum calcium to within 0"05 mmol 1-t of the original level accompanied by recurrence of symptoms. Only three of the 17 patients in this group were re-treated as the majority were terminally ill. Ten patients failed to respond, three of whom died within a week of starting therapy (two of pneumonia and one of PTE). Twenty-five patients (49%) were discharged home. This related to the control of hypercalcaemia, in that 79% of patients whose post-treatment calcium was less than 2 . 8 m m o l l -~ were discharged home compared with none of those whose calcium remained greater than 3-4 mmol 1-l. The life expectancy of the group was very poor with a median survival of 42 days (range 0-1450) and did not differ significantly between treatment groups. The
226
J. H. Campbell et al.
Responders 45 (82%) /
/ " ~
.~, Response maintained28 Terminallyill, treatment 14 /nofurtheractive.. Retreated 3 Symptomatic relapse17140%) ~ ,
55
"•k
. ~ Rapidlydeteriorated N°n-resp°nders/'~. from underTyingcancer7 IO (18%)
"%k Diedfrom concurrent illness withinone weekof treatment 3
Fig. 3. Diagrammatic representation of patient outcome.
main predictor of a longer term survival (greater than 6 months) was the use of specific anticancer treatment: of the four patients who survived for more than 6 months, three had received such therapy (one chemotherapy, one radiotherapy and one surgery). The only long-term survivor (still alive and normocalcaemic after 4 years) was a man with squamous cell cancer who underwent a curative resection. Discussion
Symptomatic hypercalcaemia is generally considered to occur in the advanced stages of cancer when there is an extensive tumour burden. Overall, our findings support this view for lung cancer and in this setting the symptoms of hypercalcaemia present a significant additional burden for which we now have effective treatment. Furthermore, almost half of our patients were hypercaicaemic at presentation and in five patients it was the symptoms attributable to hypercalcaemia rather than the tumour that directly led the patient to seek medical advice. None of our group had a normal chest X-ray, so occult lung cancer would appear to be an extremely uncommon cause of symptomatic hypercalcaemia. Squamous cell cancer was the commonest cell type (73%) but in contrast to the perceived wisdom a significant number of our group (9%) had small cell c a n c e r - a cell type not conventionally associated with hypercalcaemia. As the diagnosis was based on samples obtained at fibreoptic bronchoscopy these tumours could represent mixed tumour type but the presentation and course of their illness were typical of small cell lung cancer. All of the small cell patients had extensive bony metastases supporting the view that metastatic disease is the likely mechanism o f hypercalcaemia in this subset. Despite recent advances in understanding the mechanism of hypercaicaemia in lung cancer, the overall prognosis of this group of patients remains very poor,
half of our group dying within 2 months of the first episode of symptomatic hypercalcaemia. The outlook was particularly bleak for patients admitted during subsequent episodes. In keeping with previous studies, the main predictor of long-term survival was the availability of specific anticancer therapy. Nonetheless, we feel that a nihilistic approach to these patients is not justified as specific antihypercalcaemic therapy resulted in considerable palliation of symptoms with few associated side effects. We were particularly impressed by the improvement in CNS and renal tract symptoms, and symptom palliation was thought to have made a significant contribution to getting patients back into their home environment. All three treatment regimes (mithramycin, steroids plus calcitonin and APD) were effective in lowering serum calcium in the short-term. This initial response was sufficient to maintain 50% of the group normocalcaemic until the very terminal stages of their disease. Only three patients were actively re-treated as the vast majority were terminally ill by the time of relapse. What conclusions can we draw from this review? Symptomatic hypercalcaemia in the context of lung cancer can occur at any stage of the disease but is usually associated with an extensive tumour burden. It is not confined to the squamous cell type occurring in a significant proportion of small cell cancer patients. Even if curative treatment aimed at the underlying cancer is not feasible, specific antihypercalcaemic therapy is very effective in the short-term control of hypercalcaemia and offers good symptom palliation. The resultant clinical improvement justifies the use of such treatment even in patients with advanced lung cancer. References
I. Bender RA, Hanswn H. Hypercalcaemia in bronchogenic carcinoma. Ann Intern Med 1974; 80: 205-208.
S y m p t o m a t i c h y p e r c a l c a e m i a in lung cancer
2. Azzopardi JG, Freeman E, Poole G. Endocrine and metabolic disorders in bronchial carcinoma. Br M e d J 1970; 4: 528-529. 3. Sura LJ, Winslow GA, Wetterhall REH et al. A parathyroid hormone-related protein implicated in malignant hypercalcaemia: cloning and expression. Science 1987; 237: 839-836. 4. Mundy GR. Hypercalcaemia of malignancy revisited. J Clin hn,est 1988; 82: 1-6. 5. Fiskin RA, Heath DA, Bold AM. Hypercalcaemia-A hospital survey. Q J Med 1980; 196:405-418. 6. Gardner MD, Dryburgh F J, Fyffe JA, Jenkins AS. Predictive value of derived calcium figures based on the measure-
227
ment of ionised calcium. Ann Clin Biochem 1981; 18: 106-109. Ralston SH, Gardner MD, Dryburgh FJ, Jenkins AS, Cowan RA, Boyle IT. Comparison of aminohydroxypropylidene bispbosphonate, mithramycin and corticosteroid/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 1985; ii: 907-910. 8. Ralston SH, Alzaid AA, Gallacher SJ, Gardner MD, Cowan RA, Boyle IT. Clinical experience with aminohydroxypropylidene bisphosphonate (APD) in the management of cancer-associated hypercalcaemia. Q J Med 1988; 258: 825-834.