Asymptomatic Primary Hyperparathyroidism: To Treat, or Not To treat?

The Journal Club Meeting POWH

14 March 2005

Presenter: Alexander Koshman

Mentor: Dr.S.Grieve

Randomized Controlled Clinical Trial of Surgery Vs No Surgery in Patients with Mild Asymptomatic Primary Hyperparathyroidism

• D.Rao, E.Phillips, G.Divine, G.Talpos

• The Journal of Clinical Endocrinology & Metabolism, 89(11):5415-5422, November 2004

• Departments of Surgery, Medicine and Biostatistics, Henry Ford Hospital, Detroit, Michigan, USA

Background

• Parathyroidectomy is the treatment of choice for patients with symptomatic primary hyperparathyroidism (PH)

• The role of surgery in mild asymptomatic PH remains controversial

• Majority of pts with PH do not manifest the symptoms traditionally attributed to this disease

• The role of parathyroidectomy, the only definitive treatment for the condition, has been called into question

Background

• Patients and clinicians are reluctant to consider Parathyroidectomy (PTE) because of the uncertainty of its benefits

• Several guidelines and algorithms have been suggested, and many divergent opinions have been expressed

• However, none are based on randomized, controlled clinical trials of PTE

BackgroundAuthors undertook the first such trial

Questions raised:

• Is it feasible to conduct a randomized clinical trial in which an invasive therapy is recommended to apparently healthy subjects in whom the disease-specific complications (kidney stones and skeletal fractures) are not always serious or inevitable?

• Are there any measurable benefits from PTE or conversely, are there any adverse health effects if left untreated?

Study design

• Patients recruited between 06/94 and 03/97 from within the Henry Ford Health System

• Inclusion criteria: age 50-75 yr ; mean serum Ca++ levels 2.52-2.87 mmol/L; intact PTH level>20 ng/L; normal RF; forearm BMD within 2SD adjusted for age, sex and race; absence of symptoms and complications attributable to Ca++ or excess PTH secretion; willingness to participate and ability to give consent; living within a 150-mile radius of the HF Hospital

Study design

Exclusion criteria:

1.Familial HPT; 2.Previous neck Sx; 3.Current Thyroid disease requiring Sx intervention; 4.Nontraumatic vertebral or hip #, or nephrolithiasis within the past 2 yr; 5.Women within 5 yr of menopause; 6.Pts taking medications known to affect bone and mineral metabolism; 7. Those with unexpected ECG findings that precluded Sx

Study designMethods:

• Of 283 eligible pts, 53 were randomized, stratified on gender and ethnicity

• Each pt seen every 6 mo for 24 mo (median 42mo; range 24-64 mo)

• Symptoms of Ca++, complications of the disease (skeletal # and kidney stones) assessed

• BMD,Ca++, PTH, and total and bone-specific ALP measured at 6 mo intervals, RF at 1yr

• X-rays Th, L spine, hands, CT abdo baseline+end

Study design• Quality of life and psychosocial well-being

assessed with 2 standardised questionnaires:

• 36-item short-form health survey to assess health-related quality of life every 6 months (8subclasses: physical function, bodily pain, general health perception, energy, social function, emotional function and mental health)

• Psychological disturbances assessed yearly with the Symptoms Checklist (quantifies psy-chological distress in 9 dimensions: somatizati-on, obsessive-compulsive,depression,phobia,etc.)

Study safety and Data Monitoring

• An independent committee consisting of endocrinologist, parathyroid surgeon, cardiologist, biostatistician, and psychiatrist met twice a year to monitor the study progress and patient safety

• None of the members were involved in the care of the patients

Statistical Methods• Unpaired Student’s test used to compare the 2

groups at baseline

• Primary analysis based on the intention-to-treat principle

• Average annual change for each variable of in-terest was estimated for and compared between treatment groups using varying intercept models with separate slopes fit for each group

• Adverse event rates compared by Fisher’s exact test

• Nominal significance level was set at P<0.05

Results• A total of 1201 pts with Ca++ identified during

the 33-month recruitment period

• 918 (76%) pts did not meet inclusion criteria

• Of remaining 283 pts, 95(33%) refused, 105 (37%) did not respond and 30 (11%) could not participate

• 53 pts (19% of 283 potentially eligible pts) were enrolled in the study: 25 randomized to Sx, 28 to regular follow-up

• Except for the older mean age in Sx group, the baseline characteristics of 2 groups were similar

Results• Surgery involved identification of four

parathyroid glands in each pt and resection of only grossly abnormal glands by experienced parathyroid surgeon

• 23 of 25 pts (92%) randomized to Sx had parathyroidectomy within 3 mo of randomization

• At least one abnormal gland was found in each pt (median weight 550 mg; range 80-9600 mg)

• No localising imaging study was performed

Results• After parathyroidectomy, there was increase in

BMD of spine, femoral neck, total hip and forearm and expected fall in serum Ca++,PTH and urine Ca++

• In contrast, Pts without Sx lost BMD at femoral neck and total hip, but gained at the spine and forearm with no significant changes in biochemical indices of the disease

• Significant effect of PTEctomy on BMD was evident only at femoral neck and total hip, but not at the spine or forearm

Results• Quality-of-life scores showed significant

declines in 5 of 9 domains (social functioning, physical problem, emotional problem, energy and health perception) in pts without Sx, but in only 1 of 9 domains (physical function) in group with PTEctomy

• Psychological function as assessed by the symptoms checklist did not change significantly in either group, except for a significant decline in anxiety and fobia in patients who had Sx in comparison with those who did not

Adverse Events• In the Sx group, 1 pt required an overnight

postoperative drain in the neck; another pt was not satisfied with PTEctomy, and 3 pts developed recurrent HPTidism

• Among 28 pts followed up without Sx, 1 pt developed a small kidney stone 2 years after randomization; another pt developed pancreatitis; and a 3rd pt developed fatigue, irritability and depression. All 3 pts underwent PTEctomy later

• Proportion of pts developing any adverse event was not significantly different between the 2 groups

Conclusions

• It is feasible to conduct a randomized, controlled clinical trial of PTEctomy in pts with mild asymptomatic primary HPTidism because very few disease-specific complications occurred in the absence of definitive treatment

• Despite the mild disease and asymptomatic status, there appears to be measurable effects of Sx on BMD, quality of life and psychological function

Conclusions

• With the advent of minimally invasive surgery, a more liberal approach to Sx is recommended, and these potential small but significant benfits of PTEctomy must be tempered by the possibility of unmet patient expectations and/or complications from surgery in these otherwise healthy individuals

Limitations of the Study• Single institution, single surgeon, no

histopathology interpretation• Only 53 of the 283 originally planned pts were

enrolled• Recruitment took 15 months longer than

anticipated 18 months• The sample size was too small and• Follow up period was too short (< 3 yr) to assess

the effect of PTEctomy on other outcome variables of interest such as nephrolithiasis, fractures, morbidity and mortality

Ideas for Future Research

• A larger trial with a longer follow up may uncover disease-specific complications in the untreated patients not seen in this smaller feasibility study.

• The lower than predicted recruitment rate is not surprising considering the invasive nature of the only definitive treatment available for patients who feel generally healthy

Ideas for Future Research

• Many pts refused PTEctomy, believing that they are well and did not need intervention

• This implies that a different recruitment and randomization strategy would be needed for any future such trials

• The ultimate balance of the risks and benefits of PTEctomy in such pts can be determined only by a larger, longer-term, multicenter study