This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Smith, T. J. Articles by Coyne, P. J. Search for Related Content PubMed Articles by Smith, T. J. Articles by Coyne, P. J. Related Articles Related Article

In reply:

Virginia Commonwealth University, Division of Hematology/Oncology and Palliative Care, Richmond, VA

Thank you for giving us the opportunity to respond to critiques of the study, "Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival" by Smith et al.¹ They raise several good points about the study, which we will attempt to clarify.

First, the study clearly does not apply to most cancer patients, as we point out. It does apply to the 14% of patients who cannot achieve satisfactory pain relief with standard measures, such as the World Health Organization pain management guidelines, even when administered by experts, and to those patients who have adequate pain relief with intolerable side effects.² Moreover, the vast majority of systemic opioid outcome studies have not carefully assessed the toxicities associated with high-dose opioid therapy. It is thus helpful for patients and their healthcare providers to have this randomized controlled trial evidence in addition to the four cohort studies showing benefit^3–6 and to the United States Food and Drug Administration (FDA) approval of the programmable implantable drug delivery system (IDDS) for cancer pain therapy.

The criteria for entry of 200 mg of morphine oral equivalent daily dose (MOED), or lesser doses with intolerable side effects, are based on several factors. First, many oncologists become uncomfortable prescribing doses higher than this.⁷ Even so, many patients require much higher opioid doses with or without opioid rotation and the additions of adjunctive medications. As reported in our article, more than half of patients enrolled in our trial were receiving MOED greater than 200 mg, with 25% receiving more than 3.5 times that dosage via oral, parenteral, and transdermal routes at study entry. Second, intolerable side effects can occasionally be overcome but often are a major reason for noncompliance.⁸ In practice, both groups are managed by opioid titration, switching, or conversion; addition of adjuvant drugs; and management of side effects to the best degree possible.⁹ The risk of implantable systems was lower than some anticipated, not a clinical burden, and offset by the superior clinical success, as noted in the study.

We anticipated that approaches to therapy might vary, even at expert centers that follow the same internationally recognized guidelines and standards for managing intractable pain in cancer patients. To avoid the introduction of bias, randomization was done in permuted small blocks, stratified by site. Enrollment was well balanced between the two study arms at all sites that achieved more than minimum enrollment, and more than 80% of patients came from these sites. Patient characteristics at baseline were well balanced, and we infer from this and from other, unpublished data, that approaches to both pain therapy and palliative cancer therapy after selection also should have been well balanced.

The mean age of the study patients was 57 years, which is younger than the mean age of cancer patients. But again, this is for the 14% of cancer patients with refractory pain, not all patients. The mean age on the Virginia Commonwealth University Health System Thomas Palliative Care Unit is only 52 years, so the patients in this study are not unusual.¹⁰

The two groups had essentially the same MOEDS at study registration, 280 (range, 120 to 686 mg) and 260 (range, 135 to 641 mg) mg respectively; these values were not statistically or clinically different. They also had equivalent adjuvant drug use and were well matched for all other relevant variables; such is the strength of a large, high-power, randomized clinical trial. We disagree that other research has shown no advantage to spinal analgesia when controlled for opioid potency. This is the only randomized controlled trial of IDDS + CMM versus CMM, and there have been no other titration studies with high levels of evidence. As Mercadante states in the article¹¹ referenced by Davis et al, "The main problems involved an attempt to find how to use the drugs and techniques to the best possible advantage."

The centers and physicians were specifically chosen for expertise in both CMM and IDDS, and all used routine methods of opioid titration and switching, in addition to adjuvant medications. Perhaps the best proof of the CMM expertise is that the CMM control group had a 39% reduction in pain! This is more than duPen et al found with an algorithm approach.¹²

We agree that pain often progresses as cancer grows, and we allowed CMM patients to cross over to IDDS for refractory pain, defined in the protocol as pain scores greater than 5 or unacceptable toxicity and central approval by T.S. or P.S. The case of each patient that crossed over was reviewed by T.S. or P.S. to ensure opioid rotation, possible use of corticosteroids and nonsteroidal anti-inflammatory agents, adjuvant analgesics, and the possible role of chemotherapeutic and radiotherapy agents. The IDDS is an FDA-cleared treatment device, so withholding it would be unethical. As noted above, opioid titration and switching was one of the strategies used; the CMM group increased its opioid median from 272 to 290 mg, and more patients had antidepressants and anticonvulsants added (data were not shown in the original article and are being prepared for publication). The CMM group that crossed over to IDDS had pain scores decrease from 6.2 ± 2.8 before IDDS implant to 4.5 ± 2.7 after IDDS implant (P = .01). In addition, the CMM group had a 50% reduction in drug toxicity and lived a median of 101 days after IDDS implant.¹³ The IDDS group reduced its systemic MOED from 250 to only 50 mg and had less adjuvant drug use—which may explain the better clinical success of intrathecal pain therapy. Thus, the paradigm of titrating to maximal pain relief with minimal toxicity was used.

An additional benefit of intraspinal delivery of analgesics is that multiple classes of analgesic agents can be and were used in this study. Physicians familiar with local anesthetics used them, and previously published protocols were followed.¹⁴

We agree that the data showing better survival associated with IDDS use was not a planned end point, and we took great pains to point out that this should be reviewed with caution. That said, it is of great interest, especially because patients will suffer almost any toxicity to have a small chance of increased survival.^15–18 Improvement in opioid toxicity and in performance status by 4 weeks after randomization was associated with better survival, and the two groups were similar at randomization (data not shown). If the survival data are confirmed in a proposed follow-up trial, patients may be able to have both increased survival and better control of both pain and associated drug toxicity. Davis et al state, "Selection bias also played a role since only half of those randomized to spinal opioids received therapy." In our analysis of outcomes beyond 4 weeks, 20% of patients assigned to IDDS either had good pain control with CMM and did not require IDDS or never received implants for other reasons.¹⁹ In both the shorter and longer term, this indicates a substantial effect size for the intervention, as shown by intention-to-treat analysis.

We are performing a pharmacoecomonic analysis, but it is not complete. One hypothesis is that the added cost of the IDDS will be offset by fewer days of hospitalization for pain, and the miniscule costs (< $1 per month) of intrathecal morphine. The unexpected survival benefit may make it possible to perform a cost-effectiveness analysis.

We have managed many of these patients within the Medicare hospice benefit. Once a device is implanted, the dramatically lower doses of opioids translate into substantial savings, which should be embraced by hospice.²⁰ In addition, the 3-month survival is sufficient for implantable device therapy to be equal in cost to external intraspinal or intrathecal therapy.²¹

Opioid rotation is a commonly used practice, and it is one of the techniques used in reducing our control CMM group’s average pain score by 39%. As noted above, more CMM patients had added adjuvant drugs as part of their pain management. Opioid rotation clearly appears to benefit some patients, as Walsh et al²² have reported. When one looks closely at opioid rotation, however, the technique has never been tested in a randomized clinical trial. There certainly is potential for placebo effect, pain score regression to the mean, dilution of opioid metabolites, and a host of confounding variables that will need a well-designed trial to ascertain the true effect of opioid rotation. It was not the intention of our randomized controlled study design to evaluate specifically opioid rotation compared with therapy with IDDS. However, it was determined during the site screening process that consistent with best practices and therapy guidelines, opioid rotation was routinely done at sites participating in our study.

We agree that it should not be a standard of care for all cancer pain patients to receive an implanted pump until more conservative therapy begins to fail, and that the risks and benefits must be weighed in each case. We have been surprised by the reluctance of some healthcare providers to even consider an epidural or intraspinal screening trial, given that it is one of the few procedures in oncology in which the outcome—and whether IDDS will help—is known within hours. Ninety-two percent of our patients responded favorably to a screening trial; only 8% did not do well with a trial and were not subjected to the risk or expense of a pump.

For the 14% of patients with refractory cancer pain, especially for those who have intolerable side effects even at low opioid doses, the benefit seen in this large randomized controlled trial of this FDA-cleared technique leads us to a welcome alternative.

REFERENCES

1. Smith TJ, Staats PJ, Pool G, et al: Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: Impact on pain, drug-related toxicity, and survival. J Clin Oncol 20:4040–4049, 2002[Abstract/Free Full Text]

2. Meuser T, Pietruck C, Radbruch L, et al: Symptoms during cancer pain treatment following WHO-guidelines: A longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93:247–257, 2001[CrossRef][Medline]

3. DeVulder J, Ghys L, Dhondt W, et al: Spinal analgesia in terminal care: Risk versus benefit. J Pain Symptom Manage 9:75–81, 1994[CrossRef][Medline]

4. Hassenbusch S, Pillay P, Magdinec M, et al: Constant infusion of morphine for intractable cancer pain using an implanted pump. J Neurosurg 73:405–409, 1990[Medline]

5. Onofrio B, Yaksh T: Long-term pain relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg 72:200–209, 1990[Medline]

6. Penn R, Paice J: Chronic intrathecal morphine for intractable pain. J Neurosurg 67:182–186, 1987[Medline]

7. O’Gorman DA, Staats PS, Traffis M. Attitudes to interventional pain management among cancer health care personnel. American Pain Society, November 1998

8. Miaskowski C, Dodd MJ, West C, et al: Lack of adherence with the analgesic regimen: A significant barrier to effective cancer pain management. J Clin Oncol 19:4275–4279, 2001[Abstract/Free Full Text]

9. O’Mahony S, Coyle N, Payne R: Current management of opioid-related side effects. Oncology 15:61–82, 2001[Medline]

10. Smith T, Coyne P, Cassel B, et al: A high volume specialist palliative care unit and team may reduce in-hospital end of life care cost. J Palliat Med (in press)

11. Mercadante S: Controversies over spinal treatment in advanced cancer patients. Support Care Cancer 6:495–502, 1998[CrossRef][Medline]

12. DuPen S, DuPen A, Polossar N, et al: Implementing guidelines for cancer pain management: Results of a randomized controlled clinical trial. J Clin Oncol 17:361–370, 1999[Abstract/Free Full Text]

13. Staats P: Neuraxial infusion for pain control: When, why, and what to do after the implant. Oncology 13:58–62, 1999[Medline]

14. Coyne P, Smith TJ, Staats PS, et al: Implantable drug delivery systems (IDDS) after failure of comprehensive medical management (CMM) can palliate even the most refractory patients. Proc Am Soc Clin Oncol 22:737, 2003 (abstr 2964)

15. Bremnes RM, Andersen K, Wist EA: Cancer patients, doctors and nurses vary in their willingness to undertake cancer chemotherapy. Eur J Cancer 31A:1955–1959, 1995[Medline]

16. Tamburini M, Buccheri G, Brunelli C, et al: The difficult choice of chemotherapy in patients with unresectable non-small-cell lung cancer. Support Care Cancer 8:223–228, 2000[CrossRef][Medline]

17. Balmer CE, Thomas P, Osborne RJ: Who wants second-line, palliative chemotherapy? Psychooncology 10:410–418, 2001[CrossRef][Medline]

18. Slevin ML, Stubbs L, Plant HJ, et al: Attitudes to chemotherapy: Comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 300:1458–1460, 1990[Medline]

19. Hassenbusch SJ, Paice JA, Patt RB, et al: Clinical realities and economic considerations: Economics of intrathecal therapy. J Pain Symptom Manage 14:36–48, 1997 (suppl 3)[Medline]

20. Smith TJ, Coyne P, Staats PS, et al: Implantable drug delivery system (IDDS) provide sustained pain control, less drug toxiity, and better survival compared to comprehensive medical management (CMM). Proc Am Soc Clin Oncol 22:738, 2003 (abstr 2967)

21. Bedder MD, Burchiel K, Laron A: Cost analysis of two implantable narcotic delivery systems. J Pain Symptom Manage 6:368–373, 1991[CrossRef][Medline]

22. Walsh D, Mahmond F, Sarill N, et al: Parenteral opioid rotation in advanced cancer: A prospectie study. Proc Am Soc Clin Oncol 12:2002 (abstr 1429)

Related Article

• Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival
  Carla Ripamonti and Cinzia Brunelli
  JCO 2003 21: 2801-2802 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Smith, T. J. Articles by Coyne, P. J. Search for Related Content PubMed Articles by Smith, T. J. Articles by Coyne, P. J. Related Articles Related Article