Sunday, April 24, 2011

Chemotherapy complications round-up...neuropathy,

A few recent studies about mitigating chemotherapy complications have caught my eye and bear mentioning.

The first couple are about neurotoxic complications of chemotherapy. I've been seeing  a lot of patients who have had quite severe problems from (usually chronic) peripheral neuropathies related to their chemotherapy. At least occasionally these complications are devastating - leading to very difficult to manage, disabling pain. I haven't seen this confirmed in the literature, not that I've gone looking, but my sense is that these sorts of complications are becoming more and more common, perhaps in part to expanding use of taxane-based chemotherapy, and other newer neuropathic agents like bortezomib. Despite this, there are no proven (ie, in well designed, controlled trials) analgesic therapies for painful chemotherapy associated neuropathies, at least the last time I looked at the literature (when I was editing this Fast Fact) - I haven't seen anything major come out since, but please leave comments if you know of controlled studies I'm missing.

Annals of Oncology has the results of a randomized, double blinded study of venlafaxine for the prevention of oxaliplatin neurotoxicity.  The patients (n=54, median age 67 years, most with metastatic colorectal cancer) all had experienced acute oxaliplatin neurotoxicity in the past.  They were randomized to 50mg of venlafaxine 1 hour prior to oxaliplatin infusion, followed by 37.5mg of venlafaxine extended release bid on days 2-11 after chemotherapy (vs matching placebo).  This same regimen was re-started for subsequent oxaliplatin cycles - they don't talk about how many cycles on average patients ended up receiving venlafaxine/placebo.  Primary outcome was the fraction of patients who had complete prevention of acute neuropathy - they looked at several secondary outcomes including chronic neuropathy symptoms.

Venlafaxine came out looking very good.  31% of patients experienced no acute neuropathy on venlafaxine, vs 5% with placebo.  For those who did have symptoms, a greater proportion on venlafaxine  reported greated than 50% relief in their symptoms (69% vs 26%) compared to placebo.  Notably, they asked patients 3 months after the cessation of oxalaplatin-based chemotherapy; fewer patients who had received venlafaxine reported serious persistent neuropathic symptoms (0% vs 33%).  All these differences achieved statistical significance (ie P less than 0.05, using 2 sided tests).  Venlafaxine had more immediate side effects (nausea, vomiting, asthenia) compared to placebo.  They did not measure unblinding effects, although they did mention they had difficulty meeting accrual because very quickly clinicians began perceiving venlafaxine as effective and stopped being comfortable referring patients to the study.  Drop outs were similar between groups.

To me this is convincing evidence that venlafaxine reduces the incidence and severity of oxalaplatin acute neuropathy, as well as prevents and attenuates its chronic neuropathy, at a modest price of its immediate side effects.  This is a small study, but I've become, lately, more of a fan of well designed small symptom studies.  You want symptom interventions to be immediately effective, have a wide therapeutic index, and have very low NNTs (less than 5 patients).  If you need 200 patients to show a marginal benefit it's probably not a highly effective therapy (cf the vertebroplasty trials - there was a trend towards effectiveness in one of the trials which may be 'real' - however if you need even more people to demonstrate a marginal benefit I just can't see how this is a great thing at least in the population in which it was studied).

The caveats here are to remember this is only about the prevention of oxalaplatin neurotoxicity.  The physiology of neurotoxicity from other agents probably is different, and one can't conclude that because agent X prevents neuropathy with chemo Y, that it is generally effective to treat/ameliorate the pain from an established neuropathy from chemo Z.  Of course it might, maybe for some patients, we don't know, and I'll probably continue to cycle through my cadre of analgesics and adjuvants, systemic and topical, hoping that something works which, you know, sometimes it does.  What are others doing?  Any luck with topical agents?

Roxy Paine: 'Dendroid Drawings & Maquettes @ James Cohan

The other novel intervention, which has some promise as a non-specific palliative intervention for chemotherapy induced peripheral neuropathy, is a cutaneous electrostimulation device ('a scrambler' device - not TENS, but in that ballpark).  This is the only (unblinded, uncontrolled, pilot) study of it I've seen, but the magnitude of the results are certainly compelling enough, and it seemed to be effective for multiple varieties of chemotherapy induced peripheral neuropathy, that one is looking forward to the controlled trials.

The other study I noted about acute chemo complications is this one from Journal of Clinical Oncology about the natural history of paclitaxel-associated acute pain syndrome.  This was something I've seen clinically now and then, but appreciated a chance of reviewing it more in depth.  About 3/5 of patients reported worsening pain with/after paclitaxel dosing, which peaked on day 4.  Development of the acute pain syndrome , which includes diffuse body achiness/myalgias as well as sensory symptoms like tingling & numbness, seemed to predict developing a chronic peripheral neuropathy.  The authors also conclude that the characteristics of the pain syndrome argue that it is a neuropathy (acute neurotoxic symptoms) despite its common manifestation of whole body myalgias which could also suggest a myopathy/myositis.

And finally, gabapentin was studied in a randomized, blinded, placebo controlled trial in the prevention of chemotherapy induced nausea and vomiting (added to ondansetron, dexamethasone, and ranitidine - this was a Brazilian-based trial group).  Patients received gabapentin for 5 days before and 5 days after chemotherapy (or placebo).  Patients receiving gabapentin had lower rates of both acute and delayed nausea & vomiting.  I've never used gabapentin for nausea (either its prevention or treatment):  anyone have any experience with this?

ResearchBlogging.orgJ. P. Durand, G. Deplanque, V. Montheil, J. M. Gornet, F. Scotte, O. Mir, A. Cessot, R. Coriat, E. Raymond, E. Mitry, P. Herait, Y. Yataghene, and F. Goldwasser (2011). Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial Journal of Clinical Oncology : 10.1093/annonc/mdr045

Smith TJ, Coyne PJ, Parker GL, Dodson P, & Ramakrishnan V (2010). Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy. Journal of pain and symptom management, 40 (6), 883-91 PMID: 20813492

Loprinzi, C., Reeves, B., Dakhil, S., Sloan, J., Wolf, S., Burger, K., Kamal, A., Le-Lindqwister, N., Soori, G., Jaslowski, A., Novotny, P., & Lachance, D. (2011). Natural History of Paclitaxel-Associated Acute Pain Syndrome: Prospective Cohort Study NCCTG N08C1 Journal of Clinical Oncology, 29 (11), 1472-1478 DOI: 10.1200/JCO.2010.33.0308

Cruz, F., Iracema Gomes Cubero, D., Taranto, P., Lerner, T., Lera, A., Costa Miranda, M., Cunha Vieira, M., Souza Fêde, Schindler, F., Carrasco, M., Afonseca, S., Pinczowski, H., & Giglio, A. (2011). Gabapentin for the prevention of chemotherapy- induced nausea and vomiting: a pilot study Supportive Care in Cancer DOI: 10.1007/s00520-011-1138-4

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