Cancer Treatment

Thalidomide for neurofibromatosis

Multiple plexiform fibromas are a hallmark of type 1 neurofibromatosis, which condition also presents with other findings and symptoms. It can appear as cafe-au-lait spots and bumps under the skin, or it can lead to complications that include blindness, scoliosis and disfigurement. Fibromas can cause pain and compromise other organs. Few treatments are available, although many novel agents are being studied. 

In regard to thalidomde, one study, termed a phase I study, with 20 patients had been performed. As per clincicaltrials.gov, not studies of this drug are registered for neurofibromatosis. Cleraly, the evidence is very preliminary.

Gupta, A., Cohen, B.H., Ruggieri, P., Packer, R.J., Phillips, P.C.

Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1

Neurology 2003 60: 130-132

V. C. Williams, J. Lucas, M. A. Babcock, D. H. Gutmann, B. Korf, and B. L. Maria

Neurofibromatosis Type 1 Revisited

Pediatrics, January 1, 2009; 123(1): 124 - 133. 

Nitric Oxide for ARDS

Nitric Oxide(NO) has been investigated in a variety of settings, from bodybuilding to premature infants to asthma, as well as for diagnostic use. Among better established uses is for ARDS. Inhaled NO therapy is successful in treating ARDS because of its vasodilator properties. It reduces pulmonary artery pressure and causes vasodilation of the blood vessels that supply the ventilated regions.Inhaled NO therapy is an effective form of treatment in acute conditions, such as ARDS and PPHN; it is particularly effective in increasing oxygen saturation and decreasing pulmonary artery pressure. It also seems to be effective in chronic disorders, such as COPD and pulmonary hypertension.

There is a general consensus that it is helpful in the management of ARDS.In a large-scale, multi-center trial of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), researchers showed that higher levels of nitric oxide (NO) in patient urine were strongly associated with improved survival, more ventilator-free days, and decreased rates of organ failure.  

Committee on Fetus and Newborn, 

Use of Inhaled Nitric Oxide

Pediatrics 2000 106: 344-345

Bloch, K. D., Ichinose, F., Roberts, J. D. Jr., Zapol, W. M. (2007). Inhaled NO as a therapeutic agent. Cardiovasc Res 75: 339-348 

Calfee, C. S., Matthay, M. A. (2007). Nonventilatory Treatments for Acute Lung Injury and ARDS. Chest 131: 913-92

Ichinose, F., Roberts, J. D. Jr, Zapol, W. M. (2004). Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential. Circulation 109: 3106-3111

Dellinger RP, Zimmerman JL, Taylor RW. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. Jan 1998;26(1):15-23. 

Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. Dec 22 2005;353(25):2683-95.

Controlled, prospective, multicenter trials that focus on whether inhaled NO significantly increases the chances of survival in patients with severe ARDS are lacking but there are many other supportive studies and reviews.

Single agent Taxol for relapsed small cell lung cancer

Small cell lung cancer that progresses after first line chemotherapy has a poor prognosis. A variety of treatments are available, among them single agent Taxol.The literature contains studies in various schedules, including weekly and dose-dense, asw well as various combinatino therapies. Single agent Taxol is also listed for sequential use by NCCN.

Yamamoto N, Tsurutani J, Yoshimura N, Asai G, Moriyama A, Nakagawa K, Kudoh S, Takada M, Minato Y, Fukuoka M. II study of weekly paclitaxel for relapsed and refractory small cell lung cancer.Anticancer Res. 2006 Jan-Feb;26(1B):777-81.

Graziano SL, Herndon JE 2nd, Socinski MA, Wang X, Watson D, Vokes E, Green MR; Cancer and Leukemia Group B.Phase II trial of weekly dose-dense paclitaxel in extensive-stage small cell lung cancer: cancer and leukemia group B study 39901.Thorac Oncol. 2008 Feb;3(2):158-62.

nccn.org, small cell lung cancer

BCNU and thalidomde for glioblastoma

Carmustine(BCNU) is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. It by itself would be an appropriate drug. 

Clinical trials of thalidomide as a single agent in malignant gliomas that have recurred following radiation therapy have shown evidence of that this drug is active and can produce responses. Thalidomide is currently being tested in combination with a chemotheraputic agent active in malignant gliomas (carboplatin), and single-agent clinical trials are being initiated in the treatment of recurrent brain metastases and in the treatment of recurrent atypical or malignant meningiomas.

There was one study of the combination.  This study involved 40 patients with high-grade gliomas, all of whom had failed radiation therapy and 50% had failed chemotherapy, including carmustine in 4 instances. The dose of carmustine was 200 mg/m2 given every 6 weeks and the dose of thalidomide was 800 mg/day with escalation to 1200 mg/day. The response rate was 24%. There was one complete response. Disease was stable in 24% of patients. The median time to progression in patients who had a response was 239 days. The main side effects were hematologic and increased sedation. This regimen is under study for a variety of solid tumors. It is also under study for gioloblatoma: Temozolomide vs. Temozolomide and Thalidomide Treatment in Recurrent Glioblastoma, NCT0052148.

Imetelstat ( GRN163L)

Imetelstat or GRN163L is a drug that blocks telomerase, and is already in clinical trials as a potential treatment for breast and lung cancer.Imetelstat is a short chain oligonucleotide that binds with high affinity and specificity to the catalytic site of telomerase, resulting in competitive inhibition of enzyme activity or cell death. Imetelstat demonstrated anti-tumor effects in a wide range of preclinical models of hematological and solid tumors. There are six ongoing phase I studies patients with solid tumors, chronic lymphoproliferative disease, multiple myeloma, lung and breast cancers, as a single agent or in combination with standard treatments.

Calin O. Marian, Steve K. Cho, Brian M. Mcellin, Elizabeth A. Maher, Kimmo J. Hatanpaa, Christopher J. Madden, Bruce E. Mickey, Woodring E. Wright, Jerry W. Shay, and Robert M. BachooThe Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth
Clin Cancer Res January 1, 2010 16:154-163; Published OnlineFirst January 4, 2010; doi:10.1158/1078-0432.CCR-09-2850

Small Molecules in Oncology Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy
Volume 184
Springer Berlin Heidelberg
Pages 221-234

Adjuvant and neoadjuvant chemotherapy for bladder cancer

The role of perioperative  chemotherapy for bladder cancer is not clear. The remains doubt about effectiveness of such chemotherapy and whether is should be given preoperatively or postoperatively. The World Health Organization and the Societe Internationale d'Urologie presented consensus recommendations in the management of patients with locally advanced and metastatic TCC. With regard to neoadjuvant chemotherapy, the panel concluded that overall survival for the whole group was not affected. Certain subsets did exhibit improved survival. Notably, patients treated with cisplatin-based combination chemotherapy had a 5% improvement in survival compared with untreated patients—from 45% to 50%. The panel further concluded that patients with clinical stage T2 tumors had at best a modest benefit, whereas patients with more advanced-stage disease potentially had a more substantial benefit.

A major benefit to adjuvant chemotherapy over neoadjuvant chemotherapy is the ability to stratify patients based on pathologic stage, or based on tumor biomarkers. The panel did not think that stage T2 disease benefits from adjuvant chemo.

NCCN recommends consideration of both neopadjuvant and adjuvant chemo on p. 10 of its bladder cancer guidelines. In its decriptive section it says that it should be considered based on risk factors and nodal status. It recommends gemcitabine and cisplatin but specifically not carboplatin; even for patients with reduced renal function it recommends split dose cisplatin instead of carboplatin.

Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.Eur Urol. 2005 Aug;48(2):189-199; discussion 199-201.

Sternberg CN, Donat SM, Bellmunt J, Millikan RE, Stadler W, De Mulder P, Sherif A, von der Maase H, Tsukamoto T, Soloway MS Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer.Urology. 2007 Jan;69(1 Suppl):62-79.

Sternberg CN, Donat SM, Bellmunt J, et al: Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer. Urology 69:62-79,2007.

Tarceva for biliary cancer

Erlotinib has shown activity individually, as single drugs, or in combination with chemotherapy in upper gastro-intestinal cancers, including esophageal and gastro-esophageal adenocarcinomas, gastric cancer and pancreatic cancer.  In a recent study, forty-two patients with biliary cancer were enrolled.  Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response These results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. The authors conclude that additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

SPhilip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman Phase II study of erlotinib in patients with advanced biliary cancer.J Clin Oncol. 2006 Jul 1;24(19):3069-74.

Philip, Philip A., Mahoney, Michelle R., Allmer, Cristine, Thomas, James, Pitot, Henry C., Kim, George, Donehower, Ross C., Fitch, Tom, Picus, Joel, Erlichman, Charles
Phase II Study of Erlotinib in Patients With Advanced Biliary Cancer
J Clin Oncol 2006 24: 3069-3074

Dragovich T, Huberman M, Von Hoff DD, Rowinsky EK, Nadler P, Wood D, Hamilton M, Hage G, Wolf J, Patnaik A. Erlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trial. Cancer Chemother Pharmacol. 2007 Jul;60(2):295-303. Epub 2006 Dec 6.

S A Khan et al, Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document Gut 2002;51:

C. D. Anderson, C. Wright Pinson, J. Berlin, and R. S. Chari
Diagnosis and Treatment of Cholangiocarcinoma
Oncologist, February 1, 2004; 9(1): 43 - 57.

S A Khan, A Miras, M Pelling, and S D Taylor-Robinson
Cholangiocarcinoma and its management
Gut, December 1, 2007; 56(12): 1755 - 1756.

F. Leone, Y. Pignochino, G. Cavalloni, and M. Aglietta
Targeting of Epidermal Growth Factor Receptor in Patients Affected by Biliary Tract Carcinoma
J. Clin. Oncol., March 20, 2007; 25(9): 1145 - 1145.

 

Topotecan for endometrial cancer

There are several trials of topotecan for recurrent metstatic uterine cancer with encouraging results.  For example, in a phase II trial, 29 patients were treated with topotecan 1.5 mg/m2 day on days 1-5 of a 21-day cycle. Of these patients, 61%, 39%, and 25% experienced grade 4 neutropenia, leukopenia, and thrombocytopenia, respectively. These preliminary results suggest that single-agent topotecan might have limited activity in patients with advanced or recurrent disease.

In an ongoing study, a regimen of weekly bolus i.v. topotecan is also being investigated in advanced recurrent metastatic endometrial carcinoma. In a preliminary report, 13 patients have tolerated weekly bolus i.v. topotecan at dose levels of 2.5-4.5 mg/m2/week. Fatigue was the most common nonhematologic toxicity, with 31% and 8% of patients experiencing grade 3 and 4 fatigue, respectively. Of the 13 patients, three have achieved a PR and six patients have died because of progressive disease. The weekly dosing schedule of topotecan appears to offer improved tolerability in this patient population compared with the 5-day topotecan dosing regimen. The authors of this article called for more studies.
Finkler NJ, Holloway RW. A phase I/II trial of weekly topotecan in the treatment of advanced recurrent metastatic endometrial carcinoma. Proc Am Soc Clin Oncol 2002;21:171b.

Tiffany A. Traina, Paul Sabbatini, Carol Aghajanian and Jakob Dupont,Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature  Gynecologic Oncology
Volume 95, Issue 1, October 2004, Pages 235-241

Wadler, Scott, Levy, Donna E., Lincoln, Sarah T., Soori, Gamini S., Schink, Julian C., Goldberg, Gary
Topotecan Is an Active Agent in the First-Line Treatment of Metastatic or Recurrent Endometrial Carcinoma: Eastern Cooperative Oncology Group Study E3E93
J Clin Oncol 2003 21: 2110-2114

Fibromyalgia and cancer

There is no reported causal association between cancer and fibromyalgia  to my knowledge and that I could fing in a literature search. However there is an association between chronic fatigue syndrome and cancer (an association does not establish a causal connection). A recent report analyzed 1361 patient records. While they found no association between fibromyalgia and cancer in patients whose fibromyalgia diagnosis was confirmed, they found that women referred to the hospital for muscle pain and/or tenderness who did not meet the fibromyalgia diagnostic criteria did have an increased overall cancer rate, with an increase specifically in breast, lympatic and hematological cancers.

Dreyer L, Mellemkjaer L, Kendall S, Jensen B, Danneskiold-Samsøe B, Bliddal H.Increased cancer risk in patients referred to hospital with suspected fibromyalgia.J Rheumatol. 2007 Jan;34(1):201-6.

McBeth J, Symmons DP, Silman AJ, Allison T, Webb R, Brammah T, Macfarlane GJ.
Musculoskeletal pain is associated with a long-term increased risk of cancer and cardiovascular-related mortality.Rheumatology (Oxford). 2009 Jan;48(1):74-7.

Lidoderm for cancer pain syndromes

The development of a lidocaine 5% patch (Lidoderm®; Endo Laboratories; Chadds Ford, PA) has facilitated the topical application of local anesthetics.  This formulation is approved in the U.S. for the treatment of postherpetic neuralgia; however, there are a variety of case reports and small studies of its use in cancer syndromes.  Clinical experience supports its use for other neuropathic pain conditions. There are a number of phase II studies that include patients with neuropathic pain related to either cancer or cancer therapy

Considering that the Lidoderm patch is fairly new and the kind an amount of evidence available and that there appear to be two phase II studies, I consider Lidoderm to be supported for local cancer pain syndromes. In addition, NCCN in its Adult Pain recommendation lists Lidoderm as an adjuvant treatment.

I.Wilhelm, N.Griessinger, W.Koppert, R.Sittl, R.LikarHigh Doses of Topically Applied Lidocaine in a Cancer Patient Journal of Pain and Symptom Management, Volume 30, Issue 3, Pages 203-204

Anjum SKJ, Jyoti B, Charu M. (2002) Intravenous lidocaine infusion for neuropathic pain in cancer patients—a preliminary study. Indian J naesth 46:360–364.

Devers A and Galer BS. (2000) Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain 16:205–8.

Meier T, Wasner G, Faust M, et al.: Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106 (1-2): 151-8, 2003.