Cancer Treatment

Stem cell transplantation for Fanconi's Anemia

Fanconi anemia, or FA, is a rare, inherited blood disorder that leads to bone marrow failure. A variety of supportive treatments is available but stem cell transplantation is the only curative option (gene transfer therapies are still experimental).  The two year survival rate is around 70%. Alternative conditioning regimens using fludarabine and avoiding irradiation have shown promising results so far. For those patients without matched sibling stem cell source, the prognosis for unrelated donors is around 20–40% survival at two years and there is a higher risk of graft rejection in somatic mosaics.
Stem cell transplantation is generally accepted as medically appropriate.

M D Tischkowitz and S V Hodgson
Fanconi anaemia
J. Med. Genet., January 1, 2003; 40(1): 1 - 10.

M Ayas et al, Stem cell transplantation for patients with Fanconi anemia with low-dose cyclophosphamide and antithymocyte globulins without the use of radiation therapy
Bone Marrow Transplantation (2005) 35, 463–466.

Rackoff WD. Treatment of bone marrow failure. In: Owen J, ed. Fanconi anemia - standards for clinical care. Fanconi Anemia Research Fund Inc, 1902 Jefferson Street, Suite 2, Eugene, Oregon 97405, 1999:9–20.55.

Guardiola P, Socie G, Pasquini R, Dokal I, Ortega JJ, van Weel-Sipman M, Marsh J, Locatelli F, Souillet G, Cahn JY, Ljungman P, Miniero R, Shaw J, Vermylen C, Archimbaud E, Bekassy AN, Krivan G, Di Bartolomeo P, Bacigalupo AL, Gluckman E. Allogeneic stem cell transplantation for Fanconi anaemia. Severe Aplastic Anaemia Working Party of the EBMT and EUFAR. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant1998;21(suppl 2):S24–7.59.

McCloy M, Almeida A, Daly P, Vulliamy T, Roberts IA, Dokal I. Fludarabine-based stem cell transplantation protocol for Fanconi’s anaemia in myelodysplastic transformation. Br J Haematol2001;112:427–9

MacMillan ML, Auerbach AD, Davies SM, Defor TE, Gillio A, Giller R, Harris R, Cairo M, Dusenbery K, Hirsch B, Ramsay NK, Weisdorf DJ, Wagner JE. Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose escalation trial. Br J Haematol2000;109:121–9

Xeloda alone for gastric cancer

5FU has been used in gastric cancer for decades. Xeloda has been found able to subtitute for 5FU in other cancer types. It is now usually used with cisplatin, oxaliplatin or with epirubicin based regimen. 

Going back to older studies of Xeloda for gastric cancer, we find that it is effective as a single agent. Phase I studies of capecitabine in various dose and administration regimens were used to test its safety, tolerability and pharmacokinetics. The recommended Phase II dose of capecitabine was set at 2510 mg/m2/day. Other Phase I trials used continuous daily dosing or a 3-weekly intermittent regimen with leucovorin. 

The efficacy and safety of 3-week intermittent capecitabine monotherapy was tested in a Korean study that included 44 chemonaive patients. The ORR was 34%, with a median TTP of 3.2 months. While this 3-week inter-mittent schedule has been adopted as the global standard, a 4-week on-and-off schedule has been evaluated in Japan. In these studies, the ORRs were 19.4-26%, the median OS was 8.2-10.0 months and the toxicity profiles were highly favorable. A randomized Phase II study of the 3-week capecitabine regimen was also evaluated in elderly patients; the ORR was 27% with a median TTP of 4.7 months, and the toxicity profile was favorable.

I am not aware of other definitive studies of single agent Xeloda. Uptodate provides a level 2B recommendation for Xeloda in elderly patients with metastatic gastric cancer. However, NCCN on p. 14 does not cite Xeloda.

Koizumi W, Saigenji K, Ujiie S, Terashima M, Sakata Y, Taguchi T: A pilot Phase II study of capecitabine in advanced or recurrent gastric cancer. Oncology 64(3), 232-236 (2003).

Sakamoto J, Chin K, Kondo K et al.: Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer. Anticancer Drugs 17(2), 231-236 (2006).

Kang Y, Lee J, Min Y et al.: A randomized multi-center Phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. J. Clin. Oncol. (Meeting Abstracts) 25(Suppl. 18), 4546 (2007).

BRCA testing in males

BRCA is best studied inthe setting of familial breast-ovarian cancer susceptibility. Reported risks for breast, prostate, pancreatic, gastric and hematologic cancers are higher in male BRCA mutation carriers vs non-carriers. Especially in male BRCA2 mutation carriers under age 65 prostate and pancreatic cancer risks are increased. The risk increase for primary cancers of organs like the liver, bone and brain is difficult to assess as these organs are common sites for metastases. Reports on colorectal cancer and melanoma risks are inconclusive.

Reported risks for breast, prostate, pancreatic, gastric and hematologic cancers are higher in male BRCA mutation carriers vs non-carriers. Especially in male BRCA2 mutation carriers under age 65 prostate and pancreatic cancer risks are increased. The risk increase for primary cancers of organs like the liver, bone and brain is difficult to assess as these organs are common sites for metastases. Reports on colorectal cancer and melanoma risks are inconclusive.

Currently there are no guidelines on which males are appropriate to screen with BRCA tests. Carcinoma of the male breast has many similarities to breast cancer in women, but the diseases have different genetic and pathologic features. Both BRCA1 and BRCA2 mutations can cause breast cancer in women, but only BRCA2 mutations confer a significant risk to men. Unfortunately, there are no established guideline on how to follow or whether and when to intervene in a male with BRCA. Without knowing what to do with the information on BRCA positivity, there is no basis for recommend BRCA testing for males, unless it can help determine a status of a female relative. There is no published clinical data or evidence-based guidelines on prophylactic mastectomy for men with a BRCA2 mutation or a family history of breast cancer.

H. Mohamad, J. Apffelstaedt Counseling for male BRCA mutation carriers – a review
The Breast, Volume 17, Issue 5, Pages 441-450, 2008

Liede, Alexander, Karlan, Beth Y., Narod, Steven A.
Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature J Clin Oncol 2004 22: 735-742

Wolpert N, Warner E, Seminsky MF, et al. Prevalence of BRCA1 and BRCA2 mutations in male breast cancer patients in Canada. Clin Breast Cancer. 2000;1(1):57-65.

Giordano SH, Buzdar AU, Hortobagyi G. Breast cancer in men. Ann Intern Med. 2002;137(8):678-687.

Stem cell transplantation for CIDP

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. The pathologic hallmark of the disease is loss of the myelin sheath (the fatty covering that protects nerve fibers) of the peripheral nerves.
First line treatment for CIDP includes corticosteroids (e.g. prednisone), plasmapheresis (plasma exchange) and intravenous immunoglobulin (IVIg) which may be prescribed alone or in combination with an immunosuppressant drug. IVIG and plasmapheresis have proven benefit in randomized, double-blind, placebo-controlled trials. A nubmer of case reprots, series and some phase II studies establish that amny patients with this condition respond with amelioration of symptoms or with a remission after a high dose therapy regimen with autologous stem cell transplantation.

Toothaker TB, Brannagan TH (2007). "Chronic inflammatory demyelinating polyneuropathies: current treatment strategies". Curr Neurol Neurosci Rep 7 (1): 63–70

S. Renaud, P. Fuhr, J. Halter, A. Gratwohl, A. Steck(2007) Autologous stem cell transplantation in therapy resistant chronic inflammatory demyelinating disease (CIDP) A phase II study. Call for patients
Clinical Neurophysiology, Volume 118, Issue 2, Pages e4-e5

Oyama, Y., Sufit, R., Loh, Y., Statkute, L., Yaung, K., Quigley, K., Gonda, E., Spahovic, D., Bronesky, D., Burt, R. K.
NONMYELOABLATIVE AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR REFRACTORY CIDP
Neurology 2007 69: 1802-1803

Brannagan, T.H., III, Pradhan, A., Heiman-Patterson, T., Winkelman, A.C., Styler, M.J., Topolsky, D.L., Crilley, P.A., Schwartzman, R.J., Brodsky, I., Gladstone, D.E.
High-dose cyclophosphamide without stem-cell rescue for refractory CIDP
Neurology 2002 58: 1856-1858

H. W Axelson, G. Oberg, and H. Askmark
Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP
BMJ Case Reports, February 2, 2009; 2009

Lehmann, Helmar C., Meyer zu Horste, Gerd, Kieseier, Bernd C., Hartung, Hans-Peter
Review: Pathogenesis and treatment of immune-mediated neuropathies
Therapeutic Advances in Neurological Disorders 2009 2: 261-281

Chest Pain: Admission versus Discharge

Chest pain accounts for approximately 6 million annual visits to emergency departments (ED) in the United States (US), making chest pain the second most common complaint.  ED evaluation focuses on distinguishing and admission of life-threatening causes of chest pain; others can be worked up on the outpatient basis.
 
The published guidelines of the American College of Emergency Physicians, the American Heart Association, and the American College of Cardiology suggest that, for all adult patients complaining of nontraumatic chest pain, a cardiac etiology for their presentation should be considered. History, physical examination, electrocardiogram, chest radiography, and to a lesser extent laboratory results can help differentiate ACS from other emergent diagnoses, e.g., aortic dissection, esophageal rupture, pulmonary embolus, pneumothorax, pneumonia, and pericarditis. No single feature of a patient's history, physical examination, or diagnostic test results can diagnose ACS to the exclusion of other causes of chest pain. Based on a general impression, patient history, risk factors, ECG and levels of myocardial infarction markers it is decided whether or not to admit the patient for clinical observation.

A recent guideline says this: "Management of patients with definite ACS

Admit and immediately treat patients with new ST segment elevation or new LBBB and a history compatible with ACS, with the intent of re-establishing perfusion.1
Admit and immediately treat patients with a history and ECG (without ST segment elevation) compatible with ischemia, plus either elevated cardiac biomarkers (>99th percentile) or hemodynamic compromise (hypotension or electrical instability), for acute myocardial ischemia.
B. Management of patients with possible ACS

It is recommended that patients with a compatible history and a non-diagnostic initial ECG and cardiac biomarkers, be observed in the ED and be re-assessed at six or more hours after the initial testing with an ECG and cardiac biomarkers. Patients with a compatible history without elevated cardiac biomarkers at 6 or more hours, and an ECG not diagnostic of ischemia are considered to be at a low or intermediate short-term risk for non fatal MI or death.
For low-risk patients without an obvious alternative explanation for the chest pain an out-patient stress test within 72 hours and out-patient physician follow-up is recommended.1
When possible, discuss intermediate-risk patients with an internist or cardiologist. A stress test prior to discharge is recommended.
For both low and intermediate risk groups:
If the patient's resting ECG is abnormal, a routine stress test will be non-diagnostic. In this scenario, stress myocardial perfusion imaging or stress echocardiography is required to detect ischemia. Therefore, referral to a facility capable of stress myocardial perfusion imaging or stress echocardiography is recommended for such patients. "

Lindsell, CJ, Anantharaman, V, Diercks, D, et al. The Internet Tracking Registry of Acute Coronary Syndromes (i*trACS): a multicenter registry of patients with suspicion of acute coronary syndromes reported using the standardized reporting guidelines for emergency department chest pain studies. Ann Emerg Med 2006; 48:666.

Ringstrom, E, Freedman, J. Approach to undifferentiated chest pain in the emergency department: a review of recent medical literature and published practice guidelines. Mt Sinai J Med 2006; 73:499.

http://www.bcguidelines.ca/gpac/guideline_chestpain.html

Afinitor to reverse Herceptin or lapatinib resistance

Afinitor (Everolimus) has been approved by the US Food and Drug Administration (FDA) as the first oral, daily therapy (5 mg and 10 mg tablets) to treat advanced kidney cancer after failure of treatment with sunitinib or sorafenib. Trastuzumab or lapatinib resistance may be related to loss/deregulation of PTEN or activating mutations in the PI3K/AKT pathway. Everolimus (E), an oral inhibitor of mTOR, enhances efficacy and reverses resistance to H, and demonstrates synergistic activity with paclitaxel (T).

Two phase I studies that tested this hypothesis have been published, one with lapatinib and one with Herceptin. We await farther developments in this area.

C. J. Hoban, A. Hoering, T. W. Synold, V. Chung, D. R. Gandara, A. F. Schott, L. Kingsbury, D. Lew, P. M. LoRusso, S. M. Gadgeel; Southwest Oncology Group/University of Michigan, Ann Arbor, MI; Cancer Research and Biostatistics, Seattle, WA; City of Hope Comprehensive Cancer Center, Duarte, CA; UC Davis Cancer Center, Sacramento , CA; University of Michigan, Ann Arbor, MI; Wayne State University/Karmanos Cancer Institute, Detroit, MI  Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528. J Clin Oncol 27:15s, 2009 (suppl; abstr 3553)

M. Campone, R. O'Regan, S. Hurvitz, M. Naughton, C. Manlius, L. Vittori, P. Mukhopadhyay, C. Massacesi, T. Sahmoud, F. André; CLCC René Gauducheau, Nantes, France; Emory Winship Cancer Institute, Atlanta, GA; UCLA Medical Center, Los Angeles, CA; Washington University, St Louis, MO; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals, Florham Park, NJ; Institut Gustave Roussy, Villejuif, France Everolimus plus weekly paclitaxel and trastuzumab in patients (pts) with HER-2+ metastatic breast cancer (MBC) with prior resistance to trastuzumab: A phase I clinical trial  2009 Breast Cancer Symposium, #218 

Nexavar with irinotecan for solid tumors.

Nexavar is currently FDA approved for renal cell carcinoma and hepatocellular carcinoma . Sorafenib (Nexavar) is designed to interfere with growth of new blood vessels and the growth of new cancer cells.Inhibition of KIT signaling provides a direct anti-tumor effect in most GIST tumors and inhibition of VEGF receptors and PDGFR-β provide antiangiogenesis effects (similar to Sutent). Since RAF is downstream of KIT, inhibition of RAF might also contribute an anti-tumor effect. While inhibition of PDGRF-β has been reported, inhibition of PDGFRα, an alternative target in about 5% of GISTs has NOT BEEN reported.

The providers aim to flollow the model of a single-centre, open-label, phase I dose-escalation study that was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafenib, a multi-kinase inhibitor, combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1–3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a Ki value of 2.7 μmol/l. The investigators concluded: "Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m2 or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended."

http://www.ejcancer.info/article/S0959-8049(06)00803-3/abstract
 

Choline PET for prostate cancer

Positron emission tomography (PET) is an imaging procedure that is unique by virtue of its ability to image biochemical reactions and physiological functions. This is accomplished by measuring concentrations of radioactive chemicals that are partially metabolized in the body region of interest.

PET with fluorodeoxyglucose (FDG) has been quite successful in the imaging evaluation of a large number of tumor types. Prostate cancer, however, has variable accumulation of FDG, which is probably a reflection of the heterogeneous nature of the disease. Early studies of FDG-PET in prostate cancer have shown that FDG accumulation in the primary prostate cancer may be low and overlap with the uptake in benign prostatic hyperplasia, in normal gland, and in postoperative scar or local recurrence. Therefore other radiopharamceutical have been tested. Among them is choline. The utility of 11C-choline and multimodality fusion imaging with integrated PET and contrast-enhanced CT (PET/CT) has been extensively investigated.

A 2009 study of 190 patients found that whole body PET/CT imaging with choline is significantly better than conventional imaging technologies in detecting prostate cancer in patients with biochemical relapse after radical prostatectomy. Researchers also found a strong association between PET/CT detection of recurrent cancer, PSA levels, and PSA kinetics. The authors suggest that based on the results, only patients with a high probability of having a positive scan based on PSA levels and kinetics should undergo choline PET/CT scans. A recent guideline (Jaffri et al) says that the technique requires more study. A 2010 study says that: "Further studies will be needed to decipher the full prognostic utility of the dynamic pattern of osseous metastatic disease from prostate cancer." Greco in 2008 wrote: "role of PET imaging in prostate cancer is gradually evolving but still remains within the experimental realm.  Well-conducted studies comparing the merits of different tracers are needed."

Morris NJ, Akhurst T, Osman I, et al. Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology. 2002;59:913-918. A

Picchio M, Messa C, Landoni C, et al. Value of [11C]choline-positron emission tomography for re-staging prostate cancer: a comparison with [18F]fluorodeoxyglucose-positron emission tomography. J Urol. 2003;169:1337-1340.

Larson SM, Morris M, Gunther I, et al. Tumor localization of 16beta-18F-fluoro-5alpha-dihdrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med. 2004;45:366-373.

P. Castellucci, C. Fuccio, C. Nanni, I. Santi, A. Rizzello, F. Lodi, A. Franceshelli, G. Martorana, F. Manferrari, and S. Fanti, S. Sharp, B. Shulkin, M. Gelfand, S. Salisbury, W. Furman, Nuclear Medicine Unit, Hematology-Oncology and Laboratory Medicine Department, and Urology Unit, Specialist Surgery and Anaesthesiology Department, Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpghi, University of Bologna, Italy; “Influence of Trigger PSA and PSA Kenetics on 11C-Choline PET/CT Detection Rate in Patients with Biochemical Relapse After Radical Prostatectomy,” The Journal of Nuclear Medicine, September 2009.

Beheshti M, Vali R, Waldenberger P, et al The Use of F-18 Choline PET in the Assessment of Bone Metastases in Prostate Cancer: Correlation With Morphological Changes on CT
Mol Imaging Biol. 2009;11:446-454

Greco C, Cascini GL, Tamburrini O. Is there a role for positron emission tomography imaging in the early evaluation of prostate cancer relapse? Prostate Cancer Prostatic Dis. 2008;11(2):121-128.

Vinorelbine for breast cancer

Navelbine(vinorelbine) is an active drug for breast cancer and it can be used as single agent, or in combinations. Vinorelbine, a novel vinca alkaloid derivative developed in France, has been widely used for the treatment of breast cancer and non-small cell lung cancer since the 1990s and there are many reports of phase II studies in the 1990s. In Japan alone, there were six trials during this time period. Response rates are around 20%. NCCN lists vinorelbine on p.46 of its Breast cancer Guideline as a single agent.

Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 19:2722-2730, 2001.

Toi M, Saeki T, Aogi K, Sano M, Hatake K, Asaga T, Tokuda Y, Mitsuyama S, Kimura M, Kobayashi T, Tamura M, Tabei T, Shin E, Nishimura R, Ohno S, Takashima S.
Late phase II clinical study of vinorelbine monotherapy in advanced or recurrent breast cancer previously treated with anthracyclines and taxanes.Jpn J Clin Oncol. 2005 Jun;35(6):310-5.

Autologous hematopoietic tissue graft

Autologous hematopoietic tissue graft is a collection of stem cells, paltelets and tissue factors that are placed into an operative site to promote healing and prevent infections. Much of the aplication has been in plastic and cardiac surgery as well as in wound healing. There are no guideliens that I could locate, cosnesnsus statemetns or large prospective studies and there are studies that show that this treatment is not effective as well as many reports of effectiveness.

Khalafi, Reza S., Bradford, Darien W., Wilson, Michael G.
Topical application of autologous blood products during surgical closure following a coronary artery bypass graft
Eur J Cardiothorac Surg 2008 34: 360-364

S Gunaydin, K McCusker, T Sari, M. Onur, A Gurpinar, H Sevim, P Atasoy, C Yorgancioglu, and Y Zorlutuna
Clinical impact and biomaterial evaluation of autologous platelet gel in cardiac surgery
Perfusion, May 1, 2008; 23(3): 179 - 186.

Gunaydin S, McCusker K, Sari T, Onur M, Gurpinar A, Sevim H, Atasoy P, Yorgancioglu C, Zorlutuna  Clinical impact and biomaterial evaluation of autologous platelet gel in cardiac surgery.
Perfusion. 2008 May;23(3):179-86.

Bhanot S, Alex JC.Current applications of platelet gels in facial plastic surgery.
Facial Plast Surg. 2002 Feb;18(1):27-33.