Cancer Treatment

DVD (Doxil) for myeloma

The VAD regimen has long been used for myeloma. It includes infusional Adriamycin but a newer drug, Doxil, may replace it. A multi-center trial is ongoing involving over 200 patients, comparing Doxil, Vincristine, and decadron (DVd) versus Vincristine, Adriamycin, and Dexamethasone (VAD). DVD is faster, does not require a prolonged infusion and is less cardiotoxic; it is more cost effective. It is supported by phase II trials and has been widely adopted in the place fo VAD.It is recommended by several guidelines and The Consensus

Statement.http://myeloma.org/pdfs/MyelomaManagementGuidelines.pdf

http://www.bcshguidelines.com/pdf/UKNordic_070705.pdf

http://www.aspb.ro/documente/protocoaleclinice/Oncologie/myeloma.pdf, p.17

Carboplatin with etoposide for small cell lung cancer

Small cell lung cancer (SCLC) is different distinct from other lung cancers, called non–small-cell lung cancers (NSCLCs), because SCLC exhibits aggressive behavior, with rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes.
Patients with disease confined to one hemithorax, with or without mediastinal, contralateral hilar, or ipsilateral supraclavicular or scalene lymph nodes are considered to have limited-stage disease.Management of limited-stage SCLC involves combination chemotherapy, usually with a platinum-containing regimen, and concurrent or subsequent chest radiation therapy. If the patient achieves a complete remission, he or she may be offered prophylactic cranial irradiation. The combination of cisplatin and etoposide (PE) currently is the most widely used regimen in both limited- and extensive-stage SCLC. Phase III studies suggest that irinotecan is as effective as etoposide with cisplatin. Carboplatin is often substituted for cisplatin and this is supprted by NCCN.

Tai P, Yu E, Battista J, Van Dyk J: Radiation treatment of lung cancer-patterns of practice in Canada. Radiother Oncol 2004 May; 71(2): 167-74
 
Takada M, Fukuoka M, Kawahara M, et al: Phase III randomized study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Onclology Group Study 9104. J Clin Oncol 2002; 20: 3054-60

http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf, p.12

Tandem transplants for testicular cancer

High dose chemotherapy with autologous stem cell rescue is an accepted and standard of care approach for relapsed or nonresponig testicualr cancer. It is recommended by several guidelines, including NCCN. however, they do not address single versus tandem transplants. A tandem transplant is on that has a pre-planned second transplant with another infusion of stem cells after competion and recovery from the first transpalnt procedure.There are no prospective studies but retrospective reviews from Indiana University, which has the largest referral base of germ cell tumors in the world suggest that tandem transplantation for testicular cancer is the treatment of choice for this malignancy. A review form the CLeveland clnic concludes: " Tandem autotransplants for testicular cancer are associated with less treatment-related mortality than a planned single transplant, with no differences in disease-related outcomes or overall survival at 3 years. Patient selection bias for either transplant approach, however, may affect the results of this observational study; a randomized trial is needed to determine which approach, if either, is better."

Einhorn L, Williams S, Chamness a, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. New England Journal of Medicine. 2007;357:340-348.

NCCN.ORG, Testicular, p.16

http://www.uroweb.org/fileadmin/tx_eauguidelines/22891_Testicular_Cancer.pdf

Lazarus HM, Stiff PJ, Carreras J, Logan BR, Akard L, Bolwell BJ, Childs RW, Gale RP, Klein JP, Lill MC, Pérez WS, Stadtmauer EA, Rizzo JD.Utility of single versus tandem autotransplants for advanced testes/germ cell cancer: a center for international blood and marrow transplant research (CIBMTR) analysis.Biol Blood Marrow Transplant. 2007 Jul;13(7):778-89.

Tamoxifen for breast pain

Tamoxifen can be used off-label to treat breast pain (mastalgia), because it reduces estrogen levels that cause breast swelling.In one study, tamoxifen relieved pain in more than two-thirds of women who had a history of severe breast pain. Experts disagree about the use of tamoxifen for breast pain, because it has important side effects and risks.

One double blind randomized comparatiove study(RCT)  compared tamoxifen 20 mg daily versus placebo. It found that significantly more women experienced pain relief (measured by visual analogue scale over 3 months) with tamoxifen compared with placebo (> 50% reduction in mean pain score: 22/31 [71%] with tamoxifen v 11/29 [38%] with placebo; P < 0.025). The second RCT (93 women) compared tamoxifen, danazol, and placebo. It found that significantly more women taking tamoxifen achieved a good outcome (> 50% reduction in mean pain score) at the end of treatment, 6 months later, and 12 months later, compared with placebo (> 50% reduction in pain score after 6 months of treatment: 23/32 [72%] with tamoxifen v 11/29 [38%] with placebo; P = 0.035). The third RCT (88 women, aged 22–44 years) found that 8 months of tamoxifen increased the proportion of women who achieved complete recovery (outcome not clearly defined) compared with placebo (40/44 [90%] with tamoxifen v 0/44 [0%] with placebo; P value not reported).

In conclusion, Tamoxifen is not licensed for mastalgia in the UK or USA. There is a consensus to limit its use to no more than 6 months at a time under expert supervision, and with appropriate non-hormonal contraception, because of the high incidence of adverse effects.

Fentiman IS (2004). Management of breast pain. In JR Harris et al., eds., Diseases of the Breast, 3rd ed., pp. 57–62. Philadelphia: Lippincott Williams and Wilkins.

Kontostolis E, Stefanidis K, Navrozoglou I, et al. Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol 1997;11:393–397. 

Fentiman IS, Caleffi M, Brame K, et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1:287–288. 

Grio R, Cellura A, Geranio R, et al. Clinical efficacy of tamoxifen in the treatment of premenstrual mastodynia. Minerva Ginecol 1998;50:101–103.   GEMB Group. Tamoxifen therapy for cyclical mastalgia: dose randomised trial. Breast 1997;5:212–213.

Thalidomide for Myelodysplasia (MDS)

Thalidomide exerts in vitro heterogeneous biological effects on hematopoiesis which have supported its possible use in treating myelodysplastic syndromes (MDS). Some recent clinical trials have confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-risk MDS (11–56%, on intention-to-treat analysis). Of interest, erythroid responses may be achieved also in transfusion-dependent subjects with high serum levels of endogenous erythropoietin, a subset of MDS patients with little chance of responding to recombinant erythropoietin, alone or in combination with G-CSF.

Although the FDA currenlty apporvies thalidomide only for the 5q- deletion, there are many trials confirming effectiveness , albeit lesser effectiveness, in patients with MDS who do not have this deletion.NCCN mentions thlidomide and notes that it has greater effectiveness in the cases with 5q- deletion.Thus, it is recognized as a reasonably effective treatment for MDS, even without the 5q- diletion.

P . Musto Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives .  Leukemia Research , Volume 28 , Issue 4 , Pages 325 - 332, 2004

http://www.moffittcancercenter.com/CCJRoot/v11s6/pdf/07.pdf

nccn.org, myelodysplastic

Capeox (Xelox) for metastatic colon cancer: NCCN Guideline

In 2007, the NCCN  update has added the regimen CapeOx, a combination of capecitabine (Xeloda, Roche) and oxaliplatin (Eloxatin, Sanofi-Aventis), as an alternative to FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) for the treatment of advanced or metastatic colon cancer. The majority of safety and efficacy data for CapeOx have come from Europe, where administration of capecitabine at a starting dose of 1000 mg/m2 twice daily for 14 days, to be repeated every 21 days, is standard. There is some evidence that North American patients may experience greater toxicity with capecitabine, and other fluoropyrimidines, than the Europeans and may require a lower dose. However, because the efficacy of the drug at lower doses has not been evaluated in large, randomized trials, NCCN still recommends a starting dose of 1000 mg/m2 with close monitoring in the first cycle for toxicity and possible dosage adjustments.

Anna Pessino, Alberto Sobrero Optimal treatment of metastatic colorectal cancer Expert Review of Anticancer Therapy 2006 6:5, 801-812

Dan S. Zuckerman, Jeffrey W. Clark Systemic therapy for metastatic colorectal cancer Cancer
112(9), 1879-1891

NCCN.ORG, Colorectal/Colon

Erytropoietin therapy for myelofibrosis

 Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is limited.There are a number of reprots of small numbers of patiens demonstrating responsiveness but also a recent report  which presents a picture of non-responsiveness of transfusion dependent myelofibrosis to erythropoietin therapy.
Initial studies failed to show significant improvements in hemoglobin levels upon administration of recombinant erythropoietin (rEpo). However, more recent investigations have demonstrated significant responses and decreased transfusion dependence in anemic patients with CIMF. The rEpo doses employed in those studies were in the range of 300–1,500 U/kg weekly. This finding underscores the current uncertainty about the optimal dose and schedule of rEpo in this disease. It is important to note that many patients with CIMF have normal serum erythropoietin levels, suggesting a potential lack of efficacy of rEpo in this setting [54]. Rodriguez et al. [ showed that a serum erythropoietin level <123 mU/ml was highly predictive of response to rEpo. This was recently corroborated by Cervantes et al. [53] in a study in which rEpo was given at an initial dose of 10,000 U three times per week to 20 patients with CIMF. Nine patients (45%) responded, including four who achieved normal hemoglobin levels. A serum erythropoietin level <125 mU/ml was associated with a favorable response to rEpo in the multivariate analysis. The combination of rEpo and thalidomide may represent a valid approach for patients with advanced CIMF
Future investigation will focus on stratification. Favorable cytogenetic findings was associated with response to erythropoietin therapy in one study.

In summary, there is sufficient evidence that Procrit raises Hblevels in many myelofibrosis patients. How to select patients is not entirely clear yet and at this time, a trial for effectivenesss is standard practice.It is not known whetehr it is a better long - term approach than periodic transfusions

Tsiara S, Kapsali H, Dimos GA, Chaidos A, Stoura M, Bourantas LK, Tzouvara E, Bourantas KL:
Treatment of anemia with recombinant human erythropoietin administration in patients with myelofibrosis, Archives of Hellenic Medicine 20 (3) : 281-285 (May 2003)

S.N. Tsiara, A. Chaidos, L.K. Bourantas, H.D. Kapsali, K.L. BourantasRecombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis Heamatoloica Vol. 117, No. 3, 2007  

EAuthor  Huang, J. Lasho, T.L. Li, C.Y. Pardanani, A.D. Mesa, R.A. Tefferi, A. 
rythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level &gt;or= 10 g/dL
 BLOOD 2007, VOL 110;  pages 3555 

Tefferi A, Lasho TL, Schwager SM et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131:320–328

Stem cell transplantation for CML

Despite improvement of treatment with Gleevec, allogeneic stem cell transplantation remains the only curative treatment for patients with CML.[1]  This form of treatment is only available for a small minority of patients due to the advanced age of most patients at the time of diagnosis and the lack of a suitable related or unrelated allogeneic stem cell donor. Despite significant progress, allogeneic transplants are associated with significant early mortality and morbidity. Until the advent of Gleevec, “young” patients with an HLA-matched related or unrelated donor were advised to undergo a transplant without a trial of IFNa.  Older patients and patients with high-risk factors for failure of transplantation were advised to have an allogeneic transplant only after failure of IFNa. The definition of who is “young” and who is at “high” risk of transplant failure varies from center to center and is evolving over time. Advising selected patients to have an immediate transplant was based on the observation that the results of transplant were worse for patients transplanted after one or two years than for patients transplanted within one year of diagnosis. Until recently, a major criterion for delay of transplant was a good initial response to IFNa treatment. Now all patients with newly diagnosed CML are receiving initial treatment with Gleevec alone or in combination with other agents before a transplant is considered. However, clinicians should identify a donor early for younger patients without significant co-morbidities since, sooner or later, the disease will progress despite Gleevec and other therapies.NCCN recommends allogeneic tansplant in blast crisis, after obtaining a remission.

Transplantation should be done sooner when there are poor-risk features, such as presentation in blast crisis.Age has consistently been an important factor for outcome of allogeneic stem cell transplantation, but the exact upper age limit for performing an allogeneic transplant in early chronic phase is controversial, with ranges from 40-65 years, depending on the institution performing the procedure. In general, treatment-related deaths increase with age in most centers. In one clinical study, no patients under age 20 died. Patients 30-40, 40-50 and 50-60 years were 1.24, 2.30 and 2.54 times more likely to die of the procedure, respectively.  Patients over age 40 had a significant increase in the risk of dying of the transplant compared to younger individuals. Thus, patients under the age of 40 had a 5-year survival of 85%, compared to 65-70% for patients over 40 years of age.

Delay of transplant can also affect outcomes of patients transplanted in chronic phase. In one study, patients transplanted from HLA-matched unrelated donors while in chronic phase within one year of diagnosis had a 5-year survival of 85% while those transplanted between 1 and 2 years from diagnosis had a survival of 78%.  Patients transplanted in chronic phase more than 2 years from diagnosis had a survival 50%, with the excess deaths all being related to complications of the transplant. However, these data were generated in the era of INF alfa treatment and the impact of Gleevec on survival from a subsequent transplant is unknown. This will be very important since patients will be coming to transplant after years of Gleevec treatment.Allogeneic stem cell transplantation can cure up to 80-85% of patients with newly diagnosed CML but can be associated with significant morbidity and mortality. There have been attempts to define risk factors associated with failure to assist in decision making concerning the appropriate timing of allogeneic stem cell transplantation for an individual patient with CML.  However, these risk factor analyses may be dated and may not be relevant to patients being treated in the Gleevec era and an era of improving results of allogeneic stem cell transplantation.

Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet . 1998;352:1087-1092.

Appelbaum FR, Clift R, Radich J, et al Bone marrow transplantation for chronic myelogenous leukemia. Semin Oncol. 1995 Aug;22(4):405-11

Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med .1998;338(14):962-8.

Radich JP, Gooley T, Bensinger W, et al. HLA-matched telated hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood.2003;102:31-35.

Crawlely C, Szdlo R, Lalancette M, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of the prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood . 2005;106:2969-2976.

Thalidomide for melanoma

Thalidomide appears to possess cytostatic activity in patients with metastatic melanoma.Thalidomide has antiangiogenic and biologic modulatory properties21 and has been used successfully in the treatment of Kaposi’s sarcoma, myeloma, and renal cell cancer. Thalidomide has been used in metastatic melanoma as a single agent with mixed results. There are a number of phase II studies that show effectiveness, singly and in combination.One randomized phase II study and six phase II studies have shown encouraging response rates when thalidomide is combined with temozolomide.It is listed in teh Drug Index for melanoma but is considered "off-label, insufficient evidence" by Caremark.However, given the number of studies, I consider thalidomide as a singel agent for melanoma to be supported by credible medical evidence.

Pawlak WZ, Legha SS.Phase II study of thalidomide in patients with metastatic melanoma.Melanoma Res. 2004 Feb;14(1):57-62.

Danson, S., Lorigan, P., Arance, A., Clamp, A., Ranson, M., Hodgetts, J., Lomax, L., Ashcroft, L., Thatcher, N., Middleton, M.R. (2003). Randomized Phase II Study of Temozolomide Given Every 8 Hours or Daily With Either Interferon Alfa-2b or Thalidomide in Metastatic Malignant Melanoma. JCO 21: 2551-2557

Eisen T, Boshoff C, Mak I, et al: Continuous low dose thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 14:17–20, 2000 (suppl 13)

Kudva G, Collins BT, Dunphy FR: Thalidomide for malignant melanoma. N Engl J Med 345:1214–1215, 2

Quirt I, Verma S, Petrella T, Bak K, Charette M, Melanoma Disease Site Group. Temozolomide for the treatment of metastatic melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Mar 20. 25 p. (Evidence-based series; no. 8-4). [38 references]

Maintenance in myeloma

The role of maintenance therapy in multiple myeloma is controversial. A number of different maintenance strategies have been evaluated without clear benefit for one therapy versus another or, a clear benefit of any specific therapy in terms of prolonging remission or overall survival.

Recently, a study by the Southwest Oncology Group (SWOG) noted that patients receiving prednisone at a starting dose of 50 mg three times a week had excellent remission duration and survival, indicating that this could be a good maintenance strategy. In the 1980s, Franco Mandelli published results suggesting that using interferon could prolong the disease-free interval for patients with multiple myeloma. Subsequent studies have failed to confirm this effect, although not all the studies have been negative.Aredia is anotehr agent that is being studied.

Total 3 regimens include a multidrug regimen maintenance phase with Revlimid and Velcade. This continues to be investigated. Guidelines currenlty do not recommend routine maintenance, except that NCCN menions interferon and steroids as level 2B evidence.

The Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol. 2001;113:1020-1034.

NCCN.org, myeloma

PET for esophageal cancer

The imaging modalities commonly used for the diagnosis and staging of esophageal cancer are upper GI study, endoscopy, endoscopic ultrasound, CT, and PET.
PET is superior to CT and EUS combined in diagnosing stage IV disease. In a study by Flamen et al., PET was more accurate 82% vs. 64% for CT and EUS combined in staging esophageal cancer. 18 out of 74 patients had discordant findings between PET vs. CT and EUS. PET was correct in 16 out of 18 patients based on surgical findings. It upstaged 11 patients and downstaged 5 patients. In 3 other studies PET demonstrated distant metastasis not seen on conventional imaging in (21/105 pts.).

NCCN recommends PET for preoperative staging only, not for restaging. While the studies on detection of distant disease suggest better diagnostic performance for PET over CT, the available body of evidence is small. Only one study clearly avoided verification bias, only one clearly interpreted PET blind to the reference standard, and none clearly interpreted the reference standard blind to PET.
Regarding evaluation of treatment response, one study of 14 patients was identified. While PET found evidence of response not shown on CT, these data are insufficient to permit conclusions regarding the value of PET in evaluating response to treatment. Various TEC Assessments have not recommended PET for restaging.

Skehan SJ, Brown AL, Thompson M, Young JE, Coates G, Nahmias C. Imaging features of primary and recurrent esophageal cancer at FDG PET. Radiographics. 2000 May-Jun;20(3):713-23.

5. Flamen P, Van Cutsem E, Lerut A, Cambier JP, Haustermans K, Bormans G, De Leyn P, Van Raemdonck D, De Wever W, Ectors N, Maes A, Mortelmans L. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 2002 Mar;13(3):361-8.

Danish Centre for Evaluation, Health Technology Assessment (DACEHTA). Paper concerning clinical PET-scanning using FDG - with focus on diagnosis of cancer. Copenhagen, Denmark: DACEHTA; 2001.

Deutsches Institut für Medizinische Dokumentation und Information (DIMDI). [Economic evaluation of positron-emission-tomography: a health economic HTA-report]. Cologne, Germany: DIMDI; 2001.
Health Technology Board for Scotland (HTBS). Health Technology Assessment Advice 2: Positron emission tomography (PET) imaging in cancer management. Glasgow, Scotland: HTBS; 2002.

BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). FDG positron emission tomography for evaluating esophageal cancer. TEC Assessment Program. Chicago, IL: BCBSA; 2001;16(21).

Xeloda for renal cell carcinoma

Amato RJ, Mohammad T. Interferon-alpha plus capecitabine and thalidomide in patients with metastatic renal cell cancer. J Exp Ther Oncol. 2008;7(1):41-7

Capecitabine is a novel fluoropyrimidine carbamate, orally administered and selectively activated to fluorouracil by a sequential triple enzyme pathway in liver and tumor cells.Oral capecitabine may be an active drug for the treatment of advanced renal cell carcinoma and is being evaluated in first- and second-line treatment schedules as monotherapy as well as in combination with immunotherapy agents.
In preclinical studies, renal cell tumors demonstrated high TP activity, suggesting that TP-activated capecitabine may be effective in this setting. In a pilot phase II study, capecitabine (1,250 mg/m2 twice daily for 14 days followed by a 7-day rest period) was administered to 22 patients with metastatic renal cell cancer that had progressed during or following immunotherapy. Among 12 patients for whom efficacy and toxicity data have been reported, one patient achieved a partial response, and disease was stabilized in all but one of the remaining patients (83%). There were no grade 4 adverse events and the only grade 3 adverse event was hand-foot syndrome, which occurred in two patients and resolved without capecitabine dose modification. Another phase II study has investigated capecitabine (1,000 mg/m2 twice daily on days 1-5 of weeks 5-8) in combination with immunotherapy (interleukin 2, interferon-, and oral 13-cis-retinoic acid) in 30 patients with metastatic renal cell carcinoma. This regimen, repeated for up to three cycles, produced an objective response rate of 34%, including two complete responses. A further 12 patients (40%) achieved disease stabilization. No grade 4 adverse events were observed, and grade 3 events were reported in only two patients (malaise and malaise, nausea/vomiting). There are published trials in combination with interferon, docetaxel and thalidomide.

*Amato RJ, Khan M. A phase I clinical trial of low-dose interferon-alpha-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2008 May;61(6):1069-73. Epub 2007 Aug 14.
*Amato RJ, Rawat A.
Interferon-alpha plus capecitabine and thalidomide in patients with metastatic renal cell carcinoma: a pilot study. Invest New Drugs. 2007 May;24(3):171-5
*Amato RJ. Thalidomide therapy for renal cell carcinoma. Crit Rev Oncol Hematol. 2003 Jun 27;46 Suppl:S59-65

Catharina Wenzel et al,Oral Chemotherapy with Capecitabine (Xeloda) in the Treatment of Metastatic Renal Cancer Failing Immunotherapy.  Proc Am Soc Clin Oncol 19: 2000 (abstr 1457)
Wenzel C, Schmidinger MP, Locker GJ et al. Oral chemotherapy with capecitabine (Xeloda) in the treatment of metastatic renal cancer failing immunotherapy. Proc Am Soc Clin Oncol 2000;19:368a.
Övermann K, Buer J, Hoffman R et al. Capecitabine in the treatment of metastatic renal cell carcinoma. Br J Cancer 2000;83:583–587

Phentermine for weight loss

Phentermine, a contraction for "phenyl-tertiary-butylamine", is an appetite suppressant of the amphetamine and phenethylamine class.It is approved as an appetite suppressant to help reduce weight in obese patients when used short-term and combined with exercise, diet, and behavioral modification. It is typically prescribed for individuals who are at increased medical risk because of their weight and works by helping to release certain chemicals in the brain that control appetite.

Generally, it is recommended by the Food and Drug Administration (FDA) that phentermine should be used short-term (usually interpreted as 'up to 12 weeks'), while following nonpharmacological approaches to weight loss such as healthy dieting and exercise. However, recommendations limiting its use for short-term treatment may be controversial. One reason given behind limiting its use to 12 weeks is drug tolerance, whereby phentermine loses its appetite-suppressing effects after the body adjusts to the drug. One study showed that phentermine did not lose effectiveness in a 36-week trial.

Phentermine hydrochloride tablets and capsules are FDA indicated as a short term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index  ≥ 30 kg/m2, or ≥ 27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia).

Guidelines for Users of Diet Pills.” Harvard Heart Letter 8.8 (Apr. 1998): 6-7. EBSCOhost Research Databases. 2005. Harvard Medical School. 5 Oct. 2005 .

SCHNEE David M. ; ZAIKEN Kathy ; MCCLOSKEY William W. ; Current medical research and opinion  2006, vol. 22, no8, pp. 1463-1474

Bray GA.A concise review on the therapeutics of obesity.Nutrition. 2000 Oct;16(10):953-60.

Vancyclovir prophylaxis

Cytomegalovirus (CMV) infection after solid organ transplantation is one of the most common viral infections, causing significant morbidity and mortality if not treated promptly. Ganciclovir has proven to be effective for the prophylaxis and treatment of CMV. However, oral absorption of ganciclovir is poor. Recently, oral administration of valganciclovir hydrochloride (Valcyte) has been observed to display 10-fold better absorption than oral ganciclovir. Valganciclovir has increasingly been used as prophylaxis against CMV after solid organ transplantation and for severely immunospuressive cehmo regimens.In kidney recipients, oral valganciclovir for 100 days has been shown to be as clinically effective as oral ganciclovir for CMV prevention. In heart recipients, valganciclovir is also presumed to be effective, but data are more limited. Alemtuzumab is an immunosuppressive antibody that depletes normal T cells and B cells. Prophylaxis for herpes virus and Pneumocystis carinii is standard with this agent. Approximately 20% to 25% of patients will experience cytomegalovirus (CMV) reactivation.A very recent randomized trial found CMV prophylaxis to be effective and beneficial in these patients.

Cincinnati Children's Hospital Medical Center. Evidence-based care guideline for cytomegalovirus prophylaxis following solid organ transplants. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2007 Jul 6. 15 p. [68 references] Susan O'Brien, Farhad Ravandi, Todd Riehl, William Wierda, Xuelin Huang, Jeffrey Tarrand, Brandi O'Neal, Hagop Kantarjian, and Michael Keating Valganciclovir prevents cytomegalovirus reactivation in patients receiving alemtuzumab-based therapy Blood 111: 1816-1819; prepublished online as DOI 10.1182/blood-2007-03-080010

TPF induction chemotherapy or head and neck cancer

A growing body of data from randomized clinical trials has demonstrated that induction chemotherapy -- in combination with chemoradiotherapy -- may play an important role in the treatment localized head and neck cancers.

The standard neoadjuvant chemotherapy regimen has consisted of a platinum agent and 5-fluorouracil (5-FU), a regimen known as PF. More recently, the addition of a taxane such as docetaxel (or, less commonly, paclitaxel) to the PF regimen (a triple combination known as TPF) is emerging as a more effective and less toxic standard for induction chemotherapy.

Two large, randomized trials -- the Veterans Affairs Laryngeal Cancer Study Group trialand a phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) -- have demonstrated the benefit of induction chemotherapy with PF (100 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of 5-FU by continuous infusion on days 1-5) with respect to organ preservation. In these trials, overall survival rates were similar in patients receiving either induction PF chemotherapy and radiation or surgery and radiation therapy. In patients with more advanced unresectable tumors, PF induction therapy has been shown to produce long-term survival benefits with overall survival times in a subset of inoperable patients receiving chemotherapy of 21% at 5 years and 16% at 10 years compared with 8% and 6%, respectively, in patients not receiving chemotherapy. In a phase 3 trial[12] of neoadjuvant chemotherapy in patients with oropharyngeal cancer conducted by the French Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC), the median overall survival time for patients with both resectable and unresectable tumors was 5.1 years when PF induction chemotherapy was followed by locoregional therapy vs 3.3 years for those who did not receive PF induction chemotherapy (P = .03).

 A number of randomized trial have demonstrated improved organ preservation or survival with TPF compared with PF. The phase 3 TAX 323 trial, a direct comparison of PF and TPF induction chemotherapy conducted by the EORTC, included patients with locally advanced and unresectable squamous cell head and neck cancer who were randomized to receive induction therapy with either PF or TPF every 3 weeks for 4 cycles, followed by radiotherapy or surgery.
The international TAX 324 trial assessed PF induction chemotherapy, with or without docetaxel, followed by chemoradiotherapy and surgical resection in patients with locally advanced head and neck cancer. Finally, a randomized phase 3 trial comparing PF induction chemotherapy with and without docetaxel in patients with laryngeal cancer demonstrated an improvement in organ preservation with the addition of the taxane to the PF regimen.

Although the question sistill being studied in the DeCIDE trial -- Docetaxel Based emotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer -- a phase 3 trial sponsored by the University of Chicago, NCCN already lists induction chemotherapy as an option.Two European randomized trials comparing a sequential treatment approach including TPF induction chemotherapy and chemoradiotherapy vs standard chemoradiotherapy alone for the treatment of head and neck cancer are in progress, and data are anticipated within 2 years.

Posner MR, Haddad RI, Wirth L, et al. Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: evolution of the sequential treatment approach. Semin Oncol. 2004;31:778-785.
Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971. Proc Am Soc Clin Oncol. 2006;24:284s. Abstract 5516.
The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;325:1685-1690.
Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88:890-899.
Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst. 1994;86:265-272. Abstract
Zorat PL, Paccagnella A, Cavaniglia G, et al. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J Natl Cancer Inst. 2004;96:1714-1717.
Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal cancer. French Groupe d'Etude des Tumeurs de la Tete et du Cou. Br J Cancer. 2000;83:1594-1598.
Vermorken JB, Remenar E, Van Herpen C, et al. Standard cisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF (TPF) as neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): a phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971). Proc Am Soc Clin Oncol. 2004;22:14s.
Posner MR, Haddad RI, Wirth LJ. The evolution of induction chemotherapy and sequential therapy for locally advanced squamous cell cancer of the head and neck. American Society of Clinical Oncology Educational Book, 2006; pp 346-352.
Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing induction chemotherapy using cisplatin (P) fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01. Proc Am Soc Clin Oncol. 2006;24:281s.

ATG for graft versus host disease

Severe acute graft-versus-host disease (GVHD) is one of the major complications after haematopoietic stem-cell transplantation (HSCT). Treatment of severe GVHD is difficult and the condition is often fatal. One proposed method of improving the therapy is to include anti-thymocyte globulin (ATG). ATG is being actively studied for prophylaxis of GVHD after allogeneic transplantation, f. e., the phase II study Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological, NCT00589563.

However, it appears to not be very effective to treat already established disease. ATG treatment can produce objective responses in patients with aGVHD, but these responses do not result in long-term survival. A recent review consluded: "Given the poor survival rates of patients treated with ATG for steroid-refractory GVHD, treatment with ATG as standard therapy should be reconsidered. Patients with steroid-refractory GVHD should be enrolled in clinical study until there are data to support a standard salvage therapy."

Neumeister P, Zinke W, Sill H, Linkesch W: Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin Clinical transplantation   ISSN 0902-0063 
2001, vol. 15, no3, pp. 147-153 (48 ref.)

S . Arai Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment .  Biology of Blood and Marrow Transplantation , Volume 8 , Issue 3 , Pages 155 - 160, 2002

Rituxan for graft vesus host disease

Chronic GVHD is a major complication of allogeneic stem cell transplantation involving the skin, musculoskeletal system and liver. Chronic GVHD is mediated primarily by T-cells. However, recently there has been emerging evidence that B-cells are also involved. The support for this concept comes from the detection of antibodies to minor HLA antigens. Several pahse II clinical trials evaluated Rituxan for the treatment of chronic GVHD based on the hypothesis that antibody suppression would be beneficial. In aggreagte they show effectiveness. The status of experimental caanot be assigned to this treatmetn because phase III trials are no possible due to the low numbers of patients avaialble for such studies. There is no expert consensus on performing such studies.

http://bloodjournal.hematologylibrary.org/cgi/reprint/2006-01-0233v1.pdf

R . Kamble , M . Oholendt , G . CarrumRituximab Responsive Refractory Acute Graft-versus-Host Disease .  Biology of Blood and Marrow Transplantation , Volume 12 , Issue 11 , Pages 1201 - 1202 2006

Stefan Deneberg etal, Relapse of preB-ALL after rituximab treatment for chronic graft versus host disease. Implications for its use?
Journal Medical Oncology Issue Volume 24, Number 3 / September, 2007

Revlimid for myelofibrosis

There are now 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. The authors concluded that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.

Ayalew Tefferi, Jorge Cortes, Srdan Verstovsek, Ruben A. Mesa, Deborah Thomas, Terra L. Lasho, William J. Hogan, Mark R. Litzow, Jacob B. Allred, Dan Jones, Catriona Byrne, Jerome B. Zeldis, Rhett P. Ketterling, Rebecca F. McClure, Francis Giles, and Hagop M. Kantarjian
Lenalidomide therapy in myelofibrosis with myeloid metaplasia
Blood 108: 1158-1164;

Tefferi, Ayalew
Pathogenesis of Myelofibrosis With Myeloid Metaplasia
J Clin Oncol 2005 23: 8520-8530
 

PET for gastric cancer

Positron emission tomography using 2-deoxy-2-[18F] fluorodeoxyglucose (FDG-PET) has been used to detect malignancies associated with certain kinds of tumors. Data regarding the use of FDG-PET scan for evaluating gastric cancer are scarce. A recent review of studies showed that PET produced an estimated 14% change was noted in management effect, based on 109 patient studies for diagnosis/staging in gastric cancer; however, this is no randomized data.NCCN sys that PET is optional for staging.

Table of studies: http://www.petscaninfo.com/zportal/portals/phys/clinical/jnmpetlit/index_html/JNM_OncoApps/JNM_Table10/article_elements_view

http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf, p.5

Imaging Gastric Cancer with PET and the Radiotracers 18F-FLT and 18F-FDG: A Comparative Analysis Ken Herrmann, Katja Ott, Andreas K. Buck, Florian Lordick, Dirk Wilhelm, Michael Souvatzoglou, Karen Becker, Tibor Schuster, Hans-Jürgen Wester, Jörg R. Siewert, Markus Schwaiger, and Bernd J. Krause J Nucl Med 48: 1945-1950; First published on November 15, 2007;

PET scan in small cell lung cancer

PET scan has not been sufficiently studied for small celll lung cancer to be considered standard. PET with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) has recently received attention, and growing evidence suggests its superiority in the staging of lung cancer. However, PET is more frequently used in evaluating patients with NSCLC to identify surgical candidates. It is less commonly used in patients with SCLC because most of these patients are not candidates for surgery. PET may be useful for evaluating cases in which recurrent disease but this is questionable.Generally, the resolution of PET is not considered good for lesions smaller than 1 cm. The PET results can also overlap with the standard uptake values (SUVs) in some benign lesions and malignant lesions.

Unfortunately, specificity, sensitivity and accuracy compared to CT are not securely known.The utility of positron emission tomography (PET) scanning in patients with SCLC has been recently reported in two small prospective studies. In a study reported by Hauber et al, PET scans detected all primary lesions, lymph node metastases, and distant metastases that had been detected by other standard staging procedures. In a second study, 30 patients with SCLC were evaluated with 36 PET scan examinations, and the results were compared with the sum of the other staging procedures. The results of 23 of the 36 PET scan examinations were concordant with those of the other staging procedures. In seven cases, the PET scan examination resulted in upward staging of the patient, and in one instance the PET scan revealed the presence of a viable tumor when conventional staging procedures had revealed no residual disease. PET scan identified all areas of tumor involvement detected by other staging procedures. A third study looked at the accuracy of PET scanning in detecting bony metastases in patients with SCLC and NSCLC, comparing the PET scans to bone scans and single-photon emission CT scans. In this study, PET scans were found to be the most accurate whole-body imaging modality for the screening of bone metastases. These studies suggested that PET scanning is likely to be a useful staging tool in patients with SCLC. However, all the above studies were small, and the experience with PET scan as a staging tool remains largely limited. Until larger prospective studies become available, PET scanning cannot be recommended for routine use in the staging and restaging of patients with SCLC.

Chirrmeister, H, Glatting, G, Hetzel, J, et al Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42,1800-1804

Hauber, HP, Bohuslavizki, KH, Lund, CH, et al Positron emission tomography in the staging of small-cell lung cancer: a preliminary study. Chest 2001;119,950-954
 
Schumacher, T, Brink, I, Mix, M, et al FDG-PET imaging for the staging and follow-up of small cell lung cancer. Eur J Nucl Med 2001;28,483-48