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

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

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]

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.

Cladribine for lymphomas

Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström’s macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin’s lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions.

Cladribine is in a phase II study for matnle lymphoma as a single agent, NCT00002879. A 2006 preliminary report suggested that caldribine in combination with rituximab regimens were highly effective and well tolerated modalities of treatment in heavily pretreated patients with indolent lymphoproliferative disorders.

http://clinicaltrials.gov/ct2/show/NCT00002879

Darren S Sigal and Alan Saven Cladribine in indolent non-Hodgkin’s lymphomaExpert Review of Anticancer Therapy April 2008, Vol. 8, No. 4, Pages 535-545

Robak T, Smolewski P, Cebula B, Szmigielska-Kaplon A, Chojnowski K, Blonski JZ.
Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma.Cancer. 2006 Oct 1;107(7):1542-50.

Alimta is not useful in small cell lung cancer

Alimta and cisplatin are FDA approved for second line therapy of non-small cell(NSC) lung cancer. It is an effective regimen in first line as well. Carboplatin can be substituted for cisplatin.

The National Comprehensive Cancer Network (NCCN), an alliance of nineteen of the world’s leading cancer centers, recently added pemetrexed (Alimta®, Eli Lilly and Company) as an option for second-line therapy for NSC lung cancer. The panel indicated that it has been shown to be equivalent to docetaxel (Taxotere®, Sanofi-Aventis) in efficacy but with less toxicity.  The U.S. Food and Drug Administration granted accelerated approval for Alimta for the treatment of locally advanced or metastatic non-small cell lung cancer in previously treated patients in 2004. It is FDA approved for mesothelioma in combination with cisplatin.

However, this is small cell lung cancer. Just presented in ASCO 2008 was a study that indicates that ALimta is not useful for small cell histology.  This trial was designed to directly compare the regimen of carboplatin/alimta to carboplatin/etoposide, which is a standard regimen for this setting. It was designed to enroll 1820 patients  and look for a significant improvement in survival. The study had enrolled 733 patients when the “Data Safety Monitoring Board”, which reviews results during the conduct of a trial to ensure that one arm isn’t doing so remarkably well or poorly that it would be unethical to continue to randomize patients, found that the carbo/alimta arm was doing so poorly that it was not possible that it would ever emerge as superior. It was closed, and Dr. Socinski presented the results.

Standard treatment for patients with extensive SCLC include VePesid® (etoposide) plus Platinol, VePesid plus Paraplatin or Camptosar® (irinotecan) plus Platinol. However, due to poor long-term outcomes in this disease with current therapies different chemotherapy combinations continue to be evaluated. Alimta is a folate acid antagonist approved by the FDA for treatment of non-small cell lung cancer (NSCLC).

Researchers from several medical institutions in the United States recently conducted a clinical trial to evaluate the addition of Alimta to Platinol or Paraplatin for the treatment of 78 patients with extensive-stage SCLC. Patients were randomly allocated to receive Alimta with either Plainol or Paraplatin. The results were similar in both arms. Alimta must be considered experimental for small cell lung cancer.

Socinski M, Weissman C, Hart L, et al. Randomized Phase II Trial of Pemetrexed Combined With Either Cisplatin or Carboplatin in Untreated Extensive-Stage Small Cell Lung Cancer. Journal of Clinical Oncology . 2006;24:4840-4847.

Socinski, ASCO 2008 (abstract # to follow)

Mitomycin for prostate cancer

Mitomycin is an older drug that has been well studied in prostate cancer. It has some anti-cancer effect but it is not substantial.It does better in combinations.Based on their previous clinical experience with VE, Logothetis et al have recently reported that the addition of mitomycin-C to the VE regimen substantially improves efficacy. The rate of PSA reduction among 31 patients with initially elevated PSA was 66% and the duration of response was 2 months. In addition, 7% of 28 patients with osseous disease experienced improved bone scans.

nccn.org, prostate

Mitomycin in prostate cancer not recommended
Source: PharmacoEconomics and Outcomes News, Volume 1, Number 273, 2000 , pp. 10-10(1)

Amato R, Logothetis C, Sella A, et al: Preliminary results of a phase II trial of estramustine (Emcyt), vinblastine (VLB) and mitomycin-C (MMC) for patients with progressive androgen independent prostate carcinoma (AIPCa) (abstract 1213). Proc Am Assoc Cancer Res 34:203, 1993.

BEACOPP and ABVD for Hodgkin's

The most widely accepted regimen for HD patients with advanced stage is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). To improve on these results, time and/or dose intensified third-line protocols were investigated. Such a protocol developed by the German Hodgkin's Lymphoma Study Group (GHSG), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) ahs been studied in various patient groups. THe results appear no better than with ABVD but also not worse.The HD9 randomized trial compared COPP/ABVD + RT with standard dose BEACOPP + RT and escalated dose BEACOPP + RT. Irradiation was given to approximately 70% of patients on all three arms based on presence of initial moderately bulky (> 5 cm) or residual nodal abnormalities. The most recent analysis, also with a median follow-up of 6.9 years, included 1195 evaluable patients and demonstrated superior freedom from treatment failure and overall survival for the patients treated with escalated dose BEACOPP + RT (Table 5).31,32 Escalated BEACOPP showed a higher but manageable rate of hematologic toxicity. Longer follow-up will be required to determine the true usefulness of escalated BEACOPP + RT. Whether the increased toxicity of this regimen (3% treatment induced mortality, 100% infertility in men, 100% infertility plus premature menopause in most women over the age of 25, increased risk of second neoplasms) can be justified remains to be determined. Of particular note is the fact that the increased efficacy of escalated BEACOPP only translated into a survival benefit in the 20% of patients with the poorest prognosis at diagnosis. The other 80% of patients with advanced Hodgkin lymphoma had the same overall survival whether initially treated with ABVD or escalated BEACOPP because of the availability of effective secondary treatment with high-dose chemotherapy and stem cell transplantation.

J. M. Connors, E. M. Noordijk, and S. J. Horning
Hodgkin's Lymphoma: Basing the Treatment on the Evidence
Hematology, January 1, 2001; 2001(1): 178 - 193.

V. Diehl, J. Franklin, M. Pfreundschuh, B. Lathan, U. Paulus, D. Hasenclever, H. Tesch, R. Herrmann, B. Dorken, H.-K. Muller-Hermelink, et al.
Standard and Increased-Dose BEACOPP Chemotherapy Compared with COPP-ABVD for Advanced Hodgkin's Disease
N. Engl. J. Med., June 12, 2003; 348(24): 2386 - 2395.

V. Ballova, J.-U. Ruffer, H. Haverkamp, B. Pfistner, H. K. Muller-Hermelink, E. Duhmke, P. Worst, M. Wilhelmy, R. Naumann, M. Hentrich, et al.
A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly)
Ann. Onc., January 1, 2005; 16(1): 124 - 131.

Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348:2386–2395.

Diehl V, Brillant C, Franklin J, et al. BEACOPP chemotherapy for advanced Hodgkin’s disease: Results of further analyses of the HD9- and HD12- trials of the German Hodgkin Study Group (GHSG)