Cancer Treatment

Afinitor for carcinoid

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. New data demonstrate that treatment with Afinitor® (everolimus) in combination with Sandostatin® LAR® (octreotide acetate suspension for injection) and Afinitor monotherapy may have the potential to stabilize tumour growth in patients with advanced pancreatic neuroendocrine tumours (NET).

Data from the study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), were first presented last year at the 12th World Congress on Gastrointestinal Cancer in Barcelona. Regulatory submissions for everolimus to treat this patient population are underway worldwide.Results from the trial showed that everolimus more than doubled median PFS from 4.6 to 11.0 months when compared with placebo and reduced the risk of cancer progression by 65% (hazard ratio [HR] =0.35 [95% confidence interval (CI), 0.27 to 0.45]; p<0.001) in patients with advanced pancreatic NET. After 18 months, 34% of patients treated with everolimus (95% CI, 26 to 43) were alive and progression-free versus 9% of those treated with placebo (95% CI, 4 to 16), showing a more prolonged benefit for patients treated with everolimus.

On February 9, 2011, The US Food and Drug Administration (FDA) has granted everolimus priority review designation for the application of advanced NET of gastrointestinal (GI), lung or pancreatic origin based on results of RADIANT-3 and another Phase III trial, RADIANT-2.

Yao, et al. A Phase II Trial of Daily Oral RAD001 (Everolimus) in Patients With Metastatic Pancreatic Neuroendocrine Tumours (NET) After Failure of Cytotoxic Chemotherapy. 33rd European Society for Medical Oncology Congress, Stockholm, Sweden.

Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New Eng J Med 2011;364:514-23.

Yao, et al. Everolimus versus placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress on Gastrointestinal Cancer, Barcelona. July 1, 2010.

Previstage GCC Colon Cancer Staging Test

Traditional methods of examining lymph nodes (LNs) for metastases involve microscopically examining hematoxylin and eosin (H&E) stained 5µm sections of each LN. However, this method has important limitations. Previstage™ GCC Colorectal Cancer Staging Test attempts to overcome problems with sampling errors, marker specificity and persistence of expression in CRC and metastases. Using ultrasensitive quantitative RT-PCR, the assay interrogates the patient’s lymph nodes to identify levels of GCC consistent with that found in LNs with histologically-confirmed, clinically significant metastases from stage III CRC patients.

This is a new and yet unproven method of lymph node sampling It may be superior to traditional methods of sampling but that needs to be proven and clincial benefit confirmed. Currently, I consider it to be investigational. 

Alex Mejia and Scott A Waldman Previstage™ GCC test for staging patients with colorectal cancer Expert Review of Molecular Diagnostics September 2008, Vol. 8, No. 5, Pages 571-578

Rituxan for Wegener's

Wegener's granulomatosis (WG) is a chronic, multisystem disease, characterized by a small vessel vasculitis. First line therapy is cyclophosphamide. Despite the use of other immunosuppressive agents, including methotrexate, azathioprine and mycophenolate mofetil, to maintain remission, relapse often occurs – with many patients requiring further courses of cyclophosphamide over many years.

Rituximab is being tested in a wide variety of small vessel vascultides but no prospective studies have been done in any of them, to my knowlledge. One pilot trial for Wegener's showed a high response rate in a small group of patients. However, there was also the RAVE trial which became the basis for the FDA approval. The U.S. Food and Drug Administration approved Rituxan (rituximab), in combination with glucocorticoids (steroids) on April 12, 2011 to treat patients with Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA), two rare disorders that cause blood vessel inflammation (vasculitis).

Alistair J. Ferraro , Clara J. Day , Mark T. Drayson , and Caroline O. Savage
Effective therapeutic use of rituximab in refractory Wegener's granulomatosis
Nephrol. Dial. Transplant. 20: 622-625

C M G Cheung, P I Murray, and C O S Savage
Successful treatment of Wegener's granulomatosis associated scleritis with rituximab
Br J Ophthalmol, November 1, 2005; 89(11): 1542 - 1542.

K. A. Keogh, S. R. Ytterberg, F. C. Fervenza, K. A. Carlson, D. R. Schroeder, and U. Specks Rituximab for Refractory Wegener's Granulomatosis: Report of a Prospective, Open-Label Pilot Trial
Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 180 - 187.

Despina Eleftheriou , Marianna Melo , Stephen D. Marks , Kjell Tullus , John Sills , Gavin Cleary , Pavla Dolezalova , Seza Ozen , Clarissa Pilkington , Pat Woo , Nigel Klein , Michael J. Dillon , and Paul A. Brogan
Biologic therapy in primary systemic vasculitis of the young
Rheumatology Advance Access published on August 1, 2009, DOI 10.1093/rheumatology/kep148.
Rheumatology 48: 978-986.

Dynasplint and Trismus

Trismus is an involuntary contraction of the jaw muscles (muscles of mastication) causing a restriction of mouth opening. This occurs when the connective tissue becomes tight and short. Serious health implications include: inability to chew and digest food properly, difficulty speaking and compromised oral hygiene. The Dynasplint® Trismus System actively stretches the muscles of the face and can be used for patients with openings as small as 9mm. The Dynasplint® Trismus System was developed for home use. It is used 3 times a day for up to 30 minutes per session, 7 days a week. The device is worn inside the middle of the mouth while the patient is relaxed. 

While I did not find guideleins addressing this paticular device, other similar interventions are effective. Exercises using a therabite device or tongue blades increase mouth opening significantly (no follow-up), effect sizes (ES) 2.6 and 1.5 respectively. There is a study of this device in progress: Dynasplint Therapy for Trismus in Head and Neck Cancer (HNO 0602), NCT00507208. Standard therapy will be the use of tongue depressors. Crossover from standard therapy to DTS will be implemented if at three months there is no improvement in mouth opening when using tongue depressors.

Shulman D, Shipman B, Willis FB “Treating Trismus with Dynamic Splinting: A Case Report”
Journal of Oral Sciences. 2009; 51(1):141-144
 
Dijkstra PU, Kalk WWI, Roodenburg JLN. Trismus in head and neck oncology: a systematic review. Oral Oncology 2004; 40: 897-889.

Shulman D, Shipman B, Willis FB “Treating Trismus with Dynamic Splinting: a Cohort, Case Series” Advances in Therapy. 2008January; 25(1):9-16

Circulating Tumor Cells (CTC)

The CellSearch™ System identifies and counts circulating tumor cells (CTCs) in a blood sample to predict progression-free survival and overall survival in patients with metastatic breast, colorectal or prostate cancer, and can do so earlier than the current standard of care. The contention is that the results of serial testing for CTCs with the CellSearch™ System provide additional information to the oncologist and does so earlier than other currently approved diagnostic modalities, thereby allowing the oncologist to make more-informed patient care decisions. The clinical use of CTCs has not been implemented for routine clinical practice for several reasons. Most notably, the lack of standardization and automation of the technology has required the use of laborious sample preparation procedures with corresponding high intra- and inter-laboratory differences in results. Furthermore, different reagents and methods are used for the staining and evaluation of immunocytochemically prepared slides in search of these rare events in blood and bone marrow, which can lead to differences concerning specificity and sensitivity. Finally, although peripheral blood is an ideal source for the detection of CTCs because of the noninvasive sampling procedure, the clinical significance of CTCs in peripheral blood is less clear than that for DTCs in bone marrow.

The technology has been validated in the sense that the CellSearch system enables the reliable detection of CTCs in blood and is suitable for the routine assessment of metastatic breast cancer patients in the clinical laboratory. Several studies show that serial estimation of CTC level up to 20 weeks correlates with progression-free and overall survival. This suggests that elevated CTC level at any time during therapy can reflect disease progression and mortality risk for MBC patients. Another subset analysis was done on 83 (of the 177) patients who were receiving first-line treatment for metastatic disease. CTC level was assessed in these patients at baseline and monthly thereafter for up to 6 months, for a median follow-up of 12.2 months. CTC levels before and after starting therapy were strong, independent prognostic factors for both progression-free and overall survival. It has not been proven, however, that it is a tool that improves clinical care.

Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897-6904, 2004.

Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

Hayes DF, Cristofanilli M, Budd GT, et al: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218-4224, 2006.

Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23:1420-1430, 2005.

Riethdorf, Sabine, Fritsche, Herbert, Muller, Volkmar, Rau, Thomas, Schindlbeck, Christian, Rack, Brigitte, Janni, Wolfgang, Coith, Cornelia, Beck, Katrin, Janicke, Fritz, Jackson, Summer, Gornet, Terrie, Cristofanilli, Massimo, Pantel, Klaus
Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System
Clin Cancer Res 2007 13: 920-928

Neulasta and neupogen for acute myeloid leukemia: An Update.

Previous review, here.

Myeloid growth factors granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been extensively studied in acute leukemias. Whether administered before, during, or after chemotherapy for acute myeloid and acute lymphoblastic leukemias, these agents reduce the duration of neutropenia and appear to be safe and well tolerated. Despite consistently demonstrating a shorter duration of neutropenia, multiple, prospective, randomized trials have documented only modest benefits in terms of reduction in the incidence and severity of infections, without substantial gains or impact in complete remission, overall survival, and disease-free survival rates. Growth factors have also been used to recruit quiescent leukemia cells into the S phase of the cell cycle to increase their susceptibility to chemotherapy with the goal to reduce relapse and resistance. Randomized trials to evaluate this priming strategy have consistently demonstrated an improvement in terms of disease-free or event free survival in the intermediate risk group of patients with acute myeloid leukemia, but no overall survival benefit.G-CSF is usually well tolerated and medullary bone pain is the most frequently reported side-effect. Other less common adverse effects include headaches, generalized musculoskeletal pain, and exacerbation of underlying inflammatory skin diseaseNeulasta is not used routinely in acute myeloid leukemia but is not harmful if used appropriately. A recent guideline says: "Similarly there is insufficient evidence to support routine use of G-colony stimulating factor (CSF) or granulocyte macrophage (GM)-CSF with induction chemotherapy in patients over 60 years of age, although this may be appropriate if it is desirable to reduce hospitalisation or antibiotic usage".

Milligan DW, Grimwade D, Cullis JO, Bond L, Swirsky D, Craddock C, Kell J, Homewood J, Campbell K, McGinley S, Wheatley K, Jackson G. Guidelines on the management of acute myeloid leukaemia in adults. London (UK): British Society of Haematology (BSH); 2005 May 23. 77 p. [202 references]

PET for anal cancer: anal canal versus anal margin

Anal canal cancer metastasize more to the iliac nodes and of anal margin go more to the inguinal nodes. A  recent review found that the accuracy of PET scan was poor for anal cancer even with palpable inguinal nodes. PET scan sensitivity was  50%, specificity = 72%, predictive value positive (PVP) = 50%, predictive value negative = 80%. 64% of scans were performed within 6 months of treatment; in these, PVP = 33% and PVN = 66%. PET scanning for anal SCC provides accurate staging of disease at presentation and may alter treatment planning by identifying inguinal node involvement not apparent on clinical examination. In this series, PET scan results did not change post-chemoradiation management in any case. Importantly, resolution of primary tumor defined by PET scan was accurate only 80% of the time. PE and Bx within 3 months of treatment were more accurate than PET scan in assessing disease. This review concludes that : "Post-treatment evaluation of anal SCC should continue to include careful PE, CT scan and Bx when appropriate".  however, this review did not distinguish between anal canal and anal margin cancers. Most cases appear to have been anal margin.

NCCN lists PET on p.4 of its anal cancer guidelines for the initial staging of anal canal (as in our cse) but not for anal margin cancer prior to 5FU/Mitomycin and radiation. A guideline says of anal canal cancer: "Positron emission tomography (PET) scanning may have a role as an adjunct to CT of the pelvis, abdomen, and chest, identifying sites of metastasis not observed on CT in 25 percent of cases. Almost 20 percent of patients with inguinal nodes that are negative by both physical examination and CT scan are positive on PET. This has prognostic significance and may influence the radiation treatment plan."

IN cnclusion, PET appears to be well established prior to but not after chemoradiation. False positives would be expected to be much higher after chemoradiation.

 Fleshner PR, Chalasani S, Chang GJ, Levien DH, Hyman NH, Buie WD, Standards Practice Task Force of the American Society of Colon and Rectal Surgeons. Practice parameters for anal squamous neoplasms. Dis Colon Rectum 2008 Jan;51(1):2-9.

Nagle, D., Henry, D., Iagaru, A., Mastoris, J., Chmielewski, L., Rosenstock, J.
The utility of PET scanning in the management of squamous cell carcinoma of the anus
J Clin Oncol (Meeting Abstracts) 2006 24: 4152

nccn.org, anal

Neoadjuvant chemotherapy for rhabdomyosarcoma

Rhabdomyosarcoma arising from skeletal muscle is the most common soft tissue sarcoma of childhood. Approximately 20% of patients present with disseminated disease and have a poor prognosis with combined modality therapy. The remaining 80% of patients present with localized disease and cure rates with combined modality therapy range from 50% to 90% depending on histology, site of disease and the ability of surgery to completely remove all gross and microscopic disease. One rhabdomyosarcoma study conducted showed that even after complete resection of all visible cancer and post-operative radiation therapy to the surrounding tissue, as many as 80% of the children will still have tumor recurrence in other parts of the body. Given this sobering finding, treatment regimens shifted towards giving neoadjuvant systemic chemotherapy and it is the current paradigm of rhabdomyosarcoma management. Patients with recurrent rhabdomyosarcoma have a very poor prognosis and are usually treated with chemotherapy. Active agents for the treatment of recurrent or refractory rhabdomyosarcoma include Cytoxan® (cyclophosphamide), Ifex® (ifosfamide), Adriamycin® (doxorubicin), Actinomycin D® (dactinomycin), Vepesid® (etoposide), Platinol® (cisplatin) and Paraplatin® (carboplatin). There is a completed study in which VAC chemo was the standard arm - results are pending : Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma. NCT00002995

Parham DM, Ellison DA. Rhabdomyosarcomas in adults and children: an update.Arch Pathol Lab Med. 2006 Oct;130(10):1454-65.

Ruymann FB.The development of VAC chemotherapy in rhabdomyosarcoma: what does one do for an encore?Curr Oncol Rep. 2003 Nov;5(6):505-9.

Dr. Jorge A. Ortega, M.D. et al, The influence of chemotherapy on the prognosis of rhabdomyosarcoma Med Ped Oncol Volume 1 Issue 3, Pages 227 - 234

 

PET in small bowel cancer

The small bowel represents approximately 75% of the length of the overall GI tract and contains 90% of the gastrointestinal tract surface area but < 5% of GI cancers occur in the small bowel. 1997 epidemiologic data from the United States demonstrated 131,200 large bowel cancers, 22,400 stomach cancers but only 4,900 small bowel cancers. PET scan is increasingly being used to stage and restage disease. Hoever, its sensitivity and specificity has only been defined for the most common cancers, such as lung, breast and others. Small bowel cancer has not been systemaically studied in this regard and, without reliable data, or guideline recommendations, restaging with PET cannot be recommended and can be misleading.

http://advanced-radiology.com/guidellines/Abdomen_Imaging_Guidelines.pdf

Can PET/CT Replace Separate Diagnostic CT for Cancer Imaging? Optimizing CT Protocols for Imaging Cancers of the Chest and Abdomen
Hilmar Kuehl, Patrick Veit, Sandra J. Rosenbaum, Andreas Bockisch, and Gerald Antoch J Nucl Med 48: 45S-57S.

Peritoneal Carcinomatosis: Role of 18F-FDG PET
Alla Turlakow, Henry W. Yeung, Aida Sanchez Salmon, Homer A. Macapinlac, and Steven M. Larson J Nucl Med 44: 1407-1412.

Gemzar carboplatin for recurrent ovarian cancer.

Although the general intent of treatment for patients with recurrent ovarian cancer is palliative, and cure does not seem to be a realistic objective in this setting, median overall survival is greater than 12 months in platinum-sensitive recurrent ovarian cancer. Patients with ovarian cancer can now expect that the time from first relapse of their disease to death will be longer than the period from diagnosis to that first relapse. There is current evidence from prospective randomized trials that carboplatin combined with either paclitaxel or gemcitabine confers a progression-free survival advantage over platinum monotherapy for patients with platinum-sensitive relapsed ovarian cancer. The combination of gemcitabine and carboplatin specifically have been tested in phase III for recurrent ovarian cancer. Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer. It is listed by NCCN on p. 10 of ovarian cancer.

Maurie Markman, Michael A. Bookman Second-Line Treatment of Ovarian Cancer The Oncologist, Vol. 5, No. 1, 26-35, February 2000

Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück HJ, Rochon J, Zimmermann AH, Eisenhauer E; AGO-OVAR; NCIC CTG; EORTC GCG.Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006 Oct 10;24(29):4699-707.

Kose MF, Meydanli MM, Tulunay G.Gemcitabine plus carboplatin in platinum-sensitive recurrent ovarian carcinoma.Expert Rev Anticancer Ther. 2006 Mar;6(3):437-43.