Local Oncologist Research Articles

Non-Relapse Mortality (NRM) after Autologous Stem Cell Transplant (ASCT) Is Reduced with Stringent Follow-up Post-Transplant.

Advances in supportive care have reduced early treatment related mortality with ASCT to approximately 1%. ASCT is so well tolerated that it is commonly thought that patients (pts) either relapse or are cured from their disease. However, registry data continues to show that NRM accounts for 25% of treatment failures following ASCT. NRM in this setting is poorly studied and represents a possible area of intervention. We previously reported on NRM at the Cleveland Clinic (ASH 2007: Abstract 1671) in which we reviewed 1573 consecutive autologous transplants performed between 1/92 and 12/05. This analysis included only adult pts receiving peripheral stem cells, single transplants, busulfan based preparative regimens, diagnoses of HL, NHL and MM (n=856). Relapse was the most common cause of death in 303 (79%) pts with NRM occurring in 82 pts (21% of deaths). The most common cause of NRM was pulmonary toxicity in 26 pts, followed by secondary malignancy (19 pts), infection (12 pts), cardiac toxicity (7 pts), other organ failure (7pts) and other causes (11 pts). The majority of NRM from pulmonary toxicity, other organ failure and infection occurred within one year of transplant. Forty-seven patients died within 100 days of transplant – 30 from relapse and 17 from NRM. In an effort to reduce NRM, we targeted pulmonary toxicity as a point of intervention. To identify pts at higher risk for pulmonary toxicity we prospectively followed 137 consecutive pts from 4/05 to 4/06 with monthly phone calls from the BMT nurses using a questionnaire focused to identify pts with symptoms of pulmonary toxicity, and obtained PFTs 1 and 6 months post-ASCT. 12/137 pts had a decrease in DLCO with 7 (58%) of events occurring within one month of transplant, an additional 4 (33%) events within 6 months and one event (9%) at 11 months. HL was the underlying diagnosis in 41% of pts, and prior radiation therapy (XRT) was also identified as a risk factor. Based on this analysis high risk pts were then defined as pts with a decline in DLCO >25% at one month post-ASCT, pts with HL and those with history of prior XRT. High risk pts received 4 and 8 months post-ASCT PFTs. Increased vigilance for the low risk group included phone calls at 3, 6 and 12 months to check for symptoms of pulmonary dysfunction. Patients experiencing a drop in DLCO of >25% at any point in time received a course of steroids and repeat PFT testing. The patient's local oncologist also received a letter which included a copy of CDC vaccination guidelines with recommendations for re-immunization at one year post-ASCT, and a list of signs and symptoms of delayed pulmonary toxicity. To evaluate if changes made to our follow-up protocol impacted on rates of NRM, we identified 149 pts undergoing ASCT from 5/06 to 12/07 (using the same inclusion criteria as the original cohort). Data regarding the original 856 patients was also updated. For the 5/06 to 12/07 study group 127 pts (85%) are alive and 22 pts (15%) have died. Twenty pts (90.9 %) died from relapse and 2 pts (9.1%) died from NRM, both due to pulmonary toxicity. Only two patients died within 100 days of transplant, both due to relapse. There was no NRM within 100 days of transplant. On multivariable analysis of risk factors for NRM for all patients, year of transplant (1/92 to 12/05) emerged as a risk factor for NRM (HR 5.24, P=0.026). Age at transplant (HR 1.26, P=.013), number of prior chemotherapy regimens (HR 1.24, P=.019), prior radiation (HR 1.81, P=.006) and time to platelet engraftment (HR 0.24, P=.001) also emerged as risk factors for NRM. We have adopted more stringent post-ASCT surveillance protocols and while follow-up is short, results suggest that it may be possible to reduce NRM after ASCT.

Health service research study with cohort design measuring survival of colorectal cancer (CRC) patients treated with and without Viscum album L.

Aim of NO Up to 64% of cancer patients complement their therapy with Viscum album (VA) treatment at some stage of their disease. This very common complementary and alternative medicine treatment is frequently used to mitigate adverse drug reactions of chemo and radio therapy, as well as to increase quality of life. However, it is currently unclear if this co-medication has detrimental effects on the patients. Building on data of the Network Oncology (NO) cancer register, the following investigation compares colorectal cancer (CRC) patients, treated with or without VA. Method Since 2001, the NO systematically collects and standardises all data on file of all cancer patients treated in Gemeinschaftskrankenhaus Havelhohe (GKH). All cases of CRC from 1996 until 2001 were included retrospectively. All patients were contacted in 2001/2, 2004 and 2007 by mail to obtain information on disease progression and therapeutic interventions, subsequent to their visit of GKH. Where necessary, a reminder was sent 8 weeks later. Whenever informed consent was given, their GP or local oncologist was also contacted. Mortality rates and time of death were calculated using data from deaths’ registries. Results Thus far 925 patients have been included (57.5% female). Average age of first diagnosis was 69 (71 female, 67 male). Of the total number, 697 were followed up or confirmed dead by 2007. Return rates by mail were approximately 60% by patients and 40% by GPs/oncologists. The majority of patients was treated according to standard guidelines at the time of consultation. About 43% of males and 54% of females received also VA between 4 weeks and several years. Early indications suggest that the median survival time of VA-treated patients was 29 month, respectively 22 month in the controls. However, average age of first diagnosis was lower (67 and 72, respectively). When adjusted for age, sex and disease state a trend for survival improvement in the viscum group is seen. Conclusion Using NO as a basis, it is possible to follow up all patients with a specific diagnosis or treatment modality. The present cohort study demonstrates that NO is well suited to carry out health service research. If VA has an effect on survival time remains a question for further follow up.

Integrative Tumor Board: Metastatic Breast Cancer

History of present illness In December 2000, a routine mammogram showed a large zone of calcification involving the right breast. A sonogram revealed a solid oval mass measuring 0.8 × 1.0 × 0.6 cm in the retroareolar portion of the right breast. A biopsy of this area showed ductal carcinoma in situ (DCIS) with comedo necrosis, nuclear grade 2/3, lymphatic invasion absent. In February 2001, the patient underwent right simple mastectomy with sentinel lymph node biopsy. Pathology revealed extensive DCIS and focal invasive, moderately differentiated ductal carcinoma. The tumor size measured 1.0 cm, and resection margins were free of tumor involvement. Sentinel lymph node was negative for malignancy. Tumor was estrogen and progesterone receptor positive and Her-2/neu negative by fluorescence in situ hybridization (FISH) assay. The patient did not receive adjuvant chemotherapy, but following surgery, she was started on tamoxifen 20 mg daily. The patient continued to have regular menstrual cycles while on tamoxifen. The patient did well until October 2005, when she began to experience postprandial abdominal pain and nausea. In addition, she noted right hip pain and lower back pain. Extensive workup and restaging studies were performed. A computed tomography (CT) scan of the thorax, abdomen, and pelvis revealed small right axillary lymph nodes, mildly prominent lymph nodes in the anterior mediastinum, bibasilar effusions, an 11-mm lesion in the dome of the liver, ascites, multiple thickened loops of small bowel with mild dilation, gallstones, and findings suspicious for an omental cake formation. A bone scan showed diffuse sclerotic metastases involving the spine, ribs, calvarium, pelvis, and left proximal femur. Magnetic resonance imaging (MRI) viously in the reference range. In November 2005, the patient underwent bilateral thoracentesis. Cell block showed malignant metastatic adenocarcinoma, estrogen receptor positive, progesterone receptor negative, Her-2/neu negative by FISH assay. Tamoxifen was discontinued, and the patient was started on Zometa, as well as chemotherapy with Taxol and Avastin every other week. The patient received 2 cycles of chemotherapy with her local oncologist in New York. In December 2005, the patient presented to the Block Center for Integrative Cancer Care for a consultation on integrative cancer treatment. Beginning in January 2006, the patient commuted for treatment from her home in New York. She continued to receive weekly Taxol (day 8 given by local oncologist), Avastin every 2 weeks, and monthly Zometa. The protocol is based on the E2100 protocol. Her baseline serum tumor markers were as follows: CA 15-3 = 1334; CA 27,29 = 1708. In February 2006, tumor markers improved; CA 15-3 = 1035; CA 27,29 = 1081. In March 2006, a repeat staging CT scan of the thorax, abdomen, and pelvis showed a significant decrease in pleural effusions and no significant change in skeletal metastases or abdomen/pelvic findings. In April 2006, serum tumor markers continued to improve: CA 15-3 = 616; CA 27,29 = 712. At this time, the patient developed significant postprandial right upper quadrant abdominal pain. A HIDA scan revealed nonvisualization of the gallbladder, suggesting occlusion of the cystic duct. Avastin was discontinued temporarily because of potential cholecystectomy and increased risk of surgical bleeding. In May 2006, Taxol was placed on hold because of an upcoming cholecystectomy. In late May, the patient

Flavopiridol, Fludarabine and Rituximab Is a Highly Active Regimen in Indolent B-Cell Lymphoproliferative Disorders Including Mantle Cell Lymphoma.

The cyclin-dependent kinase inhibitor flavopiridol was inactive when given by 24–72-hr infusion, but 1-hr IV bolus dosing demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis independent of p53 and may be able to eliminate tumor cells resistant to fludarabine and rituximab. We performed a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with MCL, CLL and indolent B-cell non-Hodgkin's lymphoma (NHL). Pts had ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), day 1–2 (cohort 2), or day 1–3 (cohort 3) of each cycle. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was prohibited. Twenty-one pts were enrolled and are evaluable for toxicity and response. Median age was 62 years (range, 43–81), and 10 pts were male. Pts had the following diagnoses: CLL (8), MCL (5), follicular lymphoma (FL; 4), small lymphocytic lymphoma (SLL; 3), and lymphoplasmacytic lymphoma (1). Nine pts had received 1-2 prior therapies; 12 pts were previously untreated. CLL pts were Rai stage III/IV (5) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. NHL pts were stage III/IV (10) or had progressive stage II disease (3). Three pts were treated in cohort 1, and dose limiting toxicity (DLT) was not observed. Six pts were treated in cohort 2. Two pts developed DLT; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Three pts in cohort 2 did not receive flavopiridol after cycles 2, 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Twelve additional pts were enrolled at the cohort 1 dose level, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 9 of 21 pts completed all 6 planned cycles. Therapy was stopped early due to cytopenias (7), infection (2), DLT (2) or progressive disease (1). One patient who received only 2 cycles of FFR due to cytopenias subsequently received 4 cycles of fludarabine and rituximab from his local oncologist. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 90%; 15 pts achieved CR (71%), and 4 pts achieved PR (19%). Six pts relapsed a median of 7.5 months (range 4–18) after completing therapy; 13 pts remain in remission a median of 11 months (range 4–23) after completing therapy. Of note, all 9 MCL/FL pts responded (8 CR, 1 PR), and 8 pts remain in remission a median of 15 months (6–23) after finishing therapy. In conclusion, FFR exhibited significant clinical activity in a small group of pts, but cytopenias limited the administration of therapy. We are currently studying a modified FFR regimen administering a more active flavopiridol schedule (30-min IV bolus followed by 4-hr IV infusion) and allowing the use of prophylactic filgrastim, prior to phase II clinical study.

An Unusual Radiologic Presentation of an Uncommon Bronchogenic Lung Carcinoma

(CHEST 2005; 127:2264–2265) A 63-year-old woman presented with a short history (a few months) of persistent cough and mild shortness of breath. On further enquiry, she admitted to having a poor appetite, with an associated weight loss of approximately 4 kg over a period of 6 months. Clinical examination was unremarkable and did not reveal any signs of lung malignancy. A chest roentgenogram showed bilateral multiple pulmonary nodules (Fig 1). Blood tests for angiotensin-converting enzyme levels, systemic vasculitic screen, antineutrophil cytoplasmic antibody, and rheumatoid factor were normal. The C-reactive protein was mildly elevated at 52 mg/L. CT with IV contrast enhancement confirmed multiple nodular lesions within both lungs (Fig 2). The majority of the lesions had an unusual appearance, with a solid rim surrounding necrotic material and a more dense opacity at the center, reminiscent of an archery target. There was a larger cavitating lesion in the left lower lobe suggesting a primary tumor with multiple metastases. CT also revealed a mass in the left ovary. However, oophrectomy and subsequent histology revealed the lesion to be a benign ovarian fibroma. An open-lung biopsy was carried out to establish the diagnosis of the multiple lung nodules. At surgery, several visceral puckering nodules were identified. Histology of a lingular biopsy revealed multiple well-circumscribed tumors with central necrosis and cavitation. The tumors consisted of pleiomorphic epithelial cells with both glandular and squamous features, each of which comprised approximately 50% of the tumor and in keeping with primary adenosquamous carcinoma of the lung. She made an uneventful recovery from the surgical intervention and was referred for further treatment to her local oncologist.

The neurosurgeon as local oncologist: cellular and molecular neurosurgery in malignant glioma therapy.

Malignant gliomas are among the most challenging of all cancers to treat successfully, being characterized not only by aggressive proliferation and expansion but also by inexorable tumor invasion into distant brain tissue. Although considerable progress has been made in the treatment of these tumors with combinations of surgery, radiotherapy, and chemotherapy, these efforts have not been curative. Neurosurgeons as oncologists have increasingly turned their attention to therapies on a molecular scale. Of particular interest to neurosurgeons is the ability to deliver therapy locally to the tumor site or to take advantage of existing immunological mediators, enhancing drug concentrations or therapeutic cell numbers while bypassing the blood-brain barrier to maximize efficacy and minimize systemic toxicity. Exciting local-therapy approaches have been proposed for these devastating tumors. In this review, we discuss the potential applications of bioreactors, neural stem cells, immunotherapies, biodegradable polymers, and convection-enhanced drug delivery in the treatment of malignant gliomas. These approaches are at different stages of readiness for application in clinical neurosurgery, and their eventual effects on the morbidity and mortality rates of gliomas among human patients are difficult to ascertain from successes in animal models. Nevertheless, we are entering an exciting era of "nanoneurosurgery," in which molecular therapies such as those discussed here may routinely complement existing surgical, radiological, and chemotherapeutic approaches to the treatment of neuro-oncological disease. The potential to deploy any of a number of eloquently devised molecular therapies may provide renewed hope for neurosurgeons treating malignant gliomas.

Wrestling with Prostate Cancer

Wrestling with Prostate Cancer