Clinical Abstracts From Overseas: June 23, 2010

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â–º SOUTH KOREA

Is Intermittent Imatinib Therapy for Chronic Myelogenous Leukemia an Option?

Taken chronically, imatinib has proved to be an extremely effective agent against chronic myelogenous leukemia (CML); however, this regimen is relatively expensive and it is not known whether intermittent treatment may provide similar outcomes in appropriate patients or whether withdrawal of therapy will promptly result in relapse.

A small study from St. Mary’s Hospital, Seoul, Korea, may provide some direction. Over six years at this facility, 555 patients had been treated with imatinib for Philadelphia chromosome—positive CML; 26 patients (median age, 35 yr; 54% men) had discontinued therapy for various reasons after achieving a complete cytogenetic (11 patients) or molecular (15 patients) response. If the patients suffered a relapse, imatinib therapy was reinitiated.

With a follow-up ranging to 48 months (mean, 7 mo), four patients suffered hematologic relapse, seven experienced cytogenetic relapse, and 10 had molecular relapses. Two patients did not suffer any relapse. One patient died. After readministration of imatinib treatment, all 23 remaining patients have maintained their best rated response compared with before discontinuing therapy.

Based on the results of this study, the researchers found that intermittent therapy is possible for appropriate patients, but that it is difficult to know which patients are best suited to discontinuation. They believe that a larger study with a longer follow-up will be necessary to answer this question more completely.

Goh H-G, Kim S-H, Lee J, et al: Outcomes of patients with chronic myeloid leukemia who received an intermittent imatinib therapy. Presented at the 49th annual meeting of the American Society of Hematology, Atlanta, December 9, 2007.

Genetic Marker Predicts Treatment Resistance and Poor Outcomes in Esophageal Cancer

Patients with localized esophageal cancer can often benefit from chemotherapy and radiation treatment, but the prognosis varies considerably, for example, depending on stage of cancer at diagnosis. Another possible determinant of prognosis may be the ability of the tumor to express certain genes. This was tested by a team of oncologists, radiologists, surgeons, and pathologists at the Asan Medical Center, Seoul, South Korea.

Some esophageal tumors express excision repair cross complementation group 1 (ERCC1), others express increased thymidylate synthase (TS) production, and yet others demonstrate expression of both genes. The researchers biopsied tumors from 129 patients and tested these samples for over-expression of these genetic markers. These patients with esophageal cancer were treated preoperatively with 5-fluorouracil/ cisplatin or capecitabine/cisplatin plus radiation from March 1993 to June 2005.

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Thirty-five percent of the biopsied samples (from 108 patients evaluable) tested positive for TS and 40% tested positive for ERCC1. The researchers found that patients who tested negative for either marker were more likely to achieve “pathologic major response.” Although negative tests for both genetic markers resulted in positive correlations for response, the test for ERCC1 was deemed the only independent variable that predicted the pathologic response ( < .001). However, the prediction of pathologic response did not portend a statistically signifi- cant relationship with overall survival ( = .10) and progression-free survival ( = .08).

The investigators conclude that although this was not a prospective study, it does show that the use of a genetic marker may help predict chemoradiation response or resistance in patients with esophageal cancer. They recommended prospective clinical trials to confirm this theory.

Kim MK, Cho KJ, Kwan GY, et al: ERCC1 predicting chemoradiation resistance and poor outcome in oesphageal cancer

2008;44:54-60.

. Eur J Cancer

â–º FRANCE

Pelvic Radiation in Addition to Prostate Radiotherapy for Localized Prostate Cancer

Can patients with localized prostate adenocarcinoma who receive prostate radiotherapy also benefit from pelvic radiation? The literature is not clear on this question, and radiologists from Lyon, France, decided to test whether the broader radiation approach influences outcomes.

Over six years, the researchers randomly assigned patients with localized prostate cancer to receive prostate radiotherapy with or without pelvic radiotherapy. Inclusion criteria included tumors that were characterized as T1b-T3, N pNx, M0. Only patients taking short-term chemotherapy who deemed to be at high risk were included in the trial; otherwise, the use of chemotherapy excluded one from the study.

The dose of pelvic radiation was 46 Gy, and the dose of prostate radiation was 66 or 70 Gy.

Over a median 42-month follow-up, the fiveyear progression-free survival and overall survival were similar in both groups of patients. Nor did the researchers find any significant differences in gut toxicity. Therefore, they concluded, pelvic radiation did not contribute to improved outcomes in patients with local prostate cancer who were undergoing prostate radiotherapy.

Pommier P, Chabaud S, Lagrange JL, et al: Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01

2007;25:5366-5373.

. J Clin Oncol

â–º MULTIPLE SITES IN EUROPE European Guidelines for Oral Mucositis ReleasedChemotherapy and radiotherapy treatment of cancer often results in oral mucositis, a serious side effect that can hamper nutritional intake, quality of life, and the ability to complete the oncologic therapeutic regimen. This side effect can occur in as many as 40% of patients receiving chemotherapy and up to half of those receiving chemotherapy and radiotherapy. It is usually treated with artificial saliva solutions, mouthwashes, and pharmacologic agents (e.g., palifermin), but protocols do not exist to provide better guidance as to what works and what does not.

Multidisciplinary experts from London and Nottingham, United Kingdom; Nijmegen, The Netherlands; Berne and Zurich, Switzerland; and Stockholm, Sweden, have developed new standards for the prevention, assessment, and treatment of oral mucositis in patients receiving chemotherapy, radiotherapy, and hematopoietic stem-cell transplants.

One of the basic problems addressed by the new guidelines is that tools to assess oral mucositis are many and their results vary considerably. The collaborators believe that the key to more accurate assessment is the existence of a standardized baseline evaluation using one standardized tool, or at the very least, a standard combination of tools. These tools should account for not only physical signs, but functional status, and subjective changes.

With regard to subjective measures, they emphasize that patient self-reports of pain associated with oral mucositis be included in the assessment. They acknowledge, however, that such a comprehensive pain-assessment instrument has not yet been validated.

Quinn B, Potting CMJ, Stone R, et al: Guidelines for the assessment of oral mucositis in adult chemotherapy, radiotherapy and haematopoietic stem-cell transplant patients

2008;44:61-72.

. Eur J Cancer

â–º JAPAN The Care of Delirium in Terminal Illness and Bereavement NeedsA Japanese Study Effectively treating delirium in patients with terminal cancer is difficult and can result in patient unwanted side effects, including excessive sedation and disorientation, and cause concern and grief for family members and caregivers alike. Multiple palliative care facilities in Japan joined together to conduct a survey of families regarding the effect of their loved ones’ delirium in their final two weeks of life.

Seventy-two percent of the 560 bereaved families completed the survey, and 160 denied that their loved ones experienced delirium episodes. Of the 242 remaining survey responses involving delirium, the families reported being “very distressed” or “distressed” by the episodes of terminal delirium 32% and 22% of the time, respectively. Only 6% stated that “much improvement” in the care of the patient was necessary, although 31% desired “some improvement” in the palliative care services provided.

Up to one-third of families expressed they perceived a burden with respect to proxy decision making and/or helplessness. More than one-half experienced guilt in not being able to stay with the patient long enough during these episodes.

The researchers found that greater emotional stress of the family and the desire for palliative care service improvement was more likely seen in younger families, if the patient had frequent episodes of agitation or incoherence, whether the delirium was thought to be a result of the disease or medications, and whether medical staffwas present or willing to explain to them the types of experiences they could expect in the last stages of life. The Table provides some recommended strategies suggested by the investigators to better inform family expectations about their loved one’s last weeks of life.

Useful Strategies in Alleviating Family Anxiety About End-stage Palliative Care Services for the Patient with Terminal Cancer

• Manage patient agitation, while carefully considering the family's wishes
• Demonstrate consideration for the patient's subjective environment
• Provide the family education about the pathology of delirium and help manage their expectations about treatment
• Relieve the famikly's burden of care to the extent possible
• Maintain a frequent presence in the palliative care unit or hospice, being available to answer family questions

Morita T, Akechi T, Ikenaga M, et al: Terminal delirium: Recommendations for bereaved families’ experiences. J Pain Symptom Manag 2007;34:579-589.

â–ºTHE NETHERLANDS

Cancer Pain and Adherence to Analgesic Treatment

Which Is the Best Measure?

For patients with asymptomatic disease, such as hypertension, maintaining compliance with the treatment can be a tremendous challenge. For patients with moderate to severe pain, having to convince patients to take their prescribed analgesics in the correct amounts and on schedule should be less of a concern. However, a study from The Netherlands indicates that even motivated patients, such as those with cancer pain, have trouble adhering to analgesic therapy.

The investigators from Amsterdam, Rotterdam, and Maastricht sought to determine whether electronic monitoring or a patient-reported diary provided the most accurate information with regard to pain medication use in 46 outpatients who experience nociceptive pain associated with a cancer diagnosis. Over four weeks, all of the participants were asked to use the Medication Event Monitoring System (Aprex Corp., Fremont, CA), which is a medication bottle cap with a microprocessor that records each time the bottle is opened, and also records any medicines they take in a written diary.

Seventy-nine percent of the patients used their medications, according to the electronic monitoring system, whereas 70% recorded their medication-taking behavior over the four-week period. The investigators revealed that these patients with cancer generally took their medication (87% compliance rate) but they did not take them at the correct intervals (53% adherence with timing instructions).

This research found that electronic adherence measurement and self-reported patient diaries are largely comparable in terms of their accuracy by patients with cancer pain, but that even these patients, motivated by their painful symptoms, do not adhere optimally to therapeutic instructions.

Oldenmenger WH, Echteld MA, de Wit R, et al: Analgesic adherence measurement in cancer patients: Comparison between electronic monitoring and diary

2007;34:639-647.

. J Pain Symptom Manag

â–º SWITZERLAND, BELGIUM, FRANCE

Confirmation of Gene Expression Link to Chemotherapy Response in Breast Cancer

Clinical evidence that gene overexpression may be related to whether one cancer therapy may work better than another for a particular patient has been fast and furious recently. A consortium of researchers primarily from Switzerland, Belgium, and France has used the results of a large phase III cancer trial to confirm the results of their earlier preclinical findings that genetic markers can provide direction in individualized cancer treatment effectiveness.

in-vitro

The EORTC 10994/BIG 00-01 trial compared the use of a six-cycle nontaxane regimen for breast cancer (5-fluorouracil, epirubicin, and cyclophosphamide) with a taxane regimen (3 cycles of docetaxel, then 3 cycles of combined epirubicin and doctaxel) in women with estrogen receptor—negative breast cancer. The researchers noted that the prediction of response based on gene expression was a secondary endpoint of the trial. They used single-agent drug sensitivity tests to obtain what they referred to as “regimen-specific gene signatures” for both treatment modalities.

One hundred twenty-five tumors were tested, including 66 tumors from the nontaxane group of patients and 59 in the taxane group (28 and 27 demonstrated complete pathologic responses, respectively). The prediction of complete pathologic response was highly correlated (P < .0001) (Table).

Predicting Response to Breast Cancer Therapy

Gene Signature for non-Taxane Regimen Response

Gene Signature for Taxane Regimen Response

Sensitivity

96%

93%

Specificity

66%

69%

PPV

68%

68%

NPV

96%

92%

PPV = Positive predictive value; NPB = negative predictive value.

The authors believe that the use of these genetic markers of chemotherapy effectiveness would have increased the proportion of patients experiencing complete pathologic responses from only 44% in the actual trial to 70%.

Bonnefoi H, Potti A, Delorenzi M, et al: Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: A substudy of the EORTC 10994/BIG 00-01 clinical trial

2007;8:1071-1078.

. Lancet Oncol