Anne[a]
Higlights Of the American Society Of Clinical Oncology conference, Day 2
Reported by Melissa Stoller
The defining moment of Sunday morning´s Central Nervous System session came when the NCI´s Richard Kaplan presented some hard but heartfelt questions to the crowd that had come to discuss the morning´s posters. Kaplan had made a survey of the presentations, and noted that 54 of the CNS posters that mentioned effect suggested that the study had been positive, using words such as "promising," "modest activity" or "suggest activity." Only 7 presenters concluded that their treatments had been ineffective. So, asked Kaplan, will our patients not be dying when we come here next year? The crowd, clearly in agreement over the weakness of the data that supported these claims of activity, tittered unhappily, shaking their heads. Kaplan attributed this "clinician´s optimism" not to any desire to deceive, but merely to the physician´s desire to "look hard for improvement," and the difficulty of admitting that a study which has consumed so much time and effort is a failure. This unwarranted optimism may have an unfortunate consequence. Kaplan questioned whether, in an effort not to abandon marginally effective agents, researchers are diluting their efforts to find real breakthroughs.
Two posters were presented on the IL-13 PE trials. In both trials, patients were biopsied, and the IL13-PE38 was infused, varying length of infusion, drug concentration, duration and number of courses. In the Ram study, the tumor was then resected. Both studies enrolled patients with recurrent malignant glioma, but the Ram study (Abstract 403) had 14 of 16 GBM, while the Weingart study (Abstract 405) had 7 of 18 patients with GBM. Mean age was not reported. Neither study has yet reached the maximum tolerated dose. Unfortunately, much of the data were presented as ranges, which are difficult or impossible to interpret. Weingart reported 4 responses in the 18 patients, but overall survival was cryptically reported as 7-126+ weeks, and progression free survival as 3-68+ weeks. The Ram study did not report any responses, and, again, survival and progression were impossible to evaluate from the ranges reported.
A number of posters evaluated tz in combination with other agents, including BCNU, O6-benzylguanine, and CPT-11(Abstracts 409,410,411,413,414,415,431). Stuart Grossman, in his discussion, questioned whether there is a survival benefit in these combination therapy trials. He referred to his own study of BCNU with cisplatin, which he believed to be promising but proved not superior to BCNU in later comparison (Journal Clinical Oncology 2003). Chang´s study of BCNU +TZ in newly diagnosed gliomas was also discussed. That a 2% complete response and a 27% partial response rate is considered a positive outcome was cited as a sobering indication of how marginally active alklylating agents remain in gliomas.
A study in anaplastic oligodendroglioma (Abstract 426), found no difference in response to tz vs. PCV. Thought the size of the study is small, non-risk-averse OD and OA patients who wish to avoid the toxicity of PCV might bring this to the attention of their oncologists.
Pudavalli (Abstract 419) was one of the exceptions to Kaplan´s "clinician´s optimism", and these authors conclude that "fenretinide [a synthetic retinoid] is not active against malignant gliomas at the dosage [600mg/m2 BID] utilized in this trial. Results for Iressa (Abstract 421) and CC-5013 (Abstract 418) were also unimpressive, though CC-5013, a thalidomide analog, was tested in an older, very heavily pretreated population. Interestingly, fatigue was not a toxicity and little neuropathy was seen. Though better responses may be seen in a different population, it is notable that another study of this analog, presented in the Melanoma Session, was clearly active in melanoma, but had little if any activity in other cancers (Abstract 2862).
A rather remarkable poster was presented in the afternoon session by Streiff (Abstract 450). It is well established that venous thromboembolism is a common occurrence in malignant brain tumor patients. Streiff, in a retrospective study, found that the frequency of thromboembolism varied by blood group. Alarmingly, two-thirds of malignant glioma patients with blood type AB were diagnosed with VTE within 18 months of diagnosis. Blood group O, on the other hand, seemed to have a protective effect.
Ravel (Abstract 452) also injected some controversy into the afternoon session, with the finding that "contrary to prior reports, MGMT promoter methylation did not predict better survival" in this study of 39 patients with malignant gliomas.
Finally, a poster that might be of some significance to brain tumor patients (Abstract 2866) "Lymphopenia and herpes zoster infection in metastatic melanoma patients treated with temozolomide and thalidomide " was not presented.
The afternoon concluded with an excellent Molecular Therapeutics session summarized on the ASCO. Sugen´s experimental VEGFR , PDGFR, Kit-FLT3 inhibitor, SU 11248, was featured. This drug is particularly appealing because it has both anti-angiogenic and signal transduction targets. It was tested in a variety of advanced malignancies, but no brain tumors. Of particular interest to brain tumor patients taking anti-angiogenic compounds was the observation that patients seemed to experience accelerated tumor growth during the two off-weeks of the four-on, two-off cycle. This was attributed to a 4-fold rise in VEGF. Presumably, cells are able to sense that the VEGF receptor is blocked and upregulate the ligand to overcome this malfunction. When the drug is withdrawn, tumor growth accelerates.