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ASCO 2001: CRITICAL COMMENTARIES PART 1 |
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Correspondence: Robert Maki, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center, Sarcoma Program, Box 223, 1275 York Avenue, New York, New York 10021-6007, USA. Telephone: 212-639-5720; Fax: 212-717-3394; e-mail: makir{at}mskcc.org
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ABSTRACT |
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 Top Abstract IntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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Key Words. Sarcoma • Treatment • ASCO
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INTRODUCTION |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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IMATINIB MESYLATE AND GIST |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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STI571, an Active Drug in Metastatic Gastro Intestinal Stromal Tumors (GIST), and EORTC Phase I Study. AT Van Oosterom, I Judson, J Verweij, E Di Paola, M van Glabbeke, S Dimitrijevic, O Nielsen (ABSTRACT 2).
FDG PET Response to Neoadjuvant Chemotherapy Predicts Survival in Patients with Soft Tissue Sarcoma. S Schuetze, E Conrad, J Bruckner, C Vernon, J Eary (ABSTRACT 1389).
Study Design and Results
These studies showed the dramatic responses of GIST to STI571 in a cohort of patients with metastatic disease for the first time after the recent case report of a single responding patient with metastatic GIST in Finland. In the European study, increasing doses of imatinib mesylate were administered until dose-limiting toxicity of nausea and vomiting was noted at a dose of 500 mg orally (p.o.) twice a day (b.i.d.). The maximum tolerated dose was defined as 400 mg p.o. b.i.d. A total of 40 patients were treated. Of the 36 GIST patients treated, 13 had a partial response (PR), defined as >30% reduction in tumor diameter. Another 12 patients had either unconfirmed PR or minor responses (20%-29% reduction in size). Four had frank progression. Positron emission tomography (PET) scans showed responses as early as 1 week after the start of imatinib mesylate therapy.
In the American study, 148 patients were treated in a randomized fashion with either 400 mg p.o. daily or 400 mg b.i.d., with 86 patients with >3 months follow-up. Twenty-five percent of evaluable patients required a dose reduction for toxicity such as peripheral edema or bleeding from tumor sites. Fifty of the 86 evaluable patients (58%) had a PR, and 11 (13%) had frank progression, most on the lower-dose arm. Interestingly, at 4.5 months median follow-up, none of the responding patients had progressed. Eighty-six percent of patients had a c-kit mutation, most commonly in exon 11, and the remainder had mutations in exon 9 or exon 17. Fourteen percent of patients had a wild type c-kit. Exon 9 mutations were associated with a better chance for a response than other c-kit phenotypes. As in the previous study, PET scans performed in this study demonstrated responses early after administration of STI571, and also showed progression of disease at an early stage.
Commentary
These remarkable findings stand in striking contrast to the <5% response rate seen in patients with GIST who receive standard chemotherapy, noted in the first patient treated in Finland [1]. These studies also confirm the utility of PET scans in providing an early indicator of response to this agent. The ongoing nationwide phase III study of 400 mg versus 800 mg a day of imatinib mesylate will help fix the starting dose in this disease. The finding that c-kit mutations correlate with response indicates that the mutated c-kit protein may have a higher affinity for the drug or a more pivotal role in cell signaling in these tumors compared with normal cells expressing c-kit, such as bone marrow-derived stem cells, mast cells, and melanocytes.
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NOVEL AGENTS IN SOFT-TISSUE SARCOMA |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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ET-743 is an Active Drug in Adult Soft-Tissue Sarcoma (STS): A STBSG-EORTC Phase II Trial. A Le Cesne, J-Y Blay, I Judson, A Van Ooosterom, J Verweij, J Radford, P Lorigan, S Rodenhuis, ED Di Paola, M Van Glabbeke, J Jimeno, O Nielsen (ABSTRACT 1407).
Ecteinascidin (ET-743) Given as a 24 Hour (H) Intravenous Continuous Infusion (IVCI) Every 3 Weeks: Results of a Phase II Trial in Patients (pts) with Pretreated Soft Tissue Sarcomas (PSTS). A Yovine, M Riofrío, E Brain, J-Y Blay, C Kahatt, S Delaloge, L Beautier, P Cottu, J Jimeno, E Cvitkovic, J-L Misset (ABSTRACT 1449).
Study Design and Results
These studies present the results of treatment with a new agent, ecteinascidin-743 (ET-743), in a large number of patients with advanced soft-tissue sarcomas. These patients were given infusions of ET-743 over 24 hours and, due to nausea and vomiting caused by ET-743, required routine antiemetics. Other common side effects included a transient but significant elevation in liver function tests and acute, reversible myelosuppression. Growth-factor support was not routinely needed at a dose of 1.5 mg/m2 ET-743 every 3 weeks. A downward dose adjustment was found necessary in patients who had grade 1 bilirubin or alkaline phosphatase toxicity following a previous treatment cycle. Those abnormalities were associated with subsequent rhabdomyolysis and renal failure, and death in two patients, when they received full doses of ET-743 in a subsequent cycle of therapy.
GIST did not respond to ET-743. The response rate of other sarcomas was in the 10%-20% range: 6%, 9%, and 11.4% in previously treated patients and as high as 18% in untreated patients in the studies presented at ASCO. Responses were durable in some responders, up to 14 months and more. The best responses were seen in patients with liposarcoma and leiomyosarcoma. These data, as well as pharmacokinetic analysis derived from this study, have led to a new study design of ET-743 in a 3-hour (not 24-hour) infusion.
Commentary
If not for the data on imatinib mesylate, the findings of this study would have received greater attention. ET-743 appears to work through a complex mechanism. It binds to DNA in the minor groove and inhibits transcription by interfering with transcription factor NF-Y at the CCAAT DNA promoter common to many genes, including multidrug resistance gene MDR1 [2, 3]. The reduction of MDR1 expression suggests that the drug should be tested in combination with doxorubicin, a substrate for MDR1 and an inducer of MDR1 expression.
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COMBINATIONS OF STANDARD AGENTS IN SOFT-TISSUE SARCOMA |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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A Phase II Trial of Gemcitabine, Paclitaxel and Carboplatin in Stage IVB Soft Tissue Sarcoma. TJ Colterelli, JF Germino, L Shanabrook, J Eid, R Dipaola, E Rubin, R Musanti, W Hait (ABSTRACT 2930).
Phase I Study of Low Dose Continuous Infusion Gemcitabine in Sarcoma Patients. BL Samuels, L Barbour, D Schiller (ABSTRACT 2935).
Study Design and Results
The common element of these studies is the use of gemcitabine in patients with soft-tissue sarcoma. Gemcitabine was given in different doses and schedules in each of these studies. The most impressive results were in combination with docetaxel. In a study that predominantly included uterine leiomyosarcoma patients, gemcitabine was given weekly for 2 of 3 weeks with week 2 administration of docetaxel (and subsequent filgrastim support). This combination gave a remarkable three complete responses (CR) and five PR in 16 evaluable patients (50% overall response rate) in this very specific patient population. Treatment in one patient was discontinued for neurotoxicity and in another for pulmonary toxicity. A second study of a lower dose of gemcitabine with paclitaxel and carboplatin demonstrated a response in a patient with an angiosarcoma, and a similar response was noted in a low-dose, 72-hour continuous infusion schedule. In the phase I study, total doses of 150 mg/m2 gemcitabine over 72 hours were achieved with mucositis up to grade 2 being observed. Dose-limiting toxicity in this phase I study had not been identified by the time of the ASCO presentation.
Commentary
Taxanes have activity in angiosarcoma [4], perhaps accounting for the benefit seen in one patient in the carboplatin/paclitaxel/gemcitabine protocol. The responses to gemcitabine and docetaxel in uterine leiomyosarcoma seem superior to the historical response rate to doxorubicin, so this combination will likely be pursued in a larger-scale study. It should be noted that responses to gemcitabine in patients with uterine leiomyosarcoma were seen in an unpublished study of gemcitabine in soft-tissue sarcoma [5], and hints of a low degree of activity have been seen in other studies of gemcitabine in soft-tissue sarcoma, calling into question the contribution of docetaxel in this setting. Finally, given the mechanism of gemcitabine serving as a chain-terminating base when incorporated into DNA, it makes sense to pursue the phase I study of this drug as a protracted infusion in patients with soft-tissue sarcoma. Also, these findings point out the need to examine specific drugs or combinations in subtypes of soft-tissue sarcoma. Because of the rarity of these tumors, such studies are most efficiently performed in multicenter trials.
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OTHER RESEARCH IN SOFT-TISSUE SARCOMA |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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Study Design and Results
This study used the powerful European Organization for Research and Treatment of Cancer (EORTC) database to examine the progression-free survival (PFS) rate of patients in the multiple sarcoma studies run through this European organization, which has been a leader in sarcoma research. This research attempted to determine whether response rates correlated with the chance of being progression free. The motivation for this analysis is the clinical observation that tumors that fail to respond by imaging criteria often have some degree of necrosis (and thus response) if resected. As a result, typical computed tomography (CT) scans and other imaging may underestimate the utility of therapy. A significant drawback to this analysis is the dilemma that if a tumor is not superficial, where it can be followed by inspection, then the PFS is markedly affected by the time it takes to obtain the subsequent imaging study.
Patients were examined in three situations: A) those receiving first-line therapy (broken down by disease subtype); B) those treated with ifosfamide or dacarbazine after failing an anthracycline, and C) those included in second-line studies of nine agents who did not respond to therapy. In situation A, 3-month PFS ranged from 77% (synovial sarcoma) to 58% (malignant fibrous histiocytoma). For patients in situation B, PFS was 44% at 3 months, and in situation C, the nonresponding group, PFS was 21% at 6-8 weeks. Thus, PFS appeared to correlate well with responses to therapy.
Commentary
The biology of metastatic sarcoma is such that even responding tumors might not shrink much on CT or magnetic resonance imaging scans. These data provide an important baseline for future sarcoma trials, using a measure different from response rate, which might more accurately reflect the biology of this group of diseases. If a scan can be arranged after a certain period of therapy, rather than a certain number of cycles of therapy (which can vary), such data might provide a more accurate indication of the usefulness of a particular therapy.
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ADVANCES IN OSTEOGENIC SARCOMA |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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Expression of HER-2/neu (HER-2) and EGFR in Osteosarcoma (OS). JC Wittig, L Cruz, F Wodajo, K Kellar-Graney, N Seibel, MM Malawer, D Kumar, D Priebat (ABSTRACT 790).
HER-2/neu Protein Overexpression is a Rare Event in Adult Soft Tissue Sarcomas. AM Oliveira, F Medeiros, SH Okuno, AG Nascimento (ABSTRACT 2926).
Study Design and Results
The investigators in the European chemotherapy study sought to determine if a less toxic regimen of therapy was as useful as a combination of drugs containing methotrexate for patients with localized osteogenic sarcoma. Therapy was given every 2 weeks (if tolerated) in a population of 34 patients aged 15.4 to 49.5 years, in essence adding ifosfamide to the more standard combination of cisplatin and doxorubicin. Patients with a good response (
95% necrosis at the time of resection) received the same therapy postoperatively; those who had poor response (>5% residual tumor) received more intensive ifosfamide with etoposide. The population appeared to be typical for this disease, with lactic dehydrogenase elevated in approximately 20% of patients, a sign of advanced disease. Therapy was well tolerated; 4% had grade 4 hematologic toxicity, but none had renal toxicity. All but three had limb-sparing surgery. Median follow-up was 5.3 years. Four-year disease-free survival was 60%, and overall survival was 73%. Of the 16 patients with a good response, only 1 had relapsed at the time of the report. Randomized trials will be required to determine whether this new regimen yields equal results to standard regimens containing high-dose methotrexate.
It had previously been reported that 40%-50% of osteogenic sarcomas expressed HER-2/neu, the family member of the epidermal growth-factor family overexpressed in breast cancer. The study presented at ASCO demonstrated no detectable HER-2/neu staining by the HercepTestTM antibody (DAKO Corporation; Carpinteria, CA) in 32 paraffin-embedded samples. Similarly, HER-2/neu staining was rare in soft-tissue sarcomas.
Commentary
Various chemotherapy regimens are used for osteogenic sarcoma, although cisplatin, doxorubicin, and methotrexate are the standard agents. Methotrexate is used by most investigators, but it has occasional life-threatening toxicity and its administration in high-dose protocols is inconvenient. It is also not clear how to incorporate ifosfamide into more standard therapy for osteogenic sarcoma or if it is helpful. These data reinforce the idea that a regimen that omits methotrexate remains active, as was borne out in a previous study comparing cisplatin and doxorubicin alone to a more complex multidrug regimen [6].
The work of Oliveira et al. indicates there is rarely overexpression of HER-2/neu in soft-tissue sarcomas. However, it is unclear why the report of Wittig et al. reports no HER-2/neu expression in osteogenic sarcomas, while a recently published study reported a 40%-50% staining for HER-2/neu in these tumors [7]. Given the number of samples examined by each group, this argues for a difference in interpretation—for example, whether cytoplasmic staining counted as positive, or if only membrane staining felt to be significant. The antibodies used in the two studies differed as well. A panel of antibodies might be required to predict response to trastuzumab in patients with osteogenic sarcoma.
Conclusion
Until this year, there have been no new agents since ifosfamide with utility against sarcoma. This year's ASCO meeting provided the first evidence that new treatments for soft-tissue sarcoma have arrived. ET-743 appears to be active in a subset of patients with soft-tissue sarcomas; it will be interesting to determine factors that predict for response to this new agent. The striking results with imatinib mesylate in patients with GIST stand out as the result of years of work in cell biology, molecular biology, and drug design, and point to the ability to treat tumors not so much based on their site of origin, but on their biological or molecular fingerprint. However, GIST patients with specific molecular variations in oncogene c-kit do not respond to this new therapy, a humbling discovery suggesting that despite these initial remarkable advances, there remains much to be learned about cancer biology.
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References |
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TopAbstractIntroductionImatinib Mesylate and GISTNovel Agents in Soft-Tissue...Combinations of Standard Agents...Other Research in Soft-Tissue...Advances in Osteogenic SarcomaReferences |
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