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© 2003 American Society for Clinical Oncology
Combining Cytotoxic Chemotherapy With Cyclooxygenase-2 InhibitionDartmouth Medical School, Hanover, NH A FUNDAMENTAL change in clinical oncology is underway. After decades of basic research, steps in carcinogenesis are now being targeted through specific pharmacologic agents. As a result, it will become possible to learn whether targeting an individual or series of alterations involved in carcinogenesis advances cancer therapy or chemoprevention. A consequence of this changing clinical paradigm is that therapeutic regimens that combine a targeted therapy with cytotoxic chemotherapy are under study, as described by Altorki et al1 in this issue of the Journal of Clinical Oncology. In their important trial, these investigators have evaluated the potential for favorable clinical interactions in the preoperative treatment of lung cancer by combining cytotoxic chemotherapy with cyclooxygenase-2 (COX-2) inhibition. The underlying hypothesis examined was whether COX-2 inhibition would enhance response to cytotoxic chemotherapy through inhibition of tumor angiogenesis, promotion of apoptosis, or other possible mechanisms. A paclitaxel-containing regimen was selected for study because prior work of this team found that this chemotherapeutic agent induced COX-2 and prostaglandin biosynthesis.2 A selective COX-2 inhibitor would be expected to prevent the possible negative action of this chemotherapeutic agent. Preclinical and clinical evidence have established COX-2 as an attractive therapeutic or chemopreventive target in the lung. Inducible COX-2 affects synthesis of prostaglandins from arachidonic acid and is frequently activated during inflammation and carcinogenesis.3 COX-2 inhibition can induce apoptosis and chemotherapy cytotoxicity as well as antagonize angiogenesis.4,5 A rationale for selectively targeting COX-2 rather than constitutive COX-1 in lung carcinogenesis comes from the finding that differential overexpression of COX-2 (in neoplastic as compared with normal lung) has a negative prognostic influence in stage 1 non–small-cell lung cancer (NSCLC).6 COX-2 is also overexpressed in preneoplastic lung lesions7 and inducible prostaglandin synthase is overexpressed in NSCLC.8 It is also notable that epidemiologic data demonstrated a role for aspirin in suppressing lung carcinogenesis.9 Celecoxib, a selective COX-2 inhibitor, also inhibits polyp formation in familial adenomatous polyposis coli,10 thus indicating a potential role for selective COX-2 inhibition in treating early steps of carcinogenesis in other malignancies. Preclinical evidence for targeting COX-2 in lung carcinogenesis was established by COX-2 inhibition, which reduced lung adenomas in the A/J murine model.11 Taken together, these and other findings provided a strong rationale for the trial reported here.1 These investigators should be commended for designing and conducting this trial, which is an excellent example of translational research, by addressing whether celecoxib can be administered preoperatively with paclitaxel- and carboplatin-based combination chemotherapy. Whether this regimen suppressed intratumoral prostaglandin E2 (PGE2) was also established. Compared with historical controls, this regimen may have enhanced clinical responses because a higher than anticipated rate of complete clinical remissions (17%) was observed. Although no complete pathologic responses occurred, seven (24%) patients had only minimal residual microscopic evidence of malignancy after treatment. It is encouraging that, at surgical staging, 13 patients were downstaged, indicating another potential benefit from this regimen. Clinical responses did not appear to depend on NSCLC cell type. There was evidence for treatment-related deaths; one patient had neutropenic sepsis and another patient had respiratory failure after pneumonectomy. Three patients stopped taking celecoxib because of a generalized skin rash. This clinical trial provides a strong rationale for confirmatory randomized clinical trials that would assess the benefit of adding celecoxib to cytotoxic chemotherapy for lung cancer treatment. In advance of such trials, it is important to determine the optimal celecoxib dosage to administer as part of this regimen. In the meantime, more could be learned from this trial, especially if pretreatment biopsies were available to assess changes in COX-2 expression, proliferation, apoptosis, and neoangiogenesis in neoplastic, preneoplastic, or normal lung tissues. If pretreatment frozen tissues were accrued, then examination of changes in PGE2 levels would become possible. This underscores the value of proof of principle trials,3 in which an initial preoperative biopsy, followed by a short course of therapy before a second biopsy at surgical resection, would permit assessment of the pharmacologic effects on the desired target as well as on tissue and plasma pharmacokinetics. Short-term clinical responses could also be assessed in these trials. This is an exciting time in clinical oncology because the molecular genetic alterations that form the basis of carcinogenesis are becoming better understood. Many of these genetic alterations are also pharmacologic targets. The current trial advances prior preclinical work that implicated synergistic effects of combining COX inhibitors with cytotoxic chemotherapy12 by assessing whether favorable interactions occur in the clinic. The results of this phase II trial are encouraging given the high proportion of clinical responses that was associated with suppression of intratumoral PGE2 levels. A relationship between inflammation and carcinogenesis has long been recognized. We do not know which pharmacologic agent or target would optimally disrupt inflammation. In addition to COX-2, other targets should be evaluated in the treatment of lung carcinogenesis, such as inducible nitric oxide synthase,13 prostacyclin synthase,14 and lipoxygenase.15,16 Future treatments for lung cancer will involve regimens that target multiple steps in carcinogenesis. We should look toward confirmatory trials to validate and extend the work of Altorki et al,1 who combined a selective COX-2 inhibitor with cytotoxic chemotherapy as preoperative treatment for lung cancer. We should also determine the optimal dose and schedule of other targeted agents to combine with COX-2 inhibitors in the clinic. In this regard, the epidermal growth factor receptor is frequently aberrantly expressed in NSCLC and has been proposed as a target for treatment of lung carcinogenesis.17 Clinical benefits might derive from a regimen that combined a COX-2 inhibitor with an epidermal growth factor receptor inhibitor. Whether this or another combination regimen would have additive or synergistic activity in the treatment of lung carcinogenesis should be determined through clinical trials. The work of Altorki et al1 helps lead the way through a hypothesis-driven clinical trial that extends important work from the bench to the clinic. REFERENCES
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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