Reply to “PET concerns in bevacizumab treatment”
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CORRESPONDENCE To the editor: In the recent article by Willett et al. 1 on neoad- juvant therapy with bevacizumab (BV) in patients with rectal cancer, treatment effects were ascribed to therapy with the VEGF-spe- cific antibody bevacizumab. However, because patients underwent concurrent treatment with 5-fluorouracil, we wonder if at least a portion of the treatment effects observed at 7 weeks might have been mediated by 5-fluorouracil, either alone or through a potentially synergistic effect of the combination. In addition, we regretted the absence of information about the marked increase in 18- fluorodeoxyglucose (FGD) uptake in a projec- tion on the cervical spine region of one patient, as shown by the PET scan 6–7 weeks after the end of neoadjuvant therapy (Fig. 1c in ref. 1). Because this finding was not observed in this patient’s prior PET examinations, it does not seem appropriate to view it as a mere technical artifact; it appears highly suggestive of a distant metastasis that has grown (and consequently become visible by PET) under bevacizumab combination therapy. Unexpected tumor growth at distant sites linked to treatment tar- geted at the primary cancer site, such as have been observed in both animal models and can- cer patients 2 , might be due to higher net sup- pression of growth-inhibiting as compared to growth-stimulating substances secreted from an individual primary tumor. The PET findings in this patient could reflect this sort of adverse effect from bevacizumab–5-fluorouracil com- bination therapy. Therefore, we would like the authors to comment on the apparent divergent efficacy at the site of the primary tumor as com- pared to distant locations. 1. Willett, C.G. et al. Nat. Med. 10, 145–147 (2004). 2. O’Reilly, M.S. et al. Cell 79, 315–328 (1994). Carsten Goessl 1 & Zarko Grozdanovic 2 1 Novartis Oncology, One Health Plaza, East Hanover, New Jersey, 07936-1080 USA Department of Radiology, 2 Charité, Campus Benjamin Franklin, Free University of Berlin, Germany e-mail: [email protected] C.G is an employee of Novartis, a pharmaceutical company that has antiangiogenic compounds in development. Willett and Jain reply: The objective of our study was to examine the biological and clinical effects on rectal cancer of an initial bevacizumab infusion, before the ini- tiation of radiation therapy and 5-fluorouracil. Six patients with clinical stage T3 or T4 rectal cancer completed the neoadjuvant therapy consisting of the first bevacizumab infusion followed by three 2-week cycles of bevacizumab administered concurrently with external beam radiation therapy (50.4 Gy in 28 1.8-Gy frac- tions over 5.5 weeks) and 5-fluorouracil (225 mg/m 2 /24 h by continuous peripheral venous infusion). Effects of the combined treatment on tumors were evaluated before surgery endo- scopically and by PET scan and perfusion CT scan. Details of the protocol may be found in a corrigendum to our article, printed in this issue 1 . The 18-fluorodeoxyglucose uptake in the neck seen on one representative sagittal image of the presurgery PET scan (patient 1 in the original figure) was, in fact, seen on all three PET scans (pretreatment, day 12 and pre- surgery) and was interpreted as upper-limit normal activity in the thyroid gland. This PET finding was not judged to represent a metasta- sis, and similarly, PET findings showed no detectable evidence of metastasis in any of the other five patients (see Fig. 1 below). Although the goal of this study was to examine the bio- logical and clinical response to a single dose of bevacizumab, the longer-term results of com- bined therapy in six consecutive patients have been promising. Christopher G Willett 1 , Daniel Duda 2 , Alan Fischman 3 & Rakesh K Jain 2 1 Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, North Carolina 27710, USA. 2 Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. 3 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. e-mail [email protected] 1. Willett, C.G. et al. Nat. Med. 10, 649 (2004). PET concerns in bevacizumab treatment NATURE MEDICINE VOLUME 10 | NUMBER 6 | JUNE 2004 561 Pre-Tx Day 12 Presurgery Patient #2 Patient #3 Patient #4 Patient #5 Patient #6 Figure 1 Effect of treatment on tumors in patients who completed the entire combined treatment regimen. Tumor FDG uptake before treatment (pre- Tx), 12 d after BV treatment and 6–7 weeks after completion of all neoadjuvant therapy (presurgery). Sagittal projections of FDG-PET scans for patient 2–5 are shown. Tumor is outlined in box, posterior to bladder. On day 12 after BV infusion, the follow-up PET scans showed no change in tumor FDG uptake in five patients and a 40% decrease in patient 3. Six weeks after completion of the BV, radiation therapy and chemotherapy regimen (presurgery), follow-up PET scans showed decreased tumor FDG uptake as compared with pretreatment values in patients 1, 2, 3, 4 and 6. Tumor FDG uptake in patient 5 was low, and was similar before and at the end of therapy. © 2004 Nature Publishing Group http://www.nature.com/naturemedicine
Transcript of Reply to “PET concerns in bevacizumab treatment”
CO R R E S P O N D E N C E
To the editor:In the recent article by Willett et al.1 on neoad-juvant therapy with bevacizumab (BV) inpatients with rectal cancer, treatment effectswere ascribed to therapy with the VEGF-spe-cific antibody bevacizumab. However, becausepatients underwent concurrent treatment with5-fluorouracil, we wonder if at least a portion ofthe treatment effects observed at 7 weeks mighthave been mediated by 5-fluorouracil, eitheralone or through a potentially synergistic effectof the combination.
In addition, we regretted the absence ofinformation about the marked increase in 18-fluorodeoxyglucose (FGD) uptake in a projec-tion on the cervical spine region of one patient,as shown by the PET scan 6–7 weeks after theend of neoadjuvant therapy (Fig. 1c in ref. 1).Because this finding was not observed in thispatient’s prior PET examinations, it does notseem appropriate to view it as a mere technicalartifact; it appears highly suggestive of a distantmetastasis that has grown (and consequentlybecome visible by PET) under bevacizumabcombination therapy. Unexpected tumorgrowth at distant sites linked to treatment tar-geted at the primary cancer site, such as havebeen observed in both animal models and can-cer patients2, might be due to higher net sup-pression of growth-inhibiting as compared togrowth-stimulating substances secreted froman individual primary tumor. The PET findingsin this patient could reflect this sort of adverseeffect from bevacizumab–5-fluorouracil com-bination therapy. Therefore, we would like theauthors to comment on the apparent divergentefficacy at the site of the primary tumor as com-pared to distant locations.
1. Willett, C.G. et al. Nat. Med. 10, 145–147 (2004).2. O’Reilly, M.S. et al. Cell 79, 315–328 (1994).
Carsten Goessl1 & Zarko Grozdanovic2
1Novartis Oncology, One Health Plaza, EastHanover, New Jersey, 07936-1080 USA Departmentof Radiology, 2 Charité, Campus BenjaminFranklin, Free University of Berlin, Germanye-mail: [email protected]
C.G is an employee of Novartis, a pharmaceuticalcompany that has antiangiogenic compounds indevelopment.
Willett and Jain reply:The objective of our study was to examine thebiological and clinical effects on rectal cancer ofan initial bevacizumab infusion, before the ini-tiation of radiation therapy and 5-fluorouracil.Six patients with clinical stage T3 or T4 rectalcancer completed the neoadjuvant therapyconsisting of the first bevacizumab infusionfollowed by three 2-week cycles of bevacizumabadministered concurrently with external beamradiation therapy (50.4 Gy in 28 1.8-Gy frac-
tions over 5.5 weeks) and 5-fluorouracil (225mg/m2/24 h by continuous peripheral venousinfusion). Effects of the combined treatment ontumors were evaluated before surgery endo-scopically and by PET scan and perfusion CTscan. Details of the protocol may be found in acorrigendum to our article, printed in thisissue1. The 18-fluorodeoxyglucose uptake inthe neck seen on one representative sagittalimage of the presurgery PET scan (patient 1 inthe original figure) was, in fact, seen on all threePET scans (pretreatment, day 12 and pre-surgery) and was interpreted as upper-limitnormal activity in the thyroid gland. This PETfinding was not judged to represent a metasta-sis, and similarly, PET findings showed nodetectable evidence of metastasis in any of theother five patients (see Fig. 1 below). Althoughthe goal of this study was to examine the bio-logical and clinical response to a single dose ofbevacizumab, the longer-term results of com-bined therapy in six consecutive patients havebeen promising.
Christopher G Willett1, Daniel Duda2,Alan Fischman3 & Rakesh K Jain2
1Department of Radiation Oncology, DukeUniversity Medical Center, Box 3085, Durham,North Carolina 27710, USA. 2Department ofRadiation Oncology, Massachusetts GeneralHospital and Harvard Medical School, Boston,Massachusetts 02114, USA. 3Department ofRadiology, Massachusetts General Hospital andHarvard Medical School, Boston, Massachusetts02114, USA.e-mail [email protected]
1. Willett, C.G. et al. Nat. Med. 10, 649 (2004).
PET concerns in bevacizumab treatment
NATURE MEDICINE VOLUME 10 | NUMBER 6 | JUNE 2004 561
Pre-Tx Day 12 Presurgery
Patient #2
Patient #3
Patient #4
Patient #5
Patient #6
Figure 1 Effect of treatment on tumors in patientswho completed the entire combined treatmentregimen. Tumor FDG uptake before treatment (pre-Tx), 12 d after BV treatment and 6–7 weeks aftercompletion of all neoadjuvant therapy (presurgery).Sagittal projections of FDG-PET scans for patient2–5 are shown. Tumor is outlined in box, posterior tobladder. On day 12 after BV infusion, the follow-upPET scans showed no change in tumor FDG uptakein five patients and a 40% decrease in patient 3. Sixweeks after completion of the BV, radiation therapyand chemotherapy regimen (presurgery), follow-upPET scans showed decreased tumor FDG uptake ascompared with pretreatment values in patients 1, 2,3, 4 and 6. Tumor FDG uptake in patient 5 was low,and was similar before and at the end of therapy.
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