International Journal of
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS IMRT With Capecitabine in Advanced Pancreatic Cancer In Regard to Passoni et al To the Editor: We read the study of Passoni and colleagues (1) with great interest. According to their report, when visible tumor receives hypofractionated irradiation, the portion of the tumor around the infiltrated vessels receives high-dose radiation therapy. Pancreatic cancer patients were treated with gbased stereotactic body radiation therapy (g-SBRT) for 10 years in our department. The dose distribution of g-SBRT can also be considered as a simultaneous integrated boost (SIB) (2). A total dose of 40 to 51 Gy was delivered in 10 to 17 fractions to the 50% isodose line covering the planning target volume, whereas a total dose of 60 to 70 Gy was delivered to the gross target volume for pancreatic cancer. The median survival time was 11.3 months (95% confidence intervals, 8.9-13.8 months) in 174 patients with localized or locally advanced pancreatic cancer who were treated with g-SBRT (3). Passoni et al adopted SIB to the tumor around the infiltrated vessels to increase R0 resection. In fact, only 1 patient underwent surgery. In addition to an increased biological dose based on positron emission tomographic images, we directly increased the dose to the tumor center because tumor cells are more anaerobic in the tumor center than in the periphery. According to the previous g-SBRT dosimetry characteristics, we prescribe a planning dose at D95 to the planning target volume at 50 Gy, the clinical target volume at 60 Gy, and the gross tumor volume at 70 Gy in 15 to 20 fractions with helical tomotherapy. Our prospective clinical trial suggested that dose escalation to target volumes of pancreatic cancer patients with helical tomotherapy is an effective method with minimal toxicity (4). We query the necessity of induction chemotherapy for pancreatic cancer. Because of tumor progression and intolerable toxicity, almost 40% of patients did not continue receiving concurrent chemoradiation therapy after induction chemotherapy in the LAP07 study (5). There was an encouraging median survival time in the study by Passoni et al and in the LAP07 trial because these patients were selected after induction chemotherapy. In fact, no randomized, phase 3 clinical trial exists confirming that induction chemotherapy followed by chemoradiation therapy is not superior to
Int J Radiation Oncol Biol Phys, Vol. 89, No. 2, pp. 431e437, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
chemoradiation. There were different induction chemotherapy regimens in the study by Passoni et al. In addition, it would have been interesting to know whether or not the escalation dose could reach level 5 if late toxicity was taken into account because the impact of an increased single-fraction dose is most often late toxicity. Furthermore, it is not clear whether or not the patient undergoing radical (R0) surgery had no residual uptake of 2-[18F] fluoro-2-deoxyglucose. Gang Ren, MD1 Tingyi Xia, MD, PhD1 Yingjie Wang, MD, PhD Department of Radiation Oncology Chinese PLA Air General Hospital Beijing, China 1
Ren G and Xia TY contributed equally to this comment
http://dx.doi.org/10.1016/j.ijrobp.2014.02.004
References 1. Passoni P, Reni M, Cattaneo GM, et al. Hypofractionated imageguided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: A phase I study. Int J Radiat Oncol Biol Phys 2013;87:1000-1006. 2. Xia TY, Li HQ, Sun QX, et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable stage I/II non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 2006;66:117-125. 3. Wang J, Xia TY, Wang YJ, et al. Long-term results of gamma raybased stereotactic body radiotherapy in treatment of medically unfit or inoperable non-metastatic pancreatic adenocarcinoma [Abstract 3587]. Int J Radiat Oncol Biol Phys 2012;84:S815-S816. 4. Xia TY, Chang DS, Wang YJ, et al. Dose escalation to target volumes of helical tomotherapy for pancreatic cancer in the phase I-II clinical trial [Abstract 2262]. Int J Radiat Oncol Biol Phys 2012;8:S303. 5. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31 (suppl): Abstr LBA4003.
In Reply to Ren et al To the Editor: We thank Ren et al for their comments and questions (1, 2). We congratulate them on the high dose
432
Comments
International Journal of Radiation Oncology Biology Physics
they managed to deliver to the pancreatic gross tumor volume (3). Their experience seems to confirm that a dose escalation to pancreatic cancer is feasible. Regarding their questions:
Paolo Passoni, MD Department of Radiation Oncology
1. Necessity of induction chemotherapy. Phase 3 trials comparing chemoradiation therapy followed by gemcitabine with gemcitabine alone produced conflicting results (4, 5), and a recent qualitative systematic review found that chemoradiation therapy followed by chemotherapy did not yield a survival advantage over chemotherapy alone (6). The LAP07 trial seems to confirm the lack of efficacy of chemoradiation therapy over chemotherapy alone in patients with controlled disease after induction chemotherapy (7). After this trial, the question could be: is chemoradiation therapy still necessary? Although the best therapeutic approach to locally advanced pancreatic cancer (LAPC) remains uncertain, considering the frequent metastatic diffusion of disease, we maintain that induction chemotherapy can select patients who more likely benefit from local treatment. In our prior experience in 91 patients with LAPC treated with up-front chemotherapy followed by chemoradiation, the median survival of the whole population was 16.2 months (8).
Giovanni M. Cattaneo, PhD Department of Medical Physics
2. Different induction chemotherapy. As previously reported (9), there is no outcome difference among the different chemotherapy regimens used in our study (1). In any case, our phase 1 study was planned to determine the maximum tolerated dose in a population of heavily pretreated patients. Survival data should be considered as supplementary information. 3. Late toxicity. We fully share the concern of Ren et al. In our study, 2 of 6 evaluable patients enrolled at level dose V experienced late grade 3 toxicity. If we had considered late toxicity, the maximum tolerated dose would probably have been 55 Gy in 15 fractions. However, 1 patient had experienced local progression 3 months before, and we guess that the symptoms, which were conservatively attributed to actinic toxicity, were more likely related to the disease itself; second, in general, owing to the unpredictable temporal occurrence of late adverse events (10), it is impossible to plan phase 1 trials on the basis of late toxicity because the expansion of the observation period (eg, to 6 months) would lead to an unacceptable duration of the study (using an observation period of “only” 90 days, our study required almost 5 years to be completed), and, in any case, it would be insufficient to cover all the possible late side effects. 4. The patient who underwent R0 resection had a slow and progressive downstaging from unresectable to resectable disease and no pathologic uptake on positron emission tomography.
Michele Reni, MD Department of Medical Oncology
Najla Slim, MD Department of Radiation Oncology Stefano Cereda, MD Department of Medical Oncology San Raffaele Scientific Institute Milan, Italy http://dx.doi.org/10.1016/j.ijrobp.2014.02.003
References 1. Passoni P, Reni M, Cattaneo GM, et al. Hypofractionated imageguided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: A phase I study. Int J Radiat Oncol Biol Phys 2013;87:10001006. 2. Ren G, Xia T, Wang Y. In regard to Passoni et al. Int J Radiat Oncol Biol Phys 2014;89:431. 3. Xia TY, Chang DS, Wang YJ, et al. Dose escalation to target volumes of helical tomotherapy for pancreatic cancer in the phase I-II clinical trial [abstract 2262]. Int J Radiat Oncol Biol Phys 2012;8:S303. 4. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer: Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2008;19:1592-1599. 5. Loehrer Sr PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105-4112. 6. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: A qualitative systematic review. J Clin Oncol 2009;27:2269-2277. 7. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. 2013 ASCO Annual Meeting [abstract LBA4003]. J Clin Oncol 2013;31. 8. Reni M, Cereda S, Balzano G, et al. Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2009;64: 1253-1259. 9. Reni M, Cereda S, Rognone A, et al. A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: Cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemother Pharmacol 2012;69:15-23. 10. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2008;72: 678-686.
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS IMRT With Capecitabine in Advanced Pancreatic Cancer In Regard to Passoni et al To the Editor: We read the study of Passoni and colleagues (1) with great interest. According to their report, when visible tumor receives hypofractionated irradiation, the portion of the tumor around the infiltrated vessels receives high-dose radiation therapy. Pancreatic cancer patients were treated with gbased stereotactic body radiation therapy (g-SBRT) for 10 years in our department. The dose distribution of g-SBRT can also be considered as a simultaneous integrated boost (SIB) (2). A total dose of 40 to 51 Gy was delivered in 10 to 17 fractions to the 50% isodose line covering the planning target volume, whereas a total dose of 60 to 70 Gy was delivered to the gross target volume for pancreatic cancer. The median survival time was 11.3 months (95% confidence intervals, 8.9-13.8 months) in 174 patients with localized or locally advanced pancreatic cancer who were treated with g-SBRT (3). Passoni et al adopted SIB to the tumor around the infiltrated vessels to increase R0 resection. In fact, only 1 patient underwent surgery. In addition to an increased biological dose based on positron emission tomographic images, we directly increased the dose to the tumor center because tumor cells are more anaerobic in the tumor center than in the periphery. According to the previous g-SBRT dosimetry characteristics, we prescribe a planning dose at D95 to the planning target volume at 50 Gy, the clinical target volume at 60 Gy, and the gross tumor volume at 70 Gy in 15 to 20 fractions with helical tomotherapy. Our prospective clinical trial suggested that dose escalation to target volumes of pancreatic cancer patients with helical tomotherapy is an effective method with minimal toxicity (4). We query the necessity of induction chemotherapy for pancreatic cancer. Because of tumor progression and intolerable toxicity, almost 40% of patients did not continue receiving concurrent chemoradiation therapy after induction chemotherapy in the LAP07 study (5). There was an encouraging median survival time in the study by Passoni et al and in the LAP07 trial because these patients were selected after induction chemotherapy. In fact, no randomized, phase 3 clinical trial exists confirming that induction chemotherapy followed by chemoradiation therapy is not superior to
Int J Radiation Oncol Biol Phys, Vol. 89, No. 2, pp. 431e437, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
chemoradiation. There were different induction chemotherapy regimens in the study by Passoni et al. In addition, it would have been interesting to know whether or not the escalation dose could reach level 5 if late toxicity was taken into account because the impact of an increased single-fraction dose is most often late toxicity. Furthermore, it is not clear whether or not the patient undergoing radical (R0) surgery had no residual uptake of 2-[18F] fluoro-2-deoxyglucose. Gang Ren, MD1 Tingyi Xia, MD, PhD1 Yingjie Wang, MD, PhD Department of Radiation Oncology Chinese PLA Air General Hospital Beijing, China 1
Ren G and Xia TY contributed equally to this comment
http://dx.doi.org/10.1016/j.ijrobp.2014.02.004
References 1. Passoni P, Reni M, Cattaneo GM, et al. Hypofractionated imageguided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: A phase I study. Int J Radiat Oncol Biol Phys 2013;87:1000-1006. 2. Xia TY, Li HQ, Sun QX, et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable stage I/II non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 2006;66:117-125. 3. Wang J, Xia TY, Wang YJ, et al. Long-term results of gamma raybased stereotactic body radiotherapy in treatment of medically unfit or inoperable non-metastatic pancreatic adenocarcinoma [Abstract 3587]. Int J Radiat Oncol Biol Phys 2012;84:S815-S816. 4. Xia TY, Chang DS, Wang YJ, et al. Dose escalation to target volumes of helical tomotherapy for pancreatic cancer in the phase I-II clinical trial [Abstract 2262]. Int J Radiat Oncol Biol Phys 2012;8:S303. 5. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31 (suppl): Abstr LBA4003.
In Reply to Ren et al To the Editor: We thank Ren et al for their comments and questions (1, 2). We congratulate them on the high dose
432
Comments
International Journal of Radiation Oncology Biology Physics
they managed to deliver to the pancreatic gross tumor volume (3). Their experience seems to confirm that a dose escalation to pancreatic cancer is feasible. Regarding their questions:
Paolo Passoni, MD Department of Radiation Oncology
1. Necessity of induction chemotherapy. Phase 3 trials comparing chemoradiation therapy followed by gemcitabine with gemcitabine alone produced conflicting results (4, 5), and a recent qualitative systematic review found that chemoradiation therapy followed by chemotherapy did not yield a survival advantage over chemotherapy alone (6). The LAP07 trial seems to confirm the lack of efficacy of chemoradiation therapy over chemotherapy alone in patients with controlled disease after induction chemotherapy (7). After this trial, the question could be: is chemoradiation therapy still necessary? Although the best therapeutic approach to locally advanced pancreatic cancer (LAPC) remains uncertain, considering the frequent metastatic diffusion of disease, we maintain that induction chemotherapy can select patients who more likely benefit from local treatment. In our prior experience in 91 patients with LAPC treated with up-front chemotherapy followed by chemoradiation, the median survival of the whole population was 16.2 months (8).
Giovanni M. Cattaneo, PhD Department of Medical Physics
2. Different induction chemotherapy. As previously reported (9), there is no outcome difference among the different chemotherapy regimens used in our study (1). In any case, our phase 1 study was planned to determine the maximum tolerated dose in a population of heavily pretreated patients. Survival data should be considered as supplementary information. 3. Late toxicity. We fully share the concern of Ren et al. In our study, 2 of 6 evaluable patients enrolled at level dose V experienced late grade 3 toxicity. If we had considered late toxicity, the maximum tolerated dose would probably have been 55 Gy in 15 fractions. However, 1 patient had experienced local progression 3 months before, and we guess that the symptoms, which were conservatively attributed to actinic toxicity, were more likely related to the disease itself; second, in general, owing to the unpredictable temporal occurrence of late adverse events (10), it is impossible to plan phase 1 trials on the basis of late toxicity because the expansion of the observation period (eg, to 6 months) would lead to an unacceptable duration of the study (using an observation period of “only” 90 days, our study required almost 5 years to be completed), and, in any case, it would be insufficient to cover all the possible late side effects. 4. The patient who underwent R0 resection had a slow and progressive downstaging from unresectable to resectable disease and no pathologic uptake on positron emission tomography.
Michele Reni, MD Department of Medical Oncology
Najla Slim, MD Department of Radiation Oncology Stefano Cereda, MD Department of Medical Oncology San Raffaele Scientific Institute Milan, Italy http://dx.doi.org/10.1016/j.ijrobp.2014.02.003
References 1. Passoni P, Reni M, Cattaneo GM, et al. Hypofractionated imageguided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: A phase I study. Int J Radiat Oncol Biol Phys 2013;87:10001006. 2. Ren G, Xia T, Wang Y. In regard to Passoni et al. Int J Radiat Oncol Biol Phys 2014;89:431. 3. Xia TY, Chang DS, Wang YJ, et al. Dose escalation to target volumes of helical tomotherapy for pancreatic cancer in the phase I-II clinical trial [abstract 2262]. Int J Radiat Oncol Biol Phys 2012;8:S303. 4. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer: Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2008;19:1592-1599. 5. Loehrer Sr PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105-4112. 6. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: A qualitative systematic review. J Clin Oncol 2009;27:2269-2277. 7. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. 2013 ASCO Annual Meeting [abstract LBA4003]. J Clin Oncol 2013;31. 8. Reni M, Cereda S, Balzano G, et al. Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2009;64: 1253-1259. 9. Reni M, Cereda S, Rognone A, et al. A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: Cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemother Pharmacol 2012;69:15-23. 10. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2008;72: 678-686.
