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Abstract

Esmaeli's request for clarification of issues regarding our study1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar involves 11 points related to both the intra-arterial cytoreductive chemotherapy (IACC) protocol design and our analysis. First, the introductory quotation attributed to us was not a statement made in our manuscript. Eight patients were in group 1, not 7, and the characterization of group 2 patients as only those without an intact lacrimal artery is inaccurate. We address each query sequentially.Second, group 1 was composed of 8 patients with an intact lacrimal artery who completed the IACC treatment protocol in sequential order and within a timeframe of implementation. None had surgical disruption of bone. Group 2 comprised patients who deviated from the protocol design or presented without an intact lacrimal artery. Ten patients had excisional biopsy by a lateral orbitotomy with bone take-down, and thus intra-arterial chemotherapy was delivered to the orbit through altered lacrimal artery anatomy. One patient, case 8, as reported in our 2006 study (cited in reference 1) had a dramatic radiographic response after 2 cycles of intra-arterial chemotherapy delivered through an intact lacrimal artery. This patient was included in group 2 because she refused exenteration, and the remaining 4 cycles of the intravenous chemotherapy, and thus deviated from the prescribed protocol.Disruption of the lacrimal artery was defined clinically. The major flow to the lacrimal gland should occur through the lacrimal artery so an intact artery would deliver the greatest drug concentration to the tumor. Although resection of the lacrimal gland mass severs the glandular branches of the lacrimal artery from the main trunk, the proximal lacrimal artery stump, through collateral vessels (facial, maxillary, and superficial temporal arteries) from the external carotid artery, can still deliver the drug to the intraorbital tumor and surrounding structures harboring microscopic tumor cells. The lacrimal artery also gives off ≥1 zygomatic branch passing through the zygomaticotemporal foramen to reach the temporal fossa, a site of potential tumor seeding. Thus, blood supply to the orbital tissues is not dependent solely on the lacrimal artery.Third, this treatment program began as an exploratory regimen to remedy the shortcoming of conventional treatments in addressing occult metastases after achieving local disease control with surgery and radiation therapy. Our original papers described our experience with small numbers of patients. In fact, we always intended to stratify patients into those receiving IACC as designed and those who did not. Our larger cohort made this possible.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Parenthetically, Table 1 includes individual case data, so anyone wishing to regroup the patients can easily do so with Kaplan–Meier analysis. Separating groups 1 and 2 underscores that the benefits of IACC will be optimal for patients with intact lacrimal arteries who receive the full course of treatment.Fourth, the definition of “tumor resection” is in the Results section. A preoperative diagnosis of the lacrimal gland mass as pleomorphic adenoma was made in 5 cases without tissue diagnosis and an in toto dacryoadenectomy was performed through a lateral orbitotomy with bone take down. The other 5 patients underwent unplanned lacrimal gland tumor resection without an incisional biopsy. Vascular supply to the lacrimal gland fossa was disrupted owing to tumor resection in these 10 patients. Gross residual orbital disease or positive tumor margins of the resected mass were present in all 10 cases at the time of referral for IACC, as was highlighted by case 11. Case 8, the only patient in group 2 who underwent an incisional “biopsy” through an eyelid crease approach, retained the lacrimal artery with gross residual tumor mass. Her dramatic response to neoadjuvant IACC and clinical course was previously reported (cited in reference 1).Our recommendation for an incisional “biopsy,” as stated in the Discussion (p. 1320) is to establish an accurate tissue diagnosis before extirpative surgery. Excising a piece of the anterior tip of the lacrimal gland will not affect the glandular branches of the lacrimal artery or its main trunk that enters the gland posteriorly on its ventral surface. Transecting three quarters of the lacrimal gland mass will alter the glandular branches within the lesion, but will not transect the main lacrimal artery trunk perfusing the tumor remnant. We do not recommend preoperative or intraoperative angiography to guide the biopsy for the purpose of avoiding the lacrimal artery but by anatomical knowledge of the region.Fifth, Esmaeli, as well as Bradley in her accompanying editorial,2Bradley E.A. Bradley D.J. Adenoid cystic carcinoma of the lacrimal gland: rare… lethal… cured?.Ophthalmology. 2013; 120: 1311-1312Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar posed a fair question regarding tumor size, histology, and nodal status of our patients at presentation. If a greater proportion of patients in the optimally treated group 1 had smaller tumors and negative lymph node involvement, they would be expected to have improved outcomes compared with group 2 or historical controls. This potential selection bias concern arises from an assessment of 53 patients with lacrimal gland adenoid cystic carcinoma (LGACC) using the American Joint Committee on Cancer (AJCC) 6th edition.3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The authors concluded that patients with ≥T3 disease at diagnosis had worse outcomes than whose with <T3 disease. This classification has been replaced with the AJCC 7th edition, which considers tumors with bone infiltration as T4b and local infiltration of adjacent structures as T4c.4Edge S.B. Byrd D.R. Compton C.C. AJCC cancer staging manual. 7th ed. Springer, New York2009: 569-571Google Scholar Applying the 7th edition classification to our patients, 75% (6/8) had ≥T3 disease in group 1, and 63.6% (7/11) had ≥T3 disease in group 2. Furthermore, 4 patients in group 1 and 3 in group 2 had ≥T4c disease. Using the 6th edition classification,3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar 62.5% in group 1 and 54.5% in group 2 had ≥T3 disease.None of our patients had lymph node involvement at presentation. Although histologic subtype was not identified as part of the AJCC staging system,3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar the observation that basaloid histologic type was worse is noted and we include these data in Table 1. Neither differences in tumor size, nor histology account for the outcome differences between the 2 groups. The combined cohort does not represent low-risk disease patients.We did not use the AJCC staging system for data analysis because there is little evidence to validate the realistic estimate of the risk of metastasis using tumor size as the principal determinant for this condition. The 7th edition staging system is still imperfect, because it fails to consider tumor differentiation, perineural invasion, and other outcomes of interest. Therefore, it seems unnecessary to evaluate disease-free survival based on size alone. As the cancer staging classification continues to evolve for LGACC, its prognostic utility remains uncertain.Sixth, our most important analytical point is that survival and recurrence percentages cannot be interpreted without reference to follow-up time, usually employing Kaplan–Meier analysis. Esmaeli cited her recent MD Anderson series (MDAS) with “about 40% cause-specific mortality.”5Williams M.D. Al-Zubidi N. Debnam J.M. et al.Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations.Ophthal Plast Reconstr Surg. 2010; 26: 403-408Crossref PubMed Scopus (39) Google Scholar This percentage is obtained by dividing 7 deaths owing to disease by 18 patients (p. 406 Clinical Outcomes5Williams M.D. Al-Zubidi N. Debnam J.M. et al.Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations.Ophthal Plast Reconstr Surg. 2010; 26: 403-408Crossref PubMed Scopus (39) Google Scholar). But MDAS follow-up times ranged from 6 to 102 months (median, 2.2 years). Undertaking the same misleading analysis combining our groups 1 and 2 yields 11% (2/19) cause-specific mortality with a median follow-up of 7.4 years. However, a clearer picture emerges when comparing our data with MDAS using Kaplan–Meier analysis. At 5 years, the MDAS cause-specific mortality is 40.2% increasing to 64.1% by 6 years, comparable with the Bascom Palmer conventional group and worse than the rate from the Esmaeli 2004 data we used in our publication.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The MDAS lacks sufficient follow-up to calculate 10-year cause-specific mortality. In contrast, the cause-specific mortality in our combined groups 1 and 2 is significantly lower, 5.9% at 5 years, increasing to 14.4% by 8 years, and persisting at 14.4% beyond 15 years (P = 0.003, log-rank test). Esmaeli more obviously fails to account for follow-up time when characterizing our conventional control group as having 100% mortality leading to the implication of “unintended effect of making the IAC treated group seem better in comparison.” Mortality is 100% because the last followed patient died after 13 years. Given enough follow-up time, all patients die. The accompanying editorial pointed out “essentially none with LGACC receiving conventional therapy live beyond 15 years.”2Bradley E.A. Bradley D.J. Adenoid cystic carcinoma of the lacrimal gland: rare… lethal… cured?.Ophthalmology. 2013; 120: 1311-1312Abstract Full Text Full Text PDF PubMed Scopus (15) Google ScholarSeventh, yes, group 1 is “IAC as designed”; group 2 is “IAC with deviation.” We agree that disease-specific mortality between group 1 and group 2 patients did not show statistical significance, although the only recurrences and deaths have been seen in the group 2 population. With additional follow-up and maturation of data, a difference may be seen.Eighth, in 3 patients (cases 1, 4, and 19) with intracranial extension and 3 patients (cases 8, 9, and 11) with tumor infiltration into the temporal fossa, disease was downstaged to an intraorbital process for exenteration. Cases 1, 4, and 9 have achieved disease-free survival of 24, 13, and 9 years, respectively, supporting the rationale of neoadjuvant therapy. On page 1319, we applied the term “excellent locoregional control” to them. Only 3 (cases 8, 9, and 11) recurred, not 4 as stated, and none received the designed treatment protocol. The clinical courses of cases 8 and 9 are chronicled in an earlier report. Of note, case 9 has not recurred 112 months after additional surgery, and cases 11 and 19 are described in our publication.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarThese data demonstrate that neoadjuvant chemotherapy can produce downstaging of tumor, but this is not sufficient to prevent distant disease relapse. Optimal management of LGACC requires adherence to all elements of the IACC protocol: Rapid cycling of therapy, treatment intensity, and timely exenteration. We identify 5 factors contributing to suboptimal response to the IACC.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarNinth, case 11 had extensive extraorbital disease at presentation with gross temporalis fossa involvement and bony infiltration; however, undetected microscopic disease cannot be ruled out. At definitive resection following IACC, all margins including the cavernous sinus were negative, rejecting Esmaeli's assertion of progression “to surgically unresectable cavernous sinus disease while receiving IAC whereas his disease prior to… IAC appears to have been surgically resectable.” Of note, case 1, whose T4c stage tumor was judged to be unresectable because of intracranial involvement, received complete IACC and experienced substantial tumor downstaging such that exenteration achieved tumor margin clearance. This patient is disease-free 25 years later.As with other tumors, such as locally advanced breast cancer or osteosarcoma, the use of neoadjuvant chemotherapy should be considered for LGACC patients having poor prognosis with conventional treatments. Although a patient may not respond to IACC or could have an adverse outcome, the noted improvement in survival outcome for the group as a whole justifies its consideration.Tenth, we did not suggest that an incisional biopsy of a lacrimal gland mass through the anterior transcutaneous approach does not cause local tumor seeding. Tumor seeding in the surgical field can occur with any procedure, but the least invasive procedure should have the least negative impact. Oncologic surgery principle teaches minimal tumor manipulation, complete resection with tumor margin clearance, and preservation of normal tissue barriers to optimize outcome. Ten patients in group 2 underwent lateral orbitotomy with bone take-down and tumor manipulation with incomplete resection; local recurrence or distant disease relapse was seen in 5 patients. No disease relapse was seen in any of the patients in group 1, in whom an anterior transcutaneous biopsy was performed.Eleventh, we agree that nodal metastases are rare and we are not recommending node dissection for the typical patient with LGACC. The only patient with nodal disease in our series had multiple and extensive locoregional recurrences before ever developing lymph node involvement (case 11). When the disease extends beyond the domain of the orbital surgeon, including extraorbital or intracranial extension, it is prudent to consult additional disciplines to define the extent of disease and to assist in tumor surveillance. Each case needs to be individualized, guided by a thorough head and neck examination, and an understanding of the tumor's biological behavior and regional anatomy. The treatment of LGACC requires a multidisciplinary approach.We believe the answer to Esmaeli's question, “Does intra-arterial chemotherapy improve survival for adenoid cystic carcinoma?”, is an unequivocal yes! Esmaeli's request for clarification of issues regarding our study1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar involves 11 points related to both the intra-arterial cytoreductive chemotherapy (IACC) protocol design and our analysis. First, the introductory quotation attributed to us was not a statement made in our manuscript. Eight patients were in group 1, not 7, and the characterization of group 2 patients as only those without an intact lacrimal artery is inaccurate. We address each query sequentially. Second, group 1 was composed of 8 patients with an intact lacrimal artery who completed the IACC treatment protocol in sequential order and within a timeframe of implementation. None had surgical disruption of bone. Group 2 comprised patients who deviated from the protocol design or presented without an intact lacrimal artery. Ten patients had excisional biopsy by a lateral orbitotomy with bone take-down, and thus intra-arterial chemotherapy was delivered to the orbit through altered lacrimal artery anatomy. One patient, case 8, as reported in our 2006 study (cited in reference 1) had a dramatic radiographic response after 2 cycles of intra-arterial chemotherapy delivered through an intact lacrimal artery. This patient was included in group 2 because she refused exenteration, and the remaining 4 cycles of the intravenous chemotherapy, and thus deviated from the prescribed protocol. Disruption of the lacrimal artery was defined clinically. The major flow to the lacrimal gland should occur through the lacrimal artery so an intact artery would deliver the greatest drug concentration to the tumor. Although resection of the lacrimal gland mass severs the glandular branches of the lacrimal artery from the main trunk, the proximal lacrimal artery stump, through collateral vessels (facial, maxillary, and superficial temporal arteries) from the external carotid artery, can still deliver the drug to the intraorbital tumor and surrounding structures harboring microscopic tumor cells. The lacrimal artery also gives off ≥1 zygomatic branch passing through the zygomaticotemporal foramen to reach the temporal fossa, a site of potential tumor seeding. Thus, blood supply to the orbital tissues is not dependent solely on the lacrimal artery. Third, this treatment program began as an exploratory regimen to remedy the shortcoming of conventional treatments in addressing occult metastases after achieving local disease control with surgery and radiation therapy. Our original papers described our experience with small numbers of patients. In fact, we always intended to stratify patients into those receiving IACC as designed and those who did not. Our larger cohort made this possible.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Parenthetically, Table 1 includes individual case data, so anyone wishing to regroup the patients can easily do so with Kaplan–Meier analysis. Separating groups 1 and 2 underscores that the benefits of IACC will be optimal for patients with intact lacrimal arteries who receive the full course of treatment. Fourth, the definition of “tumor resection” is in the Results section. A preoperative diagnosis of the lacrimal gland mass as pleomorphic adenoma was made in 5 cases without tissue diagnosis and an in toto dacryoadenectomy was performed through a lateral orbitotomy with bone take down. The other 5 patients underwent unplanned lacrimal gland tumor resection without an incisional biopsy. Vascular supply to the lacrimal gland fossa was disrupted owing to tumor resection in these 10 patients. Gross residual orbital disease or positive tumor margins of the resected mass were present in all 10 cases at the time of referral for IACC, as was highlighted by case 11. Case 8, the only patient in group 2 who underwent an incisional “biopsy” through an eyelid crease approach, retained the lacrimal artery with gross residual tumor mass. Her dramatic response to neoadjuvant IACC and clinical course was previously reported (cited in reference 1). Our recommendation for an incisional “biopsy,” as stated in the Discussion (p. 1320) is to establish an accurate tissue diagnosis before extirpative surgery. Excising a piece of the anterior tip of the lacrimal gland will not affect the glandular branches of the lacrimal artery or its main trunk that enters the gland posteriorly on its ventral surface. Transecting three quarters of the lacrimal gland mass will alter the glandular branches within the lesion, but will not transect the main lacrimal artery trunk perfusing the tumor remnant. We do not recommend preoperative or intraoperative angiography to guide the biopsy for the purpose of avoiding the lacrimal artery but by anatomical knowledge of the region. Fifth, Esmaeli, as well as Bradley in her accompanying editorial,2Bradley E.A. Bradley D.J. Adenoid cystic carcinoma of the lacrimal gland: rare… lethal… cured?.Ophthalmology. 2013; 120: 1311-1312Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar posed a fair question regarding tumor size, histology, and nodal status of our patients at presentation. If a greater proportion of patients in the optimally treated group 1 had smaller tumors and negative lymph node involvement, they would be expected to have improved outcomes compared with group 2 or historical controls. This potential selection bias concern arises from an assessment of 53 patients with lacrimal gland adenoid cystic carcinoma (LGACC) using the American Joint Committee on Cancer (AJCC) 6th edition.3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The authors concluded that patients with ≥T3 disease at diagnosis had worse outcomes than whose with <T3 disease. This classification has been replaced with the AJCC 7th edition, which considers tumors with bone infiltration as T4b and local infiltration of adjacent structures as T4c.4Edge S.B. Byrd D.R. Compton C.C. AJCC cancer staging manual. 7th ed. Springer, New York2009: 569-571Google Scholar Applying the 7th edition classification to our patients, 75% (6/8) had ≥T3 disease in group 1, and 63.6% (7/11) had ≥T3 disease in group 2. Furthermore, 4 patients in group 1 and 3 in group 2 had ≥T4c disease. Using the 6th edition classification,3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar 62.5% in group 1 and 54.5% in group 2 had ≥T3 disease. None of our patients had lymph node involvement at presentation. Although histologic subtype was not identified as part of the AJCC staging system,3Ahmad S.M. Esmaeli B. Williams M. et al.American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma.Ophthalmology. 2009; 116: 1210-1215Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar the observation that basaloid histologic type was worse is noted and we include these data in Table 1. Neither differences in tumor size, nor histology account for the outcome differences between the 2 groups. The combined cohort does not represent low-risk disease patients. We did not use the AJCC staging system for data analysis because there is little evidence to validate the realistic estimate of the risk of metastasis using tumor size as the principal determinant for this condition. The 7th edition staging system is still imperfect, because it fails to consider tumor differentiation, perineural invasion, and other outcomes of interest. Therefore, it seems unnecessary to evaluate disease-free survival based on size alone. As the cancer staging classification continues to evolve for LGACC, its prognostic utility remains uncertain. Sixth, our most important analytical point is that survival and recurrence percentages cannot be interpreted without reference to follow-up time, usually employing Kaplan–Meier analysis. Esmaeli cited her recent MD Anderson series (MDAS) with “about 40% cause-specific mortality.”5Williams M.D. Al-Zubidi N. Debnam J.M. et al.Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations.Ophthal Plast Reconstr Surg. 2010; 26: 403-408Crossref PubMed Scopus (39) Google Scholar This percentage is obtained by dividing 7 deaths owing to disease by 18 patients (p. 406 Clinical Outcomes5Williams M.D. Al-Zubidi N. Debnam J.M. et al.Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations.Ophthal Plast Reconstr Surg. 2010; 26: 403-408Crossref PubMed Scopus (39) Google Scholar). But MDAS follow-up times ranged from 6 to 102 months (median, 2.2 years). Undertaking the same misleading analysis combining our groups 1 and 2 yields 11% (2/19) cause-specific mortality with a median follow-up of 7.4 years. However, a clearer picture emerges when comparing our data with MDAS using Kaplan–Meier analysis. At 5 years, the MDAS cause-specific mortality is 40.2% increasing to 64.1% by 6 years, comparable with the Bascom Palmer conventional group and worse than the rate from the Esmaeli 2004 data we used in our publication.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The MDAS lacks sufficient follow-up to calculate 10-year cause-specific mortality. In contrast, the cause-specific mortality in our combined groups 1 and 2 is significantly lower, 5.9% at 5 years, increasing to 14.4% by 8 years, and persisting at 14.4% beyond 15 years (P = 0.003, log-rank test). Esmaeli more obviously fails to account for follow-up time when characterizing our conventional control group as having 100% mortality leading to the implication of “unintended effect of making the IAC treated group seem better in comparison.” Mortality is 100% because the last followed patient died after 13 years. Given enough follow-up time, all patients die. The accompanying editorial pointed out “essentially none with LGACC receiving conventional therapy live beyond 15 years.”2Bradley E.A. Bradley D.J. Adenoid cystic carcinoma of the lacrimal gland: rare… lethal… cured?.Ophthalmology. 2013; 120: 1311-1312Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Seventh, yes, group 1 is “IAC as designed”; group 2 is “IAC with deviation.” We agree that disease-specific mortality between group 1 and group 2 patients did not show statistical significance, although the only recurrences and deaths have been seen in the group 2 population. With additional follow-up and maturation of data, a difference may be seen. Eighth, in 3 patients (cases 1, 4, and 19) with intracranial extension and 3 patients (cases 8, 9, and 11) with tumor infiltration into the temporal fossa, disease was downstaged to an intraorbital process for exenteration. Cases 1, 4, and 9 have achieved disease-free survival of 24, 13, and 9 years, respectively, supporting the rationale of neoadjuvant therapy. On page 1319, we applied the term “excellent locoregional control” to them. Only 3 (cases 8, 9, and 11) recurred, not 4 as stated, and none received the designed treatment protocol. The clinical courses of cases 8 and 9 are chronicled in an earlier report. Of note, case 9 has not recurred 112 months after additional surgery, and cases 11 and 19 are described in our publication.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar These data demonstrate that neoadjuvant chemotherapy can produce downstaging of tumor, but this is not sufficient to prevent distant disease relapse. Optimal management of LGACC requires adherence to all elements of the IACC protocol: Rapid cycling of therapy, treatment intensity, and timely exenteration. We identify 5 factors contributing to suboptimal response to the IACC.1Tse D.T. Kossler A.L. Feuer W.J. Benedetto P.W. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.Ophthalmology. 2013; 120: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Ninth, case 11 had extensive extraorbital disease at presentation with gross temporalis fossa involvement and bony infiltration; however, undetected microscopic disease cannot be ruled out. At definitive resection following IACC, all margins including the cavernous sinus were negative, rejecting Esmaeli's assertion of progression “to surgically unresectable cavernous sinus disease while receiving IAC whereas his disease prior to… IAC appears to have been surgically resectable.” Of note, case 1, whose T4c stage tumor was judged to be unresectable because of intracranial involvement, received complete IACC and experienced substantial tumor downstaging such that exenteration achieved tumor margin clearance. This patient is disease-free 25 years later. As with other tumors, such as locally advanced breast cancer or osteosarcoma, the use of neoadjuvant chemotherapy should be considered for LGACC patients having poor prognosis with conventional treatments. Although a patient may not respond to IACC or could have an adverse outcome, the noted improvement in survival outcome for the group as a whole justifies its consideration. Tenth, we did not suggest that an incisional biopsy of a lacrimal gland mass through the anterior transcutaneous approach does not cause local tumor seeding. Tumor seeding in the surgical field can occur with any procedure, but the least invasive procedure should have the least negative impact. Oncologic surgery principle teaches minimal tumor manipulation, complete resection with tumor margin clearance, and preservation of normal tissue barriers to optimize outcome. Ten patients in group 2 underwent lateral orbitotomy with bone take-down and tumor manipulation with incomplete resection; local recurrence or distant disease relapse was seen in 5 patients. No disease relapse was seen in any of the patients in group 1, in whom an anterior transcutaneous biopsy was performed. Eleventh, we agree that nodal metastases are rare and we are not recommending node dissection for the typical patient with LGACC. The only patient with nodal disease in our series had multiple and extensive locoregional recurrences before ever developing lymph node involvement (case 11). When the disease extends beyond the domain of the orbital surgeon, including extraorbital or intracranial extension, it is prudent to consult additional disciplines to define the extent of disease and to assist in tumor surveillance. Each case needs to be individualized, guided by a thorough head and neck examination, and an understanding of the tumor's biological behavior and regional anatomy. The treatment of LGACC requires a multidisciplinary approach. We believe the answer to Esmaeli's question, “Does intra-arterial chemotherapy improve survival for adenoid cystic carcinoma?”, is an unequivocal yes! Does Intra-arterial Chemotherapy Improve Survival for Lacrimal Gland Adenoid Cystic Carcinoma?OphthalmologyVol. 121Issue 1PreviewTse et al1 summarize the long-term outcomes in 19 patients with adenoid cystic carcinoma of lacrimal gland who underwent treatment on an investigational protocol that entailed receiving intra-arterial chemotherapy (IAC) followed by orbital exenteration followed by postoperative adjuvant chemoradiation; 19 patients were enrolled in 24 years.1 The authors conclude that the prescribed protocol led to a “significantly higher disease-free survival in the 7 patients who had an intact lacrimal artery (group 1) compared with the 11 patients who did not have an intact lacrimal artery (group 2) and also compared with historical controls.” Clarification of several issues would be appreciated. Full-Text PDF