Neoadjuvant Intra-Arterial Cytoreductive Chemotherapy for Lacrimal Gland Adenoid Cystic Carcinoma: A Long-Term Follow-up Study of a Trimodal Strategy





Purpose


To report the therapeutic efficacy of integrating neoadjuvant chemotherapy with conventional bimodal therapies for lacrimal gland adenoid cystic carcinoma by providing an additional 8 years of follow-up data on the same cohort of patients whose cumulative 10-year disease-free survival outcomes were reported in 2013.


Design


Non-randomized, retrospective, interventional case series.


Methods


Nineteen consecutive patients treated with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC), orbital exenteration, chemoradiotherapy, and adjuvant intravenous chemotherapy at a single institution were included. Analyses were undertaken of locoregional recurrences and distant metastases, disease-free survival time, TNM tumor stage at presentation, response to IACC, and prognostic impact of positive resection margins. The main outcome measures were overall survival, disease-free survival, disease relapse, positive tumor resection margins, and tumor stage at presentation.


Results


Eight patients with an intact lacrimal artery (group 1), 7 with AJCC stage T4a-c, had significantly better overall survival (87.5% versus 14.3% at 15 years), disease-specific mortality, and recurrences (all < .001, log-rank test) than prior conventionally treated patients from the Bascom Palmer Eye Institute. Group 1 was superior to group 2, patients lacking an intact lacrimal artery, concerning overall survival ( P = .042) and recurrence ( P = .017), but with no significant difference in disease-specific mortality ( P = .23). Group 2 was associated with a significantly lower cause-specific mortality than the institutional comparator group ( P = .039). Prior tumor resection with lateral wall osteotomy and failure to adhere to all protocol elements were adverse prognostic factors for suboptimal outcomes. Positive tumor margins increased the risk of all-cause mortality 4.1 times ( P = .036, stratified Cox proportional hazards regression) and disease-specific mortality 8.0 times ( P = .043, stratified Cox proportional hazards regression) than a patient with negative margins.


Conclusions


Extended follow-up supplemented with AJCC staging data supports neoadjuvant IACC as an integral component of a trimodal treatment strategy in patients with an intact lacrimal artery. Protocol elements implemented as designed appear to have improved overall survival and decreased disease relapse in this cohort. This extended long-term IACC dataset suggests that a critical bar of at least 15 years of follow-up is appropriate for assessing the efficacy of current conventional and future globe-sparing bimodal therapies.


Introduction


L acrimal gland adenoid cystic carcinoma (LGACC) is a rare orbital malignancy notorious for its unpredictability and universal devastating lethality. The difficulty in achieving a cure for this disease is principally attributable to the complex regional orbital anatomy, the tumor’s aggressive biological behavior, infiltrative growth pattern, distinct propensity for perineural infiltration with retrograde intracranial extension, hematogenous dissemination, and delay in diagnosis. The tumor often infiltrates and spreads through bone. , Intracranial involvement and metastatic disease are the principal causes of death. ,


Controversy remains regarding the optimal treatment strategy for this orbital tumor, ranging from globe-sparing tumor resection, proton beam therapy, bimodal therapy of exenteration with or without adjacent bone removal followed by external beam radiation therapy to radical multidisciplinary intervention with cranio-orbital resection. , , Much of the early management philosophy was influenced by Halsted’s doctrine of radical mastectomy for breast cancer: cutting more equals living more. , , , , However, the dogma that cutting more orbital tissues for local disease control in LGACC equals living more has not proven to be true. Despite various surgery and radiation therapy permutations, these patients’ survival outcomes remain dismal. , , , , , Font and Gamel reported an actuarial survival rate of < 50% at 5 years and a bleak 20% at 10 years, regardless of treatment methods, with virtually no patients surviving beyond 15 years with conventional therapies. Improvements in local disease control are unlikely to impact survival until LGACC is viewed as a systemic disease rather than a local orbital disease. A multimodal treatment strategy integrating a systemic approach needs to be developed to prevent local recurrence and distant metastatic disease.


To address the principal shortcomings of prior conventional bimodal locoregional therapies, Meldrum and associates introduced a trimodal protocol in 1998. This treatment paradigm has 3 integral components: chemotherapy, orbital exenteration, and radiation therapy. The core element of the strategy is neoadjuvant intra-arterial cytoreductive chemotherapy (IACC) – delivery of a high concentration of chemotherapeutic agent to the tumor through an intact lacrimal artery before exenteration. The rationale of regional infusion of cisplatin is the delivery of a concentration of drug that otherwise cannot be safely delivered through the venous route, achieving local drug concentration exceeding the usual blood level to increase efficacy. This first-pass effect may result in the drug concentration overwhelming the tumor’s nucleotide excision repair system to prevent DNA replication. The principal intent of the neoadjuvant phase of chemotherapy is to induce tumor cell death and cytoreduction to enhance tumor margin clearance at the time of exenteration and to minimize dissemination of viable tumor cells before and during surgical manipulation. It also offers the theoretical advantage of eliminating occult tumor cells beyond the surgical margins.


In 2013, Tse and associates reported this trimodal therapy’s long-term outcomes in a non-randomized, retrospective treatment comparison study of 19 consecutive patients from a single institution. The 19 patients were stratified into 2 groups in a post-hoc analysis. Group 1 (intact lacrimal artery and protocol adherence) comprised patients with an intact lacrimal artery and no prior tumor resection or surgical disruption of the bone barrier who completed all aspects of the treatment protocol as designed – in sequential order and within an optimal timeframe. Group 2 (non-intact lacrimal artery or protocol non-adherence) comprised patients without an intact lacrimal artery and disruption of the bone barrier from tumor resection before referral for IACC treatment, except 1 patient who failed to adhere to the integral elements of exenteration and adjuvant chemotherapy. The study’s findings demonstrated a beneficial long-term advantage of an IACC-anchored trimodal protocol in achieving local disease control and disease-free survival even for patients with advanced-stage tumors.


The main objective of the current report is to provide an additional 8 years of follow-up data on the same cohort of patients and to scrutinize the therapeutic benefits of this treatment strategy. Additionally, it proposes a new standard for future survival follow-up time reporting in assessing the treatment efficacy of current and globe-preservation therapies for LGACC. This study provides the longest follow-up time in the literature to evaluate the therapeutic effectiveness of integrating chemotherapy into conventional bimodal treatment for a disease in which effective therapy has remained elusive. This case series reports that IACC delivered through an intact lacrimal artery appears to prolong disease-free survival in this cohort of patients with LGACC.


Materials and methods


The University of Miami Miller School of Medicine Institutional Review Board approved the case series review. The treatment was conducted under the Declaration of Helsinki provisions and was performed in compliance with the Health Insurance Portability and Accountability Act.


PROTOCOL DESCRIPTION


The chemotherapy arm of the trimodal protocol consists of 6 cycles of chemotherapy – 2 or 3 neoadjuvant cycles and 4 or 3 adjuvant cycles. A neoadjuvant cycle consists of intra-arterial perfusion of cisplatin 100 mg/m 2 on day 1 and intravenous doxorubicin 25 mg/m 2 on days 1 to 3. To avoid direct brain or retina perfusion through an internal carotid artery access, the internal maxillary artery (IMA), a branch of the external carotid artery is cannulated. A second intra-arterial cycle is administered in 3 weeks. Three to 4 weeks after completing the second cycle, MRI or CT of the orbits is obtained to assess tumor response, which typically shows visible shrinkage of tumor volume, in some cases downstaging the tumor to a surgically resectable mass. However, if the posterior tumor margin shrinkage in the orbital apex is incomplete, rendering tumor resection margin clearance less likely, a third cycle is administered to achieve further cytoreduction. The decision to implement the third cycle is also guided by the patient’s tolerance or side effects to the initial cycles. After 2 (or possibly 3) intra-arterial chemotherapy cycles and following hematologic recovery, orbital exenteration is performed without delay to prevent tumor progression. Surgery is followed by adjuvant radiotherapy 2 to 4 weeks later with concomitant weekly IV cisplatin 20 mg/m 2 for radiosensitization. Following chemoradiation therapy, 3 or 4 cycles of adjuvant IV cisplatin 100 mg/m 2 on day 1 and intravenous doxorubicin 20 mg/m 2 on days 1 to 3 every 3 weeks are administered, so patients would optimally receive a total of 6 cycles of systemic chemotherapy.


PARTICIPANTS


The clinical records of 19 consecutive patients with LGACC treated with neoadjuvant IACC were retrieved from the Bascom Palmer Eye Institute (BPEI) and University of Miami Hospital and Clinics. The study period extended from 1988 to 2021. The American Joint Committee on Cancer TNM Classification , 7 th edition for tumor staging was added. Seven patients were treated consecutively by conventional therapies between 1967 and 1984, with information gathered for the 2013 study remaining unchanged. This previously reported cohort of patients constituted the institutional comparator of the treatment group (Supplementary Figures 1-3). Disease-related mortality was defined as death due to LGACC. The 2 previously reported cases with alternate histology were excluded.


All the surviving participants from the 2013 study were contacted in January 2021 in a telephone interview regarding their overall medical status, with particular emphasis on disease-free survival. Referring ophthalmologists or medical oncologists were contacted for medical status confirmation, supplemental information relating to late sequelae of chemotherapy complications, or cause of death. The cause of death was confirmed by medical records and the primary treating physician. Information on locoregional recurrence, distant metastases, disease-free survival time, and medical status were updated.


STATISTICAL ANALYSES


The efficacy of treatments with Kaplan-Meier survival analyses for 3 endpoints was compared: mortality from all causes (overall survival), mortality due to LGACC with patients censored at death due to other reasons (disease-specific survival), and time to recurrence (progression-free survival). There is some controversy in the oncology literature regarding the most appropriate assessment of mortality: all-cause or disease-specific. This is a particular issue for small retrospective studies wherein 2 considerations come into play: (1) the uncertainty of obtaining accurate cause of death information from contacting relatives and (2) the reduction in statistical power associated with fewer endpoints in cause-specific mortality. For both reasons, all-cause mortality is preferred but disease-specific mortality is also reported. The survival time was calculated as the number of days from protocol initiation to the endpoint, last follow-up examination, or contact date. Statistical significance was assessed with the log-rank test. The reporting of progression-free survival and overall survival are well accepted standards for assessing cancer therapies in oncologic literature and they are universally utilized to compare data across studies. Instead of demonstrating overall survival advantages, especially for diseases with multiple lines of treatment or long-term survivorship, which may take years to confirm, progression-free survival has been used as a surrogate endpoint for which new treatments for malignant disease have been FDA approved. These endpoints are therefore reported here, consistent with clinical trial assessments.


Patients were divided into 2 groups receiving IACC: group 1 and group 2, depending on the integrity of the lacrimal artery. The latter group included 1 patient (case 8) with an intact lacrimal artery who received neoadjuvant therapy but deviated from protocol by refusing exenteration and adjuvant treatment. Survival was measured by specific cumulative proportions illustrated in the Kaplan-Meier curves, the benchmark statistic for interpreting survival. In addition to standard median follow-up (F/U) time-all for all patients, median F/U time-alive only for patients surviving at the end of the time of this report was also reported. Because LGACC mortality manifests only after many years, recently treated patients with short follow-up contribute little to treatment efficacy assessment. The median F/U time-alive is a gauge for identifying studies including patients with short follow-up.


Cumulative proportions were compared with the log-rank test of statistical significance. The risk ratio associated with positive tumor margins on each endpoint was studied with univariate Cox survival regression stratified by group and employing the likelihood ratio test for statistical significance.


Results


The patient demographics, treatment characteristics, clinical data, TNM stage at presentation, length of follow-up, and cause of death are summarized in Table 1 . No patients were lost to follow-up.



TABLE 1

Patient Characteristics of IA Cytoreductive Chemotherapy for Lacrimal Gland Adenoid Cystic Carcinoma






















































































































































































































































Patient No. Age/ Gender/ Affected Side ACC Subtype/ Perineural/ Bone Infiltration IACC Cycle/Total Cycles Prior Tumor Resection Radiographic Tumor Response/Tissue Margins TNM Treatment Survival Time in Months (Years) and Status at Last Follow-Up Time (Months) of Local Recurrence/Met Remarks
Group 1
1 29/M/OD Basa/P/B 3/4 NO Yes /- T4cN0M0 Ex/RT 389 (32.4); A,ND NED Intracranial extension
3 73/F/OS Basa/P 2/6 NO Yes /- T4bN0M0 Ex/RT 222 (18.5); D,ND NED Kidney transplant, died SCC
4 58/M/OS Crib/P 2/6 NO Yes/- T4cN0M0 Ex/RT/GK 238 (19.8); D,ND NED Intracranial, ethmoid sinus ACC, died of aspiration pneumonia
5 35/M/OS Crib/P 3/6 NO Yes/+ T4aN0M0 Ex/RT 251 (20.9); A,ND NED Non-healing apex; free flap
7 30/M/OS Basa/P 2/4 NO Yes /- T2aN0M0 Ex/B/RT 216 (18); A,ND NED
10 29/F/OD Basa 2/6 NO Yes /- T4bN0M0 Ex/RT 198 (16.5); A,ND NED
17 53/F/OD Basa/B 2/6 NO Yes/- T4cN0M0* Ex/RT 131 (10.9); A,ND NED Bone erosion, dural enhancement, – neck dissection
18 44/M/OS Basa/Crib/P/B 3/6 NO Yes/+ T4cN0M0 Ex/RT 98 (8.17); D,D (74); Lung Pitting of lateral wall; bone burring, jaw
Group 2
2 32/M/OD Crib/P/B 3/6 YES Yes/- T4bN0M0 Ex/B/RT 159 (13.25); D,ND NED HIV, died of oral SCC
6 42/F/OD Crib/P/B 3/6 YES Yes/- T4bN0M0 Ex/B/RT 135 (11.25); D,D (50); Lung Bone necrosis, hearing deficit; 7 th N palsy
8 36/F/OS Basa/P/B 2/2 NO Yes/+ T4bN0M0 Ex/RT 32 (2.7); D,D (20); LR/Liver Delayed exent, refused final 4 cycles
9 64/F/OD Crib/B 2/2 YES Yes/+ T4cN0M0 Ex/B/RT 120 (10); D,ND (13); LR/Sinus ACC in sinus mucosa, died of breast CA
11 54/M/OS Crib/Basa 2/6 YES Yes/+ T4bN0M0 Ex/B/TM/RT 88 (7.3); D,D (20); LR/Lung/Brain Extensive disease at presentation
12 32/F/OD Crib 2/5 YES Yes/+ T3aN0M0 Ex/B/RT/GK 134 (11.25); D,ND NED Died of leukemia
13 34/M/OD Crib 2/6 YES Yes/- T4bN0M0 Ex/B/RT 190 (15.8); A,D (168); Lung Lung nodules
14 49/M/OS Crib/Basa 2/5 YES Yes/- T2aN0M0 Ex/B/RT 184 (15.3); A,D (57); Lung Lung nodule resection; Lung and liver metastases after disease-free for 10.8 years
15 20/M/OD Crib/Basa/P/B 3/5 YES Yes/- T3aN0M0 Ex/B/RT 175 (14.6); A,ND NED
16 38/F/OS Basa 2/6 YES Yes/+ T4aN0M0 Ex/RT 154 (12.8); A,ND NED
19 56M/OS Basa/P 5/5 YES Yes/+ T4cN0M0 Ex/RT 33 (2.75); D,D (22) Globe-sparing resection of a T2 tumor and radiotherapy. Recurrence as a T4c tumor with intracranial and ethmoid sinus involvement

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Sep 11, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Neoadjuvant Intra-Arterial Cytoreductive Chemotherapy for Lacrimal Gland Adenoid Cystic Carcinoma: A Long-Term Follow-up Study of a Trimodal Strategy
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