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Impact of omission of elective nodal irradiation on treatment outcomes in locally advanced pancreatic adenocarcinoma patients treated with definitive concurrent chemoradiotherapy
Pancreatology 12 (2012) 434e439
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Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Impact of omission of elective nodal irradiation on treatment outcomes in locally advanced pancreatic adenocarcinoma patients treated with definitive concurrent chemoradiotherapy Erkan Topkan a, *, Cem Parlak a, Fuat Yapar b a b
Department of Radiation Oncology, Baskent University Adana Medical Faculty, Kisla Saglik Yerleskesi 01120, Adana, Turkey Department of Nuclear Medicine, Baskent University, Adana Medical Faculty, Kisla Saglik Yerleskesi,01120 Adana, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2012 Received in revised form 21 August 2012 Accepted 25 August 2012
Background: We evaluated influence of limited-field radiotherapy with no elective nodal irradiation (ENI) on outcomes and toxicity profile in patients with locally advanced pancreatic adenocarcinoma (LAPAC), treated with definitive concurrent chemoradiotherapy (C-CRT). Methods: Thirty-five patients with histological proof of LAPAC underwent 50.4 Gy of C-CRT with 5-FU followed by maintenance gemcitabine. Target volume included primary tumor and lymph nodes that appeared to be involved on either contrast-enhanced computerized tomography or 18F-fluoro-deoxyglucose positron emission tomography. Results: No grade 4/5 acute/late toxicity was reported at median 15.7 months. Acute hematologic plus non-hematologic grade 3 toxicity was noted in 10 (28.6%) patients. At long-term, 2 patients (5.7%) experienced grade 3 gastric outlet obstructions at 8.7 and 10.9 months, respectively. No isolated regional relapses were noted. Median overall-survival (OS), progression-free survival (PFS), and locoregional-PFS (LRPFS) were 15.2, 9.1 and 7.3 months, respectively. Corresponding 1- and 2-year survival estimates were 60.0% and 20.0% for OS, 41.9% and 17.4% for LRPFS, and 34.0% and 12.7% for PFS, respectively. Conclusions: Compared to ENI literature, first report of a limited-field C-CRT study carried out in Turkey showed that omission of ENI was relatively well tolerated without compromising survival and locoregional control rates in patients with LAPAC. Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Locally advanced pancreatic carcinoma Concurrent chemoradiotherapy Limited-field irradiation Survival outcomes
1. Introduction Although, there is no randomized controlled evidence, and therefore, no consensus on the optimal size of portals in radiotherapy (RT) for locally advanced pancreatic adenocarcinoma (LAPAC), given that the surgical series report up to 80% rates of lymphatic spread [1], clinical target volume (CTV) commonly includes not only the primary tumor plus grossly involved lymph nodes (LN) but also electively the regional lymphatic basins, irrespective of their clinical/radiological status [2,3]. With such a field design, size of anterior-posterior opposed ports usually ranges from 10 10 to 14 14 cm, and even larger if para-aortic LNs included [4]. Therefore, traditional planning target volume (PTV) unavoidably involves some part of critical organs including stomach, duodenum, small intestine, liver, and kidney(s) limiting delivery of * Corresponding author. Tel.: þ90 5337381069. E-mail address: [email protected] (E. Topkan).
effective total doses. Although some patients may theoretically benefit from elective nodal irradiation (ENI), such port designs have the potential to cause severe gastrointestinal toxicity, particularly when concurrent chemoradiotherapy (C-CRT) is the preferred treatment option. Additionally, despite the use of larger RT fields, locoregional control rates in the range of 32e58% is still poor [5], questioning the feasibility of relatively smaller radiation fields with non-inferior clinical outcomes and comparable toxicity rates. At any tumor site, including the pancreas, improved local control rates with RT or C-CRT can only be achieved with accurate definition of primary tumor and its local/regional extensions. In this respect, coregistration of functional 18F-fluoro-deoxyglucose positron emission tomography (PET) and anatomic computerized tomography (CT) has been demonstrated to be potentially valuable [6,7]. Reasonable PETCT based RT planning (RTP) have been shown to significantly alter RT fields by change in gross tumor volume (GTV) and its subsequent derivative CTV in various tumors [8]. For LAPAC, in our previous study, an average of 29.7% enlargement in GTV in 5 of 14 (35.7%) patients due
1424-3903/$ e see front matter Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2012.08.006
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to detection of CT-occult additional LN metastases and/or primary tumor extensions outlined by PET-CT was notable, suggesting a theoretical advantage of co-registered PET-CT based RTP to reduce geographical misses [9]. Based on these results, our current institutional standard is to use contrast-enhanced CT/PET-CT fusion data for both staging and RTP in LAPAC patients. Herein, in an attempt to assess the feasibility of a relatively smaller radiation field, we report the results of contrast-enhanced CT/PET-CT based limited-field three-dimensional RT (LFRT) without ENI, given concurrently with 5-FU and followed by maintenance gemcitabine and compare our results with the available ENI and non-ENI literature on LAPC in terms of toxicity and survival outcomes. 2. Methods 2.1. Study population Thirty-five consecutive patients referred to our department from June 2007 to July 2010 were included in this feasibility study. The eligibility criteria included histologically proven diagnosis of surgically unresectable LAPC, receipt of full course of C-CRT, no history of previous chemotherapy or abdominal RT, an age of 18e70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, presence of measurable or evaluable lesion, no contraindication for FDG-PET-CT imaging, an adequate bone marrow reserve (hemoglobin value of 10 g/dL, leucocyte of 4.000/mL, and thrombocyte of 100.000/mL), hepatic (aspartate aminotransferase or alanine aminotransferase of <5 times the upper limit) and renal function (serum creatinine <2 mg/dL). Disease extent was determined in all patients with laparotomy or laparoscopy, and radiological imaging studies including contrastenhanced abdominal CT, magnetic resonance imaging (MRI) and/ or MR-cholangiopancreaticography. All patients were restaged with FDG-PET-CT obtained for RTP. Disease was considered to be unresectable if contrast-enhanced CT or staging laparoscopy/laparotomy revealed a low likelihood of complete resection and/or any of the following: involvement of superior mesenteric artery/ celiac trunk, encasement of 180 degrees or more of the circumference of superior mesenteric/portal vein, and/or evidence of narrowing of or thrombus within the superior mesenteric/portal vein. All patients signed informed consent, and The Institutional Ethical Committee, in accordance with Helsinki Declaration and the rules of Good Clinical Practice on human projects, approved the study design. 2.2. Treatment planning and delivery Our current institutional treatment flowchart for patients presented with LAPAC is as shown Fig. 1. FDG-PET-CT scans for restaging and RT planning purposes were performed according to the institutional protocol described previously, within 10 days prior to treatment [9]. An enhanced CT scan [with intravenous (i.v.) plus oral contrast media through 5 mm slice thickness] from the base of the skull to the inferior border of the pelvis was first acquired, using a standardized protocol with 140 kV, 80 mA, and thereafter, the FDG-PET scan was acquired in 3D mode from the base of the skull to the inferior border of the pelvis (6e7 bed positions, 3 min per bed position) without repositioning the patient on the table. Both CT and FDG-PET images were acquired with the patient breathing shallowly. Attenuation was corrected by using the CT images. Areas of FDG uptake were categorized as malignant based on location, intensity, shape, size, and visual correlation with CT images to differentiate physiologic from pathologic uptake. To avoid unintentional geographic misses, any regional lymph node(s) with shortest diameter 1 cm, irrespective of FDG avidity, were determined to be pathologically involved [10].
Fig. 1. Our current institutional management algorithm for patients presented with LAPAC. C-CRT; concurrent chemoradiotherapy; FDG-PET-CT, 18F-fluoro-deoxyglucose positron emission tomography/computerized tomography, LAPAC. locally advanced pancreatic adenocarcinoma, RT; radiotherapy.
Image registration and RTP were performed via Eclipse 7.5 (Varian Medical Systems, Palo Alto, CA, USA) RTP system. Two experienced radiation oncologists defined the target volumes, with the assistance of a nuclear medicine physician, and contoured the GTV, PTV, and the organs at risk (OAR) on the contrast-enhanced CT/PET-CT fusion images. For each patient, GTV included the primary tumor and the lymph nodes that appeared to be involved on either of CT (1 cm in short axis) and/or PET images (pathologic FDG uptake irrespective of size). PTV was defined as GTV þ 1.5 cm in each direction, to allow for microscopic extension and set-up errors. However, in an effort to minimize toxic events, margins were decreased appropriately when GTV was located close to OAR. In an effort to prevent excessive toxicity, ENI was not permitted. A typical RT plans with and without ENI is as depicted in Fig. 2. A single target volume with no cone down volumes utilizing a four-field technique (postero-anterior, antero-posterior, and laterals; with appropriate gantry angles) was intended to be irradiated. Treatment volumes were defined by using customized multi-leaf collimators. All patients received the RT protocol utilizing 18 MV photon energy linear accelerators. A dose of 50.4 Gy (1.8 Gy/fr, 5 days a week) was prescribed to encompass the defined PTV with isodose lines 95e107%. To achieve this, dosimetric practice wedges were utilized to modify beams. Dose-volume histograms (DVH) were generated for each patient to assess PTV coverage and OAR doses. The maximum dose limits were set at 45 Gy for spinal cord, 50 Gy for small bowel and stomach, 50 Gy for 1/3, 35 Gy for 2/3, and 30 Gy for 3/3 volume for liver, and V20 (volume receiving 20 Gy) not more than 50% of one functioning kidney and V20 not more than 30% for the other. 2.3. Chemotherapy All patients received continuously infused 5-FU (225 mg/m2/day, 7 days/week) throughout the RT course as a radiosensitizer, and additional 2e6 courses of maintenance gemcitabine (1000 mg/m2 i.v. over 30 min, days 1 and 8, every 21-days) after completion of the RT. 2.4. Toxicity assessment Patients were assessed weekly during C-CRT course, every 2 months for the first year, every 3 months for the second year and every 6 months, thereafter, or more frequently if necessary. Early
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Fig. 2. Typical examples of radiotherapy planning with (AeC) and without (DeF) elective nodal irradiation. (A, D) Target volumes, (B, E) 95% isodose coverage, (C, F) doseevolume histograms.
and late clinical toxicity was recorded and blood samples were collected for hematology and biochemistry assays at each assessment. Toxicity was assessed and scored with the aid of CTC 3.0 (Common Toxicity Criteria). 2.5. Response evaluation and follow-up Response to treatment was assessed by re-staging contrastenhanced CT and FDG-PET-CT scans carried out 8 weeks after the completion of the treatment. The time interval of 12-week for the first follow-up FDG-PET-CT was mandatorily chosen as the shortest possible time for response assessment according to our national health insurance policies, rather than an evidence based practice. Thereafter, all patients were monitored by bimonthly studies including blood chemistry; serum CEA and CA 19e9 levels, contrastenhanced CT of the abdomen and FDG-PET-CT; and, additional abdominal ultrasound, chest CT, and cranial MRI were utilized when necessary. In case of suspected local/regional and/or distant disease progression necessary investigations were performed irrespective of the date of last visit. Progression pattern was specified as “distant” when disease was identified at distant organs, such as peritoneal membranes, liver, bone, lung etc., “local” when progressive disease included the primary tumor and/or involved lymph nodes that were covered in the original PTV and “regional” when progressive disease comprised of previously uninvolved regional lymphatic basin(s). We chose to use “progression” here instead of “recurrence”, because complete responses are rarely seen in this setting and complete sterilization of disease may not be identifiable with certainty in absence of confirmatory surgery or at least pathologic examination of biopsy specimens. 2.6. Statistical analyses The primary endpoint was to assess the efficacy of an LFRT with concurrent chemotherapy followed by adjuvant chemotherapy in terms of locoregional progression-free survival (LRPFS), progression-free survival (PFS), and overall survival (OS). LRPFS was defined as survival without local/regional failure, and was
calculated as the time between the first day of the treatment and the date of local/regional failure or death/last visit. PFS and OS were calculated as the time between the first day of the treatment and any type of disease progression or death, and the date of death or last visit, respectively. Survival analysis was performed by the Kaplan-Meier method and Cox proportional hazard model was applied for evaluation of the relationship between different variables and survival. P values of 0.05 were considered to be statistically significant. 3. Results 3.1. Toxicity outcomes Pretreatment patient and disease characteristics were as detailed in Table 1. All 35 patients were able to tolerate the intended C-CRT protocol with no grade 4/5 acute or late toxicity. Rates of maximum grade acute toxicities during C-CRT for all patients were as listed in Table 2. Overall grade 3 toxicity has been reported in 10 (28.6%) patients; non-hematologic in 6 (17.2%) and hematologic in 4 (11.4%). Unplanned treatment interruption was mandated in 3 patients (8.6%) for 2, 5, and 6 days, respectively. Main reasons for these breaks were grade 3 diarrhea in 2, and leukopenia in another patient. However, all 3 were able to complete the planned C-CRT course after symptomatic and supportive treatment. Hospitalization was mandated only in 2 (5.7%) patients due to grade 3 toxicity; diarrhea refractory to conventional loperamide and leukopenia, respectively. At long-term, treatment protocol was well tolerated with no toxicity related deaths. Two patients (5.7%) developed symptoms of Grade 3 gastric outlet obstruction at 8.7 and 10.9 months after the CRT, respectively. Although late toxicity cannot be excluded as a cause, because of simultaneous evidence of disease progression in both patients at 6.8 and 8.5 months, progressive disease was probably associated with the symptoms. An additional (2.9%) patient experienced grade 2 gastric ulcer at 10.6 months, which could be managed with medication. No patients developed liver or renal dysfunction.
E. Topkan et al. / Pancreatology 12 (2012) 434e439 Table 1 Patient characteristics.
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Table 3 Patterns of initial and ultimate disease progression (N ¼ 34).
Characteristic
Value
Site
Initial N (%)
Ultimate N (%)
Median age (year) Range Sex (%) Male Female Performance (ECOG; %) 0 1 2 Chief complaint Pain Weight loss Appetite loss Jaundice Tumor location (N; %) Head Body Clinical stage (N; %) T4 N0 T4N1 Pretreatment CA 19e9 (kU/L) Median Range Nadir CA 19e9 (kU/L) Median Range
54.8 39 e68
Local only Regional lymph node Distant only Liver Peritoneum Liver þ peritoneum Non-regional lymph node Bone Bone þ liver Brain þ liver Adrenal gland þ liver Local þ distant þLiver þPeritoneum þLiver þ peritoneum þLiver þ lung Total progression
2 0 24 10 9 4 0 1 0 0 0 2 2 0 0 0 28
0 0 11 4 2 1 0 1 1 1 1 17 6 6 3 2 28
26 (74.3) 9 (25.7) 9 (25.7) 19 (54.3) 7 (20.0) 23 (65.7) 6 (17.1) 3 (8.6) 3 (8.6) 30 (85.7) 5 (14.3)
(5.7) (0) (68.6) (28.6) (25.7) (11.4) (0) (2.9) (0) (0) (0) (5.7) (5.7) (0) (0) (0) (80.0)
(0%) (0%) (31.6) (11.4) (5.7) (2.9) (0) (2.9) (2.9) (2.9) (2.9) (48.4) (17.1) (17.1) (8.5) (5.7) (80)
17 (48.6) 18 (51.4)
4. Discussion 297.6 29.2e1718.3 118.3 18.2e2618.3
ECOG; Eastern Cooperative Oncology Group.
3.2. Survival outcomes At median 15.7 months of follow-up, 7 (20%) patients were free of disease progression. Analysis of initial and ultimate failure patterns following concurrent CRT were as depicted in Table 3. No marginal or regional failures were reported as initial or ultimate sites of disease progression. Distant metastasis consisted the commonest initial type of failure (68.4%), with liver (28.6%) and peritoneal membranes (25.7%) being the leading sites involved. Initial infield progression was evident only in 4 (11.4%) patients, 2 (5.7%) of which were isolated local failures. At long-term, although all of the 28 (80%) failures involved distant metastasis, starkly contrasting with initial failure rates, local disease progression was reported in 17 (48.6%) patients. At the time of this analysis 26 patients (74.3%) were dead. Curves of OS, LRPFS, and PFS are shown in Fig. 3. Median OS, LRPFS, and PFS were 15.2 (95% CI: 11.7e18.7), 9.1 (95% CI: 8.2e10.0), and 7.3 (95% CI: 4.7e9.9) months, respectively. Corresponding survival estimates at 1- and 2-year were 60.0% and 20.0% for OS, 41.9% and 17.4% for LRPFS, and 34.0% and 12.7% for PFS, respectively.
Compared to ENI literature, results of this first report of a LFRT study carried out in Turkey demonstrated that LFRT administered concurrent with continuous 5-FU is relatively well tolerated and efficacious in multidisciplinary management of LAPAC. Besides its favorable tolerability, no regional progression indicates that irradiation of only the primary tumor and involved LNs may offer similar outcome, but with better acute and late complication rates compared to large-field ENI. However, the ultimate rates of 48.6% infield and 80.0% distant failures strongly suggest intensification of both local and systemic therapies rather than irradiation of noninvolved lymphatic basins. In our study, despite the respective 2, 5, and 6 days of unplanned treatment breaks in 3 of 35 patients (8.6%) due to grade 3 diarrhea (n ¼ 2) and leukopenia (n ¼ 1), all patients were able to complete the C-CRT protocol. In studies of ENI, varying hematologic and non-hematologic grade 3 toxicity rates have been reported [11e15]. In a small study by Li et al. [16], grade 3 hematologic toxicity was notable in 14 of 18 patients (77.8%). In
Table 2 Frequency of maximum grade acute toxicities. Toxicity
Nausea Vomiting Diarrhea Tumor pain Anorexia Fatigue Gastritis Leukopenia Anemia Thrombocytopenia
Grade 1
2
3
13 10 10 0 14 13 3 8 8 6
4 3 4 2 10 3 2 7 6 5
2 1 2 0 0 1 0 2 1 1
Fig. 3. Survival outcomes for overall study population. Solid line, overall survival (OS); dashed line, progression-free survival (PFS); dotted line, local-regional progressionfree survival (LRPFS).
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other two studies, Brade et al. [17] reported overall 48% nonhematological toxicity, and similarly Okusaka et al. [18] presented rates of grade 3 anorexia and nausea as 57% and 21%, respectively. Although it is not easy to make direct comparison between these trials, rates of 11.4% hematologic and 17.2% nonhematologic grade 3 acute toxicity observed here seems to be substantially lower than the comparative rates of large-field ENI studies [11e15]. Similar to other LAPAC studies, current median survival, which is slightly longer than 1-year, limits our ability to conclude on true incidence and grade of late toxicity here. However, absence of Grade 4/5 toxicity and a rate of 5.7% grade 3 late toxicity seems to be better than those observed in largefield ENI regimens [11e15], and parallel with most LFRT studies [19e22]. Although randomized evidence is gold standard, these results may at least partially be related with smaller irradiation volumes compared to large-field ENI studies, reflecting the advantage expected from use of a limited radiation field. In the absence of randomized evidence favoring the use of ENI, to increase the tolerability of C-CRT, we elected to irradiate only the primary tumor and involved LNs. This was based on the assumption that the majority of benefit from RT would be brought by control of the primary tumor rather than the subclinical disease in these nodes, which could potentially be managed by the systemic chemotherapy. Although comparisons with other data should be made cautiously, an observation of no isolated regional recurrences, and a median OS of 15.2 months is similar or slightly better than other scarcely reported limitedfield C-CRT studies in LAPAC [23]. In a phase I radiation dose escalation study of 34 unresectable or incompletely resected PAC patients treated with concurrent gemcitabine, McGinn et al. [24] reduced RT fields (PTV ¼ GTV þ 1 cm) which was even smaller than our current PTV size, and observed only 3 (8.8%) regional failures. In another LFRT study of 26 patients, Tokuuye et al. [25] reported no isolated regional failures outside the radiation field, which was later confirmed by Yamazaki et al. [21], and Jackson et al. [23]. More recently investigators from MD Anderson Cancer Center, in a dose escalation study with relatively more strict PTV definition similar to McGinn et al [24], demonstrated encouraging local control, resectability and survival rates with full dose gemcitabine and conventionally fractionated 55 Gy delivered by IMRT with motion tracking in 50 patients with LAPAC [26]. The approach of omitting the elective irradiation of regional nodes is further supported by the current radiosurgical practice in PAC [27e31], which demonstrated locoregional control rates far beyond that of conventional large-field ENI studies with only millimetric margins around the GTV. Taken together, these results support the use of LFRT to increase tolerability of aggressive C-CRT protocols with no reduction in efficacy, and with the potential to further escalate RT doses in patients with LAPAC. Based on the outcomes in our previous study [9] that demonstrated the need for an enlargement of GTV in 5 out of 14 patients (35.7%) with the use of co-registered PET-CT compared to CT-alone; herein, we utilized contrast-enhanced CT/PET-CT fusion as the imaging tool of choice for RTP in an effort to theoretically reduce geographic misses. Although data from a larger cohort may be worthy, absence of regional disease progression in the present cohort is demonstrative for success of PET-CT in target volume definition in LAPAC. However, an ultimate infield relapse rate of 48.6% indicates the failure of our effort to improve local control rates beyond the available literature. Although it is not possible to assign this finding to a single cause, such results may either be associated with inadequacy of 50.4 Gy dose, or insufficient radiosensitizing efficacy of 5-FU given in the dose and schedule utilized
here. In this setting, gemcitabine appears to be a promising radiation sensitizer [32], and its concurrent use with escalated doses of RT may offer a theoretical chance for improved outcomes. This is supported by the results of recent linear accelerator or Cyberknifebased stereotactic body RT (SBRT) studies reporting 1-year local control rates of up to 94% in LAPAC [27e31]. Notably, in the most recent study consisting of 20 LAPAC patients, Schellenberg et al. [30] administered gemcitabine on Days 1, 8, and 15 followed by a single fraction 25 Gy SBRT on day 29, and depicted an outstanding freedom from local progression rate of 94% at 1-year, which is significantly better than rates achieved with any reported CRT study. Many clinical trials demonstrated distant relapses as the predominant failure pattern in LAPAC following C-CRT [32e34]. Consistent with them, in the present cohort, 28 patients (80.0%) progressed distantly. However, at long term, besides distant relapses, local disease progression became apparent in 48.6% patients, which is also in the reported range of 42e68% [32e34]. In prevention of local failures, results of emerging SBRT studies are promising with reported local control rates higher than 90% [27e 31]. In this setting, results of the aforementioned SBRT study published by Schellenberg et al. [30] in 20 LAPAC patients is impressive in terms of realizing the importance of controlling systemic microscopic disease spread. Authors reported that despite an excellent 1-year infield control rate of 94%, 17 of all 19 patients (89.5%) with failure experienced distant progression as the first site of recurrence, reasonably suggesting distant progression as the major cause of treatment failure and death in LAPAC patients with excellent rates of local control. This is almost the same with our 26/ 28 (92.8%) distant failure rate. Therefore, available literature emphasizes the urgent need for any improvements in systemic component of C-CRT to prevent and/or efficiently treat subclinical dissemination of disease to achieve acceptable survival rates in this frankly aggressive tumor. In conclusion, results of this report showed that omission of ENI was relatively well tolerated without comprising survival and locoregional control rates. However, despite absence of isolated regional failures, rates of overall 48.6% infield and 80.0% distant recurrences also emphasizes the urgent need for more efficient radiosensitizers, chemotherapy and/or targeted agents preferably with stronger radiosensitizing and systemic efficacy to improve overall disease control and survival rates in this highly fatal tumor group. Conflict of interest We have no personal or financial conflict of interest and have not entered into any agreement that could interfere with our access to the data on the research, or upon our ability to analyze the data independently, to prepare manuscripts, and to publish them. Authors contribution Conception and design, or analysis and interpretation of data: Erkan Topkan, Cem Parlak, Fuat Yapar. Drafting the article or revising it critically for important intellectual content: Erkan Topkan, Cem Parlak, Fuat Yapar. Final approval of the version to be published: Erkan Topkan, Cem Parlak, Fuat Yapar. References [1] Katz MH, Hwang R, Fleming JB, Evans DB. Tumor-node-metastasis staging of pancreatic adenocarcinoma. CA: A Cancer Journal for Clinicians 2008;58(2): 111e25.
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in patients with locally advanced pancreatic cancer. Radiotheraphy & Oncology 2009;92(2):226e30. Spry N, Harvey J, Macleod C, Borg M, Ngan SY, Millar JL, et al. 3D radiotherapy can be safely combined with sandwich systemic gemcitabine chemotherapy in the management of pancreatic cancer: factors influencing outcome. International Journal of Radiation Oncology. Biology Physics 2008;70(5):1438e46. Yamazaki H, Nishiyama K, Koizumi M, Tanaka E, Loka T, Uehara H, et al. Concurrent chemoradiotherapy for advanced pancreatic cancer: 1,000 mg/m2 gemcitabine can be administered using limited-field radiotherapy. Strahlentherapie und Onkologie 2007;183(6):301e6. Goldstein D, Van Hazel G, Walpole E, Underhill C, Kotasek D, Michael M, et al. Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer. British Journal of Cancer 2007;97(4):464e71. Jackson AS, Jain P, Watkins GR, Whitfield GA, Green MM, Valle J, et al. Efficacy and tolerability of limited field radiotherapy with concurrent capecitabine in locally advanced pancreatic cancer. Clinical Oncology (Royal College of Radiologists) 2010;22(7):570e7. McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, et al. Phase I trial of radiation dose escalation with concurrent weekly fulldose gemcitabine in patients with advanced pancreatic cancer. Journal of Clinical Oncology 2001;19(22):4202e8. Tokuuye K, Sumi M, Kagami Y, Murayama S, Ikeda H, Ikeda M, et al. Small-field radiotherapy in combination with concomitant chemotherapy for locally advanced pancreatic carcinoma. Radiotheraphy & Oncology 2003;67(3):327e30. Ben-Josef E, Schipper M, Francis I, Khan G, Hadley S, Lawrence T, et al. Phase I/ II radiation dose-escalation trial of intensity modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer. International Journal of Radiation Oncology. Biology Physics 2011;81(Suppl. 2):127e8. Koong AC, Le QT, Ho A, Fong B, Fisher G, Cho C, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. International Journal of Radiation Oncology. Biology Physics 2004;58(4):1017e21. Koong AC, Christofferson E, Le QT, Goodman KA, Ho A, Kuo T, et al. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. International Journal of Radiation Oncology. Biology Physics 2005;63(2):320e3. Rwigema JC, Heron DE, Parikh SD, Zeh HJ, Moser JA, Bahary N, et al. Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. Journal of Gastrointestinal Cancer 2012;43(1):70e6. Schellenberg D, Kim J, Christman-Skieller C, Chun CL, Columbo LA, Ford JM, et al. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. International Journal of Radiation Oncology. Biology Physics 2011;81(1):181e8. Chang ST, Goodman KA, Yang GP, Koong AC. Stereotactic body radiotherapy for unresectable pancreatic cancer. Frontiers of Radiation Theraphy & Oncology 2007;40:386e94. Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Annals of Surgical Oncology 2011;18(5):1319e26. Gastrointestinal Tumor Study Group. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Cancer 1985;56(11):2563e8. Klaassen DJ, MacIntyre JM, Catton GE, Engstrom PF, Moertel CG. Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil e an Eastern Cooperative Oncology Group study. Journal of Clinical Oncology 1985;3(3):373e8.
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Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Impact of omission of elective nodal irradiation on treatment outcomes in locally advanced pancreatic adenocarcinoma patients treated with definitive concurrent chemoradiotherapy Erkan Topkan a, *, Cem Parlak a, Fuat Yapar b a b
Department of Radiation Oncology, Baskent University Adana Medical Faculty, Kisla Saglik Yerleskesi 01120, Adana, Turkey Department of Nuclear Medicine, Baskent University, Adana Medical Faculty, Kisla Saglik Yerleskesi,01120 Adana, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2012 Received in revised form 21 August 2012 Accepted 25 August 2012
Background: We evaluated influence of limited-field radiotherapy with no elective nodal irradiation (ENI) on outcomes and toxicity profile in patients with locally advanced pancreatic adenocarcinoma (LAPAC), treated with definitive concurrent chemoradiotherapy (C-CRT). Methods: Thirty-five patients with histological proof of LAPAC underwent 50.4 Gy of C-CRT with 5-FU followed by maintenance gemcitabine. Target volume included primary tumor and lymph nodes that appeared to be involved on either contrast-enhanced computerized tomography or 18F-fluoro-deoxyglucose positron emission tomography. Results: No grade 4/5 acute/late toxicity was reported at median 15.7 months. Acute hematologic plus non-hematologic grade 3 toxicity was noted in 10 (28.6%) patients. At long-term, 2 patients (5.7%) experienced grade 3 gastric outlet obstructions at 8.7 and 10.9 months, respectively. No isolated regional relapses were noted. Median overall-survival (OS), progression-free survival (PFS), and locoregional-PFS (LRPFS) were 15.2, 9.1 and 7.3 months, respectively. Corresponding 1- and 2-year survival estimates were 60.0% and 20.0% for OS, 41.9% and 17.4% for LRPFS, and 34.0% and 12.7% for PFS, respectively. Conclusions: Compared to ENI literature, first report of a limited-field C-CRT study carried out in Turkey showed that omission of ENI was relatively well tolerated without compromising survival and locoregional control rates in patients with LAPAC. Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Locally advanced pancreatic carcinoma Concurrent chemoradiotherapy Limited-field irradiation Survival outcomes
1. Introduction Although, there is no randomized controlled evidence, and therefore, no consensus on the optimal size of portals in radiotherapy (RT) for locally advanced pancreatic adenocarcinoma (LAPAC), given that the surgical series report up to 80% rates of lymphatic spread [1], clinical target volume (CTV) commonly includes not only the primary tumor plus grossly involved lymph nodes (LN) but also electively the regional lymphatic basins, irrespective of their clinical/radiological status [2,3]. With such a field design, size of anterior-posterior opposed ports usually ranges from 10 10 to 14 14 cm, and even larger if para-aortic LNs included [4]. Therefore, traditional planning target volume (PTV) unavoidably involves some part of critical organs including stomach, duodenum, small intestine, liver, and kidney(s) limiting delivery of * Corresponding author. Tel.: þ90 5337381069. E-mail address: [email protected] (E. Topkan).
effective total doses. Although some patients may theoretically benefit from elective nodal irradiation (ENI), such port designs have the potential to cause severe gastrointestinal toxicity, particularly when concurrent chemoradiotherapy (C-CRT) is the preferred treatment option. Additionally, despite the use of larger RT fields, locoregional control rates in the range of 32e58% is still poor [5], questioning the feasibility of relatively smaller radiation fields with non-inferior clinical outcomes and comparable toxicity rates. At any tumor site, including the pancreas, improved local control rates with RT or C-CRT can only be achieved with accurate definition of primary tumor and its local/regional extensions. In this respect, coregistration of functional 18F-fluoro-deoxyglucose positron emission tomography (PET) and anatomic computerized tomography (CT) has been demonstrated to be potentially valuable [6,7]. Reasonable PETCT based RT planning (RTP) have been shown to significantly alter RT fields by change in gross tumor volume (GTV) and its subsequent derivative CTV in various tumors [8]. For LAPAC, in our previous study, an average of 29.7% enlargement in GTV in 5 of 14 (35.7%) patients due
1424-3903/$ e see front matter Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2012.08.006
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to detection of CT-occult additional LN metastases and/or primary tumor extensions outlined by PET-CT was notable, suggesting a theoretical advantage of co-registered PET-CT based RTP to reduce geographical misses [9]. Based on these results, our current institutional standard is to use contrast-enhanced CT/PET-CT fusion data for both staging and RTP in LAPAC patients. Herein, in an attempt to assess the feasibility of a relatively smaller radiation field, we report the results of contrast-enhanced CT/PET-CT based limited-field three-dimensional RT (LFRT) without ENI, given concurrently with 5-FU and followed by maintenance gemcitabine and compare our results with the available ENI and non-ENI literature on LAPC in terms of toxicity and survival outcomes. 2. Methods 2.1. Study population Thirty-five consecutive patients referred to our department from June 2007 to July 2010 were included in this feasibility study. The eligibility criteria included histologically proven diagnosis of surgically unresectable LAPC, receipt of full course of C-CRT, no history of previous chemotherapy or abdominal RT, an age of 18e70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, presence of measurable or evaluable lesion, no contraindication for FDG-PET-CT imaging, an adequate bone marrow reserve (hemoglobin value of 10 g/dL, leucocyte of 4.000/mL, and thrombocyte of 100.000/mL), hepatic (aspartate aminotransferase or alanine aminotransferase of <5 times the upper limit) and renal function (serum creatinine <2 mg/dL). Disease extent was determined in all patients with laparotomy or laparoscopy, and radiological imaging studies including contrastenhanced abdominal CT, magnetic resonance imaging (MRI) and/ or MR-cholangiopancreaticography. All patients were restaged with FDG-PET-CT obtained for RTP. Disease was considered to be unresectable if contrast-enhanced CT or staging laparoscopy/laparotomy revealed a low likelihood of complete resection and/or any of the following: involvement of superior mesenteric artery/ celiac trunk, encasement of 180 degrees or more of the circumference of superior mesenteric/portal vein, and/or evidence of narrowing of or thrombus within the superior mesenteric/portal vein. All patients signed informed consent, and The Institutional Ethical Committee, in accordance with Helsinki Declaration and the rules of Good Clinical Practice on human projects, approved the study design. 2.2. Treatment planning and delivery Our current institutional treatment flowchart for patients presented with LAPAC is as shown Fig. 1. FDG-PET-CT scans for restaging and RT planning purposes were performed according to the institutional protocol described previously, within 10 days prior to treatment [9]. An enhanced CT scan [with intravenous (i.v.) plus oral contrast media through 5 mm slice thickness] from the base of the skull to the inferior border of the pelvis was first acquired, using a standardized protocol with 140 kV, 80 mA, and thereafter, the FDG-PET scan was acquired in 3D mode from the base of the skull to the inferior border of the pelvis (6e7 bed positions, 3 min per bed position) without repositioning the patient on the table. Both CT and FDG-PET images were acquired with the patient breathing shallowly. Attenuation was corrected by using the CT images. Areas of FDG uptake were categorized as malignant based on location, intensity, shape, size, and visual correlation with CT images to differentiate physiologic from pathologic uptake. To avoid unintentional geographic misses, any regional lymph node(s) with shortest diameter 1 cm, irrespective of FDG avidity, were determined to be pathologically involved [10].
Fig. 1. Our current institutional management algorithm for patients presented with LAPAC. C-CRT; concurrent chemoradiotherapy; FDG-PET-CT, 18F-fluoro-deoxyglucose positron emission tomography/computerized tomography, LAPAC. locally advanced pancreatic adenocarcinoma, RT; radiotherapy.
Image registration and RTP were performed via Eclipse 7.5 (Varian Medical Systems, Palo Alto, CA, USA) RTP system. Two experienced radiation oncologists defined the target volumes, with the assistance of a nuclear medicine physician, and contoured the GTV, PTV, and the organs at risk (OAR) on the contrast-enhanced CT/PET-CT fusion images. For each patient, GTV included the primary tumor and the lymph nodes that appeared to be involved on either of CT (1 cm in short axis) and/or PET images (pathologic FDG uptake irrespective of size). PTV was defined as GTV þ 1.5 cm in each direction, to allow for microscopic extension and set-up errors. However, in an effort to minimize toxic events, margins were decreased appropriately when GTV was located close to OAR. In an effort to prevent excessive toxicity, ENI was not permitted. A typical RT plans with and without ENI is as depicted in Fig. 2. A single target volume with no cone down volumes utilizing a four-field technique (postero-anterior, antero-posterior, and laterals; with appropriate gantry angles) was intended to be irradiated. Treatment volumes were defined by using customized multi-leaf collimators. All patients received the RT protocol utilizing 18 MV photon energy linear accelerators. A dose of 50.4 Gy (1.8 Gy/fr, 5 days a week) was prescribed to encompass the defined PTV with isodose lines 95e107%. To achieve this, dosimetric practice wedges were utilized to modify beams. Dose-volume histograms (DVH) were generated for each patient to assess PTV coverage and OAR doses. The maximum dose limits were set at 45 Gy for spinal cord, 50 Gy for small bowel and stomach, 50 Gy for 1/3, 35 Gy for 2/3, and 30 Gy for 3/3 volume for liver, and V20 (volume receiving 20 Gy) not more than 50% of one functioning kidney and V20 not more than 30% for the other. 2.3. Chemotherapy All patients received continuously infused 5-FU (225 mg/m2/day, 7 days/week) throughout the RT course as a radiosensitizer, and additional 2e6 courses of maintenance gemcitabine (1000 mg/m2 i.v. over 30 min, days 1 and 8, every 21-days) after completion of the RT. 2.4. Toxicity assessment Patients were assessed weekly during C-CRT course, every 2 months for the first year, every 3 months for the second year and every 6 months, thereafter, or more frequently if necessary. Early
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Fig. 2. Typical examples of radiotherapy planning with (AeC) and without (DeF) elective nodal irradiation. (A, D) Target volumes, (B, E) 95% isodose coverage, (C, F) doseevolume histograms.
and late clinical toxicity was recorded and blood samples were collected for hematology and biochemistry assays at each assessment. Toxicity was assessed and scored with the aid of CTC 3.0 (Common Toxicity Criteria). 2.5. Response evaluation and follow-up Response to treatment was assessed by re-staging contrastenhanced CT and FDG-PET-CT scans carried out 8 weeks after the completion of the treatment. The time interval of 12-week for the first follow-up FDG-PET-CT was mandatorily chosen as the shortest possible time for response assessment according to our national health insurance policies, rather than an evidence based practice. Thereafter, all patients were monitored by bimonthly studies including blood chemistry; serum CEA and CA 19e9 levels, contrastenhanced CT of the abdomen and FDG-PET-CT; and, additional abdominal ultrasound, chest CT, and cranial MRI were utilized when necessary. In case of suspected local/regional and/or distant disease progression necessary investigations were performed irrespective of the date of last visit. Progression pattern was specified as “distant” when disease was identified at distant organs, such as peritoneal membranes, liver, bone, lung etc., “local” when progressive disease included the primary tumor and/or involved lymph nodes that were covered in the original PTV and “regional” when progressive disease comprised of previously uninvolved regional lymphatic basin(s). We chose to use “progression” here instead of “recurrence”, because complete responses are rarely seen in this setting and complete sterilization of disease may not be identifiable with certainty in absence of confirmatory surgery or at least pathologic examination of biopsy specimens. 2.6. Statistical analyses The primary endpoint was to assess the efficacy of an LFRT with concurrent chemotherapy followed by adjuvant chemotherapy in terms of locoregional progression-free survival (LRPFS), progression-free survival (PFS), and overall survival (OS). LRPFS was defined as survival without local/regional failure, and was
calculated as the time between the first day of the treatment and the date of local/regional failure or death/last visit. PFS and OS were calculated as the time between the first day of the treatment and any type of disease progression or death, and the date of death or last visit, respectively. Survival analysis was performed by the Kaplan-Meier method and Cox proportional hazard model was applied for evaluation of the relationship between different variables and survival. P values of 0.05 were considered to be statistically significant. 3. Results 3.1. Toxicity outcomes Pretreatment patient and disease characteristics were as detailed in Table 1. All 35 patients were able to tolerate the intended C-CRT protocol with no grade 4/5 acute or late toxicity. Rates of maximum grade acute toxicities during C-CRT for all patients were as listed in Table 2. Overall grade 3 toxicity has been reported in 10 (28.6%) patients; non-hematologic in 6 (17.2%) and hematologic in 4 (11.4%). Unplanned treatment interruption was mandated in 3 patients (8.6%) for 2, 5, and 6 days, respectively. Main reasons for these breaks were grade 3 diarrhea in 2, and leukopenia in another patient. However, all 3 were able to complete the planned C-CRT course after symptomatic and supportive treatment. Hospitalization was mandated only in 2 (5.7%) patients due to grade 3 toxicity; diarrhea refractory to conventional loperamide and leukopenia, respectively. At long-term, treatment protocol was well tolerated with no toxicity related deaths. Two patients (5.7%) developed symptoms of Grade 3 gastric outlet obstruction at 8.7 and 10.9 months after the CRT, respectively. Although late toxicity cannot be excluded as a cause, because of simultaneous evidence of disease progression in both patients at 6.8 and 8.5 months, progressive disease was probably associated with the symptoms. An additional (2.9%) patient experienced grade 2 gastric ulcer at 10.6 months, which could be managed with medication. No patients developed liver or renal dysfunction.
E. Topkan et al. / Pancreatology 12 (2012) 434e439 Table 1 Patient characteristics.
437
Table 3 Patterns of initial and ultimate disease progression (N ¼ 34).
Characteristic
Value
Site
Initial N (%)
Ultimate N (%)
Median age (year) Range Sex (%) Male Female Performance (ECOG; %) 0 1 2 Chief complaint Pain Weight loss Appetite loss Jaundice Tumor location (N; %) Head Body Clinical stage (N; %) T4 N0 T4N1 Pretreatment CA 19e9 (kU/L) Median Range Nadir CA 19e9 (kU/L) Median Range
54.8 39 e68
Local only Regional lymph node Distant only Liver Peritoneum Liver þ peritoneum Non-regional lymph node Bone Bone þ liver Brain þ liver Adrenal gland þ liver Local þ distant þLiver þPeritoneum þLiver þ peritoneum þLiver þ lung Total progression
2 0 24 10 9 4 0 1 0 0 0 2 2 0 0 0 28
0 0 11 4 2 1 0 1 1 1 1 17 6 6 3 2 28
26 (74.3) 9 (25.7) 9 (25.7) 19 (54.3) 7 (20.0) 23 (65.7) 6 (17.1) 3 (8.6) 3 (8.6) 30 (85.7) 5 (14.3)
(5.7) (0) (68.6) (28.6) (25.7) (11.4) (0) (2.9) (0) (0) (0) (5.7) (5.7) (0) (0) (0) (80.0)
(0%) (0%) (31.6) (11.4) (5.7) (2.9) (0) (2.9) (2.9) (2.9) (2.9) (48.4) (17.1) (17.1) (8.5) (5.7) (80)
17 (48.6) 18 (51.4)
4. Discussion 297.6 29.2e1718.3 118.3 18.2e2618.3
ECOG; Eastern Cooperative Oncology Group.
3.2. Survival outcomes At median 15.7 months of follow-up, 7 (20%) patients were free of disease progression. Analysis of initial and ultimate failure patterns following concurrent CRT were as depicted in Table 3. No marginal or regional failures were reported as initial or ultimate sites of disease progression. Distant metastasis consisted the commonest initial type of failure (68.4%), with liver (28.6%) and peritoneal membranes (25.7%) being the leading sites involved. Initial infield progression was evident only in 4 (11.4%) patients, 2 (5.7%) of which were isolated local failures. At long-term, although all of the 28 (80%) failures involved distant metastasis, starkly contrasting with initial failure rates, local disease progression was reported in 17 (48.6%) patients. At the time of this analysis 26 patients (74.3%) were dead. Curves of OS, LRPFS, and PFS are shown in Fig. 3. Median OS, LRPFS, and PFS were 15.2 (95% CI: 11.7e18.7), 9.1 (95% CI: 8.2e10.0), and 7.3 (95% CI: 4.7e9.9) months, respectively. Corresponding survival estimates at 1- and 2-year were 60.0% and 20.0% for OS, 41.9% and 17.4% for LRPFS, and 34.0% and 12.7% for PFS, respectively.
Compared to ENI literature, results of this first report of a LFRT study carried out in Turkey demonstrated that LFRT administered concurrent with continuous 5-FU is relatively well tolerated and efficacious in multidisciplinary management of LAPAC. Besides its favorable tolerability, no regional progression indicates that irradiation of only the primary tumor and involved LNs may offer similar outcome, but with better acute and late complication rates compared to large-field ENI. However, the ultimate rates of 48.6% infield and 80.0% distant failures strongly suggest intensification of both local and systemic therapies rather than irradiation of noninvolved lymphatic basins. In our study, despite the respective 2, 5, and 6 days of unplanned treatment breaks in 3 of 35 patients (8.6%) due to grade 3 diarrhea (n ¼ 2) and leukopenia (n ¼ 1), all patients were able to complete the C-CRT protocol. In studies of ENI, varying hematologic and non-hematologic grade 3 toxicity rates have been reported [11e15]. In a small study by Li et al. [16], grade 3 hematologic toxicity was notable in 14 of 18 patients (77.8%). In
Table 2 Frequency of maximum grade acute toxicities. Toxicity
Nausea Vomiting Diarrhea Tumor pain Anorexia Fatigue Gastritis Leukopenia Anemia Thrombocytopenia
Grade 1
2
3
13 10 10 0 14 13 3 8 8 6
4 3 4 2 10 3 2 7 6 5
2 1 2 0 0 1 0 2 1 1
Fig. 3. Survival outcomes for overall study population. Solid line, overall survival (OS); dashed line, progression-free survival (PFS); dotted line, local-regional progressionfree survival (LRPFS).
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E. Topkan et al. / Pancreatology 12 (2012) 434e439
other two studies, Brade et al. [17] reported overall 48% nonhematological toxicity, and similarly Okusaka et al. [18] presented rates of grade 3 anorexia and nausea as 57% and 21%, respectively. Although it is not easy to make direct comparison between these trials, rates of 11.4% hematologic and 17.2% nonhematologic grade 3 acute toxicity observed here seems to be substantially lower than the comparative rates of large-field ENI studies [11e15]. Similar to other LAPAC studies, current median survival, which is slightly longer than 1-year, limits our ability to conclude on true incidence and grade of late toxicity here. However, absence of Grade 4/5 toxicity and a rate of 5.7% grade 3 late toxicity seems to be better than those observed in largefield ENI regimens [11e15], and parallel with most LFRT studies [19e22]. Although randomized evidence is gold standard, these results may at least partially be related with smaller irradiation volumes compared to large-field ENI studies, reflecting the advantage expected from use of a limited radiation field. In the absence of randomized evidence favoring the use of ENI, to increase the tolerability of C-CRT, we elected to irradiate only the primary tumor and involved LNs. This was based on the assumption that the majority of benefit from RT would be brought by control of the primary tumor rather than the subclinical disease in these nodes, which could potentially be managed by the systemic chemotherapy. Although comparisons with other data should be made cautiously, an observation of no isolated regional recurrences, and a median OS of 15.2 months is similar or slightly better than other scarcely reported limitedfield C-CRT studies in LAPAC [23]. In a phase I radiation dose escalation study of 34 unresectable or incompletely resected PAC patients treated with concurrent gemcitabine, McGinn et al. [24] reduced RT fields (PTV ¼ GTV þ 1 cm) which was even smaller than our current PTV size, and observed only 3 (8.8%) regional failures. In another LFRT study of 26 patients, Tokuuye et al. [25] reported no isolated regional failures outside the radiation field, which was later confirmed by Yamazaki et al. [21], and Jackson et al. [23]. More recently investigators from MD Anderson Cancer Center, in a dose escalation study with relatively more strict PTV definition similar to McGinn et al [24], demonstrated encouraging local control, resectability and survival rates with full dose gemcitabine and conventionally fractionated 55 Gy delivered by IMRT with motion tracking in 50 patients with LAPAC [26]. The approach of omitting the elective irradiation of regional nodes is further supported by the current radiosurgical practice in PAC [27e31], which demonstrated locoregional control rates far beyond that of conventional large-field ENI studies with only millimetric margins around the GTV. Taken together, these results support the use of LFRT to increase tolerability of aggressive C-CRT protocols with no reduction in efficacy, and with the potential to further escalate RT doses in patients with LAPAC. Based on the outcomes in our previous study [9] that demonstrated the need for an enlargement of GTV in 5 out of 14 patients (35.7%) with the use of co-registered PET-CT compared to CT-alone; herein, we utilized contrast-enhanced CT/PET-CT fusion as the imaging tool of choice for RTP in an effort to theoretically reduce geographic misses. Although data from a larger cohort may be worthy, absence of regional disease progression in the present cohort is demonstrative for success of PET-CT in target volume definition in LAPAC. However, an ultimate infield relapse rate of 48.6% indicates the failure of our effort to improve local control rates beyond the available literature. Although it is not possible to assign this finding to a single cause, such results may either be associated with inadequacy of 50.4 Gy dose, or insufficient radiosensitizing efficacy of 5-FU given in the dose and schedule utilized
here. In this setting, gemcitabine appears to be a promising radiation sensitizer [32], and its concurrent use with escalated doses of RT may offer a theoretical chance for improved outcomes. This is supported by the results of recent linear accelerator or Cyberknifebased stereotactic body RT (SBRT) studies reporting 1-year local control rates of up to 94% in LAPAC [27e31]. Notably, in the most recent study consisting of 20 LAPAC patients, Schellenberg et al. [30] administered gemcitabine on Days 1, 8, and 15 followed by a single fraction 25 Gy SBRT on day 29, and depicted an outstanding freedom from local progression rate of 94% at 1-year, which is significantly better than rates achieved with any reported CRT study. Many clinical trials demonstrated distant relapses as the predominant failure pattern in LAPAC following C-CRT [32e34]. Consistent with them, in the present cohort, 28 patients (80.0%) progressed distantly. However, at long term, besides distant relapses, local disease progression became apparent in 48.6% patients, which is also in the reported range of 42e68% [32e34]. In prevention of local failures, results of emerging SBRT studies are promising with reported local control rates higher than 90% [27e 31]. In this setting, results of the aforementioned SBRT study published by Schellenberg et al. [30] in 20 LAPAC patients is impressive in terms of realizing the importance of controlling systemic microscopic disease spread. Authors reported that despite an excellent 1-year infield control rate of 94%, 17 of all 19 patients (89.5%) with failure experienced distant progression as the first site of recurrence, reasonably suggesting distant progression as the major cause of treatment failure and death in LAPAC patients with excellent rates of local control. This is almost the same with our 26/ 28 (92.8%) distant failure rate. Therefore, available literature emphasizes the urgent need for any improvements in systemic component of C-CRT to prevent and/or efficiently treat subclinical dissemination of disease to achieve acceptable survival rates in this frankly aggressive tumor. In conclusion, results of this report showed that omission of ENI was relatively well tolerated without comprising survival and locoregional control rates. However, despite absence of isolated regional failures, rates of overall 48.6% infield and 80.0% distant recurrences also emphasizes the urgent need for more efficient radiosensitizers, chemotherapy and/or targeted agents preferably with stronger radiosensitizing and systemic efficacy to improve overall disease control and survival rates in this highly fatal tumor group. Conflict of interest We have no personal or financial conflict of interest and have not entered into any agreement that could interfere with our access to the data on the research, or upon our ability to analyze the data independently, to prepare manuscripts, and to publish them. Authors contribution Conception and design, or analysis and interpretation of data: Erkan Topkan, Cem Parlak, Fuat Yapar. Drafting the article or revising it critically for important intellectual content: Erkan Topkan, Cem Parlak, Fuat Yapar. Final approval of the version to be published: Erkan Topkan, Cem Parlak, Fuat Yapar. References [1] Katz MH, Hwang R, Fleming JB, Evans DB. Tumor-node-metastasis staging of pancreatic adenocarcinoma. CA: A Cancer Journal for Clinicians 2008;58(2): 111e25.
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