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Keywords:

  • Chemoradiotherapy;
  • intensity modulated radiation therapy;
  • esophageal cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Chemoradiation plays a core role in the definitive and preoperative management of esophageal cancer. Remarkable advances in technology now allow for the implementation of intensity modulated radiation therapy (IMRT) to minimize normal organ damage and to maximize coverage of tumorous targets. While IMRT is commonly accepted in the treatment of prostate and head and neck cancers, there have been clinical and dosimetric studies supporting the use of IMRT in esophagus cancer. In addition, the IMRT technique was recently enhanced by the availability of volumetric intensity modulated arc therapy (VMAT). VMAT may allow for faster delivery of IMRT with the advantage of normal organ protection compared to the stop-and-shoot IMRT, with faster delivery time and reduced monitor units. This review summarizes the use of chemoradiation in esophageal cancer, discusses current dosimetric data and clinical outcomes with the use of IMRT, and reviews IMRT as part of multi-modality treatment in esophageal cancer.


Introduction: Chemoradiation in the treatment of esophageal cancer

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

The majority of patients with esophageal cancer are diagnosed with disease invasion deep into the submucosa and likely nodal involvement or beyond, rendering them ineligible for surgical resection or radiation treatment alone. Addition of chemotherapy to radiation has been shown to achieve sustainable disease control and overall survival. The Radiation Therapy Oncology Group (RTOG) conducted a trial (RTOG 85-01) in patients with locally advanced esophageal cancers, T1-3N0-1M0. Patients were enrolled between 1985 and 1990 with follow up of at least 5 years, followed by a prospective cohort study conducted between 1990 and 1991.1 It confirmed the benefit of combined therapy. This was a prospective, randomized, phase 3 trial comparing concurrent chemoradiation with cisplatin and fluorouracil (5-FU) with radiation (RT) alone. After 5 years 25% of the patients in the randomized combined modality group and 14% of the patients in the non-randomized combined modality group were alive versus no patients alive in the RT only group. In the subgroup of patients with at least 8 years follow up, the survival rate was 22%. The randomized trial by RTOG demonstrated overall survival improvement in combining 50 Gy of external beam radiation with 5-FU and cisplatin versus radiation alone of up to 64 Gy. Subsequent intergroup trials studied the role of radiation dose escalation in chemoradiation.2,3 Intergroup-0123 concluded that a higher radiation dose with concurrent chemotherapy did not increase survival or local/regional control. The authors concluded that the standard dose of chemoradiation should be 50.4 Gy.3

In RTOG 85-01, the entire esophagus was included as the target and this was associated with significant side effects. Modern targeting in three-dimensional (3D) conformal planning most commonly defines the planning target volume (PTV) with 1.5 to 2 cm of radial-lateral margins and up to 5 cm cephalad and caudal to the gross tumor volume (GTV). The clinical target volume (CTV) includes the areas at risk for microscopic disease. The typical 3D conformal beam arrangement consists of anterior-posterior, posterior-anterior, right posterior oblique and left posterior oblique beams to give an adequate dose to targets while keeping the dose to bilateral lungs and the spinal cord under tolerance levels. Advances in radiation technologies allow daily image-guidance for setup confirmation and/or adjustment in conjunction with intensity modulated radiation therapy (IMRT) and volumetric intensity-modulated arc therapy (VMAT). Available technologies allow for improvement in the speed of delivery; they enhance automation, such as the use of dynamic multi-leaf collimators during IMRT and VMAT, increase opportunities to improve target dose coverage and homogeneity while maintaining normal organ protection (i.e. of the lungs and heart), and enable the use of simultaneous integrated boost (SIB) with or without accelerated hypofractionation.4,5 These are potential advantages over 3D conformal techniques.

Recent advances in radiation techniques: IMRT and VMAT

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

VMAT is the next evolutionary step from IMRT in static beam therapy. Existing step-and-shoot IMRT typically uses a number of static beams, a larger amount of monitor units, and longer delivery time than VMAT. As the number of IMRT beams increase using rotational arc(s) for IMRT delivery is a logical next step.6 Using rotation of the gantry on a linear accelerator, modulated dose distribution can be delivered faster with reduced monitor units. VMAT is possible with recent advancements in software and hardware availability. A sibling of VMAT is helical tomotherapy, a form of IMRT that is delivered on a continuous helix, with the source being collimated to a fan beam which is modulated with a binary multileaf collimator.7 See Fig. 1.

image

Figure 1. Example of volumetric intensity modulated arc therapy (left panel) and intensity modulated radiation therapy (right panel). Both techniques provided excellent tumor coverage and spared heart and lungs in a patient with esophageal cancer.

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Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Nine recent dosimetric studies of IMRT and VMAT (referred to as helical tomotherapy in the studies reviewed here) are reviewed (see Table 1). The studies most commonly used 6MV photons as the treatment energy. They will be discussed in respect to the tumor locations being studied (i.e. cervical, upper, mid, distal, and gastroesophageal junction (GEJ)).

Table 1.  Recent studies of intensity modulated radiation therapy (IMRT) in esophageal cancers between 2001 and 2009
Author, institutionYearTumor locationNumber of patientsStudy typeIMRT (number of beams)
  1. N/A, not applicable.

Nutting, Royal Marsden, UK82001N/A5Dosimetric4, 9
Wu, Polytechnic U, Hong Kong92004Mid15Dosimetric5
Fu, Peking, MDACC, China42004Upper, cervical5Dosimetric3, 5, 7, 9
Chandra, MDACC, USA102005Distal, gastroesophageal junction10Dosimetric4, 7, 9
Wang, Peking, MDACC, USA112006Upper, cervical7Clinical5, 7, 8, 9
Chen, City of Hope, USA52009Mid, distal6DosimetricTomotherapy, 7
Fenkell, Princess Magaret, Canada122008Cervical5Dosimetric7, 9
Chen, City of Hope, USA132009Mid, distal20ClinicalTomotherapy
Hsu, National Taiwan U, Taiwan142009Upper, mid, distal52Clinical3, 4, 5

Cervical and upper esophageal locations

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Fu et al. reported on dosimetric comparison of 3D versus IMRT plans in five sample patients with cervical and upper sophageal cancers.4 The authors studied the dosimetric possibility of SIB in patients with tumors located in upper and cervical esophageal locations. The 3-beam arrangement was deemed to be unacceptable due to the high skin and spinal cord dose. Conformality index was improved by using 5-beam IMRT, there were no significant improvements using 7-beam or 9-beam plans. In regards to lungs, the mean lung dose was better in IMRT plans. Lung V20 (volume receiving at least 20 Gy) and V30 were better in IMRT plans. Authors concluded that the 5-beam IMRT was optimal for tumors in upper and cervical esophageal locations. From the same institutions, Wang et al. conducted a retrospective clinical review of patients with cervical and upper esophageal tumors using the dosimetric methodology in seven patients with a median follow up of 15 months.11 Patients received IMRT and concurrent chemotherapy using various beam arrangements (5 to 9 beams), and five patients received SIB with the IMRT. None of the patients had definitive surgery. One patient was successfully treated with photodynamic therapy for local recurrence and remained disease free at the time of reporting. Clinically there was no pneumonitis. These patients had locally extensive disease (four patients had T4 disease and most had nodal disease). Early clinical results were encouraging. Six evaluable patients had complete response initially. Three patients were free of disease at last follow up, the others were deceased or alive with disease. Fenkell et al. reported a recent dosimetric study in cervical esophageal patients.12 Because of the location of the tumor, the dose to GTV was 70 Gy, the highest among the nine studies reviewed here. Comparison plans were made between 3D and IMRT plans. Although lungs were not completely scanned by computed tomography (CT) in most patients, crude lung V20 was similar between plans. In the cervical location, 9-beam IMRT provided superior dose coverage in terms of homogeneity and conformality for targets with the trade-off of an increased dose to oral lips in four patients. Overall IMRT gave a lesser dose to the spinal cord, brainstem and parotids than 3D plans. In conclusion, authors established that IMRT had become the standard treatment for cancers of the cervical esophagus at their institution because IMRT showed superior target coverage and normal tissue sparing with results consistent with other institutions.12

Mid, distal and GEJ locations and the use of tomotherapy (VMAT)

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Nutting et al. described the use of IMRT in five sample patients by comparing dosimetry of 3D conformal and IMRT plans.8 Locations of the esophageal lesions were not clearly stated in this study. Judging from the representative CT images, locations of the tumor were consistent with disease in the mid section. The authors reported that coverage of PTV was similar among 3D conformal RT, 4-beam IMRT and 9-beam IMRT plans. Organs at risk included the spinal cord and lungs. The authors did not include the heart as an organ at risk with the assumption that cardiac toxicity was not a major clinical concern because of relatively small number of long-term survivors. The study found the mean lung dose (MLD) to be similar among the three planning techniques. Lung V18 was worse in 9-beam IMRT than 3D plan, but the normal tissue complication probability (NTCP) for lungs was not significantly different between 3D and 9-beam IMRT plans. The 4-beam IMRT had improved lung V18 with a mean value of 14.4% and better NTCP than the 3D conformal plan. All plans achieved similar protection and dose to the spinal cord. In conclusion, 9-beam arrangement seemed inferior in this study. IMRT using 4-beam arrangement was best in this study. However, authors acknowledged that further development of a beam direction optimization algorithm for the thorax was needed since scatter and tissue homogeneity effects were not incorporated in this study.

Wu et al. reported on dosimetric comparison of 15 sample patients with mid esophagus cancers.9 This report was unique in that it compared a forward-planned and highly 3D conformal technique (6 to 16 beams combination) with an inverse-planned 3D conformal technique and 5-beam IMRT. Organs at risk included the spinal cord, heart, and lungs. Additional factors such as conformality, homogeneity, tumor control probability (TCP) and NTCP were also compared. The study found that the methods of planning achieved similar dose volume histograms (DVH) for treatment targets such as CTV and PTV with an increase of maximal dose using IMRT. As a result, IMRT was best for TCP, followed by inverse-planned conformal treatment and forward-planned conformal treatment, respectively. Left lung V25 (volume of the lung receiving at least 25 Gy) was best using IMRT. Right lung V25 was similar in the three methods. Regarding the heart as an organ at risk, IMRT was marginally better in DVH with improvement in NTCP. All three methods met dosimetric constraint for the spinal cord. According to the report, there was considerable reduction in the lung V25 in the IMRT plans compared with the inverse-planned 3D conformal plans (24.6% for left lungs and 18.2% for right lungs). This reduction in the lung V25 might also reduce the risk of developing radiation pneumonitis and/or pulmonary complications. In another study by Chen et al. image-guided tomotherapy was used in a neoadjuvant setting. Two patients who developed postoperative pneumonitis had lung V10 of 65% and 40%, respectively.5 Overall, when IMRT is able to reduce lung volume exposed to radiation in operative or non-operative patients, it may offer clinical advantage over 3D conformal treatments with a dosimetric goal of limiting lung V10 to less than 40%.15 Interestingly, Wu et al. noted that the average time spent in IMRT and inverse planning was less time-consuming than forward planning (19, 15 and 36 minutes, respectively), but the authors acknowledged that more time was required after planning in the dose verification and dose delivery processes of IMRT, an aspect that was not accounted for in their study.9

In addition to conventional IMRT, VMAT (in the form of rotational linear accelerator-based treatment or a dedicated machine such as tomotherapy units) is becoming more available. Chen et al. first published a study of a dosimetric comparison of tomotherapy, 3D, and IMRT in six sample patients with tumors in mid and distal locations.13 A form of SIB using standard fraction size was used to deliver 2 Gy to PTV of the gross disease and 1.8 Gy to PTV of subclinical areas simultaneously over 25 fractions. Therefore, a total dose of 50 Gy and 45 Gy was given to 95% of the targeted volumes, respectively. Using tomotherapy, lung V20 was significantly improved, but V10 volumes were larger than that of 3D plans. Lee et al. suggested that in order to minimize postoperative pulmonary complications, lung V10, V15, and V20 should be kept at less than 40%, 30% and 20%, respectively.15 Chen et al. conducted a clinical study to follow their initial dosimetric study. The authors reported on 20 patients (10 of which underwent definitive surgery) who were treated with tomotherapy and concurrent chemotherapy using a similar technique to SIB in their dosimetric study. Clinical results were encouraging and comparable to other published series. Two patients had pneumonitis, and their lung V10 were 65% and 40%, respectively, indicating the potential importance of keeping V10 to less than 40% in operative patients.5

Chandra et al. studied 10 sample patients with distal and GEJ cancers and compared IMRT with 3D plans dosimetrically.10 Similar to Fu et al. and Nutting et al., lung V20 and mean lung dose were improved by 15 to 18% with IMRT plans. In certain patients, the absolute improvement in lung V20 was up to 20%. On the other hand, lung V5 showed the trend to increase with the increasing number of beams used in IMRT plans, but the difference was not significant (P > 0.05).10 The total body integral dose was not significantly different between 3D or IMRT plans. The authors acknowledged that the role of V5, especially in operative patients, was not yet well defined. The authors also noted that the degree of dose sculpting and normal tissue sparing achievable from using IMRT strongly relied on the planner's interaction with the treatment-planning software in prioritizing planning objectives, which can be highly planner dependent. Planning objectives and constraints might not be considered automatically or by default.10 Using IMRT there is potential to further reduce the dose to liver and heart, but clinical relevance has yet to be fully studied.9,16

Postoperative pulmonary complications and trimodality treatment

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Treatment of locally advanced esophageal cancer involves a multidisciplinary approach. When chemoradiation is delivered in a neoadjuvant fashion, there is potential for downstaging and an increase in resectability of the tumor. Trimodality treatment is associated with a perioperative mortality rate of about 5 to 12%, compared with chemoradiation alone, with a 2 to 4% of treatment related mortality.1,17,18 Whether neoadjuvant treatment is negatively associated with perioperative mortality remains controversial.19 While trimodality treatment was found to show a promising survival outcome in a recent meta-analysis with an absolute survival increase of 13% at 2 years,20 great care in patient selection and treatment planning must be considered for a potential association of treatment related complications and mortality with trimodality treatment.21 Commonly reported postoperative morbidities include pulmonary complications, anastomotic leaks, and infection. Studies were done in an attempt to identify clinical and dosimetric predictors of these morbidities.5,14,22 One area of research interest postoperative pulmonary complications, which is the leading cause of postoperative morbidity, accounting for up to about one third of patients undergoing an esophagectomy.14,18

Radiation-induced pneumonitis is different from postoperative pulmonary complications.23–25 Depending on the location of the esophageal cancer, the risk of radiation-induced pneumonitis varies with the volume of normal lungs being included in the radiation treatment. Radiation-induced pneumonitis usually occurs within a few weeks of completion of RT, peaking at 2 months, and is stabilized or resolved by around 6 to 12 months. Lung fibrosis occurs a few months after radiation and becomes chronic. Radiographic studies commonly show a change in pulmonary parenchyma in areas that have been irradiated along the beam paths and/or the focus of irradiation. It is commonly characterized by pneumonia-like symptoms with persistent coughing and/or dyspnea. Steroids such as prednisone may be used to curb symptoms.

Various dosimetric and clinical studies suggested that dosimetric perimeters, primarily lung DVH and mean lung dose, might predict radiation-induced pneumonitis in patients treated with thoracic irradiation.26–28 Kwa et al. studied the incidence of pneumonitis in 540 patients (399 had lung cancer, 78 had lymphoma, 59 had breast cancer, and 1 had lung cancer).26 The authors concluded that an increasing rate of grade 2 or above pneumonitis (as defined by Southwest Oncology Group criteria for when steroid use is required) was observed with an increasing mean lung dose as described by normalized total dose distribution (NTD). It is important to note that both lungs were regarded as a single organ in this study. Therefore, if a single lung was irradiated at a high dose, this model would show an acceptable lung NTCP of 13 to 24% with a mean NTD of 20 Gy, as if both lungs were partially exposed to radiation. Use of lung DVH such as V10, V15, V18, and V20 serve as general guide to keep grade 2 or above radiation-induced pneumonitis to an acceptable rate of about 20%.8,21,27,28 Overall, there is not a single most consistent reference point for radiation-induced pneumonitis for individual patients due to differences in underlying physiologic and treatment related factors.

The largest clinical series of IMRT in esophageal cancer was by Hsu et al..14 Retrospectively the study focused on postoperative pulmonary complications (PPC) in patients receiving IMRT and concurrent chemotherapy followed by thoracic esophagectomy. Fifty-two patients received neoadjuvant chemoradiation with IMRT and were followed up postoperatively. This study used a lowered dose of radiation with a median dose of 40 Gy. IMRT plans used a 3- to 5-beam arrangement. Lung constraints were set at V10 ≤ 45%, V15 ≤ 35%, and V20 ≤ 30%. Authors found that preoperative, rather than prechemoradiation, FEV1 lung volume was the only clinical factor that significantly predicted development of postoperative pulmonary complications on multivariate analysis. The right lung volume spared from 15 Gy or more (VS15) was the only significant dosimetric factor on univariate analysis. On average, patients who had an average right lung VS15 of 1609 cc did not experience pulmonary complications, compared to patients with VS15 of 1299 cc who experienced complications (P = 0.034). This echoed the findings by Lee et al.15 Additionally, authors discussed the potential association of inflammatory responses in the right lung, which was collapsed during the one lung ventilation procedure of right transthoracic surgery. The mechanical trauma to the collapsed lung might lower its tolerance to irradiation, as shown by right lung VS15 being a predictor, while neither both lungs combined, nor the left lung spared, volumes were significantly associated for postoperative pulmonary complications. The authors theorized a two event hypothesis that pulmonary injury by radiation and surgical trauma was linked to postoperative pulmonary complications. Therefore, postoperative pulmonary complication likely involves factors that are beyond dosimetric constraints.

In a previous study by Wang et al. on PPC in esophageal cancer patients treated with concurrent chemotherapy followed by surgery, the importance of lung volume sparing was also noted.22 In this study, patients were treated with 3D conformal radiation treatment instead of IMRT to a total dose of 45 Gy to 50.4 Gy. One hundred and ten patients were available for analysis. In multivariate analysis, the lung volume spared from 5 Gy or more (VS5) was the only independent dosimetric predictor for pulmonary complications. By dividing the patients into five groups based on mean VS5 volumes, the order of decreasing incidence of PPC was: 7/22 in VS5 of 913 cc; 5/22 in VS5 of 1560 cc; 3/22 in VS5 of 1926 cc; 2/22 in VS5 of 2230 cc; and 1/22 in VS5 of 3079 cc. The incidence of PPC inversely correlated with the lung volume spared from 5 Gy or more of radiation dose. On univariate analysis, being female predicted for increased PPC. Although men and women had similar VS5, authors speculated that women had smaller total lung volume and therefore they were left with less unexposed lung after irradiation. The authors suggested from their data that the volume of remaining undamaged lung, rather than the volume of damaged lung, also determined the risk of pulmonary complications. Therefore, attention should be paid to total lung volume and not only to dose-volume relationship of radiation to exposed lung.22

Cardiac effects and potential toxicities related to RT in patients with esophageal cancer

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

Radiation related heart changes and potential disease can occur from cardiac exposure to radiation during thoracic RT. This is likely due to inclusion of substantial heart volume within the PTV. A study from Roswell Park Cancer Institute demonstrated a detectable and significant decrease in cardiac ejection fraction 6 weeks after 50.4 Gy of chemoradiation in 20 patients, but the magnitude of the difference was not clinically significant. The median heart V20, V30 and V40 was 61.5%, 58.5%, and 53.5%, respectively.16 Similar detectable physiological changes using serial single-photon emission CT (SPECT) imaging were reported by Marks et al. in left side breast cancer patients.29 The authors prospectively followed the patients with sequential SPECT scans after irradiation. It was found that RT caused volume dependent perfusion defects in about 40% of patients within 2 years of irradiation. There were corresponding wall-motion abnormalities, but clinical significance remained to be proven over long-term follow up. Wei et al. studied the risk factors for pericardial effusion (PCE) in 101 patients with esophageal cancers that were treated with 3D conformal chemoradiation.30 They found a crude incidence of 27.7% and the actuarial incidence at 18 months was 48%. The median onset of PCE was 5.3 months. The authors identified the pericardium V30 as a significant predictor of PCE on multivariate analysis. Although there are relatively few long-term survivors with esophageal cancer, it is prudent to minimize their chance of cardiac complications by dosimetrically protecting the heart using available technologies such as IMRT. The current clinical and dosimetric studies demonstrated that IMRT is capable of protecting the heart while delivering excellent dose to tumor targets.

Esophageal mobility and setup variability: Implications of IMRT treatment

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

The esophagus is situated mainly in the thorax with extension into the upper abdomen. Its anatomical location can vary according to the patient's physiology and the accuracy of radiation treatment targeting depends on the treatment margins that are added during treatment planning and the capabilities of the radiation treatment center, such as with image-guidance techniques. While IMRT has the advantage of improving tumor target homogeneity and normal organ protection, the effort is futile if the target is missed when treatment margins do not account for setup errors and/or organ motion. In a study by Hashimoto et al. 2 mm gold markers were inserted into the organs, including the submucosal layer of the esophagus, and the extent of internal organ motion was studied in real time using multiple fluoroscopic units by tracking the fiducial marker. This study considered the esophagus an organ at risk or an organ to be avoided by radiotherapy. Thirteen patients, mostly diagnosed with lung cancer, had the markers placed in the upper (two patients), mid (eight patients), and lower (three patients) esophageal locations. There was a trend that the marker deviated more at the location below the level of the carina than in the upper esophageal location, but the difference was not statistically significant. Authors suggested that the mean range of the internal margin to account for esophageal motion to be 4, 8, and 4 mm in the lateral (RL), cephalad-caudal (CC), and anterior-posterior (AP) directions, respectively.31 Besides internal organ motion, setup errors should be accounted for during radiotherapy. In a study by Chen et al. the authors had the opportunity of deploying pretreatment daily image-guidance using a helical radiation delivery system or a tomotherapy unit.32 This unit generated daily megavoltage (MV) CT images that were used to compare to planning kilovoltage (KV) CT images. This allowed online verification and adjustment of targeting. In addition to studying the typical RL, CC, and AP setup deviations, authors were able to study the pitch (rotation around the RL axis), yaw (rotation around the AP axis), and row (rotation around the CC axis) using the 3D CT image data sets. Authors found that systematic and random setup errors were smaller in the AP directions than RL or CC directions. Rotational variations should be corrected prior to treatment because such variations could cause displacement of the target in the CC directions. MV imaging is known to have inferior soft tissue contrast when compared to KV imaging. Authors found that MV images were sufficient to show the anatomical details needed to compare the bony and organ structures for the purpose of online verification and adjustment. With the advent of KV on-board imaging, cone-beam CT comparison is becoming accessible and allowing for broader opportunities in the application of image-guided radiotherapy.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References

IMRT and VMAT offer the opportunity to sculpture radiation dose by improving target homogeneity while sparing normal organs by taking advantage of a sharp dose gradient. Dosimetrically, the new techniques were demonstrated to be well suited to definitive chemoradiation of esophageal cancers in the various anatomical locations. IMRT consistently provides conformal coverage of tumor targets with the potential for improvement in limiting the dose-volume to lungs. Other potential organs at risk, such as the heart, can also be well protected. In the context of a trimodality treatment approach caution is needed and the patient's preoperative condition must be taken into account. Radiation oncologists must pay close attention to not only the relative dose or dose-volume relationship of lung tissues, but to the total lung volume and the total volume of spared lung tissue from radiation dose. At present, clinical outcomes of IMRT use in trimodality treatment is promising. Further studies to identify the biological, clinical, and dosimetric predictors will continue to minimize toxicities of chemoradiation using IMRT in patients with esophageal cancers.

References

  1. Top of page
  2. Abstract
  3. Introduction: Chemoradiation in the treatment of esophageal cancer
  4. Recent advances in radiation techniques: IMRT and VMAT
  5. Dosimetric and clinical studies of IMRT in the treatment of esophageal cancer
  6. Cervical and upper esophageal locations
  7. Mid, distal and GEJ locations and the use of tomotherapy (VMAT)
  8. Postoperative pulmonary complications and trimodality treatment
  9. Cardiac effects and potential toxicities related to RT in patients with esophageal cancer
  10. Esophageal mobility and setup variability: Implications of IMRT treatment
  11. Conclusion
  12. Acknowledgments
  13. Disclosure
  14. References
  • 1
    Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA 1999; 281: 16237.
  • 2
    Minsky BD, Neuberg D, Kelsen DP et al. Final report of Intergroup trail 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 1999; 43: 51723.
  • 3
    Minsky BD, Pajak TF, Ginsberg RJ et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combine-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20: 116774.
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