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Modern view on multimodality treatment of esophageal cancer

Thoughts on Patient Selection and Outcome
PhD ceremony:Ms Z. (Zohra) Faiz
When:October 14, 2019
Supervisors:J.T.M. (John) Plukker, prof. dr. V. Lemmens
Co-supervisors:dr. B.P.L. Wijnhoven, dr. C.T. (Kristel) Muijs
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
Modern view on multimodality treatment of esophageal cancer

The studies described in this thesis aim to provide novel insights into the association ofclinicopathological factors with treatment outcome and response to chemoradiotherapy inpatients with esophageal cancer. This may impact the individual clinical decision makingprocess and the development of new treatments.I: Clinical factors: age and co-morbidityThe prognosis of patients with potentially curable esophageal cancer (EC) has improvedduring the last two decades. Some 30% of patients are above the age of 75 at the time ofdiagnosis. These patients are judged to be less suitable for surgery not only because ofadvanced age, but also due to associated co-morbidities or decreased performance status.During the last 10 years, a shift has been observed toward a potentially more aggressivetreatment with curative intent including the use of definitive chemoradiotherapy (dCRT) andneoadjuvant CRT (nCRT) followed by surgery. Earlier diagnosis, improved tumorstaging, better medical and perioperative support may explain this change. Improvements insurgical and anesthesia techniques, perioperative risk evaluation and intensive care supporthave contributed to the increased survival and reduced operative morbidity and mortality. On the other hand, pathologic complete response (pCR) has been observed in about 25%(19-43%) of the EC patients, introducing the use of a more conservative “wait andsee” approach. However, staging methods are still not adequate enough to encourage thisoption without any serious doubt. Therefore further research has to be performed particularlyfor better staging and prediction of treatment response.However, esophagectomy remains a high-risk major surgical procedure associated withrelatively high postoperative complications and mortality, particularly in patients above theage of 75 years. Many elderly patients have one or more co-morbidities and are at anincreased risk for pulmonary and cardiac complications postoperatively.Hence, it is still challenging to determine which patients are fit enough for surgery based onpre-treatment co-morbidity profiles and to incorporate risk profiles in existing treatmentguidelines. Some of these patients may benefit from neoadjuvant chemoradiation withsurgery, as the standard treatment, whereas others will not tolerate such multimodal treatment.For these patients, alternative approaches are available like dCRT, but selection may bedifficult regarding equivalent long-term results.In chapter 1-3 of this thesis the use of definitive chemoradiotherapy (dCRT) as a lessaggressive alternative treatment approach in elderly patients and in patients with severe comorbiditieswas studied. Although the reported results seem promising, long-term outcomedata following dCRT for potentially curable EC are scarce. Therefore, guidelines forselecting the best treatment for patients with severe co-morbidity and older age are still notavailable.We showed that the use of nCRT plus surgery in operable patients with a potentially curativeresectable esophageal adenocarcinoma (EAC) was associated with a better overall survival(OS) irrespective of age, number and type of co-morbidities. The administration of dCRT waspreferably given in patients with esophageal squamous cell carcinoma (ESCC) with at least 2co-morbidities or >75 years old. There was no difference in OS in patients who underwentdCRT compared to patients with nCRT plus surgery. These findings suggest a similar longtermsurvival after both treatment modalities in elderly patients with ESCC.In patients with EAC, nCRT plus surgery resulted in a better survival than dCRT, includingpatients with diabetes mellitus, hypertension or cardiovascular disease, as has been shown byothers.Differences in treatment response pertaining histologic type (EAC and ESCC) seem to beassociated with tumor aggressiveness based on different molecular aberrations. Tumorsite and related pulmonary disorders due to usually larger fields of radiotherapy in lower ECalso contribute to different outcomes between EAC and ESCC following dCRT.. Withcurrent radiation techniques, including intensity-modulated and respiratory gated radiotherapyor intensity-modulated proton therapy, the radiation dose can be delivered more accuratelywith less damage to normal tissues. In diminishing toxicity of chemotherapyregimens, the carboplatin/paclitaxel combination proved to be a good alternative to the currentstandard with cisplatin/5-Fluorouracil in dCRT, especially in patients with cardiovascular andpulmonary co-morbidities. Generally, dCRT seems a well-tolerated alternative forpatients with EC who are not fit enough to undergo surgery. To better selectpatients who may benefit from dCRT prospective studies are needed. The presence of aconsulted geriatric physician in multidisciplinary EC boards may be helpful to define thetreatment with largest benefit and lowest harm to the patient.II: Pathological factors: circumferential resection margin and extramural venous invasionThe prognostic value of the circumferential margin (CRM) after neoadjuvantchemoradiotherapy (nCRT) is not well defined yet. As described in chapter 4, nCRTaffected the CRM cutoff values. After nCRT, the CRM-R0 as defined according to theCollege of American Pathologists (CAP; >0 mm) was only prognostic for 2-year localrecurrence-free survival (LRFS). However, in the surgery-alone group, it was also prognosticfor the 2-year disease-free survival (DFS). CRM assessment depends on accurate histologicalexamination of residual tumor, which might be related to tumor heterogeneity. Several studiesreported conflicting results regarding prognostic significance of CRM in patients treated withnCRT. Hence, differences between the studies may be explained by inclusion of differenthistological tumor types. CRM involvement is related to advanced disease rather thanbeing an indicator of completeness of resection. Moreover, it is also associated with thesurgical method. Transhiatal esophagectomy resulted in a higher proportion of patients withCRM involvement (i.e. R1 resection) compared to the transthoracic approach. In patientstreated with nCRT, the definition of CRM is unclear. One meta-analysis indicated thatnodal metastases appeared to negate the prognostic value of the CRM [40]. Both, the presenceof lymph node metastases and a positive CRM indicate a more advanced-staged disease.Invasion of tumor cells into blood vessels is another important marker for the metastaticpotential of malignant tumors. Current TNM classifications recognize lymphovascularinvasion (LVI) as a prognostic factor in EC. It is important to report the type ofvascular invasion (VI). Pathologists stress on the presence of extramural venous invasion(EMVI), i.e. tumor cells in the vasculature of vessels beyond the muscularis propria, as anindependent predictor of poor prognosis in colorectal cancer (CRC) [45, 46]. In chapter 5and 6, we described the presence of EMVI in approximately 25% of patients with a at least pT3tumor after surgery alone, and in 21.6% after nCRT. EMVI was common in tumors withadvanced T- and N-stage and also in tumors with perineural tumor growth and with LVI.There is wide variability regarding current practice and agreements among pathologists on thedetection of EMVI was seen more often in university hospitals among experiencedgastrointestinal pathologists and in specimens with routine use of elastin stains.Staining with Elastica van Gieson for the detection of endothelial cells doubles the detectionof EMVI and increases the interobserver agreement. EMVI may suggest a positiveeffect of nCRT on microscopic distant disease, whereas failure of EMVI to regress afternCRT indicates lack of response and poor prognosis in CRC.. Whether thepresence and grading of EMVI following nCRT can be accurately assessed earlier ondiffusion-weighted imaging (DWI/MRI), which is sensitive to microstructural cellularalterations should be investigated in ongoing or future studies.EMVI is associated with an increased recurrence risk and based on our study, it should beconsidered as a routine part of pathological reporting of the resection specimen. Theprognostic impact of EMVI after nCRT in ESCC is still unclear and its prognostic andpredictive value should be studied prospectively in larger series following nCRT for differenttumor stages and histological types.III: Treatment-related factors: salvage surgeryRadiotherapy, a key element in the curative treatment for esophageal cancer, is usually givenin combination with chemotherapy either in a neo-adjuvant setting (nCRT) followed bysurgery, or as definitive chemoradiotherapy (dCRT). Radiotherapy in EC is challenging witha considerable risk for radiation-induced toxicity in surrounding vital organs, including heartand lungs. Especially for tumors in the distal esophagus and gastroesophageal junction, thediaphragm position is related to the actual lengths of radiation beams and subsequentlyinfluenced the delivered radiation dose. In chapter 7 we showed that even though theamplitude of breathing seemed relatively constant, offsets of the diaphragm positions, andconsequently tumor positions, were large. This might result in geographical misses of tumoror dose deviations in terms of hot or cold spots in dose distribution. The magnitude of andvariation in breathing amplitude and offset position can be determined more specific on 4DCTscan. The mean diaphragm expiration and inspiration delineations offset of thediaphragm that we observed were in the same order of magnitude as found in other studieswith 4 D-CT scan. The determined respiratory-induced diaphragm motion does not accuratelypredict the daily respiratory-induced diaphragm movement on 3D-ConeBeam CT-images(CCBCTs). Although, monitoring of respiratory motion during treatment with CBCTs issuggestible, the use of fiducial markers at the tumor borders improves the visibility of thetarget, and consequently the quality of the tumor position verification with CBCTs. Aspointed earlier the position of the diaphragm with respect to the radiation target can influencedose distributions, which play an important role in the future use of protons radiotherapy, asprotons are more sensitive to density changes in the beam path. A methods to minimize targetmotion due to diaphragm motion is the use of a breath-hold technique, while abdominalcompression or mechanical ventilation may minimize breathing motion.Several studies have found a significantly better survival in patients achieving a pathologiccomplete response (pCR: EAC: 23% and ESCC: 50%) after nCRT compared to those withresidual disease in the resected specimens. Esophagectomy after clinical completeresponse might be less beneficial, especially when considering the substantially high risk ofmortality and morbidity during surgical resection. For a good decision-making, accuratepreoperative selection is necessary to identify complete responders. We described amethod to adequately guide the pathologic examination of resected specimens after nCRT,which may allow accurate evaluation of the location of residual cancer based on radiotherapydelineations of tumor volumes. In chapter 8 we have evaluated the site of residualdisease related to tumor target volumes at pathologic examination. In radical resected (R0)specimens, 19.8% had a pCR and 14% nearly no response (TRG 4-5). Residual tumor waslimited to the esophagus (ypT+N0) in 57.8% and commonly in the adventitia (43.1%), while7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymphnodes (ypT0N+). In TRG 2-5 R0 specimens, macroscopic residue was in- and outside thegross tumor volume (GTV) in 33.3% and 8.9%, while microscopic residue in- and outside theclinical target volume (CTV) margin only in 58.9% and 1.1%, respectively. Residual nodaldisease was observed proximally in two and distally to the CTV in 5 patients. Disease FreeSurvival (DFS) decreased if macroscopic tumor was outside the GTV (9 vs. 27 months;p=0.009) and in ypT2-4aN+.About 3%-10% of the EC patients have isolated residual lymphatic disease after nCRT.Moreover, about 11% of cCR patients have TRG1 or TRG2 in the mucosa, which might bedetected with (sub)mucosal biopsies. Also deeper biopsies at the EUS before surgery aresuggested to avoid false negative results. Others have shown the highest percentages of TRG1in the surrounding stroma, reflecting effective tumor downstaging with increased distancebetween residual tumor and the circumferential resection margin. It is crucial todetect residual cancer as early as possible with a view to the prognosis and treatmentapproach. At the moment EUS-FNA and CT or PET-CT scan are the most used imagingtechniques. The use of MR is becoming increasingly frequent due to technicalimprovements and the addition of new diffusion-weighted imaging (DWI) with the highestspecificity for T stage and the same sensitivity of EUS for lymph node involvement.Recently, Qiu et al. have shown that tumor response assessed by the combined of MRI,endoscopy and CT was highly predictive of prognosis after dCRT. The differencebetween results of the combined modalities and the traditional methods was primarily theresult of the discrimination of CR from PR. Using CT and endoscopy, a substantial portion ofthe patients with true CR might be misdiagnosed as non-CR and could be offered unnecessaryfurther management after dCRT like salvage surgery, additional CRT or palliative therapy. Future efforts to improve the outcome using CRT should be directed at reducing thehigh rate of both in-field and distant relapses by intensifying local therapy or systemictherapy, or both, rather than extending the RT fields.Given the risk of perioperative morbidity and mortality, it is questionable whetheresophagectomy is needed in all patients with cCR after nCRT. Because current staging is stillinaccurate in over 25% of the EC patients, selection remains difficult. Delayed resection maybe performed for local recurrences after nCRT with a wait and see strategy when patient’sphysical and mental condition refrains from having additional operation after nCRT. Asshown in chapter 9, the variation in the rate of these so-called salvage surgery after dCRTand the reported 5-year OS of 0-33% stresses the need for better selection. We haveshown that salvage surgery is a feasible and may be potentially curative in patients withlocoregional regrowth EC after dCRT and nCRT.Although considered as a valid treatment option, the salvage surgery of loco-regional residualor recurrent disease after CRT remains controversial. Besides a R0 resection, the presence ofearly and small tumor remnants (cT>2/N0) is the most favorable prognostic factor in patientsafter dCRT. This stresses the importance of better locoregional control throughimproved chemoradiation strategies in dCRT and adequate staging with accurate imagingmethods to ensure a complete tumor resection. Likewise, to select candidates for surgerywith curative intent, a standard surveillance protocol is likely needed during the first 2-3 yearsafter initial dCRT in localized tumors to detect residual disease at an early stage.The choice for salvage surgery is frequently limited by poor condition and coexisting comorbiditiesin patients with isolated locoregional cancer. Similarly, pulmonary andcardiovascular postoperative complications often occur in patients with regrowth of persistentEC, probably based on early surgery in biologically more aggressive tumors with inadequateresponse to dCRT. Salvage surgery after dCRT is more challenging than surgery afternCRT with even more surgery related complications. This is not surprising, as the givenradiation dose is higher (50.4 to 60 Gy) with subsequently more fibrotic tissues, hamperingan adequate identification and dissection of recurrent tumor mass. Modernradiotherapy techniques may decrease the risk of cardiac and pulmonary toxicities bylowering radiation dose to normal tissues during the initial treatment in combination withlower toxic profiles of new chemotherapeutic schemes. However, a very importantfactor in lowering the risk of morbidity and mortality, is the concentration of salvage anddelayed surgery in specialized high-volume centers.