Original article Strahlenther Onkol 2014 ∙ 190:515–520 DOI 10.1007/s00066-014-0650-0 Received: 23 October 2013 Accepted: 25 February 2014 Published online: 9 April 2014 © Springer-Verlag Berlin Heidelberg 2014

Ovidio Hernando-Requejo1,3,4 · Mercedes López1 · Antonio Cubillo2,3 · Almudena Rodriguez1 · Raquel Ciervide1 · Jeannette Valero1 · Emilio Sánchez1 · Mariola Garcia-Aranda1 · Jesus Rodriguez2,3 · Guillermo Potdevin1 · Carmen Rubio1,3 1Department of Radiation Oncology, Hospital Universitario Sanchinarro, Madrid, Spain 2Department of Medical Oncology, Hospital Universitario Sanchinarro, Madrid, Spain 3CEU San Pablo University, Hospital Universitario Sanchinarro, Madrid, Spain 4Centro Integral Oncológico Clara Campal, HM Universitario Sanchinarro, Madrid, Spain

Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation Rectal cancer, defined as a tumor arising in the distal large bowel less than 12 cm from the anal verge as assessed by rigid sigmoidoscopy [1], is one of the most frequent cancers in Western countries, affecting 40,000 new patients per year in the USA [2]. In Spain the crude rate for rectal cancer is 40.1/100,000 males and 14.2/100,000 females. Radical treatment of locally advanced disease has been developed in the last few years with the implantation of chemoradiation. Although 5-Fu based chemoradiation (CRT) has become the standard neoadjuvant approach worldwide for suspected stage IIA to IIIC malignancies [3], surgery remains the main curative treatment for locally advanced rectal cancer. Compared with postoperative chemoradiation, preoperative CRT demonstrated an improvement of both locoregional tumor recurrence (6 vs. 13 %) and acute toxicity (27 vs. 40 %). Another advantage is that in more than half of the patients who received neoadjuvant radiotherapy, a downstaging effect of the tumor was achieved [4–6]. Standard chemoradiation with 5-Fu results in 15 % of complete pathological responses (ypCR) [3, 7] with grade 3 diarrhea and proctitis occurring in 15–40 % of the patients [3, 7, 8]. To improve these results, other combinations such as capecitabine and oxaliplatin have also been tested concurrently with standard radiotherapy [9–13],

trying to achieve higher levels of ypCR. These studies resulted in a 25–30 % average ypCR, but grade 3–4 toxicity rates increased up to 40 % [13–15]. The use of accelerated radiotherapy has also been tested in other solid tumors, aiming for the benefit of a shorter treatment time and lower probability of tumor repopulation [16]. In rectal cancer, a Korean group tested the use of a small field boost [17, 18] using pelvic radiation therapy of 43.2 Gy in 24 fractions plus a concomitant boost of 7.2 Gy in 12 fractions, delivered to the pelvis and tumor, respectively, for 5 weeks; they achieved 11.6 % ypCR with downstaging rates of 40.5 and 68.1 % for tumors of T and N classification, respectively. In our institution, we performed a prospective pilot study of target-guided personalized chemotherapy and escalated-dose radiotherapy with an integrated boost IMRT technique. Results were published elsewhere [19]; 15 patients were enrolled with 50 % of ypCR and acceptable toxicity, with only 25 % of patients developing grade 3 toxicity. On the basis of these results, we questioned whether escalated-dose radiotherapy and conventional capecitabine-based chemoradiation could achieve similar results.

Patients and materials From July 2008 to December 2012, 74 patients were treated with neoadjuvant

chemoradiation and concomitant boost IMRT. All patients were evaluated and discussed by our multidisciplinary GI Tumors Board (including radiation oncology, medical oncology, surgery, gastroenterology, nuclear medicine, radiology, and anatomical pathology services), all had cT2-4, N0/+, and cM0 tumors, except one cM1 (single liver metastases) tumor considered locally advanced but potentially resectable. All patients underwent colonoscopy and biopsy, echoen-­ doscopy, and computed tomography (CT) imaging. Positron emission tomography (PET)-CT and pelvic magnetic resonance imaging (MRI) were performed at the discretion of the treating physician. All patients gave written informed consent before treatment. Although pelvic MRI and PET-CT were not mandatory, all patients underwent preoperative MRI and it was used for primary staging. All but four patients had a preoperative PET-CT that was performed to explore distant metastasis. Radiation therapy simulation was performed either in a Somatom Sensation Open Siemens CT or a Biograph PET-CT scanner (Siemens®, Germany). Patients were immobilized using a BellyBoard (CIVCO®, USA) device and helicoidal CT images were taken with 3-mm reconstruction. Oral and intravenous contrast agents were administered with our standard protocol to enhance the bowels, vesStrahlentherapie und Onkologie 6 · 2014 

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Original article Table 1  Patient and tumor characteristics

Table 2  UICC-TNM classification

Table 3  Changes in T classification after

Median age (years) Sex Male Female Clinical T stage cT2 cT3 cT4 Clinical N stage cN0 cN1 cN2 Median distance from anal verge (cm) Location of the tumor Upper third Middle third Lower third

UICC group T2N1 T3N0 T3N1 T3N2 T4N0 T4N1 T4N2

chemoradiation (55/72 patients)

61.77 (33–80) 44 (59.5%) 30 (40.5%) 13 (17.6%) 56 (75.7%) 5 (6.8%) 26 (35.1%) 41 (55.4%) 7 (9.5%) 7.49 (1–15)

27 (36.48%) 33 (44.59%) 14 (18.9%)

Table 4  Changes in N classification after

chemoradiation (34/72 patients) cN1 cN2

pN0 28 4

pN1 2

sels, tumor, and lymph nodes during the CT acquisition. The contouring workup was done using a Focal system (Elekta®, Sweden); the treatment volume included two planning target volumes (PTVs). The first one encompassed the pelvic lymph nodes (presacral and internal iliac nodes), mesorectum, and tumor bed with a 5-mm margin; the second PTV (considered the concomitant boost) included the tumor and pathological lymph nodes detected in the simulation CT/PET-CT with a 5-mm margin. Additional information found in the diagnostic work-up was also used for the contouring by the radiation oncologist. The PTV margin of 5 mm was chosen after measures of the standard error were made by our physicists for different treatment locations with conebeam CT image-guided correction. Dose planning was done with XIO (Elekta®. Sweden) using a 7-field IMRT step-andshoot technique with 6-MV photons generated by an ONCOR LINAC (Siemens®, Germany). During treatment, the correct position of the isocenter was ensured by MV cone-beam CT-based image-guided radiotherapy.

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Number of patients 13 25 25 6 1 3 1

Table 5  Acute chemoradiation toxicity

Acute gastrointestinal Acute genitourinary Acute skin

Grade 1 (n/%) 25/33.8

Grade 2 (n/%) 21/28.4

Grade 3 (n/%) 7/9.5

12/16.2

7/9.5

4/5.4

9/12.2

16/21.6

2/2.7

Radiation therapy was completed in 4.5 weeks with a total of 23 fractions. The dose for the first PTV (pelvic PTV) was 46 Gy in 23 fractions, and the concomitant boost (PTV2) was 57.5 Gy in 23 fractions (BED = 71.8 Gy [α/β = 10] & Eq2 Gy/f ≈ 70 Gy). All patients received concurrent standard capecitabine-based chemotherapy (825 mg/m2 bid), and a blood count was performed every 14 days.

Results We treated and analyzed 74 patients between July 2008 and December 2012. Median Follow up was 17 months. . Tables 1 and 2 show the patient and tumor characteristics. All but one patient completed chemoradiation as scheduled; treatment was interrupted for one patient due to grade 2 proctitis with two remaining fractions. Of the 74 patients, 73 underwent surgery; one patient was lost before diagnostic reevaluation. Surgery was performed after diagnostic reevaluation of the local disease and verification of no further dissemination (reevaluation test included: blood count tests, tumor markers, CT scan, PET-CT scan, MRI and echoendoscopy). Surgery was planned to take place around 8 weeks after treatment; the median time from the end of radiation therapy to surgery was 67.6 days. The surgical procedures were low anterior resection in 56 (77.7 %) and abdominoperineal resection in 16 patients (22.2 %).

cT2 cT3 cT4

pTis 1

pT0 6 15 1

pT1 4 7

pT2

pT3

18 3

Primary tumor downstaging was achieved in 55 out of 72 patients (76.38 %), while nodal downstaging was achieved in 34 patients (47.2 %). The surgical information of two of the 74 patients, as mentioned previously, was lost during followup. . Tables 3 and 4 show the changes in staging after chemoradiation. Twenty-two out of 72 patients (30.6 %) achieved ypRC at final histological analysis; 21 patients (29.2 %) had near complete regression, 17 (23.6 %) moderate regression, and 12 patients (16.7 %) minimal regression, with measures based on Rödel’s regression criteria [4]. The circumferential resection margin (CRM) was free of tumor in 70 (97.2 %) of 72 patients. The 3-year estimated overall survival and disease-free survival rates were 95.4 and 85.9 %, respectively (. Fig. 1), and no local relapse was found; however, ten patients (13.8 %) developed distant metastases. The most common sites for distant metastases were the lung (six patients) and the liver (three patients), and one patient developed CNS metastases. The patients who achieved pT downstaging to pT0-2 had better disease-free survival in the log-rank analysis when compared with patients with tumors that still had deep penetration beyond the rectal wall (p = 0.013; . Fig. 2). In the analysis of factors influencing ypCR, only cTN was a significant factor on uni- and multivariate analysis (p = 0.007), showing that patients with cN0 tumors had higher rates of ypCR than patients presenting with cN1/2 tumors. Toxicity analysis revealed a safe profile for our new radiotherapy scheme. Grade 3 or more (CTCAE v.4) acute chemoradiation-related toxicity was 17.6 %. A more detailed analysis of grade 3 toxicity revealed seven patients (9.5 %) with gastrointestinal toxicity, four patients (5.4 %) with genitourinary toxicity, and two patients (2.7 %) with cutaneous toxicity. . Table 5 shows the chemoradiation acute

Abstract · Zusammenfassung Strahlenther Onkol 2014 ∙ 190:515–520  DOI 10.1007/s00066-014-0650-0 © Springer-Verlag Berlin Heidelberg 2014 O. Hernando-Requejo · M. López · A. Cubillo · A. Rodriguez · R. Ciervide · J. Valero · E. Sánchez · M. Garcia-Aranda · J. Rodriguez · G. Potdevin · C. Rubio

Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation Abstract Background and purpose.  To analyze the efficacy and safety of a new preoperative intensity-modulated radiotherapy (IMRT) and integrated-boost chemoradiation scheme. Patients and methods.  In all, 74 patients were treated with IMRT and concurrent standard dose capecitabine. The dose of the planning target volume (PTV) encompassing the tumor, mesorectum, and pelvic lymph nodes was 46 Gy in 23 fractions; the boost PTV, at a dose of 57.5 Gy in 23 fractions, included the macroscopic primary tumor and pathological lymph nodes. The patients underwent surgery 6–8 weeks after chemoradiation. Results.  The complete treatment data of 72 patients were analyzed. Tumor downstag-

ing was achieved in 55 patients (76.38 %) and node downstaging in 34 (47.2 %). In 22 patients (30.6 %), there was complete pathological response (ypCR). The circumferential resection margin was free of tumor in 70 patients (97.2 %). The 3-year estimated overall survival and disease-free survival rates were 95.4 and 85.9 % respectively, and no local relapse was found; however, ten patients (13.8 %) developed distant metastases. High pathologic tumor (pT) downstaging was shown as a favorable prognostic factor for disease-free survival. No grade 4 acute radiotherapy-related toxicity was found. Conclusions.  The IMRT and integrated-boost chemoradiation scheme offered higher rates

of ypCR and pT downstaging, without a significant increase in toxicity. The circumferential margins were free of tumors in the majority of patients. Primary tumor regression was associated with better disease-free survival. Keywords Rectal carcinoma · Chemoradiation · Intensity-modulated radiotherapy · Downstaging · Pathological complete response

Komplette pathologische Remissionen bei lokal fortgeschrittenem Rektalkarzinom nach präoperativer IMRT- und integrierter Boost-Radiochemotherapie Zusammenfassung Hintergrund und Ziel.  Analyse von Wirksamkeit und Sicherheit eines neuen präoperativen intensitätsmodulierten Bestrahlungsschemas (IMRT) mit integriertem Boost. Patienten und Methodik.  Insgesamt 74 Patienten wurden simultan mit IMRT und Capecitabin (Standarddosis) behandelt. Die Dosis des Planungszielvolumens (PTV) umfasste den Tumor, das Mesorektum sowie die Beckenlymphknoten und betrug 46 Gy in 23 Fraktionen. Das Boost-PTV betrug 57,5 Gy in 23 Fraktionen und umfasste den makroskopischen Primärtumor und die erkrankten Lymphknoten. Die Patienten wurden 6–8 Wochen nach der Radiochemotherapie operiert. Ergebnisse.  Es wurden die vollständigen Behandlungsdaten von 72 Patienten analysiert.

toxicity profiles. After surgery, 19 patients (25.7 %) developed toxicity of any grade. .  Table 6 shows the postoperative toxicity. Grade 4 toxicity was seen in two patients with anastomosis leakage, one sepsis, one rectum necrosis, and one ureter section during surgery that required reimplantation posteriorly. We found only one patient with anemia (≥ grade 3) resulting from the chemotherapy regimen. Most of the patients

Ein Tumor-Downstaging zeigten 55 Patienten (76,38 %) und ein Lymphknoten-Downstaging 34 Patienten (47,2 %). Ein vollständiger Rückgang des Tumors (pCR) war bei 22 Patienten zu beobachten (30,6 %). Der tumorumgebende Resektionsrand war bei 70 Patienten tumorfrei (97,2 %). Das allgemeine 3-Jahres-Überleben und das krankheitsfreie Überleben lagen jeweils bei 95,4 bzw. 85,9 %. Lokalrezidive traten nicht ein, jedoch haben sich bei 10 Patienten Fernmetastasen entwickelt (13,8 %). Ein Primärtumor-Downstaging wirkte sich positiv auf die Prognose bezüglich eines krankheitsfreien Überlebens aus. Es wurde keine Grad-4-Toxizität beobachtet. Schlussfolgerungen.  Das untersuchte IMRTBestrahlungsschema mit integriertem Boost

start treatment with hemoglobin levels slightly under normal values due to rectal bleeding and/or the diagnostic workup. Four patients developed neutropenia (three patients, grade 1; one patient, grade two) and no case of thrombocytopenia was detected. Only one patient had to discontinue chemotherapy due to grade two neutropenia.

zeigt eine höhere Wahrscheinlichkeit einer vollständigen Rückbildung und eines pathologischen Downstagings ohne wesentliche Toxizitätserhöhung. Der umgebende Resektionsrand war bei den meisten Patienten tumorfrei. Die beobachtete Primärtumorregression wurde mit besseren krankheitsfreien Überlebenschancen in Zusammenhang gebracht. Schlüsselwörter Rektumkarzinom · Strahlenchemotherapie · Intensitätsmodulierte Strahlentherapie · Downstaging · Pathologisch vollständige Remission

Discussion To our knowledge, our institution is the first to use this concomitant-boost IMRT dose fractionation scheme. After having tested the safety and efficacy of the scheme with concurrent personalized chemotherapy in our feasibility study [19], our aim was to find out the isolated influence of modified-dose radiation therapy on the high ypCR achieved (50 %). Strahlentherapie und Onkologie 6 · 2014 

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Original article Table 6  Postoperative toxicity Complication (cases) Presacral mass Ileus Anastomotic leakage Ileostomy infection Fistula Sepsis Peritonitis Lymphedema Colitis Necrosis (rectum) Ureter section (intraoperative)

Grade 1 3

Grade 2 1 1

Grade 3

Grade 4

2 2

1

2 1 1 1

1

Few previous studies have tested the possibility of achieving higher percentages of ypCR by reducing the total radiotherapy time and increasing the dose per fraction in the tumor. A phase I trial [20] was conducted by various centers in the US, with the aim of testing the safety and efficacy of preoperative hypofractionated radiotherapy using IMRT and an incorporated boost with concurrent capecitabine. The dose to the pelvis was 45 Gy in 25 fractions while the gross tumor volume (GTV) plus 2-cm margin received 55 Gy in 25 fractions. The study was discontinued due to six cases of grade 3 toxicity occurring in three out of eight patients (38 %). A phase II study in Asia [21] tested the scheme of 41.8 Gy to the pelvic lymph nodes and mesorectal region in 22 fractions with a concomitant boost of 50.6 Gy to the GTV. The PTV margins in this study were 5 mm. The ypCR was 31 % with T and N downstaging of 56.9 and 79.2 %, respectively—the levels of toxicity were acceptable. In our study, the ypCR achieved with concomitant-boost IMRT was 30.6 % with a T and N downstaging of 76.38 and 47.2 %, respectively. Grade 3 toxicity was found in 13 cases (17.6 %), observed in 11 out of the 74 patients (14.86 %; as two of them presented with genitourinary and gastrointestinal toxicity, and genitourinary and skin toxicity at the same time). When assessing other similar concomitant-boost IMRT studies, the phase I trial shows an excessive toxicity profile when compared with the phase II study and our study. It is likely that the 1-cm margin from the GTV to the CTV and the 1-cm margin from the CTV to the PTV (2 cm

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1 1 1

final margin from GTV to PTV) was excessive and made toxicity unacceptable; the safety profiles of the phase II trial at 14.3 % and our study at 17.6 % are similar and have the same PTV expansion of 5 mm. The 30.6 % ypCR achieved in our study and in the phase II trial differs radically from the lack of ypCR in the discontinued phase I trial. We achieved more T downstaging than N downstaging, in contrast to the higher N downstaging of the phase II trial (76.38 and 47.2 % vs. 56.9 and 79.2 %, respectively). This could be explained by the differences in dose intensity, as we overdosed the GTV (taking into account the primary tumor and visible pathologic nodes) while maintaining the pelvic CTV at a standard dose of 46 Gy, which is not enough to achieve complete responses in the nodes affected but missed in our boost. However, the 30.6 % ypCR achieved with the boost technique is clearly superior to the standard radiotherapy and capecitabine combination of 15 % [3, 7]. Other strategies have been tested to obtain higher rates of ypCR—the addition of other chemotherapeutic agents to 5-Fu is well known [12, 14, 21, 22] but the low increase in response is related to higher toxicities. An improvement in ypCR by increasing the dose in the GTV and maintaining the dose in the pelvic CTV seems to be useful without an increase of toxicity. The pelvic volume only receives 46 Gy in 23 fractions, generally enough for microscopic disease, and in this way, since we only increase the dose to reduced volumes encompassing the primary tumor

and pathologic lymph nodes as seen on CT or PET-CT scans, the toxicity levels are maintained. We can only do this with an IMRT technique where dose fluencies are possible and where isodoses can be modulated to save the organs at risk. The grade 3 acute chemoradiation-related toxicity in our study (17.6 %) was found to be genitourinary, gastrointestinal, and skin toxicity (9.5, 5.4, and 2.7 %, respectively); previous studies report rates of up to 40 % when combining the two chemotherapeutic agents [12, 15]. Anastomosis leakage has been previously reported with rates of 11 % [3]—in our experience, there were only two cases (2.7 %). Eleven of 21 patients (52.28 %) initially considered borderline for preserving surgery underwent sphincter-preserving surgery, in close agreement to other published data [3, 23–25]; all were treated with prophylactic ileostomy in order to prevent complications. The median time from the end of radiation therapy to surgery was 67.6 days (9.5 weeks). The Lyon R90-01 trial reported that the time interval from radiotherapy to surgery could be related to the rates of sphincter preservation, although results were nonsignificant. These results could not be validated in a more recent study, the Stockholm III trial, where short-course radiotherapy followed by surgery after 1 week or 4–8 weeks showed only the same trend toward more conservative surgery in the long-course treatment [26, 27]. In our series, the time interval was longer than 8 weeks; this also did not show any benefit in terms of preserving surgery. The main cause of death is the development of distant metastases, which are present in 20–40 % of rectal cancer patients [28]. In our series, 13.8 % of patients presented with distant metastases, although we know that a longer followup could increase this rate. We found that the 3-year overall survival and disease-free survival rates were 95.4 and 85.9 %, respectively; other studies reported similar overall survival and disease-free survival rates but with a 5-year estimation [3, 17]. Survival can range from 47 to 92 % depending of the nodal involvement and mural penetration [28]. We also found a significant correla-

treatment time, the lower the capacity of interfraction growth). We acknowledge the limitations of our series, of which the most important are: the lack of randomization and of a comparison of our concomitant-boost IMRT technique with standard chemoradiation; the small sample size; and the need for a longer follow-up.

1.0

Overall survival

0.8

0.6

0.4

0.2

Conclusion

0.0 0.00

10.00

20.00

30.00

40.00

50.00

Time (months)

Fig. 1 9 Overall survival

pT and disease-free survival 1.0

0.8

0.6

0.4

In summary, concomitant-boost IMRT with standard capecitabine is a well-tolerated treatment that acquires high rates of downstaging and high rates of ypCR. No significant differences in overall and disease-free survival were found in patients with ypCR; however, the patients with major primary tumor response to preoperative chemoradiation (ypT0-T2) had better disease-free survival rates. A larger sample size and longer follow-up time, as well as randomized comparative studies, are needed to test the real benefits of altered treatment schemes over standard radiotherapy.

Corresponding address

0.2

0.0 0.00

10.00

20.00

30.00

Time (months)

tion between the consecution of a major pT downstaging before surgery (pT0-2 vs. pT3-4) and a benefit in disease-free survival. Previous studies report the possibility of reducing distant metastases with neoadjuvant treatment [29, 30]. One explanation for our results is that radioresistant tumors may have a major tendency to spread or that by achieving early responses we can lower the risk of tumor spreading. There is some evidence that a negative circumferential resection margin is related to low rates of local and distant failure and to better overall and disease-free survival [31, 32]. We achieved a negative cir-

40.00

50.00

Fig. 2 9 Disease-free survival for patients with pT0-2 (continuous line) or pT3-4 (dashed line) downstaging after preoperative treatment (p = 0.013)

cumferential resection margin in all but two patients (97.2 %), considering a margin of ≥ 1 mm as negative [1]. After our initial experience combining concomitant-boost IMRT with personalized chemotherapy, in which we found a 50 % ypCR, we tested the influence of the radiotherapy technique with standard capecitabine on the rate of ypCR, which was up to 30.6 %. The toxicity profiles are quite acceptable and there is also the advantage of shortening the overall treatment time, not only for patients, but also for LINAC schedules and tumor repopulation (the shorter the

O. Hernando-Requejo MD Centro Integral Oncológico Clara Campal HM Universitario Sanchinarro C/Oña 10, 28050 Madrid [email protected]

Compliance with ethical guidelines Conflict of interest.  O. Hernando-Requejo, M. López, A. Cubillo, A. Rodriguez, R. Ciervide, J. Valero, E. Sánchez, M. Garcia-Aranda, J. Rodriguez, G. Potdevin, and C. Rubio state that there are no conflicts of interest.

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