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Keywords:

  • esophageal cancer;
  • weekly chemotherapy;
  • chemoradiotherapy;
  • docetaxel

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

BACKGROUND:

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5-fluorouracil (5-FU) and concomitant radiotherapy (RT) in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus.

METHODS:

The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU c.i. (180 mg/m2 on days 1-21 and 150 mg/m2 on days 29-63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation.

RESULTS:

A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3-4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow-up was 55 months (range, 3-108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3- and 5-year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001).

CONCLUSIONS:

This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long-term durable survival rates. Cancer 2013. © 2012 American Cancer Society.

To date, the benefits and risks of neoadjuvant chemoradiotherapy (CRT) in esophageal cancer have been investigated in randomized phase 3 clinical trials (RCTs), phase 2 or retrospective studies.1-6

RCTs compared neoadjuvant CRT with surgery alone and, although most of them demonstrated higher survival rates in the combination arm, overall survival (OS) and disease-free survival (DFS) were statistically improved in 4 trials7-10 and 2 trials only,11, 12 respectively. These inconsistencies are likely due to patient selection and differences in chemotherapy and/or radiotherapy doses and schedules. Nevertheless, the meta-analyses2-5 proved that neoadjuvant concomitant CRT significantly increased the survival rate, reducing the risk of death by approximately 20%4, 5 in comparison with surgery alone.

In order to improve the results, a modification was made to traditional chemotherapy protocols, mostly based on cisplatin and 5-fluorouracil (5-FU), introducing the use of weekly administration. In preclinical studies, cytotoxicity was increased and emergence of drug-resistant cell clones was reduced by frequent and prolonged drug administration, such as by weekly therapy. Moreover, the toxicity of 3-week platinum fluorouracil protocols is likely to be reduced by weekly administration. In the clinical setting, this hypothesis was supported by the results of the recently presented CROSS trial,10 which demonstrated statistically improved survival with weekly paclitaxel and carboplatin chemotherapy and concomitant radiotherapy.

Among the factors that may contribute to improved survival, the achievement of complete pathologic response (pCR) is generally deemed to be of relevance. Many studies13-17 reported that patients achieving pCR had improved outcome, with survival rates exceeding 50% at 5 years.

Docetaxel, cisplatin, and 5-FU are at the same time synergistic and radiosensitizers18 and, consequently, a weekly therapy based on these drugs with concomitant radiation was considered a rational approach. In a phase 1 study,19 we previously reported the feasibility of this neoadjuvant schedule. Using the doses of the last dose level (docetaxel at 35 mg/m2/week, cisplatin at 25 mg/m2/week, 5-FU at 150 mg/m2/day continuous infusion [c.i.] and radiotherapy [RT] of 50 Gy), we performed a phase 2 study with the pCR rate as the first endpoint and survival and toxicity as the secondary endpoints. Here, we report the long-term results of this study.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Eligibility and Pretreatment Evaluation

Untreated patients with stage II-III adenocarcinoma (type I and II) and squamous cell carcinoma (SCC) of the mid and distal thoracic esophagus were eligible. Pretreatment characteristics of the patients are reported in Table 1. Eligibility criteria and work-up procedures were reported in detail.19 Briefly, work-up procedures consisted of medical history, physical examination, laboratory assessment (hemogram and chemistry profile), computed tomography (CT) scan of thorax and abdomen, electrocardiogram, esophagogastroscopy with biopsies, barium swallow, and endoscopic ultrasound; in SCC patients, broncoscopy and cervical ultrasound were also performed. All patients had placement of an indwelling central venous access catheter. Other inclusion criteria were Eastern Cooperative Oncology Group performance status ≤ 2 and life expectation of at least 3 months. Patients with type III tumors or other malignancies within 5 years of esophageal cancer diagnosis were ineligible. Inclusion criteria were verified by a multidisciplinary team. The protocol was approved by local ethical committees, and informed consent was obtained from all patients.

Table 1. Pretreatment Characteristics of the Patients
CharacteristicValue
  1. aSiewert type I was considered together with lower third tumors and Siewert type II with cardia cancer.

Total no. of patients74
Median age, y (range)59 (42-73)
Male/female60/14
Histology 
 Squamous cell carcinoma37
 Adenocarcinoma37
Tumor sitea 
 Middle third11 (15%)
 Lower third35 (47%)
 Cardia28 (38%)
Clinical stage 
Stage IIa 
 cT2N06 (8.1%)
 cT3N021 (28.4%)
Stage IIbcT2N17 (9.5%)
Stage III 
 cT3N135 (47.3%)
 cT4 anyN5 (6.7%)

Treatment Plan

Cisplatin was given in 30 minutes with a total of 1750 mL hydration; docetaxel was administered in 30 minutes after premedication with 8 mg dexamethasone given 1 hour before docetaxel; 5-FU was given as a protracted venous infusion. Blood tests and physical examination were repeated before each weekly cycle.

Treatment plan was as follows: docetaxel 35 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU 180 mg/m2 c.i. on days 1 to 21 and 150 mg/m2 c.i. on days 29 to 63. Concurrent RT at 50 Gy in 25 fractions was started at day 29 (Table 2). Radiation therapy was delivered with 6 or 15 MV external-beam X-photons, using a 2- or 3-field technique. The gross tumor volume included all known gross disease: the primary lesion and regionally involved lymph nodes as shown by CT scan.

Table 2. Treatment Schedule
  First Phase (Chemotherapy)Second Phase (Concomitant Chemoradiotherapy)
Drug(mg/m2)DayDay
  1815222936435057
  1. Abbreviations: c.i., continuous infusion; D, docetaxel; P, cisplatin; RT, radiotherapy.

  2. Doses of 5-FU are given as mg/m2/day.

D35[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW] [DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]
P25[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW] [DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]
5-FUc.i.180 × 21 days 150 × 35 days
      RT = 50 Gy/25 fractions

The clinical target volume, encompassing the gross tumor volume, included a margin of 2 to 5 cm in the craniocaudal and width of at least 1.5 cm, in order to cover subclinical or microscopic disease.

Surgery and Staging Criteria

Patients were restaged with the pretreatment work-up procedures between the fourth and sixth week after completion of treatment. Surgery with radical intent was performed 6 to 8 weeks after completion of CRT. The standard surgery was an Ivor-Lewis procedure, with a subtotal esophagectomy and a right intrathoracic esophagogastric anastomosis. The preferred lymphadenectomy was a D2 abdominal and standard mediastinal, extended to the right recurrent nerve chain nodes for SCC.

The patients were staged according to the TNM (tumor-node-metastasis) classification (6th edition). Pathological complete response (pCR) was defined as the absence of residual tumor (ypT0N0). Near pathological complete remission (npCR) was defined as the presence of cancer microfoci at the primary site without nodal metastases (ypN0). The remaining patients were defined as ResT (presence of residual tumor). Peritoneal lavage cytology was evaluated in all adenocarcinoma patients and positive cytology was considered as metastatic (ie, ResT).

Statistical Design

Sample size was computed for the optimal 2-stage design, using the method proposed by Simon. Assuming 25% response as a bad result and 40% response as a good result, 71 patients would be required with alpha of 5% and beta of 20%. After testing the treatment on 20 patients in the first stage, the trial would be terminated if 5 or fewer respond. If the trial goes on to the second stage, a total of 71 patients would be studied. If the total number responding was less than or equal to 23, the treatment had to be rejected.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

From January 2003 to November 2007, 74 consecutive patients fulfilling admission criteria were prospectively enrolled. Of these, 37 had SCC; of the 37 patients with adenocarcinoma, 19 were Siewert type I and 18 were type II. The median age was 59 years (range, 42-73 years), and 60 patients were male and 14 were female.

Overall, 580 weekly cycles were administered, 222 during the first phase and 358 during the concomitant phase (96.7% of the theoretical 370). During the concomitant phase, 8 patients had a dose modification with reduction of the number of the weekly cycles for a total of 12 cycles: 5 patients omitted the last week of chemotherapy, 2 patients omitted the last 2 weeks, and 1 patient omitted the last 3 weeks. There was a 1-week delay in 5% of the cycles (18 of 358). According to physician's judgment, 24 cycles (7%) were supported with granulocyte-macrophage colony-stimulating factor. The relative dose intensity for each drug was 92%.

Hematological Toxicity

During the first phase, there was only 1 case of transient grade 4 neutropenia and 2 cases of grade 2 neutropenia. As for the concomitant phase, grade 1-2 neutropenia occurred in 27 patients (36.5%), grade 3 in 7 patients (9.5%), and grade 4 in 3 patients (4%) (Table 3). Of these patients, 6 had also grade 3-4 nonhematological toxicity. One patient with chronic hepatitis C received only 2 courses of chemotherapy and proceeded with radiation only, because of persistent grade 2-3 neutropenia. Grade 1 thrombocytopenia occurred in 5 patients.

Table 3. Toxicity During the Concomitant Phase (74 Patients)
 Toxicity Grade
Toxicity1234
Granulocytopenia No. of patients (%)10 (13.5)17 (23)7 (9.5)3 (4)
Nonhematological No. of patients (%)20 (27)24 (32.4)21 (28.4)3 (4)

Nonhematological Toxicity

Toxicity was very modest during the first phase: 31 patients (42%) had grade 1 and 12 patients (16%) had grade 2 toxicities. During the concomitant phase, toxicities were of grade 3-4 in 24 patients (32.4%) (or in 33 of the 358 cycles, 9%) (Tables 3 and 4). Of the 24 patients with grade 3-4 toxicities, 4 patients (17%) had chronic hepatitis C. Grade 3-4 toxicities were recorded almost exclusively during the last 2 weeks of the treatment, and consisted mainly of asthenia and esophagitis. Because patients often complain of multiple related symptoms at the same time, for the sake of simplicity, the reported symptom was that deemed prevalent by the treating physician.

Table 4. Type of Prevalent Nonhematological Toxicities Per Patient During the Concomitant Phase
 Grade
Type of Toxicity1–2%3–4%
Nausea1216.2  
Diarrhea3422.7
Asthenia1317.51317.6
Esophagitis1520912.1

Pathological Response

Patients were divided into 3 groups: pCR, pnCR, and ResT. pCR was detected in 47% of the patients (35 of 74 patients) and pnCR in 15% (11 of 74 patients); therefore, the overall major pathological response rate was 62% (46 of 74 patients). ResT patients were found to have pTany N0 M0 in 3 patients, pTany N+ M0 in 9 patients, pTany N+ M1 (all extraregional lymph nodes) in 4 patients; 5 patients had R-2 resection and 7 were not operated on (3 had progression before surgery, 1 experienced toxic death, 3 due to refusal) (Table 5). The pCR rate in patients who were operated on was 52% (35 of 67 patients). The operability rate was 90% (67 of 74 patients) and the R0 resection rate was 84% (62 of 74 patients).

Table 5. Histological Results (74 Patients)
 pN0 M0pN+ M0pN+ M1 
  1. Abbreviations: pnCR, residual microfoci; R2, macroscopic residual tumor.

pT0352  
pnCR11   
pT1 2  
pT214  
pT311  
pT41   
pT any  4 
R2 resection   5
No surgery   7
Total499412

Survival

Median follow-up of all patients was 55 months (range, 3-108 months), 64 months in responding patients (pCR and npCR), and 72 months in the pCR subset. Median survival of all 74 patients was 55 months (range, 3-108 months) (Fig. 1), median survivals of ResT, pnCR, and pCR subsets were 16 months, 53 months, and not reached, respectively (ResT versus pnCR, P = .009; pnCR versus pCR, P = .07; pCR versus ResT, P < .001) (Fig. 2).

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Figure 1. Overall survival is shown for all patients.

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Figure 2. Overall survival is shown according to pathological response.

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The 3-year overall survival rates for pCR, pnCR, and ResT subsets were 83%, 73%, and 21%, respectively; the 5-year overall survival rates for pCR, pnCR, and ResT subsets were 77%, 44%, and 14%, respectively (P < .001). There was no survival difference between adenocarcinoma and squamous cell carcinoma.

Thirty-nine patients died: 33 of disease, 3 of causes unrelated to esophageal cancer (1 non–small cell lung cancer, 1 myocardial infarction, 1 liver failure, after 30, 40, and 75 months from diagnosis), and 3 (4%) of toxicity (1 in-hospital mortality after surgery, 1 at home due to unknown causes 1 month after surgery, 1 of probable pulmonary embolism after completing chemoradiation). There were 21 (28.4%) systemic relapses (1 patient is alive in relapse after 57 months from diagnosis), 4 locoregional and systemic (5%), and 9 locoregional (12%). Overall, 6 patients (8%), all in pCR, developed a second primary tumor (2 breast cancer, 2 non–small cell lung cancer, 1 melanoma, 1 rectal cancer) at a median of 30 months (range, 2-90) after the diagnosis of esophageal cancer.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

In locally advanced esophageal and gastroesophageal junction tumors, pCR after neoadjuvant treatment is one of the most relevant prognostic factors so far identified in the literature; these patients have the best chances to become long-term survivors, with a 5-year survival probability exceeding 50%.13-17 However, the pCR rate achieved is, on the whole, unsatisfactory, because it accounts for approximately 20% (range, 10%-33%) following chemoradiation and less than 10% after chemotherapy alone.1, 2, 6, 13, 16, 17

In a series of studies including up to 235 patients, pathological stage 0 was reported in 29% of the patients with a 5-year survival rate of 65% to 70% compared with 29% of patients with residual carcinoma.14, 16 In another series, pCR was documented in 19% of the cases, with a 3-year survival rate for this subset of 70%.20 In phase 2 studies using concomitant chemoradiotherapy with conventional schedule of paclitaxel, the pCR rate was mostly lower than 30% (range, 8%-41%).21-27 Recent phase 1/2 and phase 2 studies tested the hypothesis that outcome and toxicity could be improved using innovative schedules based on weekly taxane administration and concomitant radiation28-33 (Table 6).

Table 6. Phase 1/2 and 2 Studies of Neoadjuvant Chemoradiation Including Taxanes
Author (Ref)No. of PatientsPhaseChemotherapy During RTRT (Gy)Median Follow-Up (mo)% pCRMedian OS (mo)
  1. Abbreviations: 5-FU, 5-fluorouracil; Cape, capecitabine; CBDCA, carboplatin; CDDP, cisplatin; c.i., continuous infusion; D, docetaxel; OS, overall survival; OXA, oxaliplatin; P, paclitaxel; RT, radiotherapy.

Van Meerten (28)54IIP 50 mg mg/m2 and CBDCA AUC=2 weekly × 541.42325Not reached 3-year, 56%
Lin 2007 (29)97IIP 35 mg/m2 and CDDP 15 mg mg/m2 weekly twice weekly × 440252528.8 3-year, 49%
Ruhstaller (30)66IID 20 mg/m2 and CDDP 25 mg/m2 weekly × 545292336.5 3-year, 53%
Orditura (31)33IIP 45 mg mg/m2 and CDDP 35 mg mg/m2 weekly × 646183015.8 3-year, 35%
Spiegel (32)49I/IID 20 mg/m2 and OXA 40 mg/m2 weekly × 5, Cape 1,000 mg/m2 bid days 1–7, 15–21, 29–3545274924.1 3-year, 37%
Ruhstaller (33)28I/IICetuximab 250 mg/m2, D 20 mg/m2 and CDDP 25 mg/m2 weekly × 5451832Not reported 3-year not reported
Present study74IID 35 mg/m2 and CDDP 25 mg/m2 weekly × 5, 5-FU 150 mg/m2 c.i × 35 days.50554755 3-year, 59%

Among these reports, our study presents by far the longest median follow-up, ie, 55 months compared with less than 30 months of the others; moreover, because the median follow-up is even longer in the group of responders (64 months), this is the only study able to provide sound overall survival data at 5 years (49%).

Pathologic complete response was achieved in 47% of the patients, a percentage among the highest so far reported1, 2, 6; it must be taken into account that this result was calculated without exclusion of patients and in a study cohort of consecutive patients selected only for the absence of overt metastases; when this trial was initiated, positron emission tomography/computed tomography (PET-CT) was not easily available, and some patients would have likely been excluded had PET-CT scan been used.

Factors influencing the achievement of pCR are still unknown: pCR patients may represent the selection of an inherently favorable subset, but it is still unclear whether different treatment strategies could also improve the pCR rate. Overall, our data support the possibility of a relation between the intensity of the treatment and pCR.

In fact, this high percentage of pCR was obtained after an intense treatment, with full dose of radiation concurrent with doses of chemotherapy approximately corresponding to 2 cycles of the classical DCF (docetaxel, cisplatin, 5-FU); in particular, the doses of docetaxel (35 mg/m2/week) were 75% higher than those of other studies.30, 32, 33 This intense treatment was feasible because, with a weekly schedule, it was possible to modify the toxicity profile reducing the incidence of severe neutropenia (13.5%); however, 32% of the patients experienced grade 3-4 nonhematological toxicity (mostly grade 3), consisting of esophagitis and asthenia increasingly worsening in the last weeks of chemoradiation. The symptoms were time-limited and toxicity, although not negligible, was manageable with careful monitoring: only 8 patients (11%) required dose reduction. Toxic deaths (4%) were consistent with the reports of other dedicated institutions.

The hypothesis of a relation between treatment intensity and pCR is indirectly supported also by our previous experience and some data in the literature. The percentage of pCR obtained in this study is significantly higher (P = .005) than the 14% achieved in the steps of our phase 1 study,19 when the radiotherapy dose was 40 Gy and docetaxel dose was ≤ 25 mg/m2/week. Accordingly lower pCR rates, between 8% and 16%, have been reported in studies using lower doses of radiation24, 34, 35 or lower doses of docetaxel.30

The role of 5-FU in terms of outcome and toxicity is still a matter of controversy; all of these new studies, except one, used 2-drug regimens, excluding fluoropyrimidines. However, considering the positive results of our study, we share the view that 5-FU remains a major component of radiochemotherapy, until proven otherwise.36, 37

The high pCR rate may also be a result of underlying mechanisms of synergistic antitumor effect of the 3 drugs used. As reported in preclinical studies, docetaxel in association with fluoropyrimidines induced biochemical modulation of the expression and activity of enzymes playing a key role in fluorouracil metabolism: down-regulation of the expression of thymidylate synthase and dihydropyridine dehydrogenase and up-regulation of orotate phosphoribosyl transferase resulted in enhanced antitumor activity of fluorouracil, although the precise mechanism of action has not yet been fully elucidated.38, 39 Docetaxel also enhances cisplatin toxicity due to accumulation of intracellular cisplatin complexes, through the suppression of the multidrug resistance–associated protein 1.40 In addition, all 3 drugs have radiosensitizing effects and lack of cross-resistance.18, 41, 42

A further and, to our knowledge, unique finding6 deserves to be pointed out: after a long median follow-up of 72 months, the 5-year survival rate of the pCR subset was 77% and these patients were also disease-free. This finding clearly shows that these pCR were long-lasting and the 5-year survival rate was steady. In this study, npCR patients showed a trend toward a lower survival compared with those achieving pCR (P = 0.07); although the group is too small to draw conclusions, this finding suggests that the 2 subsets had a different sensibility to the treatment. In the literature, there is uncertainty of whether these subsets have a distinct outcome, and they are reported either as a single group or separately.20, 30, 43

In our series, 8% of the patients developed a second primary tumor. There have been limited reports in the literature on this topic, likely because of historic poor survival of patients with esophageal cancer. Population-based registries reported percentages of second primary tumors of 1.8%44 and 8%45 and confirmed the association with aerodigestive tract cancers for SCC, within the context of “field cancerization.” However, it is risky to compare a single study including carefully monitored patients with the data of epidemiological registries; with the improvement of survival, development of second primary tumors may become a special concern in the near future.

One potential criticism is related to the phase 2 nature of this trial; we are familiar with the phenomenon of good results in phase 2 studies that are not reproduced in larger trials, because dedicated teams are required to manage this type of critical treatment and the associated toxicities.

In conclusion, the present study shows that by using an intensive weekly schedule, a high pathological response rate was achieved and the subset of pCR patients had a statistically higher and durable long-term survival rate.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosure.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES
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