High pathological response rate in locally advanced esophageal cancer after neoadjuvant combined modality therapy: dose finding of a weekly chemotherapy schedule with protracted venous infusion of 5-fluorouracil and dose escalation of cisplatin, docetaxel and concurrent radiotherapy

F. Pasini1,*, G. de Manzoni2, C. Pedrazzani2, A. Grandinetti3, E. Durante1, M. Gabbani3, A. Tomezzoli4, C. Griso1, A. Guglielmi2, G. Pelosi5, S. Maluta3, G. L. Cetto1 and C. Cordiano2

1 Divisione di Oncologia Medica, 2 1a Divisione Clinicizzata di Chirurgia Generale, 3 Divisione di Radioterapia Oncologica, 4 Servizio di Anatomia Patologica, Azienda Ospedaliera-Università di Verona, Verona; 5 Divisione di Anatomia Patologica e Medicina di Laboratorio, Istituto Europeo di Oncologia, Milan, Italy

* Correspondence to: Dr F. Pasini, Divisione di Oncologia Medica, Ospedale Civile Maggiore, Piazzale Stefani 1, 37 126 Verona, Italy. Tel: +39-(0)45-8072342; Fax: +39-(0)45-8341277; Email: felice.pasini{at}univr.it


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: This phase I study was aimed at defining the toxicity profile and pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, protracted venous infusion (PVI) of 5-FU and concomitant radiotherapy (RT) in locally advanced esophageal cancer.

Patients and methods: The schedule consisted of a first phase of chemotherapy alone and a second phase of concurrent chemoradiation. Initial doses were: docetaxel and cisplatin 20 mg/m2 on days 1, 8, 15, 29, 36 and 43 plus 5-FU 150 mg/m2 PVI on days 1–21 and 29–49; RT (40 Gy) started on day 29. In the following steps the doses were escalated up to 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 PVI on days 1–21 and 150 mg/m2 PVI on days 29–63 concurrently with RT 50 Gy.

Results: Forty-seven patients were enrolled and 46 completed the planned treatment. During the concomitant phase, grade 3–4 hematological toxicities occurred in three patients (6.5%) (or 3/174 cycles) and non-hematological toxicities in six patients (13%) (or 7/179 cycles). A pathological downstaging was obtained in 59.6% of the cases (28/47): complete remission (pCR) in 14 patients, near pCR (residual microfoci on the primary pN0) in eight patients, pT2 pN0 in three patients and partial response on the primary with positive lymph nodes in three patients. Six (13%) and 13 (28%) patients were considered stable and non-responders, respectively. In the last dose level, eight pCR and four near-pCR were obtained out of 15 patients. The maximum tolerable dose was not formally defined because dose escalation was stopped at the last dose level.

Conclusion: This schedule represents a feasible treatment and the high pathological response rate is extremely encouraging; the doses found in the last dose-level are the basis for an ongoing phase II study at our institution.

Key words: esophageal cancer, chemoradiotherapy, docetaxel, weekly chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Although surgery is considered the standard treatment in clinically resectable esophageal and gastro-esophageal junction (GEJ) carcinomas, there has not been a significant change in long-term survival for surgically treated patients during the last decade [1Go]. In our experience, as well as that of others [1Go–5Go], the 5-year survival rate is in the range of 20–30%.

In an attempt to improve survival, preoperative chemotherapy or chemoradiotherapy has been used. Several randomized trials have compared preoperative chemoradiation with surgery alone. Only one trial [6Go] demonstrated a clear survival benefit for patients with adenocarcinoma, but the surgical arm performed unusually poorly. The EORTC study [7Go] showed a better disease-free survival rate, but no difference in overall survival in the chemoradiation arm, most likely because of the substantially higher postoperative mortality rate in this arm. The Australian trial [8Go] detected a survival advantage for only a small subgroup of patients with squamous cell carcinoma. The other studies included no more than 50 patients per arm and therefore were statistically powered to detect only a large survival difference [9Go–11Go]. On the whole, these conflicting results may be explained by the heterogeneity in patient selection and in the treatment delivered (radiotherapy dose and fractionation, chemotherapy drugs, dose and scheduling).

Despite this, two recent meta-analyses [12Go, 13Go] have demonstrated that neoadjuvant concomitant chemoradiation significantly improved the 3-year survival rate compared with surgery alone; on the other hand, they showed an increased postoperative mortality in the preoperative group.

The most common drugs used in combination with radiotherapy are cisplatin and 5-fluorouracil (5-FU) given every 3–4 weeks. However, the toxicity of the schedule is not negligible; in the principal trials [9Go, 14Go, 15Go] grade 3–4 toxicities (mostly esophagitis and hematological toxicities) have been reported in 61–78% of the patients, requiring dose modification of the planned schedule in about 25–39% of cases [9Go, 15Go, 16Go]. Concern about the high rates of severe toxicity and efforts to improve the outcome have suggested the modification of conventional schedules.

Preclinical data suggested that duration of exposure is an important factor in cytotoxic activity. One method of producing extended exposure is frequent repetitive drug administration (e.g. on a weekly schedule) which gives less opportunity for the emergence and regrowth of drug-resistant cell clones. Another potential advantage of weekly administration is the favorable toxicity profile with a reduced incidence of side-effects and hence a greater therapeutic index (i.e. the ratio of the antitumor effect to the toxic effects).

Docetaxel, cisplatin and 5-FU have synergistic effects and radio-sensitizing activity [17Go–20Go]; therefore weekly chemotherapy with these drugs in association with radiotherapy can be a strategy for improving therapeutic results.

We have designed a novel neoadjuvant protocol based on weekly administration of docetaxel and cisplatin, continuous infusion of 5-FU and concurrent radiation. The primary aim of this phase I study was to assess the pattern of toxicity of the schedule and the maximum tolerable dose (MTD), with special reference to docetaxel; the secondary aim was to assess the pathological response rate.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility and pretreatment evaluation
Patients with newly diagnosed stage II and III squamous cell carcimoma of the mid-distal thoracic esophagus and type I and II adenocarcinoma [21Go] were eligible for the study. The pretreatment characteristics of the patients are summarized in Table 1. Tumors of the stomach extending to the cardia (type III) and patients with other malignancies within 5 years of trial enrolment were ineligible. Patients were evaluated by a multidisciplinary team for confirmation of eligibility, staging and treatment planning. At diagnosis investigations included history, physical examination, complete blood count and routine blood chemistry, ECG, barium swallow, esophagogastroduodenoscopy with biopsies, endoscopic ultrasound, thorax and abdominal CT. Tracheobroncoscopy and cervical ultrasonography were reserved for squamous cell carcimoma. Other investigations were performed according to the physician's judgment. All patients had a central venous catheter placement for continuous ambulatory infusional chemotherapy.


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Table 1. Pretreatment characteristics of the patients

 
Patients were required to have an ECOG performance status ≤2, life expectancy of >3 months, a total white blood cell count ≥4000/mm3 or neutrophil count ≥1500/mm3, a platelet count ≥100 000/mm3, hemoglobin ≥10 g/dl, aspartate transaminase ≤1.5 times the upper normal value, alkaline phosphatase ≤2.5 times the upper normal value, total serum bilirubin ≤2.5 times theupper normal value and creatinine ≤120 µmol/l. Informed consent was obtained from all patients.

Treatment plan
Cisplatin was administered for 30 min according to standard rules with a total of 1750 ml hydration, docetaxel infusion was given for 30 min with premedication consisting of dexamethasone 8 mg administered intravenously 1 h previously and 5-FU was administered as a protracted venous infusion (PVI). Physical evaluation, complete blood count, serum creatinine, serum electrolytes and aspartate transaminase were evaluated weekly at each treatment, the day after the completion of the therapy (day 64) and when clinically required.

The following interpatient escalation algorithm was used. If none of three patients at a given dose level experienced dose-limiting toxicity (DLT) during any cycle of the treatment, the three subsequent patients were treated at the next dose level. If one patient experienced a DLT, three additional patients were entered at that dose level. If one or two of the six patients experienced DLT, there was a new dose escalation. If three or more of the six patients experienced a DLT, the previous dose level was defined as the maximum tolerated dose (MTD). DLT was defined as the occurrence of any one of the following: absolute neutrophil count <500/mm3 for >7 days; platelet count <20 000/mm3 for >7 days; any grade 3 toxicity requiring discontinuation of the treatment for >2 weeks; any grade 4 toxicity according to the National Cancer Institute Common Toxicity Criteria requiring discontinuation of the treatment.

External beam radiotherapy (RT) was delivered with X-photons of 6 or 15 MV using the two- or three-field technique. The gross tumor volume was defined as the primary tumor and enlarged lymph nodes as shown by CT scan; the clinical target volume included the gross tumor volume with a margin width of at least 1.5 cm and 2–5 cm in the craniocaudal extension. The delivered dose was 40 Gy in 20 fractions in steps 1–4 and 50 Gy in 25 fractions in steps 5–7. RT courses started on day 29 concomitantly with the second cycle of chemotherapy.

The treatment plan was as follows (Tables 2 and 3). In step 1, docetaxel and cisplatin 20 mg/m2 were administered on days 1, 8 and 15 plus 5-FU 150 mg/m2 PVI on days 1–21. After a 1-week rest, the same cycle (days 29–49) was repeated concurrently with RT (40 Gy). In step 2, docetaxel and cisplatin were escalated to 25 mg/m2 and 5-FU was escalated to 180 mg/m2 for the first 21 days. In step 3, 5-FU infusion was prolonged for 1 week during RT (150 mg/m2 on days 29–57). In step 4, docetaxel and cisplatin 25 mg/m2 were added at day 50. In step 5, RT doses were increased to 50 Gy. In step 6, docetaxel was escalated to 30 mg/m2. In step 7, docetaxel was escalated to 35 mg/m2 and added with cisplatin 25 mg/m2 at day 57 and 5-FU infusion was prolonged by 1 week.


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Table 2. Treatment schedule

 

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Table 3. Number of patients treated per step and cumulative doses for each patient

 
Surgery and staging criteria
Patients were restaged 4–6 weeks after completion of chemoradiation, repeating the pretreatment staging work-up. Surgery was performed 6 to 8 weeks after completion of RT. The standard surgical technique was a subtotal esophagectomy with proximal gastric resection and a right intrathoracic esophago-gastrostomy (Ivor–Lewis procedure) [22Go]. The preferred thoracic nodal dissection was a standard mediastinal, extended to the right paratracheal and right recurrent nerve chain nodes for squamous cell carcimoma. The abdominal lymph nodal dissection was a D2 or D3 lymphadenectomy according to the Japanese Gastric Cancer Association rules [23Go].

Tumors were staged according to the TNM classification of the International Union Against Cancer [24Go]. Pathological complete remission (pCR) was defined as the complete disappearance of the tumor at histological examination (pT0 pN0). Pathological near complete remission (pNCR) was defined as the presence of residual microfoci of tumor cells at the site of the primary with histologically negative lymph nodes (pN0). Peritoneal lavage cytology was evaluated in every case of GEJ adenocarcinoma and positive cases were considered to be metastatic.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From January 2000 to October 2003, 47 patients (14 squamous cell carcinomas and 33 adenocarcinomas) were enrolled. The median age of the cohort was 61 (range 47–76) years with a male-to-female ratio of 2.9 to 1 (Table 1).

Three hundred and twenty cycles were administered on an outpatient basis, 141 in the phase of chemotherapy alone and 179 in the concomitant phase.

Hematological toxicity (Tables 4, and 6)
During the first phase only a 74-year-old woman in step 1 experienced grade 4 neutropenia (along with mucositis grade 3) after completion of chemotherapy; subsequently she received only radiotherapy. For safety, because of the lack of information about toxicity, more patients were included in step 1.


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Table 4. Hematological and non-hematological toxicity per patient

 

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Table 6. Patients with grade 3–4 adverse events

 
As for the second phase, cycles evaluable for hematological toxicity are 174 out of 179 because, in step 7, a 73-year-old woman with chronic hepatitis C was supported with granulocyte colony-stimulating growth factors. Overall, hematological toxicity occurred in 24 patients (51%) or 39 cycles (22.2%). Grade 1–2 toxicity occurred in 21 patients, or 36 cycles (20.5%), and grade 3–4 in three patients, or three cycles (1.7%). Of these last three patients, one required a delay of 1 week in chemotherapy because of grade 3 neutropenia and two were admitted for grade 3 non-hematological toxicity (asthenia and esophagitis) after completion of the treatment. During hospitalization both developed grade 4 hematological toxicity, complicated in one case by febrile neutropenia; only these two patients required admission.

Non-hematological toxicity
During the first phase, 66% of cycles (93/141) were asymptomatic; the others had toxicities, mostly of grade 1. During the concomitant phase, toxicities of grades 1–2 and grade 3 were reported in 79% and 4% of the cycles, respectively (Table 7). Overall, during the concomitant phase, grade 3–4 toxicities were recorded in six patients (13%) (Tables 4 and 6) without chemoradiation-related deaths.


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Table 7. Non-hematological toxicities per cycle during the concomitant phase

 
Toxicities increased significantly in step 7 compared with steps 1–6. Hematological and non-hematological toxicities were present in 31% compared with 14.5% (P= 0.01) and in 79% compared with 45% (P < 0.001) of the cycles, respectively. In step 7 toxicity worsened, starting from the third week of the treatment. In fact, during the first 2 weeks 53% of the cycles were asymptomatic (16/30) compared with only 2.2% (1/45) in the last 3 weeks (P < 0.001).

Pathological response (Table 8)
The overall pathological response rate was 59.6% (28/47): pCR was achieved in 14 patients, pNCR in eight, pT2 N0 in three and a partial response on the primary with positive lymph nodes in three. Six patients had stable disease (13%) (pT2-3 N+). Thirteen patients (28%) were considered as failures for the following reasons: two had exploratory laparotomy only because of the detection of liver metastases, three underwent R2 resections, three were not operated on (two progression before surgery; one no concomitant chemoradiation). The remaining five patients had response on the primary (two had pT0 and three had residual microfoci), but were considered metastatic after surgical staging: two had nodal metastases in extra-regional nodes (para-aortic nodes in one case of adenocarcinoma and celiac nodes in a squamous cell carcimoma patient), and three adenocarcinoma patients had peritoneal metastases detected by either biopsy or cytology on peritoneal lavage. In step 7, a major pathological response was obtained in 12 of the 15 patients (80%): eight pCR (53%) and four pNCR.


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Table 8. Histological results (47 patients)

 
The operability rate was 93.5% (44/47), the resection rate was 89% (42/47) and the curative resection (R0) rate was 83% (39/47). There was no in-hospital mortality. Two patients died at home 61 and 57 days after surgery; no autopsy was performed.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary objective of this study was to assess the feasibility of a novel neoadjuvant schedule including weekly docetaxel and cisplatin, 5-FU PVI and concomitant radiotherapy. Assessing the pathological response rate was the secondary objective.

Overall, toxicity was acceptable as grade 3–4 occurred in only 15% of the patients. Virtually no toxicity was recorded during the phase of chemotherapy alone, except in one patient in step 1 who did not proceed to the concomitant phase. At that time we were worried about the unpredictable side-effects of a schedule never previously reported in the literature; because of this, more patients were enrolled in step 1 to ensure a reasonable level of security. Therefore this interruption must be ascribed, at least partially, to the learning curve of the study.

During the critical period of the concomitant phase, moderate to severe toxicities (grade ≥3) complicated only 5% of the cycles (nine cycles) and treatment never had to be discontinued. Hematological toxicity was recorded in 22.5% of the cycles, increasing significantly, as reasonably expected, during step 7, although only three patients (6.5%) had grade 3–4. In addition, non-hematological toxicity complicated a higher number of cycles in step 7 (79%, P < 0.001), although only 6.6% were of grade 3. In addition to nausea, patients complained of asthenia and esophagitis, progressively worsening in the final weeks of the treatment (P < 0.001); however, since the symptoms were time limited, enteral tube feeding was never required. Two patients (4.4%) were admitted after completion of the treatment and one of them developed a life-threatening febrile neutropenia. This fact suggests the risk of a cumulative toxic effect in the weeks following completion of chemoradiation.

Comparison of the toxicity data of this study is difficult, since to our knowledge there are no published reports with a similar schedule in the neoadjuvant setting of upper gastrointestinal tract tumors. A recent study with weekly cisplatin, PVI of paclitaxel and concomitant RT reported hospital admission in 46% of 37 patients [25Go]. Our toxicity data also compare favorably with the toxicity of classical 5-FU–cisplatin-based regimens; however, direct comparison is flawed because in dose-finding studies toxicity is expected to change with dose escalation. Other studies in advanced gastric cancer using conventional 3-week schedules of docetaxel without radiotherapy have reported 40–68% grade 3–4 non-hematological toxicity, 81–84% hematological toxicity and 16–19% febrile neutropenia [26Go, 27Go]. With these rates of toxicity the concomitant administration of a full dose of radiation seems hardly possible; however, this was feasible in our protocol because the weekly therapy modified the toxicity profile, reducing the incidence of severe neutropenia compared with an equivalent dose delivered on a 21-day schedule. It is of note that, in fact, the dose intensity of the drugs achieved in step 7 was similar to that administered with three cycles of docetaxel–cisplatin–5-fluorouracil [28Go]. Unquestionably, toxicity, mainly asthenia and esophagitis, increased significantly in step 7: during the last 2 weeks of the therapy; a third of the patients (5/15) experienced adverse events of grade 3–4 (Table 6). Nevertheless, all the patients were able to complete the planned treatment. At this point, three considerations were taken into account: first, the level of toxicity was increasing critically; secondly, the pathological response rate achieved was indeed promising; thirdly, lacking analogous studies, comparison had to be made with experiences in non-small-cell lung cancer, where the MTD of docetaxel and cisplatin in combination with radiotherapy was 20–25 mg/m2 per week [29Go, 30Go], i.e. lower than the doses reached in our study. Therefore the investigators deemed it prudent to stop the dose escalation, which, even if hypothetically possible, was likely to cause unacceptable toxicity. For this reason the MTD has not been formally reached in our study.

Also of interest is the fact that premedication of the weekly docetaxel was possible with low doses of dexamethasone; this avoided the side effects of high doses of corticosteroids and at the same time prevented the occurrence of hypersensitivity reactions.

The secondary objective of the study was the pathological response rate. Some considerations in the evaluation of the pathological results need to be pointed out: first, the percentages of the pathological responses were computed without exclusion of patients; secondly, the cohort was composed of consecutive patients selected only for the absence of overt metastases; thirdly, pathology was the result of an extensive staging achieved by transthoracic esophagectomy, extended lymphadenectomy and peritoneal washing.

Above all, it should be highlighted that the percentage of major pathological downstaging (pT0-2 N0 M0) is in excess of 50%; this includes 30% of pCR (14/47) and 17% of pNCR (8/47). In particular, the percentage response appears remarkable in step 7 where, out of 15 patients, eight achieved pCR and four achieved pNCR (P=0.03). It seems reasonable to affirm that the increased doses of docetaxel and radiotherapy are the basis of this result; however, before drawing conclusions, a larger number of patients should be treated at this dose level. A comparison with other studies is shown in Table 9.


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Table 9. Comparison of pathological complete responses

 
In this series pathological negative lymph nodes were found in 55% of patients (26/47). This is nearly three times the percentage of pN0 (18.7%) we reported after surgery alone in another series in which lymph node involvement represented the most powerful prognostic factor [22Go]. Furthermore, 62% of the patients achieved a major pathological response at the site of the primary tumor.

Patients with pCR have the best chance of becoming long-term survivors; in the literature this group has a 5-year survival probability of ~60% [5Go]. In our experience, chances of survival for pNCR patients are only slightly inferior (unpublished data). Therefore achievement of pCR seems to be necessary in order to improve survival. In this context, we believe that surgery plays a key role because, as it is the only way to assess pCR at present, it permits a real evaluation of the efficacy of the therapy, especially when new strategies are tested. Moreover it removes the residual tumor which inevitably would regrow. This study shows that, even among patients achieving a major pathological response, approximately a third had residual microfoci at the site of the primary. Surgery is not universally accepted as a standard treatment, mainly because of surgery-related morbidity and mortality even in high-volume units. However, in our study preoperative chemoradiation did not increase postoperative mortality compared with our previous experience with surgery alone [22Go].

In summary, this schedule comprising weekly docetaxel and cisplatin with 5-FU PVI and concurrent radiation represents a feasible treatment. Antitumor efficacy, as demonstrated by the high pathological response rate, is also extremely encouraging.

A phase II study in esophageal cancer using the doses found in the last dose level (docetaxel 35 mg/m2/week, cisplatin 25 mg/m2/week, 5-FU 150 mg/m2/day PVI and RT 50 Gy) is currently being performed at our institution.


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Table 5. Number of cycles with granulocytopenia during the concomitant phase

 
Received for publication September 15, 2004. Revision received January 28, 2005. Accepted for publication February 1, 2005.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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