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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Radiation therapy of esophageal cancer

, M.D.

Department of Radiation Oncology, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston MA, USA

Introduction

This chapter will review the randomized trials comparing: the value of radiotherapy, compared to supportive treatment only; the use of radiotherapy alone to radiotherapy in conjunction with chemotherapy for patients with medically or surgically inoperable esophageal cancer; definitive treatment with surgery alone to that with radiotherapy alone; and the use of radiotherapy (either alone or in conjunction with chemotherapy) for patients with potentially resectable cancers as an adjunct to surgery.

Inoperable cancers: chemoradiotherapy versus supportive care

A trial conducted in Paris included 50 patients with inoperable disease (Gisselbrecht 1986). Preliminary results showed that sequential chemotherapy (5-fluorouracil, doxorubicin, and cisplatin) and radiotherapy (65 Gy) resulted in improved median survival, compared to patients treated with supportive care only (9.2 and 5 months, respectively). However, the study results have not been updated subsequently.

Inoperable cancers: radiotherapy versus chemoradiotherapy

Several randomized studies have demonstrated the superiority of concurrent chemoradiotherapy to radiotherapy alone for patients who are medically or surgically inoperable (Al-Sarraf 1997; Araújo 1991; Herskovic 1992; Kolarić 1992). The largest of these trials was conducted from 1985–1990 as an American Intergroup study (Al-Sarraf 1997; Herskovic 1992). Patients were randomized to receive radiotherapy alone (total dose to primary, 64 Gy in 32 fractions) or concurrent chemotherapy with cisplatin and 5-fluorouracil and radiation (50 Gy in 25 fractions). For those patients randomized to the combined-modality arm, 2 cycles of chemotherapy were to be given during irradiation and 2 courses after the completion of radiotherapy. With a minimum follow-up of 5 years for all surviving patients from the 121 evaluable patients entered on study, the 5-year survival rates in the combined arm was 27%, with no survivors in the radiotherapyalone group. The failure rate within the radiotherapy field was lower in the combined-modality group (44% vs. 68%). There were no treatment-related deaths in the radiotherapy-only group, compared to 2 (2% risk) in the combined-modality arm.

Two trials in which chemotherapy was given prior to, but not concurrently with, radiotherapy have not shown an advantage in outcome for the combined-modality arm (Hatlevoll 1992; Roussel 1994). The largest of these, conducted by the EORTC from 1983–1989, included 221 inoperable patients. Patients were given either radiotherapy alone (given as two courses of 20 Gy of radiotherapy, given in 5 fractions each, with a break between them) or radiotherapy plus cisplatin (given before the two courses radiotherapy, as well as for 4 further cycles afterwards). There was no difference in 4year survival rates between patients treated with chemoradiotherapy (8%), compared to radiotherapy alone (10%) (Roussel 1994).

Resectable cancers: radiotherapy versus surgery

The only published trial examining whether radiotherapy or chemoradiotherapy alone might yield equivalent long-term results to resection was conducted at the Tata Memorial Hospital in Mumbai, India from 1993–1994 (Badwe 1999). Ninety-nine patients with operable squamous cell carcinoma were randomized to undergo either radiation alone (total dose to the primary tumor, 65 Gy) or to transthoracic esophagectomy with limited lymphadenectomy (without subsequent adjuvant radiotherapy or chemotherapy). With a maximum follow-up of 3 years, both swallowing ability and overall survival were superior in the patients on the surgery arm (55% crude survival rate at 3 years in the surgery arm, compared to 33% in the radiotherapy arm). However, 12 of the patients randomized were considered inevaluable, of whom 10 were on the radiotherapy arm. The 2 patients excluded from the surgery arm were found to have unresectable disease at exploration. Hence, the results of this trial may not be entirely unbiased. A similar randomized trial began in 1987 in the United Kingdom, but only 31 patients were entered onto this study in 18 months, necessitating its premature closure (Earlam 1991). More recently, the French Gastrointestinal Cancer Cooperative Group began a trial (FFCD 9102) in which patients with T3N1M0 squamous cell carcinomas are randomized following chemoradiotherapy to undergo surgery or not. No results are yet available.

Resectable cancers: preoperative or postoperative radiotherapy versus surgery alone

Five randomized trials have compared the results obtained with surgery alone to those with preoperative radiotherapy followed by surgery (Arnott 1992; Gignoux 1987; Huang 1990; Launois 1981; Launois 1983; Nygaard 1992; Wang 1989) and three trials have randomized patients to receive postoperative radiotherapy or not (Fok 1993; Ténière 1991; Zieren 1995). One trial has compared preoperative radiotherapy to preoperative chemotherapy (Kelsen 1990), although many patients in both arms received treatment with the other modality postoperatively, making its interpretation very difficult. One trial has compared postoperative radiotherapy to postoperative chemotherapy with cisplatin and vindesine (Japanese Esophageal Oncology Group 1993).

The results of these trials have shown little, if any difference in outcome between the arms. In general, preoperative radiotherapy did not markedly increase the ability of the surgeon to perform a complete gross resection. When radiotherapy was given in doses that would be considered potentially effective today, it did substantially reduce the risk of local-regional failure in those trials with a stated follow-up of 3 years or longer in two trials (Gignoux 1987; Ténière 1991), although not in one (Japanese Esophageal Oncology Group 1993). This effect was not seen in the trials with unstated or short follow-up (Fok 1993; Huang 1990; Wang 1989). In the one trial in which disease-free survival rates were reported, no difference was seen between the two arms (Zieren 1995). Survival rates were little different, if at all, between the control and irradiated patients in these trials.

There was little difference in postoperative mortality rates in patients undergoing curative resection in randomized studies comparing surgery alone to preoperative radiotherapy plus surgery, even in the two studies using very large daily doses (Gignoux 1987; Launois 1988; Launois 1981). Nonfatal postoperative complications were less well reported; in two series there were no differences between the treatment arms in the incidences of anastamotic leaks (Huang 1990) or other complications (Arnott 1992). However, in a randomized study of postoperative radiotherapy performed in Hong Kong, extremely large daily doses were given (3.5 Gray, or “Gy”) to a large total dose (49 Gy). As a result, 5 patients in the experimental arm died of radiation-induced gastritis in the pulled-up gastric remnant, and 16 other patients suffered milder gastric ulcerations (Fok 1993). Such severe radiotherapy-related complications did not occur in the Cologne trial, in which a high dose of radiotherapy was given (55.8 Gy) but in small daily fractions (1.8 Gy) (Zieren 1995). However, there was an increased incidence of fibrotic strictures of the anastamosis in the irradiated patients (approximately 50%, compared to 25% in the control group).

A recent meta-analysis using individual patient data which included most of these preoperative radiotherapy trials was performed under the sponsorship of the British Medical Research Council (Arnott 1998). This showed the hazard ratio for mortality associated with the use of radiotherapy was 0.89 (95% confidence interval, 0.78–1.01) with a median follow-up time of 9 years (p = 0.062). This resulted in a 5-year survival rate of approximately 18% in the irradiated patients, compared to 15% in the control patients. No interactions with patient or tumor characteristics were found to suggest that some subgroups benefitted more than others.

The interpretation of these trials is not straightforward. By today's standards, patients in most of these studies received doses likely to be only marginally effective at best. Of note, the study using the highest effective dose (Launois 1988; Launois 1981) showed the greatest proportional improvement in resectability rates. Also, the period between the end of radiotherapy and surgery varied from 8 days or less (Gignoux 1987; Launois 1988; Launois 1981) to 2 to 4 weeks (Huang 1990; Nygaard 1992; Wang 1989). Since tumor regression may continue for a much longer period, resectability rates might have increased more had surgery been delayed until 4 to 8 weeks following radiotherapy. Thus, most of the randomized studies performed have used ineffective radiotherapy doses and timed surgery too closely to the end of radiotherapy to see any improvement in resectability rates.

Resectable cancers: preoperative chemotherapy and radiotherapy versus surgery alone

Two randomized trials, conducted at the University of Michigan from 1989–1994 (Urba 1997; Urba 1995) and in Dublin, Ireland from 1990–1995 (Walsh 1996), in which patients received preoperative chemotherapy and radiotherapy concurrently have shown statistically significant improvements in survival, compared to treatment with surgery alone. The 3-year actuarial survival rates in the control groups in these two trials were 15% and 6%, respectively, compared to 32% in the chemoradiotherapy arms. However, both studies were relatively small (approximately 100 patients), and a substantial number of protocol violations occurred in one of them (Walsh 1996). About 75% of patients in the University of Michigan trial and all patients in the Dublin trial had adenocarcinomas. The Dublin group also began a trial comparing preoperative chemoradiotherapy to surgery alone for patients with squamous cell carcinoma in 1990; however, except for an interim report (Walsh 1993) no results from this trial have been published. Another randomized trial was conducted by the Eastern Cooperative Oncology Group (EST 1282), comparing concurrent chemoradiotherapy to radiotherapy alone in patients treated either preoperatively or definitively. There was no difference in the numbers of survivors (2/24 and 2/21 patients, in the radiotherapy and combined-modality arms, respectfully) (Smith 1998). However, the interpretation of these results is complicated by a provision in the protocol that the attending surgeon could decide whether or not to proceed with surgery after a dose of 40 Gy or not; hence, there may have been selection bias data that could have affected the results. Further studies comparing the role of preoperative concurrent chemoradiotherapy are currently being conducted by the United States Intergroup mechanism and in Australia and New Zealand.

The results in trials using sequential chemotherapy and radiotherapy have been more ambiguous. The largest trial of this approach, conducted by the EORTC from 1985–1988, showed statistically-significant improvements in the chemoradiotherapy arm compared to the surgery-alone arm in disease-free survival rates (crude rates of relapse of 56% and 70%, respectively), as well as a substantially reduced risk of local recurrence, but no difference in overall survival rates (Bosset 1997). However, postoperative mortality in the treatment arm of this study was substantial (17%, compared to 5% in the control arm), perhaps because of the very large fraction size used (3.7 Gy, given for 10 treatments). Also, chemotherapy (singleagent cisplatin) was given 0–2 days prior to radiotherapy, rather than more continuously during irradiation. In a trial conducted in Scandinavia (Nygaard 1992), administration of sequential chemotherapy and radiotherapy resulted in an increased 3-year survival rate compared to surgery alone (17% versus 9%), but there was no advantage compared to preoperative radiotherapy alone (21%). A smaller trial in which sequential (not concurrent) chemotherapy and radiotherapy were given showed no difference in outcome compared to surgery alone at 1 year (Le Prise 1994). However, a totally inadequate radiotherapy dose was given (20 Gy in 10 fractions).

Preoperative chemoradiotherapy appeared to increase postoperative mortality in some trials (Bosset 1997; Nygaard 1992) but not in others (Le Prise 1994). Postoperative mortality appeared to increase for patients with adenocarcinomas in the Dublin trial (Walsh 1996), but mortality and morbidities were not increased when these patients were combined with those in their trial for patients with squamous cell carcinomas (30-day mortality rates of 11% and 10% in the chemoradiotherapy and control arms, respectively) (Mulligan 1998).

Discussion

The randomized trials discussed above were generally quite small, and therefore had limited power to detect differences in outcome of clinical importance. There especially continues to be controversy about the strength of the evidence supporting the routine use of preoperative combined-modality treatment in resectable patients. However, I believe the weight of evidence is sufficient to support the routine use of chemoradiotherapy as definitive therapy for inoperable patients and as an adjunct to surgery for operable patients. It appears that partially concurrent administration of chemotherapy and radiotherapy, rather than purely sequential administration, is needed to obtain the benefits of such combined-modality therapy.

There remain many unresolved issues in the best approach to using such therapy. For example, it is not known whether postoperative administration of chemoradiotherapy is inferior to preoperative administration. The optimal dose, fraction size, and scheduling of radiotherapy are unknown, as are the optimum radiotherapy treatment volumes; similar questions pertain to the choice of chemotherapy drugs, doses, and scheduling. However, experience shows that regimens giving approximately 50 Gy in 1.8–2 Gy daily fractions with concurrent cisplatin and 5-fluorouracil are quite tolerable when used either preoperatively or definitively.

Finally, the correlates of response to chemoradiotherapy have not been well established. Preliminary data suggest that overexpression of certain biologic markers, such as the epidermal growth factor receptor predicts a decreased likelihood of response to chemoradiotherapy. Increased expression of HER2 was associated with increased responsiveness to preoperative chemoradiotherapy in one study. However, not all studies are in agreement on such effects. Better methods are also needed to assess response to chemoradiotherapy, as these might enable some patients to be spared surgery.

Conclusions

Randomized trials have shown that the use of chemoradiotherapy modestly increases survival rates compared to supportive care or to radiotherapy alone for inoperable patients. It is not yet possible to say whether chemoradiotherapy or surgery is better with regards to the long-term control of local symptoms or cure rates for operable patients. The use of chemoradiotherapy in addition to surgery in operable patients also increases survival rates when compared to surgery alone.

Table IRandomized Trials Comparing Radiotherapy Alone to Chemoradiotherapy in Inoperable Patients

InstitutionDatesDose/ FxsChemo# PtsFUTreatment Deaths (%)Local-Regional recurrence (%)Survival (%)Ref
Rio de Janeiro1982–8550/25MB (C)59?0/084/616/16 (act. 5-yr)Araújo 1991
EORTC1983–8940/10P221??67/5910/8Roussel 1994
Scandinavia1983–8863/36PB100??/?49/556/0 (act. 3-yr)Hatlevoll 1992
Intergroup1986–9064/32–50/25PF (C)12960 (min S)0/268/440/27 (act. 5-yr)Al-Sarraf 1997;Herskovic 1992
Zagreb?60/?–40/?PF (C)84????Kolarić 1992

Treatment Deaths: Rate in radiotherapy arm/rate in chemoradiotherapy arm.

Local-Regional Recurrence: recurrence rate in thorax in radiotherapy arm/rate in chemoradiotherapy arm with or without distant metastases; includes persistent disease.

Survival: rate in radiotherapy arm/rate in chemoradiotherapy arm; includes all evaluable patients entered on study unless otherwise noted. (In parentheses: how measured and at what time-point.)

Table IITrials Comparing Radical Surgery Alone to Surgery With or Without Adjuvant Pre- or Postoperative Radiotherapy

InstitutionDatesDose/ Fxs# PtsFUPostop Deaths (%)Curative Resection (%)LRR (%)Survival (%)Ref
Rennes, France1973–7640/10124?21/2858/70?/?18/20* (act. 5-yr)Launois 1988;Launois 1981
EORTC1976–8233/1020843 (ave)18/1758/4750/319/15 (crude)Gignoux 1987
Beijing1977–8740/20360??/?65/7312/1234/35% (crude 5-yr)Huang 1990;Wang 1989
Edinburgh1979-8320/1017660(mins)13/1572/74?/?17/9 (act. 5-yr)Arnott 1992
AURC, France †1979–8545–55/25–3022136 (min.)N.A.N.A.30/1519/19 (act. 5-yr)Ténière
Scandinavia1983–8835/208936 (min)13/1137/40?/?9/21 (act. 5-yr)Nygaard 1992
Japan †ˆ1985–8750/2525336 (min)N.A.N.A.19/15 (crude)42/44 (act. 5-yr)Japanese Esophageal Oncology Group 1993
Queen Mary Hospital, Hong Kong †1986–8949/146012 (ave)N.A.N.A.13/1060/57 (crude)Fok 1993
Cologne, Germany †1988–9155.8/316818 (min)N.A.N.A.?/?20/22 (act. 3-yr)Zieren 1995
*

excludes patients dying postoperatively; rates estimated from graph.

radiotherapy given postoperatively (in all other trials, given preoperatively).

ˆ

patients in control arm received chemotherapy postoperatively.

Dose/fxs: dose in Gray/number of fractions (treatments) given.

Postop, deaths: rate given only for paents undergoing curative resection, in control arm/radiotherapy arm.

Resectable for Cure: No gross residual disease or distant metastases; rate in control arm/rate in radiotherapy arm.

Local-Regional Recurrence: recurrence rate in thorax in radiotherapy arm/rate in surgery arm

Survival: rate in radiotherapy arm/rate in surgery arm; includes all evaluable patients entered on study unless otherwise noted. (In parentheses: how measured and at what time-point.)

Table IIIRandomized Trials Comparing Radical Surgery Alone to Surgery With or Without Adjuvant Preoperative Chemoradiotherapy

InstitutionDatesDose/ FxsChemo# PtsFUPostop DeathsResectable for CureLRRSurvivalRef
Scandinavia1983–8835/20PB10336 (min)13/2437/55?/?9/17 (act. 3-yr)Nygaard 1992
FFCD/EORTC1985–8837/10P282554/1269/81?/?30/31Bosset 1997
Rennes, France1988–9120/10PF86167/981/90?/?14/19 (act. 3-yr)Le Prise 1994
Michigan1989–9445/30PFC (C)10062 (S)?/??/?39/1915/32 (act. 3-yr)Urba 1997
Dublin1990–9540/15PF (C)11318 (S)4/9?/??/?6/32 (act. 3-yr)Walsh 1996

Dose/fxs: dose in Gray/number of fractions (treatments) given.

Postop. deaths: rate given only for patients undergoing curative resection, in control arm/radiotherapy arm.

Resectable for Cure: No gross residual disease or distant metastases; rate in control arm/rate in radiotherapy arm.

LRR (Local-Regional Recurrence): recurrence rate in thorax in radiotherapy arm/rate in surgery arm

Survival: rate in radiotherapy arm/rate in surgery arm; includes all evaluable patients entered on study unless otherwise noted. (In parentheses: how measured and at what time-point.)

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Bookshelf ID: NBK6936

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