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High dose rate brachytherapy for superficial cancer of the esophagus
Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 1, pp. 71–76, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter
PII S0360-3016(99)00377-6
CLINICAL INVESTIGATION
Esophagus
HIGH DOSE RATE BRACHYTHERAPY FOR SUPERFICIAL CANCER OF THE ESOPHAGUS PHILIPPE MAINGON, M.D.,* ANNE D’HOMBRES, M.D.,* GILLES TRUC, M.D.,* ISABELLE BARILLOT, M.D.,* CHRISTOPHE MICHIELS, M.D.,† LAURENT BEDENNE, M.D.,† AND JEAN CLAUDE HORIOT, M.D.* *Radiotherapy Department, Centre Georges-Franc¸ois-Leclerc, Dijon Cedex and †Gastroenterology Department, C.H.U. Dijon, Dijon, France Purpose: We analyzed our experience with external radiotherapy, combined modality treatment, or HDR brachytherapy alone to limited esophageal cancers. Methods and Materials: From 1991 to 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43– 86 years). Five patients showed superficial local recurrence after external radiotherapy. Eleven patients without invasion of the basal membrane were staged as Tis. Fourteen patients with tumors involving the submucosa without spreading to the muscle were staged as T1. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases. External beam radiation was administered to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. In cases of HDR brachytherapy alone (13 patients), 6 applications were performed once a week. Results: The mean follow-up is 31 months (range 24 –96 months). Twelve patients received 2 applications and 13 patients received 6 applications. Twelve patients experienced a failure (48%), 11/12 located in the esophagus, all of them in the treated volume. One patient presented an isolated distant metastasis. In the patients treated for superficial recurrence, 4/5 were locally controlled (80%) by brachytherapy alone. After brachytherapy alone, 8/13 patients were controlled (61%). The mean disease-free survival is 14 months (1–36 months). Overall survival is 76% at 1 year, 37% at 2 years, and 14% at 3 years. Overall survival for Tis patients is 24% vs. 20% for T1 (p ⴝ 0.83). Overall survival for patients treated by HDR brachytherapy alone is 43%. One patient presented with a fistula with local failure after external radiotherapy and brachytherapy. Four stenosis were registered, two were diagnosed on barium swallowing without symptoms, and two required dilatations. Conclusion: High dose rate brachytherapy permits the treating of patients with superficial esophageal cancer with good tolerance. Early tumors, located in the mucosa, might be treated by HDR brachytherapy alone or by a combined modality treatment in which HDR brachytherapy can take place like a boost. This approach may cure localized recurrences. © 2000 Elsevier Science Inc. Cancer of esophagus, High dose rate brachytherapy, Radiotherapy, Concurrent chemoradiation.
Local control is highly correlated to total dose for patients treated with radiation alone (3). In early-stage cancer, local control should be improved with altered fractionation (4). High dose rate (HDR) esophageal brachytherapy has been advocated as a technique enabling irradiation of loco-regional disease to deliver a high dose sparing of the surrounding tissues (lung and heart), in order to increase tumor control rate, while minimizing acute and late toxicities. Some retrospective studies using external beam irradiation with endoluminal brachytherapy suggest that it could enhance local control rate (5). We analyzed our experience with HDR brachytherapy to limited esophageal cancers.
INTRODUCTION Surgical resection is the treatment of choice for early esophageal cancers. Today, operative mortality of ⬍ 5% is commonly achieved, although complications are still significant. Because of the extent of surgery, insufficient cardiac or respiratory reserves, advanced age, and poor medical conditions (cirrhosis or portal hypertension), surgical procedures might be rejected. There is now evidence that concomitant treatment with radiotherapy and chemotherapy improves survival and local control compared to radiotherapy alone in locally advanced esophageal cancers (1, 2).
Acknowledgments—Supported by Grant from Ligue Bourguignonne, Ligue 52 and Ligue 71 Contre le Cancer. Accepted for publication 30 August 1999.
Reprint requests to: Philippe Maingon, Centre Georges-Franc¸ois-Leclerc, 1 rue du Professeur Marion, 21034 Dijon Cedex France. E-mail: [email protected] Presented in part at the 84th Annual Meeting of the Radiological Society of North America, 29 November– 4 December 1998, Chicago, Illinois. 71
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Table 1. Patients characteristics Age Stage Tis T1 Localization upper third middle lower third Histology squamous cell adenocarcinoma Grading well differentiated moderately differentiated undifferentiated NA Macroscopy ulcerated polypoid infiltrating normal Stenosis 1⁄4 circumference 1⁄2 circumference 3⁄4 circumference all circumference NA Dysphagia none semisolids liquids only Strategy HDR alone RT ⫹ BT RT/CT ⫹ BT
63 (43–86) 11 14 10 8 7 23 2 15 2 3 5 5 13 2 5 1 16 3 3 2 11 8 6 13 8 4
NA ⫽ not available; RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
METHODS AND MATERIALS From October 1991 to December 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43– 86); the mean weight was 52 kg (40 – 86); and the mean weight loss 5 kg (2–20). Patients characteristics are described in Table 1. Three patients presented superficial local recurrence after external radiotherapy (60 Gy/30 fractions). Two superficial local recurrence developed after combined chemoradiotherapy. Twenty patients presented with de novo carcinoma. Initial evaluation included physical examination, chest X ray, bronchial and esophageal endoscopy with biopsy and iodine test, liver ultrasound, barium swallow, and CT scans of the thorax and upper abdomen. Blood tests including complete blood count, serum multianalysis, blood urea nitrogen, and creatinine levels were routinely performed. The length of the tumor was determined from CT scan, barium swallow, and endoscopic findings with iodine test. The endoscopic findings were documented, paying special attention to growth patterns and circumferential extension. The depth of infiltration of the tumors and nodal
Volume 46, Number 1, 2000
spread were analyzed with echoendoscopy when available (23/25). Eleven patients were staged as Tis with malignant cells on the biopsies without invasion of the basal membrane and no infiltration detectable with echoendoscopy. Fourteen patients with tumors involving the mucosa and submucosa without spreading to the muscle were staged as T1. One patient with T1 tumor and normal CT scan presented with a suspected node at the echoendoscopy. Twenty-three patients had squamous cell carcinoma (92%) which was well differentiated in 60%. Radiotherapy External beam radiation was administered using three fields of 18 MV photons (one anterior, and two posterior oblique fields) to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. Positioning of the fields and dosimetry were studied using a CT scan and 3D treatment planning. The dose to the spinal cord was limited to 40 Gy. The treatment fields encompassed the tumor bed with 3- to 5-cm proximal and distal margins and 2-cm lateral. Supraclavicular nodes were included in the treatment portals to a dose of 45 Gy for upper thoracic tumors; celiac nodes were included to a dose of 45 Gy for lower carcinomas. Chemotherapy Concomitant chemoradiotherapy was prescribed in four cases for patients in good medical condition for T1 (4/4 patients) or for suspected nodal involvement (1/1 patient). Chemotherapy consisted of 5-Fluorouracil (5-FU) (350 mg/ m2) administered as a continuous infusion over 5 to 6 weeks and cisplatin (CDDP) (100 mg/m2) administered as 2 bolus injection on day 1 and 28. No further chemotherapy was given. Brachytherapy Applications of intracavitary HDR brachytherapy were performed using a high dose rate Nucletron remote afterloader with 192Ir source. The first application was performed during the final week of external beam radiation (fifth week) and the second a week after external radiotherapy (sixth week). In case of HDR brachytherapy alone (13 patients), six applications were performed once a week. Insertion of the tube was applied under neuroleptanalgesia with a modified Savary applicator (13-mm diameter). The rules of prescription were adapted to the tumor. The prescribed dose per fractions was 5 Gy in 19 cases, 7 Gy in 5 cases, and 8 Gy in 1 case. The dose was prescribed at the interface applicator-mucosa in 12 cases (11 Tis and 1 T1) at 0.5 cm from the surface of the applicator (1.15 cm from the axis of the source in case of modified Savary tube) in 10 patients with tumor limited to the mucosa (11 T1), and at 10-mm depth under the mucosa in 2 cases (2 T1). The prescription point did not vary for any one patient during the treatment. We reported the dose at the point of dose specification chosen at 5-mm interface between mucosa and applicator according to the recommendations of Marinello (6). The active treated length was pretreatment tumor length plus a
HDR brachytherapy in superficial esophageal cancer
Table 2. Distribution of treatment according to the TNM classification
Tis T1 N0 N1
HDR alone
RT ⫹ BT
RT/CT ⫹ BT
8 5 13 —
3 5 8 —
— 4 3 1
11 14 24 1
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
2-cm margin proximal and distal margin. Nonequal dwell time positions were calculated in order to optimize the dose distribution in treated length. In all cases, we calculated and reported the dose delivered to the surface (interface of the tube and the mucosa). The treated volume, defined as the volume encompassed in the isodose of the prescribed dose, was also reported. Follow-up evaluation Follow-up consisted of repeat barium swallow and/or endoscopy at 3 months following completion of treatment. Endoscopy and biopsies, subsequent CT scan of the thorax were not routinely obtained unless clinically indicated. The swallowing function was assessed by patient reports at each follow-up visit. Statistical methods Follow-up time was calculated from the time of diagnosis for de novo patients or from the time of recurrence. Data were analyzed with STATISTICA epicenter software release 5. Overall survival, disease-free survival were calculated using the Kaplan-Meier method. Log rank statistics were used for comparison of the groups. Complications were recorded using the WHO grading system. RESULTS The mean follow-up is 68 months (range: 24 –96 months; median: 72 months); 102 applications were performed. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases (Table 2). The mean treated length was 7.7 cm and no difference was observed between the different treatment groups. The mean treated volume (including the 5 Gy isodose) was 22 cc, significantly higher in patients treated with HDR brachytherapy alone. No difference was observed in the comparison of the total dose delivered to the mucosa by brachytherapy and the cumulative dose delivered by external radiotherapy and brachytherapy in groups receiving external radiotherapy or combined treatment (Table 3). The insertion of the tube was carried out under neuroleptanalgesia. Twelve patients received two applications, and 13 patients received six applications. Results and sites of failures are described in Table 4.
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Twelve patients experienced a failure (48%), 11/12 located in the esophagus, and all of them in the treated volume. One patient presented with isolated distant metastasis. In the patients treated for superficial recurrence (5), 4 were locally controlled (80%) by brachytherapy alone, were alive and free of disease, and were long-term survivors. After brachytherapy alone, 8/13 patients were controlled (61%). A similar proportion of patients failed after external radiation (3/8) or after radio-chemotherapy (2/4). Four patients staged Tis failed in nodes (4/11, 36%) vs. one patient staged T1 (1/14, 7%). Three months after the end of irradiation, the complete response rate was 75% (18/25), partial response was obtained for five patients (21%), and no response in one case (4%). The mean disease-free survival is 16 months (1–56). Mean overall survival is 21 months (5–56), 20 months for Tis, and 21 months for T1. Overall survival is 76% at 1 year, 37% at 2 years, and 21% at 3 years (Fig. 1). Three-year overall survival for Tis patients is 24% vs. 20% for T1 (p ⫽ 0.83). Three-year overall survival for patients treated by HDR brachytherapy alone is 43%. With unlimited followup, 19 patients died, 4 of second head and neck cancer, 1 of cerebral hemorrhage. There were no treatment-related deaths. One patient presented with a fistula at the time of local failure. He was treated by external radiotherapy and brachytherapy. Four stenoses were registered. In two cases, after brachytherapy alone, stenosis was diagnosed on barium swallowing without symptoms. In two cases, patients treated by combined modality treatment, stenosis required dilatations. No grade 3 or treatment-related death was observed. DISCUSSION Esophageal cancer remains a relatively uncommon malignancy. Because of this low overall incidence, general screening for this disease is impractical and in a large majority of cases, at the time of clinical presentation, they
Table 3. Treatment characteristics (mean value and standard deviation)
Length (cm) Surface dose (Gy) Specified dose (Savary) Treated volume (Savary, cm3) Dose to the mucosa by BT Total surface dose (RT ⫹ BT)
HDR alone
RT ⫹ BT
RT/CT ⫹ BT
8.3 ⫾ 1.9 9.7 ⫾ 2.8
6.5 ⫾ 1.6 6.2 ⫾ 1.2
8.2 ⫾ 1 8.8 ⫾ 3.7
4.8 ⫾ 1.2
3.2 ⫾ 0.6
4.6 ⫾ 1.9
31.2 ⫾ 14
8.2 ⫾ 2.1
20.6 ⫾ 13
54 ⫾ 10
18.3 ⫾ 12
17.5 ⫾ 7
—
62.7 ⫾ 11
65 ⫾ 8
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
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Table 4. Pattern of failures according to the strategy, to the stage, and to the indication No failure
Esophageal
Esophageal and nodal
Esophageal and distant
Distant
RT ⫹ BT BT alone RT/CT ⫹ BT
3 8 2
2 2 —
2 3 —
— — 2
1 — —
8 13 4
Tis T1
6 7
1 3
4 1
— 2
— 1
11 14
Recurrent No recurrent
4 9
1 3
— 5
— 2
— 1
5 20
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ combined radio- and chemotherapy.
are usually incurable. This might explain the rarity of superficial esophageal cancer. The mainstay of treatment for these diseases remains surgery because resection alone has been shown to provide the best chance of cure. The selection of superficial esophageal cancer would be a major problem. The main goals of the evaluation have been to define the extent of wall invasion by esophageal malignancy. The extend of the wall invasion is an important prognostic indicator, a fact reflected in the pathologic TNM staging classification introduced in 1987 (7). In this regard, endoscopic ultrasound (EUS) proved statistically more accurate than a dynamic CT scan to define the extension of the tumor in the esophageal wall (8). For all TN stages of esophageal tumors, correct preoperative staging was accomplished by EUS in 89% for stage T and 69 % for N stage, compared with 51% and 51%, respectively, by CT (9). The accuracy of EUS may be improved, especially in differentiating mucosal carcinoma from submucosal carcinoma, by using an ultrasound probe (10). Previous studies have had limited success to clarify the role of EUS in the characterization of lymph nodes. Although no statistical difference
existed in the capacity of EUS and dynamic CT to enable detection of adenopathies (8). CT scan remains useful to measure the thickness of the esophagus in order to accurately define the dose distribution during brachytherapy. There are two methods to increase the radiation dose to the esophagus, brachytherapy and external beam irradiation. In a selection of superficial cancers endoluminal irradiation with its steep dose gradient offers the possibility of intensive local irradiation with a higher cure rate and minimal risk to the surrounding structures. Brachytherapy allows the escalation of dose to the primary tumor while protecting the dose limiting structures such as the lungs, heart, and spinal cord. The major limitation and the best advantage in superficial tumors is the effective treatment distance. The most commonly used isotope is 192Ir, which is usually prescribed to treat to a distance of 1 cm from the source. Therefore, any tumor larger than 1 cm will receive a suboptimal radiation dose. Okawa (11) treated 21 patients with superficial cancer of the esophagus by definitive radiotherapy (70 Gy). Three patients received intraluminal brachytherapy in addition.
Fig. 1. Overall survival.
HDR brachytherapy in superficial esophageal cancer
The 5-year survival rate was 41%, 8 patients failed but no local recurrence was observed among the cases treated with intraluminal radiotherapy. In the Hishikawa series (12), 92 patients were treated with HDR brachytherapy (two fractions of 6 Gy twice a week) following external radiotherapy (60 Gy). Of the 46 patients with limited disease (no evidence of extra-esophageal spread), 48% showed a complete response rate, and a 2- and 5-year survival rates of 39% and 17%, respectively. In the same trial, six patients were treated by HDR brachytherapy alone (four fractions of 6 Gy, twice a week). All of them presented a complete response rate and only one failed, but the follow-up was insufficient (12). Hareyama (13), in a series of 277 patients, presented the results of treatment of 33 patients with T1 tumors. The treatment consisted of external radiotherapy delivering 55 Gy and two fractions of 4 –10 Gy brachytherapy 2 weeks after. The complete response rate was of 88%, and local control after a 5-year follow-up was 54.5%. In the same period, 15 patients with superficial tumors received the same protocol with 100% complete response rate and local control after a 5-year follow-up of 53.3%. In a series of 54 patients, Schraube (14) treated 1 Stage I and 19 Stage II patients with a curative intent. Neither percutaneous dose nor endoluminal dose in the applied range nor stage seemed to influence the occurrence of local progression. The patients with Stages I and II had a median survival of 12.3 months, compared with 6.2 months for patients with Stages III and IV. An altereted external radiotherapy schedule for esophagus cancer has been reported by De Paoli (15). The patients were treated with a three times per day treatment schedule (48 Gy total dose). They reported a 9% 5-year survival rate. In spite of these poor results, different radiation fractionation schedules may provide better local control. Girinsky (4) demonstrated that accelerated fractionation can be carried out with encouraging results, in terms of local control, in patients with early-stage esophageal cancer. Overall treatment time (⬍ 35 days) was a prognostic factor in the univariate and multivariate analysis when the end point was the cause of specific survival, and only of border significance when the end point was local control. Several protocols proposed high dose rate brachytherapy after a rest period of 1 week (12, 14), 2 weeks (13, 16), or 3 weeks at the end of external radiotherapy regimen (17). The mean duration of treatment was 10 weeks. Nevertheless, our results do not demonstrate any improvement in local control by this approach. Radiation with concomitant chemotherapy is now the standard treatment for locally advanced nonresected esophageal cancers. It is not necessary to stress that a large proportion of patients cannot receive chemotherapy due to bad medical conditions. In several studies combined modality treatment was superior to radiation alone (1, 2). These trials included a small number of patients with early cancer staged as T1 (10% in the RTOG 85-01 trial). No analysis of this group of patients is available in the RTOG trial and the stage of disease is not described in the Araujo trial (1). The
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50 Gy delivered in 5 weeks is the reference treatment; therefore, a higher dose of radiation was considered tolerable (16) and used in the experimental arm of the ongoing RTOG 94-05 trial. The potential benefit of giving high dose radiotherapy with concomitant chemotherapy remains controversial and requires a good selection of patients to avoid a detrimental effect on survival by a high rate of toxicity (18). Apart from the occurrence of distant metastases, tumors after radiotherapy is an ongoing problem in advanced disease. We observed 10/25 failures in mediastinum and/or distant metastasis even in this selected population (40%). Two were recorded after combined modality treatment. In this group of patients treated by chemo-radiotherapy, no local recurrence occurred. Severe toxicity (grade 3) was documented in 29/50 patients (58%) treated in the RTOG 92-07 trial. Life-threatening toxicity was registered in 26%, and toxic death in four patients (8%). Life-threatening strictures occurred in two patients, and fistulas in six patients, leading to the death of three. The authors concluded that extreme caution is urged in the use of external beam radiation, brachytherapy boost, and concurrent chemotherapy as used in their study (17). The high incidence of fistula has not been reported in series using radiation therapy or combined modality therapy without brachytherapy. Currently, it is important to notice that 5/6 fistulas developed in patients receiving three applications of 5 Gy, before the reduction in December 1994 to two fractions of 5 Gy. Furthermore, brachytherapy was delivered during the third course of chemotherapy and we must analyse with caution the effect of concurrent chemotherapy and high dose rate brachytherapy on normal tissue. This is in agreement with recommendations of the American Brachytherapy Society (19). Finally, the investigators used a 10 –12-Fr applicator (external diameter 4 – 6 mm) and specified the dose at 1 cm from the mid-dwell position. It was demonstrated that the radius of the hyperdose sleeve volume receiving a dose equal to more than twice the reference dose, depends essentially on the distance from the point of dose specification to the source center (6). The small diameter of the catheter explains that the dose delivered to the mucosa and normal tissue may exceed the normal tissue tolerance. In the pilot study of Calais (16), with an applicator of 14 mm (rather the same as we used) and a dose prescribed at 5 mm under the surface, only two patients developed fistulas (4%), in patients with local tumor evolution.
CONCLUSIONS High dose rate brachytherapy permits the treating of patients with superficial esophageal cancer with a good tolerance. Early tumors, located in the mucosa might be treated by HDR brachytherapy alone or by a combined modality treatment in which HDR brachytherapy can take place like a boost. This approach may cure localized recurrences.
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REFERENCES 1. Araujo CM, Souhami L, Gil RA, et al. A randomized trial comparing radiation therapy versus concomitant radiation therapy and chemotherapy in carcinoma of the thoracic esophagus. Cancer 1991;67:2258 –2261. 2. Herskovic A, Marz, K, Al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992; 326:1593–1598. 3. de-Ren S. Ten years follow-up of esophageal cancer treated by radical radiation therapy: Analysis of 869 patients. Int J Radiat Oncol Biol Phys 1989;16:329 –334. 4. Girinsky T, Auperin A, Marsiglia H, et al. Accelerated fractionation in esophageal cancers: A multivariate analysis on 88 patients. Int J Radiat Oncol Biol Phys 1997;38:1013–1018. 5. Sur RK, Singh DP, Sharma SC. Radiation therapy of esophageal cancer. Role of high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1992;22:1043–1046. 6. Marinello G, Pierquin B, Grimard L, Barret C. Dosimetry of intraluminal brachytherapy. Radiother Oncol 1991;23:213– 216. 7. Sobin LH, Hermanek P, Hutter RVP. TNM classification of malignant tumors: A comparison between the new (1987) and old edition. Cancer 1988;6:2310 –2314. 8. Botet JF, Lightdale CJ, Zauber AG, et al. Preoperative staging of esophageal cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991;181:419 – 425. 9. Ziegler K, Sanft C, Friedrich M, et al. Evaluation of endosonography in TN staging of esophageal cancer. Gut 1991; 32:16 –20. 10. Hasegawa N, Yasumasa N, Arisawas T, et al. Preoperative staging of superficial esophagael carcinoma: comparison of an ultrasound probe and standard endoscopic ultrasonography. Gastrointest Endosc 1996;44:388 –393.
11. Okawa T, Tanaka M, Kita M, et al. Radiotherapy for superficial esophageal cancer. Int J Radiat Oncol Biol Phys 1994; 30:959 –964. 12. Hishikawa Y, Kurisi K, Tanigushi M, et al. High dose rate brachytherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 1991;21:1133–1135. 13. Hareyama M, Nishio M, Kagami Y, et al. Intracavitary brachytherapy combined with external beam irradiation for squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 1992;24:235–240. 14. Schraube P, Fritz P, Wannenmacher MF. Combined endoluminal and external irradiation of inoperable esophageal carcinoma. Radiother Oncol 1997;44:45–51. 15. De Paoli A, Boz G, Trov MG, et al. Multiple fraction per day radiation therapy for inoperable esophageal cancer. Int J Radiat Oncol Biol 1988;14:855– 860. 16. Calais G, Dorval E, Louisot P, et al. Radiotherapy with high dose rate brachytherapy boost and concomitant chemotherapy for stage IIB and III esophageal carcinoma: Results of a pilot study. Int J Radiat Oncol Biol Phys 1997;38:769 –775. 17. Gaspar L, Chunlin Qian, Kocha WI, et al. A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207): Preliminary toxicity report. Int J Radiat Oncol Biol Phys 1997;37:593–599. 18. Minsky B, Neuberg D, Kelsen D, et al. Neoadjuvant chemotherapy plus concurrent chemotherapy and high dose radiation for squamous cell carcinoma of the esophagus. A preliminary analysis of the phase II intergroup trial 0122. J Clin Oncol 1996;14:149 –155. 19. Gaspar LE, Nag S, Herskovic A, et al. American Brachytherapy Society consensus guidelines for brachytherapy of esophageal cancer. Int J Radiat Oncol Biol Phys 1997;38:127–132.
PII S0360-3016(99)00377-6
CLINICAL INVESTIGATION
Esophagus
HIGH DOSE RATE BRACHYTHERAPY FOR SUPERFICIAL CANCER OF THE ESOPHAGUS PHILIPPE MAINGON, M.D.,* ANNE D’HOMBRES, M.D.,* GILLES TRUC, M.D.,* ISABELLE BARILLOT, M.D.,* CHRISTOPHE MICHIELS, M.D.,† LAURENT BEDENNE, M.D.,† AND JEAN CLAUDE HORIOT, M.D.* *Radiotherapy Department, Centre Georges-Franc¸ois-Leclerc, Dijon Cedex and †Gastroenterology Department, C.H.U. Dijon, Dijon, France Purpose: We analyzed our experience with external radiotherapy, combined modality treatment, or HDR brachytherapy alone to limited esophageal cancers. Methods and Materials: From 1991 to 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43– 86 years). Five patients showed superficial local recurrence after external radiotherapy. Eleven patients without invasion of the basal membrane were staged as Tis. Fourteen patients with tumors involving the submucosa without spreading to the muscle were staged as T1. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases. External beam radiation was administered to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. In cases of HDR brachytherapy alone (13 patients), 6 applications were performed once a week. Results: The mean follow-up is 31 months (range 24 –96 months). Twelve patients received 2 applications and 13 patients received 6 applications. Twelve patients experienced a failure (48%), 11/12 located in the esophagus, all of them in the treated volume. One patient presented an isolated distant metastasis. In the patients treated for superficial recurrence, 4/5 were locally controlled (80%) by brachytherapy alone. After brachytherapy alone, 8/13 patients were controlled (61%). The mean disease-free survival is 14 months (1–36 months). Overall survival is 76% at 1 year, 37% at 2 years, and 14% at 3 years. Overall survival for Tis patients is 24% vs. 20% for T1 (p ⴝ 0.83). Overall survival for patients treated by HDR brachytherapy alone is 43%. One patient presented with a fistula with local failure after external radiotherapy and brachytherapy. Four stenosis were registered, two were diagnosed on barium swallowing without symptoms, and two required dilatations. Conclusion: High dose rate brachytherapy permits the treating of patients with superficial esophageal cancer with good tolerance. Early tumors, located in the mucosa, might be treated by HDR brachytherapy alone or by a combined modality treatment in which HDR brachytherapy can take place like a boost. This approach may cure localized recurrences. © 2000 Elsevier Science Inc. Cancer of esophagus, High dose rate brachytherapy, Radiotherapy, Concurrent chemoradiation.
Local control is highly correlated to total dose for patients treated with radiation alone (3). In early-stage cancer, local control should be improved with altered fractionation (4). High dose rate (HDR) esophageal brachytherapy has been advocated as a technique enabling irradiation of loco-regional disease to deliver a high dose sparing of the surrounding tissues (lung and heart), in order to increase tumor control rate, while minimizing acute and late toxicities. Some retrospective studies using external beam irradiation with endoluminal brachytherapy suggest that it could enhance local control rate (5). We analyzed our experience with HDR brachytherapy to limited esophageal cancers.
INTRODUCTION Surgical resection is the treatment of choice for early esophageal cancers. Today, operative mortality of ⬍ 5% is commonly achieved, although complications are still significant. Because of the extent of surgery, insufficient cardiac or respiratory reserves, advanced age, and poor medical conditions (cirrhosis or portal hypertension), surgical procedures might be rejected. There is now evidence that concomitant treatment with radiotherapy and chemotherapy improves survival and local control compared to radiotherapy alone in locally advanced esophageal cancers (1, 2).
Acknowledgments—Supported by Grant from Ligue Bourguignonne, Ligue 52 and Ligue 71 Contre le Cancer. Accepted for publication 30 August 1999.
Reprint requests to: Philippe Maingon, Centre Georges-Franc¸ois-Leclerc, 1 rue du Professeur Marion, 21034 Dijon Cedex France. E-mail: [email protected] Presented in part at the 84th Annual Meeting of the Radiological Society of North America, 29 November– 4 December 1998, Chicago, Illinois. 71
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Biology
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Table 1. Patients characteristics Age Stage Tis T1 Localization upper third middle lower third Histology squamous cell adenocarcinoma Grading well differentiated moderately differentiated undifferentiated NA Macroscopy ulcerated polypoid infiltrating normal Stenosis 1⁄4 circumference 1⁄2 circumference 3⁄4 circumference all circumference NA Dysphagia none semisolids liquids only Strategy HDR alone RT ⫹ BT RT/CT ⫹ BT
63 (43–86) 11 14 10 8 7 23 2 15 2 3 5 5 13 2 5 1 16 3 3 2 11 8 6 13 8 4
NA ⫽ not available; RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
METHODS AND MATERIALS From October 1991 to December 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43– 86); the mean weight was 52 kg (40 – 86); and the mean weight loss 5 kg (2–20). Patients characteristics are described in Table 1. Three patients presented superficial local recurrence after external radiotherapy (60 Gy/30 fractions). Two superficial local recurrence developed after combined chemoradiotherapy. Twenty patients presented with de novo carcinoma. Initial evaluation included physical examination, chest X ray, bronchial and esophageal endoscopy with biopsy and iodine test, liver ultrasound, barium swallow, and CT scans of the thorax and upper abdomen. Blood tests including complete blood count, serum multianalysis, blood urea nitrogen, and creatinine levels were routinely performed. The length of the tumor was determined from CT scan, barium swallow, and endoscopic findings with iodine test. The endoscopic findings were documented, paying special attention to growth patterns and circumferential extension. The depth of infiltration of the tumors and nodal
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spread were analyzed with echoendoscopy when available (23/25). Eleven patients were staged as Tis with malignant cells on the biopsies without invasion of the basal membrane and no infiltration detectable with echoendoscopy. Fourteen patients with tumors involving the mucosa and submucosa without spreading to the muscle were staged as T1. One patient with T1 tumor and normal CT scan presented with a suspected node at the echoendoscopy. Twenty-three patients had squamous cell carcinoma (92%) which was well differentiated in 60%. Radiotherapy External beam radiation was administered using three fields of 18 MV photons (one anterior, and two posterior oblique fields) to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. Positioning of the fields and dosimetry were studied using a CT scan and 3D treatment planning. The dose to the spinal cord was limited to 40 Gy. The treatment fields encompassed the tumor bed with 3- to 5-cm proximal and distal margins and 2-cm lateral. Supraclavicular nodes were included in the treatment portals to a dose of 45 Gy for upper thoracic tumors; celiac nodes were included to a dose of 45 Gy for lower carcinomas. Chemotherapy Concomitant chemoradiotherapy was prescribed in four cases for patients in good medical condition for T1 (4/4 patients) or for suspected nodal involvement (1/1 patient). Chemotherapy consisted of 5-Fluorouracil (5-FU) (350 mg/ m2) administered as a continuous infusion over 5 to 6 weeks and cisplatin (CDDP) (100 mg/m2) administered as 2 bolus injection on day 1 and 28. No further chemotherapy was given. Brachytherapy Applications of intracavitary HDR brachytherapy were performed using a high dose rate Nucletron remote afterloader with 192Ir source. The first application was performed during the final week of external beam radiation (fifth week) and the second a week after external radiotherapy (sixth week). In case of HDR brachytherapy alone (13 patients), six applications were performed once a week. Insertion of the tube was applied under neuroleptanalgesia with a modified Savary applicator (13-mm diameter). The rules of prescription were adapted to the tumor. The prescribed dose per fractions was 5 Gy in 19 cases, 7 Gy in 5 cases, and 8 Gy in 1 case. The dose was prescribed at the interface applicator-mucosa in 12 cases (11 Tis and 1 T1) at 0.5 cm from the surface of the applicator (1.15 cm from the axis of the source in case of modified Savary tube) in 10 patients with tumor limited to the mucosa (11 T1), and at 10-mm depth under the mucosa in 2 cases (2 T1). The prescription point did not vary for any one patient during the treatment. We reported the dose at the point of dose specification chosen at 5-mm interface between mucosa and applicator according to the recommendations of Marinello (6). The active treated length was pretreatment tumor length plus a
HDR brachytherapy in superficial esophageal cancer
Table 2. Distribution of treatment according to the TNM classification
Tis T1 N0 N1
HDR alone
RT ⫹ BT
RT/CT ⫹ BT
8 5 13 —
3 5 8 —
— 4 3 1
11 14 24 1
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
2-cm margin proximal and distal margin. Nonequal dwell time positions were calculated in order to optimize the dose distribution in treated length. In all cases, we calculated and reported the dose delivered to the surface (interface of the tube and the mucosa). The treated volume, defined as the volume encompassed in the isodose of the prescribed dose, was also reported. Follow-up evaluation Follow-up consisted of repeat barium swallow and/or endoscopy at 3 months following completion of treatment. Endoscopy and biopsies, subsequent CT scan of the thorax were not routinely obtained unless clinically indicated. The swallowing function was assessed by patient reports at each follow-up visit. Statistical methods Follow-up time was calculated from the time of diagnosis for de novo patients or from the time of recurrence. Data were analyzed with STATISTICA epicenter software release 5. Overall survival, disease-free survival were calculated using the Kaplan-Meier method. Log rank statistics were used for comparison of the groups. Complications were recorded using the WHO grading system. RESULTS The mean follow-up is 68 months (range: 24 –96 months; median: 72 months); 102 applications were performed. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases (Table 2). The mean treated length was 7.7 cm and no difference was observed between the different treatment groups. The mean treated volume (including the 5 Gy isodose) was 22 cc, significantly higher in patients treated with HDR brachytherapy alone. No difference was observed in the comparison of the total dose delivered to the mucosa by brachytherapy and the cumulative dose delivered by external radiotherapy and brachytherapy in groups receiving external radiotherapy or combined treatment (Table 3). The insertion of the tube was carried out under neuroleptanalgesia. Twelve patients received two applications, and 13 patients received six applications. Results and sites of failures are described in Table 4.
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Twelve patients experienced a failure (48%), 11/12 located in the esophagus, and all of them in the treated volume. One patient presented with isolated distant metastasis. In the patients treated for superficial recurrence (5), 4 were locally controlled (80%) by brachytherapy alone, were alive and free of disease, and were long-term survivors. After brachytherapy alone, 8/13 patients were controlled (61%). A similar proportion of patients failed after external radiation (3/8) or after radio-chemotherapy (2/4). Four patients staged Tis failed in nodes (4/11, 36%) vs. one patient staged T1 (1/14, 7%). Three months after the end of irradiation, the complete response rate was 75% (18/25), partial response was obtained for five patients (21%), and no response in one case (4%). The mean disease-free survival is 16 months (1–56). Mean overall survival is 21 months (5–56), 20 months for Tis, and 21 months for T1. Overall survival is 76% at 1 year, 37% at 2 years, and 21% at 3 years (Fig. 1). Three-year overall survival for Tis patients is 24% vs. 20% for T1 (p ⫽ 0.83). Three-year overall survival for patients treated by HDR brachytherapy alone is 43%. With unlimited followup, 19 patients died, 4 of second head and neck cancer, 1 of cerebral hemorrhage. There were no treatment-related deaths. One patient presented with a fistula at the time of local failure. He was treated by external radiotherapy and brachytherapy. Four stenoses were registered. In two cases, after brachytherapy alone, stenosis was diagnosed on barium swallowing without symptoms. In two cases, patients treated by combined modality treatment, stenosis required dilatations. No grade 3 or treatment-related death was observed. DISCUSSION Esophageal cancer remains a relatively uncommon malignancy. Because of this low overall incidence, general screening for this disease is impractical and in a large majority of cases, at the time of clinical presentation, they
Table 3. Treatment characteristics (mean value and standard deviation)
Length (cm) Surface dose (Gy) Specified dose (Savary) Treated volume (Savary, cm3) Dose to the mucosa by BT Total surface dose (RT ⫹ BT)
HDR alone
RT ⫹ BT
RT/CT ⫹ BT
8.3 ⫾ 1.9 9.7 ⫾ 2.8
6.5 ⫾ 1.6 6.2 ⫾ 1.2
8.2 ⫾ 1 8.8 ⫾ 3.7
4.8 ⫾ 1.2
3.2 ⫾ 0.6
4.6 ⫾ 1.9
31.2 ⫾ 14
8.2 ⫾ 2.1
20.6 ⫾ 13
54 ⫾ 10
18.3 ⫾ 12
17.5 ⫾ 7
—
62.7 ⫾ 11
65 ⫾ 8
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ concomitant chemo- and radiotherapy.
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Table 4. Pattern of failures according to the strategy, to the stage, and to the indication No failure
Esophageal
Esophageal and nodal
Esophageal and distant
Distant
RT ⫹ BT BT alone RT/CT ⫹ BT
3 8 2
2 2 —
2 3 —
— — 2
1 — —
8 13 4
Tis T1
6 7
1 3
4 1
— 2
— 1
11 14
Recurrent No recurrent
4 9
1 3
— 5
— 2
— 1
5 20
RT ⫽ external radiotherapy; BT ⫽ brachytherapy; RT/CT ⫽ combined radio- and chemotherapy.
are usually incurable. This might explain the rarity of superficial esophageal cancer. The mainstay of treatment for these diseases remains surgery because resection alone has been shown to provide the best chance of cure. The selection of superficial esophageal cancer would be a major problem. The main goals of the evaluation have been to define the extent of wall invasion by esophageal malignancy. The extend of the wall invasion is an important prognostic indicator, a fact reflected in the pathologic TNM staging classification introduced in 1987 (7). In this regard, endoscopic ultrasound (EUS) proved statistically more accurate than a dynamic CT scan to define the extension of the tumor in the esophageal wall (8). For all TN stages of esophageal tumors, correct preoperative staging was accomplished by EUS in 89% for stage T and 69 % for N stage, compared with 51% and 51%, respectively, by CT (9). The accuracy of EUS may be improved, especially in differentiating mucosal carcinoma from submucosal carcinoma, by using an ultrasound probe (10). Previous studies have had limited success to clarify the role of EUS in the characterization of lymph nodes. Although no statistical difference
existed in the capacity of EUS and dynamic CT to enable detection of adenopathies (8). CT scan remains useful to measure the thickness of the esophagus in order to accurately define the dose distribution during brachytherapy. There are two methods to increase the radiation dose to the esophagus, brachytherapy and external beam irradiation. In a selection of superficial cancers endoluminal irradiation with its steep dose gradient offers the possibility of intensive local irradiation with a higher cure rate and minimal risk to the surrounding structures. Brachytherapy allows the escalation of dose to the primary tumor while protecting the dose limiting structures such as the lungs, heart, and spinal cord. The major limitation and the best advantage in superficial tumors is the effective treatment distance. The most commonly used isotope is 192Ir, which is usually prescribed to treat to a distance of 1 cm from the source. Therefore, any tumor larger than 1 cm will receive a suboptimal radiation dose. Okawa (11) treated 21 patients with superficial cancer of the esophagus by definitive radiotherapy (70 Gy). Three patients received intraluminal brachytherapy in addition.
Fig. 1. Overall survival.
HDR brachytherapy in superficial esophageal cancer
The 5-year survival rate was 41%, 8 patients failed but no local recurrence was observed among the cases treated with intraluminal radiotherapy. In the Hishikawa series (12), 92 patients were treated with HDR brachytherapy (two fractions of 6 Gy twice a week) following external radiotherapy (60 Gy). Of the 46 patients with limited disease (no evidence of extra-esophageal spread), 48% showed a complete response rate, and a 2- and 5-year survival rates of 39% and 17%, respectively. In the same trial, six patients were treated by HDR brachytherapy alone (four fractions of 6 Gy, twice a week). All of them presented a complete response rate and only one failed, but the follow-up was insufficient (12). Hareyama (13), in a series of 277 patients, presented the results of treatment of 33 patients with T1 tumors. The treatment consisted of external radiotherapy delivering 55 Gy and two fractions of 4 –10 Gy brachytherapy 2 weeks after. The complete response rate was of 88%, and local control after a 5-year follow-up was 54.5%. In the same period, 15 patients with superficial tumors received the same protocol with 100% complete response rate and local control after a 5-year follow-up of 53.3%. In a series of 54 patients, Schraube (14) treated 1 Stage I and 19 Stage II patients with a curative intent. Neither percutaneous dose nor endoluminal dose in the applied range nor stage seemed to influence the occurrence of local progression. The patients with Stages I and II had a median survival of 12.3 months, compared with 6.2 months for patients with Stages III and IV. An altereted external radiotherapy schedule for esophagus cancer has been reported by De Paoli (15). The patients were treated with a three times per day treatment schedule (48 Gy total dose). They reported a 9% 5-year survival rate. In spite of these poor results, different radiation fractionation schedules may provide better local control. Girinsky (4) demonstrated that accelerated fractionation can be carried out with encouraging results, in terms of local control, in patients with early-stage esophageal cancer. Overall treatment time (⬍ 35 days) was a prognostic factor in the univariate and multivariate analysis when the end point was the cause of specific survival, and only of border significance when the end point was local control. Several protocols proposed high dose rate brachytherapy after a rest period of 1 week (12, 14), 2 weeks (13, 16), or 3 weeks at the end of external radiotherapy regimen (17). The mean duration of treatment was 10 weeks. Nevertheless, our results do not demonstrate any improvement in local control by this approach. Radiation with concomitant chemotherapy is now the standard treatment for locally advanced nonresected esophageal cancers. It is not necessary to stress that a large proportion of patients cannot receive chemotherapy due to bad medical conditions. In several studies combined modality treatment was superior to radiation alone (1, 2). These trials included a small number of patients with early cancer staged as T1 (10% in the RTOG 85-01 trial). No analysis of this group of patients is available in the RTOG trial and the stage of disease is not described in the Araujo trial (1). The
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50 Gy delivered in 5 weeks is the reference treatment; therefore, a higher dose of radiation was considered tolerable (16) and used in the experimental arm of the ongoing RTOG 94-05 trial. The potential benefit of giving high dose radiotherapy with concomitant chemotherapy remains controversial and requires a good selection of patients to avoid a detrimental effect on survival by a high rate of toxicity (18). Apart from the occurrence of distant metastases, tumors after radiotherapy is an ongoing problem in advanced disease. We observed 10/25 failures in mediastinum and/or distant metastasis even in this selected population (40%). Two were recorded after combined modality treatment. In this group of patients treated by chemo-radiotherapy, no local recurrence occurred. Severe toxicity (grade 3) was documented in 29/50 patients (58%) treated in the RTOG 92-07 trial. Life-threatening toxicity was registered in 26%, and toxic death in four patients (8%). Life-threatening strictures occurred in two patients, and fistulas in six patients, leading to the death of three. The authors concluded that extreme caution is urged in the use of external beam radiation, brachytherapy boost, and concurrent chemotherapy as used in their study (17). The high incidence of fistula has not been reported in series using radiation therapy or combined modality therapy without brachytherapy. Currently, it is important to notice that 5/6 fistulas developed in patients receiving three applications of 5 Gy, before the reduction in December 1994 to two fractions of 5 Gy. Furthermore, brachytherapy was delivered during the third course of chemotherapy and we must analyse with caution the effect of concurrent chemotherapy and high dose rate brachytherapy on normal tissue. This is in agreement with recommendations of the American Brachytherapy Society (19). Finally, the investigators used a 10 –12-Fr applicator (external diameter 4 – 6 mm) and specified the dose at 1 cm from the mid-dwell position. It was demonstrated that the radius of the hyperdose sleeve volume receiving a dose equal to more than twice the reference dose, depends essentially on the distance from the point of dose specification to the source center (6). The small diameter of the catheter explains that the dose delivered to the mucosa and normal tissue may exceed the normal tissue tolerance. In the pilot study of Calais (16), with an applicator of 14 mm (rather the same as we used) and a dose prescribed at 5 mm under the surface, only two patients developed fistulas (4%), in patients with local tumor evolution.
CONCLUSIONS High dose rate brachytherapy permits the treating of patients with superficial esophageal cancer with a good tolerance. Early tumors, located in the mucosa might be treated by HDR brachytherapy alone or by a combined modality treatment in which HDR brachytherapy can take place like a boost. This approach may cure localized recurrences.
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