Adjuvant radiation therapy in gall bladder cancers: 10 years experience at Tata Memorial Hospital
http://www.100md.com
《癌症研究与疗法杂志》
1 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India
2 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, India
Abstract
Introduction and Purpose: In gall bladder cancers, even after curative surgery, survivals are dismal and loco-regional failure accounts for 40-86%. Although these are considered radio-resistant, adjuvant radiation, with or without chemotherapy, has been tried to improve loco-regional control and overall survival rates. With an aim to evaluate the natural history of gall bladder cancers, role of radiation therapy (RT) and prognostication, a retrospective analysis was undertaken. Materials and Methods: Between 1991-2000, 60 patients with gall bladder cancer, treated with radical intent, were evaluated. Patients details including history, physical examination, liver function tests, ultrasonography of the abdomen and chest X-ray; and CT scan Abdomen if done, were noted. In patients who underwent surgery, surgical details, histopathology and pathological staging, were recorded. The details of post-operative adjuvant treatment, including radiation therapy details, as well as chemotherapeutic agents, number of cycles and type of infusion [bolus/infusion], were noted. Results: Sixty patients underwent surgery. On histopathological staging, 28 patients (46.5%) had stage II, 19 (32%) had stage III, 12 (20%) had stage-I and 1 patient had stage IV disease. Thirteen (21%) patents did not receive any adjuvant treatment, 32 (53%) patients received adjuvant RT alone, 8(14%) received post-operative CT+RT and 7 (12%) patients received CT alone. With a median follow-up of 18 months (12-124 months), 27 (45%) patients were disease free, 11 (19%) had local failures, 7 (11%) had loco-regional, 7 (11%) loco-regional+ distant, 4 (7%) distant and 4 (7%) patients had local+ distant failures. The Overall Disease Free Survival (DFS) and overall survival was 30% and 25%, at 5 years, respectively. Stage grouping (' P' =0.007), Pathological T (' P '= 0.01) had significant impact on DFS on univariate analysis, where as histological grade (' P '= 0.06) showed trend towards significance. Conclusion: Gall bladder cancers are aggressive and lethal. Early diagnosis and curative surgery, followed by appropriate adjuvant radiation therapy, may improve survivals, with no established consensus till date. Following curative surgery, pathological T stage and stage grouping, are the significant prognostic factors for outcome.
Keywords: Gall bladder cancers, staging, adjuvant treatment, surgery, radiation therapy.
Introduction
Primary gall bladder cancers are relatively uncommon, accounting for <1% of all cancers and <10% of all G. I. Cancers.[1] In the Indian Cancer Registry, it ranks 5th in all G.I Cancers.[2] In general, the prognosis of patients with gall bladder cancers is poor, with overall 5 year survival rates less than 10%.[1] Surgery in the form of complete resection remains the mainstay of treatment, but complete resection is possible only in 10-30% patients, undergoing surgery.[3] Even after curative surgery, 5-year survivals rates are as follows: Stage 0-I, 33-100%; Stage II, 9-33%; Stage III, 0-25%; and Stage IV, 0-5%.[4],[5],[6] The definite role of adjuvant therapy after curative resection, is still uncertain. Loco-regional failure is the predominant pattern; improvement in loco-regional control rates with adjuvant radiation with/without chemotherapy or chemotherapy alone, has been tried. Although these tumors are considered to be radio-resistant, radiation has been tried since several years in the form of external in radical/postoperative/recurrent settings, Intra-operative radiation therapy (IORT) and brachytherapy for palliation.[7],[8],[9],[10],[11] However, there are only small numbers of series reported in literature, addressing the issue of adjuvant radiation therapy. In these small series, due to differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to define the exact role of adjuvant therapy in gall bladder cancers.[1] Despite lack of proven efficacy, adjuvant therapy and particularly radiation therapy, is recommended and used frequently. Because of the rarity of these tumors, it is difficult to resolve these issues by randomized trials.
With an aim to study natural history of gall bladder cancers, role of adjuvant radiation therapy and prognostic factors affecting survivals, a retrospective analysis of all the patients with gall bladder cancers treated with radical intent, between 1991-2000 was undertaken and is the basis of this report.
Materials and methods
Between 1991-2000, 60 patients with diagnosed gall bladder cancers, treated with radical intent, were evaluated and analyzed. All patients had undergone primary evaluation, including history, physical examination, complete hemogram, liver function tests, ultrasonography of the abdomen and chest X-ray. The CT scan of abdomen, if done, was also noted. In patients who underwent surgery, the type of surgery, nature of resection and residual disease if any, were recorded. Histo-pathology, including histology, grade, type of resection and lymph node status, were noted. All these patients were staged according to AJCC TNM Staging and Grouping system, 5th Edition 1997.[12] The patients' referral for adjuvant therapy was at random, without any set protocols and at the discretion of the treating surgical oncologist. The details of post-operative adjuvant treatment, including radiation therapy details, as well as chemotherapeutic agents, number of cycles and type of infusion [bolus/infusion], were noted.
Statistical analysis
Statistical analysis was carried out using SPSS for Windows Version 11.5. For calculation of loco-regional or overall disease free survival, the date of first failure, either local or distant respectively, were used, whereas last follow-up date was used for overall survival. The Kaplan - Meier method was used for calculating survival, with log rank test for statistical significance, using different prognostic parameters.[13] All 60 patients were eligible for the analysis.
Observations and results
Patient characteristics are as shown in [Table - 1] . With a mean age of 49 years (range: 22-71 years), 42 patients were females and the remaining 18 were males, with a ratio of 2.3:1, in favor of females. Sixty patients underwent surgery in the form of simple cholecystectomy (48 patients), cholecystectomy with wedge resection of liver (8 patients) and cholecystectomy with thorough nodal clearance (4 patients), with Ro resection (margins negative), achieved in 90% of the patients. Out of 48 patients who underwent simple Cholecystectomy, 20 were operated outside, with incidental finding of gall bladder cancers and referred for further treatment evaluation. On histopathological staging, 28 patients (46.5%) had stage-II, 19 (32%) stage III, 12 (20%) stage-I and the remaining 1 (1.5%) patient had stage IV. Pathological T and pathological N staging after surgery are as shown in [Table - 1]. The commonest histology was adenocarcinoma, seen in 57 (95%) patients, the remaining 3 being adeno-squamous carcinoma. According to the grade, 26 (44%) patients had moderately differentiated, 17 (28%) had well differentiated and 17 (28%) had poorly differentiated tumors.
Post-operative adjuvant therapy
Thirteen (21%) patients (12 patients had pathological stage I and I patient stage II [T2N0]), received no further treatment after surgery, 32 (53%) patients received adjuvant radiation therapy alone, 8 (14%) patients post-operative chemo-radiation and the remaining 7 (12%) patients, received chemotherapy alone. Chemotherapeutic drugs used were 5FU +/- Mitomycin, every 3-4 weeks for 3-6 cycles.
Radiotherapy details
Post-operative adjuvant radiation therapy was delivered within a median of 48 days (range: 24-110 days) of surgery, with 3 patients receiving radiation after 75-100 days, because of post-operative wound complications. Radiation therapy was delivered to the upper abdomen using Telecobalt or Linear Accelerator machines, with either parallel beam opposing AP / PA, or Antero-lateral beam arrangements. The target volume consisted of tumour bed and immediate draining lymph nodes, including hilar and/ or coeliac nodes. The portal arrangements, technique, total dose and fractionation, were at the discretion of various treating radiation oncologists. The mean dose of radiation was 47 Gy (median: 50 Gy; range 30-55 Gy), with fractionation ranging from 1.8-2.5 Gy/# with 5# / week and the majority of patients completed the treatment within a mean of 40 days (median: 40 days range: 23-55 days). Six patients received <40 Gy because of progressive disease during radiation, or defaulted on treatment. However, treatment- related toxicities could not be reported, because of poor documentation and compilation.
With a median follow-up of 18 months (mean 46 months and range: 12-156 months) for all patients and 24 months (mean: 46 months; range: 12-156 months) for alive patients, 27 (45%) patients were disease free, 11 (19%) had local failures, 7 (11%) loco-regional, 4 (7%) distant, 7 (11%) loco-regional + distant and remaining, 4 (6%) patients had local+ distant failures. Out of 38 deaths, 33 died of disease, one due to other causes, 4 were lost to follow-up and considered dead.
Survivals
The Overall disease Free Survival (DFS) for the whole group was (30%) at 5 years [Figure - 1] . Various prognostic factors were also evaluated to know the impact on the survival by univariate analysis. Stage grouping (' P'= 0.007) and pathological T status (' P'= 0.01), had a significant impact on univariate parametric analysis, whereas N status (' P'= 0.72), did not affect the outcome and grade of the disease; ( 'P' = 0.06) showed trend towards significance . Disease free survival (at 5 years) for stage I (12 pts) was 40%, 38% for stage II and 15% for stage III patients, with 'P' value of 0.007 [Figure - 2] . Disease free survival (at 5 years) was 50 % for pT1 (15 pts), 38% for pT2 (28 pts) and median of only 6 months for pT3 (17 pts) with 'P' value of 0.01. Disease free survival (at 5 years) was 38% for negative nodes (52 pts), 20% for pN1 (8 pts) with 'P' value of 0.72. [Figure - 3]. Similarly, well-differentiated tumors (17 pts) had a DFS of 35%, moderately differentiated (26 pts) of 38% and 20% for poorly differentiated tumors (17 pts) with a significant ' P ' value of 0.06. Other factors namely; (i) Type of Surgery ( P = 0.84), (ii) Gap between surgery and radiation therapy ( P = 0.77) and (iii) dose of radiation <50 Gy Vs >50 Gy ( P = 0.96), had no impact on disease free survival. The overall survival for the radical group was (25%) at 5 years.
Discussion
In our country, Primary gall bladder cancers ranks 5-6th of all G.I Cancers according to the Indian Cancer Registry and in general, it accounting for <1% of all cancers and <10% of all G. I. Cancers.[1],[2] In general, the prognosis of patients with gall bladder cancers is poor, with overall 5-year survival rates less than 10%.[1] Although, surgery in the form of complete resection remains the mainstay of treatment, it is possible only in 10-30% patients. In fact, only about 10% of cases will have the disease confined to the gallbladder and another 10 to 20% will involve associated local spread, that is respectable.[3] The patients who do best, are those where the disease is found incidentally. Even after curative surgery, 5-year survival rates are as follows: Stage 0-I, 33-100%; Stage II, 9-33%; Stage III, 0-25% and Stage IV, 0-5%.[4],[5],[6]
In our series too, out of 60 patients treated with radical intent, 28 patients (47%) had stage II, 18 (32%) stage III, 12 (20%) stage I and the remaining 1 patient had stage IV, suggesting advanced stage at presentation. Stage- wise 5 year DFS was 40%, 38%, 15%, at 3 months respectively, suggesting that loco-regional extension after curative surgery, remains the major prognostic factor for outcome. Lymph node involvement is also an important prognostic factor in gall bladder cancers, with overall metastatic rates of 63.4%.[14] Overall survival rates with surgery alone, as correlated with the extent of metastatic lymph node involvement, are reported to be 22% in N0 patients and 0 - 5% in N+ patients[5],[6] with 38% and 20% DFS in N0 and N1 nodal staging, respectively, in our series.
The standard surgery is a cholecystectomy with nodal clearance, for patients with stages I - III disease. More radical procedures have also been performed, including resection of the gallbladder fossa, adjacent liver, regional nodes and the gall bladder for stage III disease, to improve loco-regional control rates; however, majority of modern surgical series have reported no difference in survival.[4],[15]
The definite role of adjuvant therapy after curative resection, is still uncertain. Although these tumors are considered to be radio-resistant, radiation has been tried since several years, in the form of external in radical / postoperative / recurrent settings, Intra-operative radiation therapy (IORT) and brachytherapy for palliation.[7],[8],[9],[10],[11]
However, there are small numbers of series reported in literature, addressing the issue of adjuvant radiation therapy. In these small series, differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to pinpoint the exact role of adjuvant therapy in gall bladder cancers.[16]
As stated earlier, in the past, this tumor were considered radio resistant, however, relief of jaundice and osseous pain with radiation, suggest that this may not be so. The limiting feature of local irradiation, is again the tolerance of surrounding critical structures, including liver, kidneys, pancreas, lesser curvature of stomach and small bowel. In general, radiotherapy and chemotherapy have offered poor results in the treatment of gallbladder cancer. Because of the rarity of this disease and the rarity of completely resected gallbladder cancers, it is not surprising that there are no prospective, randomized studies, examining the utility of adjuvant therapy. Nonetheless, many retrospective studies have addressed the issue of adjuvant therapy. All these are small retrospective studies, showing no much benefit of adjuvant therapy. Hence it is difficult to draw firm conclusions from these data. Todoroki et al[11] examined intraoperative radiotherapy after complete resection, for stage IV gallbladder cancer and reported a 10% 3-year survival for patients receiving intraoperative radiotherapy, versus 0% for surgery alone. Hanna and Rider[17] reviewed results for 51 patients with gallbladder cancer and found survival to be significantly longer in patients receiving postoperative radiotherapy, as compared with those who underwent only surgery. In another retrospective study, the median survival of patients receiving postoperative irradiation was 63 months, as compared to 29 months, for patients undergoing surgery alone.[18] Definitive data for adjuvant radiotherapy only, also are lacking, but the existing data are a bit more encouraging than are those for chemotherapy.[15],[17],[18]
In the current series, thirty-two (53%) patients received adjuvant radiation therapy alone, 8 (14%) patients post-operative chemo-radiation and the remaining 7 (12%) patients received chemotherapy alone, with overall DFS and OAS of 30% and 25% at 5 years respectively, with an insignificant difference in survivals, when compared to the type of adjuvant therapy. However, pTstage and stage grouping did have a significant impact on survivals, suggesting that loco-regional control has a major impact on the outcome of the disease. Despite these patients receiving a mean dose of 47 Gy (median: 50 Gy), the disease free survivals are poor, suggesting a higher radiation doses. Dose escalation to the tumor bed with various critical structures around, still remains a challenge.
Kresl et al reported 21 patients treated with adjuvant concurrent chemo radiotherapy, with a 5-year survival of 64%, as compared to historical series of 33% in completely resected tumors and also concluded that greater doses of radiation are required for loco-regional control rates, although not significant in the report.[19]
The results of chemotherapy in gall bladder cancers have also been poor. A European Co-operative Oncology Group study examined bolus Mitomycin C in advanced gallbladder and biliary tree carcinoma, with no significant activity identified and an objective response of <10% only.[20] Other regimens based on 5-FU, Adriamycin, or nitrosoureas alone and in combination for gallbladder cancer, result in only minimal responses. In a study that treated 30 patients with advanced gallbladder carcinoma with 5-FU, Leucovorin and Hydroxyurea, 9 had a partial response. However, the median duration of response was only 6.5 months and the median survival was only 8 months. Regional therapy has recently been examined using intra-arterial Mitomycin C for gallbladder cancer. A 48% overall response rate and a prolongation of median survival from 5 months to 14 months, as compared to historic controls, was reported.[21],[22],[23] However, a regional approach is rarely indicated, since the major reasons for unresectability usually are disseminated disease and extensive involvement of the porta hepatis. Hence, most of studies with chemotherapy have resulted in nonstatistically significant improvements compared to surgery alone and on the contrary, add to the toxicities, jeopardizing the quality of life further.
Conclusion
Based on our series and that reported in the literature, it can be concluded that gall bladder cancers are generally associated with advanced disease at presentation and poor prognosis. Surgery with complete resection, should be the objective for the favorable outcome. Though the data are encouraging, firm support for adjuvant- therapy, awaits confirmation by prospective trials. Nevertheless, given the high incidence of loco - regional recurrence of gallbladder cancers and the low morbidity of radiotherapy, it is not unreasonable to recommend some form of radiotherapy, particularly for patients with advanced-stage disease. Adjuvant radiation therapy with dose escalation, with newer techniques available, may be tried. The role of 5FU based adjuvant chemotherapy and radiation needs further validation, although they have shown to favor local control and survivals.
References
1. Lotze MT, Flickinger JC, Carr BI, et al . Hepatobiliary Neoplasms. In : Devita VT, Helman S, Rosenburg SA, editors. Cancer: Principles and Practice of Oncology. 4th ed. Lippincott: Philadelphia PA; 1993. p. 883-914.
2. Dhir V, Mohandas KM. Epidemiology of Digestive tract Cancers in India, IV, Gall Bladder and Pancreas. Indian J Gastroenterol 1999;18:24-8.
3. Misra S, Chaturevedi A, Misra NC, Sharma ID. Carcinoma of the gall bladder. Lancet Oncol 2003;4:167-76.
4. Cubertafond P, Gainant A, Cucchiaro G. Surgical treatment of 724 carcinomas of the gall bladder. Results of the French Surgical Association Survey. Ann Surg 1994;219:275-80.
5. Ruckert JC, Ruckert RI, Gellert K, Hecker K, Muller JM. Surgery for carcinoma of the gall bladder. Hepatogastroenterology 1996;43:527-33.
6. Arnaud JP, Casa C, Georgeac C, Serra-Maudet V, Jacob JP, Ronceray J, et al . Primary Carcinoma of the gall bladder: Review of 143 cases. Hepatogastroenterology 1995;42:811-5.
7. Houry S, Schlienger M, Huguier M, Lacaine F, Penne F, Laugier A. Gallbladder carcinoma: Role of radiation therapy. Br J Surg 1989;76:448-50.
8. Fields J, Emami B, Carcinoma of the extrahepatic biliaryt system-Results of primary and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1987;13:331-8.
9. Kopelson G, Gunderson LL. Primary and adjuvant radiation therapy in gall bladder and extrahepatic biliary tract carcinoma. J Clin Gastroenerol 1983;5:43-50.
10. Buskirk SJ, Gundersin LL, Adson Ma. Analysis of failure following curative irradiation of gall bladder and extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 1984;10:2013-23.
11. Todoroki T, Gunderson LL, Nagorney D, et al . Biliary tract IORT: Bile duct and gall bladder. Intraoperative irradiation techniques and results. Humana Press: Totowa, NJ; 1999. p. 223-49.
12. American Joint Committee on Cancer, Aerican Cancer Society, American College of Surgeons, AJCC Cancer Staging Handbook. 5th ed. Fleming ID, Cooper JS, Henson D, et al , editors. Lippincott-Raven Publishers: Philadelphia, PA; 1997.
13. Kaplan EL, Meier P. Patient survival analysis. J Am Stat Assoc 1958;53:457-81.
14. Shimada H, Endo I, Togo S, Nakano A, Izumi T, Nakagawara G. The role of lymph node dissection in the treatment of Gall bladder carcinoma. Cancer 1997;79:892-9.
15. Frezza EE, Mezghebe H. Gallbladder Carcinoma: A 28 years Experience. Int Surg 1997;82:295-300.
16. Todoroki T. Chemotherapy for gallbladder carcinoma-a surgeon's perspective. Hepatogastroenterology 2000;47:948-55.
17. Hanna SS, Rider WD. Carcinoma of the gallbladder or extrahepatic bile ducts: the role of radiotherapy. Can Med Assoc J 1978;118:59.
18. Vaittinen E. Carcinoma of the gall-bladder. A study of 390 cases diagnosed in Finland 1953-1967. Ann Chir Gynaecol 1970;168:1-81.
19. Kresl JJ, Schild Se, Henning GT, Gunderson LL, Donohue J, Pitot H, et al . Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gall bladder carcinoma. Int J Radiat Oncol Biol Phys 2002;52:167-75.
20. Falkson G, McIntrye JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gall bladder and bile duct cancer. Cancer 1984;54:965-9.
21. Wils JA, Kok T, Wagener DJ. Activity of cisplatin in adenocarcinoma of the pancreas. Eur J Cancer 1993;29:203.
22. Feng M, Cabrera G, Deshane J, Scanlon KJ, Curiel DT. Neoplastic reversion accomplished by high efficiency adenoviral-mediated delivery of an anti-ras ribozyme. Cancer Res 1995;55:2024.
23. Mulvihill SJ, Warren RS, Fell S. A phase I trial of intratumoral injection with an E1B-attenuated adenovirus, ONYX-015, into unresectable carcinomas of the exocrine pancreas. Proc Am Soc Clin Oncol 1998;17:211a.(Mahantshetty Umesh M, Pal)
2 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, India
Abstract
Introduction and Purpose: In gall bladder cancers, even after curative surgery, survivals are dismal and loco-regional failure accounts for 40-86%. Although these are considered radio-resistant, adjuvant radiation, with or without chemotherapy, has been tried to improve loco-regional control and overall survival rates. With an aim to evaluate the natural history of gall bladder cancers, role of radiation therapy (RT) and prognostication, a retrospective analysis was undertaken. Materials and Methods: Between 1991-2000, 60 patients with gall bladder cancer, treated with radical intent, were evaluated. Patients details including history, physical examination, liver function tests, ultrasonography of the abdomen and chest X-ray; and CT scan Abdomen if done, were noted. In patients who underwent surgery, surgical details, histopathology and pathological staging, were recorded. The details of post-operative adjuvant treatment, including radiation therapy details, as well as chemotherapeutic agents, number of cycles and type of infusion [bolus/infusion], were noted. Results: Sixty patients underwent surgery. On histopathological staging, 28 patients (46.5%) had stage II, 19 (32%) had stage III, 12 (20%) had stage-I and 1 patient had stage IV disease. Thirteen (21%) patents did not receive any adjuvant treatment, 32 (53%) patients received adjuvant RT alone, 8(14%) received post-operative CT+RT and 7 (12%) patients received CT alone. With a median follow-up of 18 months (12-124 months), 27 (45%) patients were disease free, 11 (19%) had local failures, 7 (11%) had loco-regional, 7 (11%) loco-regional+ distant, 4 (7%) distant and 4 (7%) patients had local+ distant failures. The Overall Disease Free Survival (DFS) and overall survival was 30% and 25%, at 5 years, respectively. Stage grouping (' P' =0.007), Pathological T (' P '= 0.01) had significant impact on DFS on univariate analysis, where as histological grade (' P '= 0.06) showed trend towards significance. Conclusion: Gall bladder cancers are aggressive and lethal. Early diagnosis and curative surgery, followed by appropriate adjuvant radiation therapy, may improve survivals, with no established consensus till date. Following curative surgery, pathological T stage and stage grouping, are the significant prognostic factors for outcome.
Keywords: Gall bladder cancers, staging, adjuvant treatment, surgery, radiation therapy.
Introduction
Primary gall bladder cancers are relatively uncommon, accounting for <1% of all cancers and <10% of all G. I. Cancers.[1] In the Indian Cancer Registry, it ranks 5th in all G.I Cancers.[2] In general, the prognosis of patients with gall bladder cancers is poor, with overall 5 year survival rates less than 10%.[1] Surgery in the form of complete resection remains the mainstay of treatment, but complete resection is possible only in 10-30% patients, undergoing surgery.[3] Even after curative surgery, 5-year survivals rates are as follows: Stage 0-I, 33-100%; Stage II, 9-33%; Stage III, 0-25%; and Stage IV, 0-5%.[4],[5],[6] The definite role of adjuvant therapy after curative resection, is still uncertain. Loco-regional failure is the predominant pattern; improvement in loco-regional control rates with adjuvant radiation with/without chemotherapy or chemotherapy alone, has been tried. Although these tumors are considered to be radio-resistant, radiation has been tried since several years in the form of external in radical/postoperative/recurrent settings, Intra-operative radiation therapy (IORT) and brachytherapy for palliation.[7],[8],[9],[10],[11] However, there are only small numbers of series reported in literature, addressing the issue of adjuvant radiation therapy. In these small series, due to differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to define the exact role of adjuvant therapy in gall bladder cancers.[1] Despite lack of proven efficacy, adjuvant therapy and particularly radiation therapy, is recommended and used frequently. Because of the rarity of these tumors, it is difficult to resolve these issues by randomized trials.
With an aim to study natural history of gall bladder cancers, role of adjuvant radiation therapy and prognostic factors affecting survivals, a retrospective analysis of all the patients with gall bladder cancers treated with radical intent, between 1991-2000 was undertaken and is the basis of this report.
Materials and methods
Between 1991-2000, 60 patients with diagnosed gall bladder cancers, treated with radical intent, were evaluated and analyzed. All patients had undergone primary evaluation, including history, physical examination, complete hemogram, liver function tests, ultrasonography of the abdomen and chest X-ray. The CT scan of abdomen, if done, was also noted. In patients who underwent surgery, the type of surgery, nature of resection and residual disease if any, were recorded. Histo-pathology, including histology, grade, type of resection and lymph node status, were noted. All these patients were staged according to AJCC TNM Staging and Grouping system, 5th Edition 1997.[12] The patients' referral for adjuvant therapy was at random, without any set protocols and at the discretion of the treating surgical oncologist. The details of post-operative adjuvant treatment, including radiation therapy details, as well as chemotherapeutic agents, number of cycles and type of infusion [bolus/infusion], were noted.
Statistical analysis
Statistical analysis was carried out using SPSS for Windows Version 11.5. For calculation of loco-regional or overall disease free survival, the date of first failure, either local or distant respectively, were used, whereas last follow-up date was used for overall survival. The Kaplan - Meier method was used for calculating survival, with log rank test for statistical significance, using different prognostic parameters.[13] All 60 patients were eligible for the analysis.
Observations and results
Patient characteristics are as shown in [Table - 1] . With a mean age of 49 years (range: 22-71 years), 42 patients were females and the remaining 18 were males, with a ratio of 2.3:1, in favor of females. Sixty patients underwent surgery in the form of simple cholecystectomy (48 patients), cholecystectomy with wedge resection of liver (8 patients) and cholecystectomy with thorough nodal clearance (4 patients), with Ro resection (margins negative), achieved in 90% of the patients. Out of 48 patients who underwent simple Cholecystectomy, 20 were operated outside, with incidental finding of gall bladder cancers and referred for further treatment evaluation. On histopathological staging, 28 patients (46.5%) had stage-II, 19 (32%) stage III, 12 (20%) stage-I and the remaining 1 (1.5%) patient had stage IV. Pathological T and pathological N staging after surgery are as shown in [Table - 1]. The commonest histology was adenocarcinoma, seen in 57 (95%) patients, the remaining 3 being adeno-squamous carcinoma. According to the grade, 26 (44%) patients had moderately differentiated, 17 (28%) had well differentiated and 17 (28%) had poorly differentiated tumors.
Post-operative adjuvant therapy
Thirteen (21%) patients (12 patients had pathological stage I and I patient stage II [T2N0]), received no further treatment after surgery, 32 (53%) patients received adjuvant radiation therapy alone, 8 (14%) patients post-operative chemo-radiation and the remaining 7 (12%) patients, received chemotherapy alone. Chemotherapeutic drugs used were 5FU +/- Mitomycin, every 3-4 weeks for 3-6 cycles.
Radiotherapy details
Post-operative adjuvant radiation therapy was delivered within a median of 48 days (range: 24-110 days) of surgery, with 3 patients receiving radiation after 75-100 days, because of post-operative wound complications. Radiation therapy was delivered to the upper abdomen using Telecobalt or Linear Accelerator machines, with either parallel beam opposing AP / PA, or Antero-lateral beam arrangements. The target volume consisted of tumour bed and immediate draining lymph nodes, including hilar and/ or coeliac nodes. The portal arrangements, technique, total dose and fractionation, were at the discretion of various treating radiation oncologists. The mean dose of radiation was 47 Gy (median: 50 Gy; range 30-55 Gy), with fractionation ranging from 1.8-2.5 Gy/# with 5# / week and the majority of patients completed the treatment within a mean of 40 days (median: 40 days range: 23-55 days). Six patients received <40 Gy because of progressive disease during radiation, or defaulted on treatment. However, treatment- related toxicities could not be reported, because of poor documentation and compilation.
With a median follow-up of 18 months (mean 46 months and range: 12-156 months) for all patients and 24 months (mean: 46 months; range: 12-156 months) for alive patients, 27 (45%) patients were disease free, 11 (19%) had local failures, 7 (11%) loco-regional, 4 (7%) distant, 7 (11%) loco-regional + distant and remaining, 4 (6%) patients had local+ distant failures. Out of 38 deaths, 33 died of disease, one due to other causes, 4 were lost to follow-up and considered dead.
Survivals
The Overall disease Free Survival (DFS) for the whole group was (30%) at 5 years [Figure - 1] . Various prognostic factors were also evaluated to know the impact on the survival by univariate analysis. Stage grouping (' P'= 0.007) and pathological T status (' P'= 0.01), had a significant impact on univariate parametric analysis, whereas N status (' P'= 0.72), did not affect the outcome and grade of the disease; ( 'P' = 0.06) showed trend towards significance . Disease free survival (at 5 years) for stage I (12 pts) was 40%, 38% for stage II and 15% for stage III patients, with 'P' value of 0.007 [Figure - 2] . Disease free survival (at 5 years) was 50 % for pT1 (15 pts), 38% for pT2 (28 pts) and median of only 6 months for pT3 (17 pts) with 'P' value of 0.01. Disease free survival (at 5 years) was 38% for negative nodes (52 pts), 20% for pN1 (8 pts) with 'P' value of 0.72. [Figure - 3]. Similarly, well-differentiated tumors (17 pts) had a DFS of 35%, moderately differentiated (26 pts) of 38% and 20% for poorly differentiated tumors (17 pts) with a significant ' P ' value of 0.06. Other factors namely; (i) Type of Surgery ( P = 0.84), (ii) Gap between surgery and radiation therapy ( P = 0.77) and (iii) dose of radiation <50 Gy Vs >50 Gy ( P = 0.96), had no impact on disease free survival. The overall survival for the radical group was (25%) at 5 years.
Discussion
In our country, Primary gall bladder cancers ranks 5-6th of all G.I Cancers according to the Indian Cancer Registry and in general, it accounting for <1% of all cancers and <10% of all G. I. Cancers.[1],[2] In general, the prognosis of patients with gall bladder cancers is poor, with overall 5-year survival rates less than 10%.[1] Although, surgery in the form of complete resection remains the mainstay of treatment, it is possible only in 10-30% patients. In fact, only about 10% of cases will have the disease confined to the gallbladder and another 10 to 20% will involve associated local spread, that is respectable.[3] The patients who do best, are those where the disease is found incidentally. Even after curative surgery, 5-year survival rates are as follows: Stage 0-I, 33-100%; Stage II, 9-33%; Stage III, 0-25% and Stage IV, 0-5%.[4],[5],[6]
In our series too, out of 60 patients treated with radical intent, 28 patients (47%) had stage II, 18 (32%) stage III, 12 (20%) stage I and the remaining 1 patient had stage IV, suggesting advanced stage at presentation. Stage- wise 5 year DFS was 40%, 38%, 15%, at 3 months respectively, suggesting that loco-regional extension after curative surgery, remains the major prognostic factor for outcome. Lymph node involvement is also an important prognostic factor in gall bladder cancers, with overall metastatic rates of 63.4%.[14] Overall survival rates with surgery alone, as correlated with the extent of metastatic lymph node involvement, are reported to be 22% in N0 patients and 0 - 5% in N+ patients[5],[6] with 38% and 20% DFS in N0 and N1 nodal staging, respectively, in our series.
The standard surgery is a cholecystectomy with nodal clearance, for patients with stages I - III disease. More radical procedures have also been performed, including resection of the gallbladder fossa, adjacent liver, regional nodes and the gall bladder for stage III disease, to improve loco-regional control rates; however, majority of modern surgical series have reported no difference in survival.[4],[15]
The definite role of adjuvant therapy after curative resection, is still uncertain. Although these tumors are considered to be radio-resistant, radiation has been tried since several years, in the form of external in radical / postoperative / recurrent settings, Intra-operative radiation therapy (IORT) and brachytherapy for palliation.[7],[8],[9],[10],[11]
However, there are small numbers of series reported in literature, addressing the issue of adjuvant radiation therapy. In these small series, differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to pinpoint the exact role of adjuvant therapy in gall bladder cancers.[16]
As stated earlier, in the past, this tumor were considered radio resistant, however, relief of jaundice and osseous pain with radiation, suggest that this may not be so. The limiting feature of local irradiation, is again the tolerance of surrounding critical structures, including liver, kidneys, pancreas, lesser curvature of stomach and small bowel. In general, radiotherapy and chemotherapy have offered poor results in the treatment of gallbladder cancer. Because of the rarity of this disease and the rarity of completely resected gallbladder cancers, it is not surprising that there are no prospective, randomized studies, examining the utility of adjuvant therapy. Nonetheless, many retrospective studies have addressed the issue of adjuvant therapy. All these are small retrospective studies, showing no much benefit of adjuvant therapy. Hence it is difficult to draw firm conclusions from these data. Todoroki et al[11] examined intraoperative radiotherapy after complete resection, for stage IV gallbladder cancer and reported a 10% 3-year survival for patients receiving intraoperative radiotherapy, versus 0% for surgery alone. Hanna and Rider[17] reviewed results for 51 patients with gallbladder cancer and found survival to be significantly longer in patients receiving postoperative radiotherapy, as compared with those who underwent only surgery. In another retrospective study, the median survival of patients receiving postoperative irradiation was 63 months, as compared to 29 months, for patients undergoing surgery alone.[18] Definitive data for adjuvant radiotherapy only, also are lacking, but the existing data are a bit more encouraging than are those for chemotherapy.[15],[17],[18]
In the current series, thirty-two (53%) patients received adjuvant radiation therapy alone, 8 (14%) patients post-operative chemo-radiation and the remaining 7 (12%) patients received chemotherapy alone, with overall DFS and OAS of 30% and 25% at 5 years respectively, with an insignificant difference in survivals, when compared to the type of adjuvant therapy. However, pTstage and stage grouping did have a significant impact on survivals, suggesting that loco-regional control has a major impact on the outcome of the disease. Despite these patients receiving a mean dose of 47 Gy (median: 50 Gy), the disease free survivals are poor, suggesting a higher radiation doses. Dose escalation to the tumor bed with various critical structures around, still remains a challenge.
Kresl et al reported 21 patients treated with adjuvant concurrent chemo radiotherapy, with a 5-year survival of 64%, as compared to historical series of 33% in completely resected tumors and also concluded that greater doses of radiation are required for loco-regional control rates, although not significant in the report.[19]
The results of chemotherapy in gall bladder cancers have also been poor. A European Co-operative Oncology Group study examined bolus Mitomycin C in advanced gallbladder and biliary tree carcinoma, with no significant activity identified and an objective response of <10% only.[20] Other regimens based on 5-FU, Adriamycin, or nitrosoureas alone and in combination for gallbladder cancer, result in only minimal responses. In a study that treated 30 patients with advanced gallbladder carcinoma with 5-FU, Leucovorin and Hydroxyurea, 9 had a partial response. However, the median duration of response was only 6.5 months and the median survival was only 8 months. Regional therapy has recently been examined using intra-arterial Mitomycin C for gallbladder cancer. A 48% overall response rate and a prolongation of median survival from 5 months to 14 months, as compared to historic controls, was reported.[21],[22],[23] However, a regional approach is rarely indicated, since the major reasons for unresectability usually are disseminated disease and extensive involvement of the porta hepatis. Hence, most of studies with chemotherapy have resulted in nonstatistically significant improvements compared to surgery alone and on the contrary, add to the toxicities, jeopardizing the quality of life further.
Conclusion
Based on our series and that reported in the literature, it can be concluded that gall bladder cancers are generally associated with advanced disease at presentation and poor prognosis. Surgery with complete resection, should be the objective for the favorable outcome. Though the data are encouraging, firm support for adjuvant- therapy, awaits confirmation by prospective trials. Nevertheless, given the high incidence of loco - regional recurrence of gallbladder cancers and the low morbidity of radiotherapy, it is not unreasonable to recommend some form of radiotherapy, particularly for patients with advanced-stage disease. Adjuvant radiation therapy with dose escalation, with newer techniques available, may be tried. The role of 5FU based adjuvant chemotherapy and radiation needs further validation, although they have shown to favor local control and survivals.
References
1. Lotze MT, Flickinger JC, Carr BI, et al . Hepatobiliary Neoplasms. In : Devita VT, Helman S, Rosenburg SA, editors. Cancer: Principles and Practice of Oncology. 4th ed. Lippincott: Philadelphia PA; 1993. p. 883-914.
2. Dhir V, Mohandas KM. Epidemiology of Digestive tract Cancers in India, IV, Gall Bladder and Pancreas. Indian J Gastroenterol 1999;18:24-8.
3. Misra S, Chaturevedi A, Misra NC, Sharma ID. Carcinoma of the gall bladder. Lancet Oncol 2003;4:167-76.
4. Cubertafond P, Gainant A, Cucchiaro G. Surgical treatment of 724 carcinomas of the gall bladder. Results of the French Surgical Association Survey. Ann Surg 1994;219:275-80.
5. Ruckert JC, Ruckert RI, Gellert K, Hecker K, Muller JM. Surgery for carcinoma of the gall bladder. Hepatogastroenterology 1996;43:527-33.
6. Arnaud JP, Casa C, Georgeac C, Serra-Maudet V, Jacob JP, Ronceray J, et al . Primary Carcinoma of the gall bladder: Review of 143 cases. Hepatogastroenterology 1995;42:811-5.
7. Houry S, Schlienger M, Huguier M, Lacaine F, Penne F, Laugier A. Gallbladder carcinoma: Role of radiation therapy. Br J Surg 1989;76:448-50.
8. Fields J, Emami B, Carcinoma of the extrahepatic biliaryt system-Results of primary and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1987;13:331-8.
9. Kopelson G, Gunderson LL. Primary and adjuvant radiation therapy in gall bladder and extrahepatic biliary tract carcinoma. J Clin Gastroenerol 1983;5:43-50.
10. Buskirk SJ, Gundersin LL, Adson Ma. Analysis of failure following curative irradiation of gall bladder and extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 1984;10:2013-23.
11. Todoroki T, Gunderson LL, Nagorney D, et al . Biliary tract IORT: Bile duct and gall bladder. Intraoperative irradiation techniques and results. Humana Press: Totowa, NJ; 1999. p. 223-49.
12. American Joint Committee on Cancer, Aerican Cancer Society, American College of Surgeons, AJCC Cancer Staging Handbook. 5th ed. Fleming ID, Cooper JS, Henson D, et al , editors. Lippincott-Raven Publishers: Philadelphia, PA; 1997.
13. Kaplan EL, Meier P. Patient survival analysis. J Am Stat Assoc 1958;53:457-81.
14. Shimada H, Endo I, Togo S, Nakano A, Izumi T, Nakagawara G. The role of lymph node dissection in the treatment of Gall bladder carcinoma. Cancer 1997;79:892-9.
15. Frezza EE, Mezghebe H. Gallbladder Carcinoma: A 28 years Experience. Int Surg 1997;82:295-300.
16. Todoroki T. Chemotherapy for gallbladder carcinoma-a surgeon's perspective. Hepatogastroenterology 2000;47:948-55.
17. Hanna SS, Rider WD. Carcinoma of the gallbladder or extrahepatic bile ducts: the role of radiotherapy. Can Med Assoc J 1978;118:59.
18. Vaittinen E. Carcinoma of the gall-bladder. A study of 390 cases diagnosed in Finland 1953-1967. Ann Chir Gynaecol 1970;168:1-81.
19. Kresl JJ, Schild Se, Henning GT, Gunderson LL, Donohue J, Pitot H, et al . Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gall bladder carcinoma. Int J Radiat Oncol Biol Phys 2002;52:167-75.
20. Falkson G, McIntrye JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gall bladder and bile duct cancer. Cancer 1984;54:965-9.
21. Wils JA, Kok T, Wagener DJ. Activity of cisplatin in adenocarcinoma of the pancreas. Eur J Cancer 1993;29:203.
22. Feng M, Cabrera G, Deshane J, Scanlon KJ, Curiel DT. Neoplastic reversion accomplished by high efficiency adenoviral-mediated delivery of an anti-ras ribozyme. Cancer Res 1995;55:2024.
23. Mulvihill SJ, Warren RS, Fell S. A phase I trial of intratumoral injection with an E1B-attenuated adenovirus, ONYX-015, into unresectable carcinomas of the exocrine pancreas. Proc Am Soc Clin Oncol 1998;17:211a.(Mahantshetty Umesh M, Pal)