Pre Operative Radiochemotherapy

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Although combined adjuvant chemoradiotherapy was standard in the USA, European centres studied the feasibility of pre-operative radiation therapy.

The principles of the neoadjuvant scheme are: higher efficacy of radiation and chemotherapy agents in well vascularised and oxygenated tissue; lower radiation fields; and excision of irradiated large bowel and less small bowel irradiation (easily dislocated), which may reduce late complications such as SBO. Pre-operative irradiation may also cause less acute toxicity and more patients will receive full-dose radiation therapy.

The consequent volume size reduction of the tumour could lead to a lower risk of dissemination of neoplastic cells during surgical handling of the rectum, a high number of sphincter-saving procedures and a higher rate of resectable rectal cancer with free margins.

A major concern for pre-operative radiation therapy is that patients with early stage tumours or disseminated disease will often receive unnecessary treatment, necessitating improved imaging techniques that allow more accurate patient selection. Moreover, neoadjuvant treatment usually postpones definitive surgery considerably and may also be associated with increased post-operative morbidity.

RT can be administered in conventional fraction-ation in long course, or in short course. The conventional fractioning uses multiple fields (usually 2-4) on a tumour volume correctly conformed. Doses of 1.8-2.0 Gy/day, 5 days/week, for 5 weeks are administered, reaching a total dose of 45-50.4 Gy. During the last week of therapy an additional boost on residual tumour volume can be administered. Several trials on radiosensitive neoplasms have shown that a dose of 50 Gy is the minimal dose to eradicate micrometastasis. In the short course, doses are higher per single fraction: 5 GyX5 days (total dose of 25) followed by surgery a week later. The supposed advantage of the short course is that reducing treatment time should prevent repopulation of tumour cells. Five doses of 5 Gy has a comparable efficacy to 45 Gy fractioned as calculated with the Cumulative Radiation Effect (CRE) formula [34]. Unsatisfying results were initially published, as pre-operative radiation therapy was used with low dose (5-25 Gy) and no benefits vs. surgery alone emerged [35, 36].

A randomised study of Swedish Authors [37] published in 1990 showed better results in terms of local recurrence in patients treated pre-operatively with RT vs. patients treated after surgery. The first group of patients were treated with short-term RT, 25.5 Gy/week, and the second group of patients underwent RT with a dose of 60 Gy post-operatively. In the first arm of the study a lower rate of local recurrence emerged vs. the second arm: 13% vs. 22% respectively (p=0.02). Nevertheless, the overall survival at 5 years did not reach a statistically relevant significance (42% vs. 38%, p=0.5).

The Authors noted a higher rate of acute toxicity, a higher rate of complications of perineal wound in patients treated with APR such as infection and delayed healing and a lower rate of late complications of RT such as bowel obstruction in patients treated with RT pre-operatively.

The Swedish Rectal Cancer Trial [38,39] showed a significant increase in overall survival in patients treated pre-operatively. The study enrolled 1 168 patients; a group of patients underwent surgery alone and the other group of patients underwent short-term RT a week before surgery (25 Gy/5 days). The local recurrence rate reported in this trial was 27 vs. 12% respectively (p<0.001) and a better overall survival at 5 years (58 vs. 48%, p=0.004). Thus, the results of this large study once again supported the oncological paradigm that survival is improved by better local control.

A Dutch trial randomising 1 805 patients with resectable rectal cancers (stages I-IV) to a short course of radiation (500 cGyX5) followed by TME compared to TME alone demonstrated no difference in overall survival at 2 years (82% for both arms) [18]. However, local recurrence rates were significantly reduced in the RT plus TME arm (2.4%) as compared to the TME only arm (8.2%, p<0.001). Patients with stage II-III rectal cancer and patients with neoplasm localised 5-10 cm from the anal verge obtained better results from the treatment.

Because surgery is performed only one week after the completion of radiation therapy, as in Swedish trials, significant tumour shrinkage is very unlikely and one of the major goals of pre-operative treatment, the preservation of sphincter, is more likely to be achieved. Prolonging the interval between RT and surgery has been studied. The longer interval (6 weeks against 2 weeks) between radiation in long course and surgery was associated with a significantly better clinical tumour response (71 vs. 53%, p=0.007) and pathological downstaging (26 vs. 10%, p=0.005), and sphincter-preserving operations (76 vs. 68%,p=0.27) [40]. Due to the short overall treatment time, such as 25 Gy in a week, radiation therapy cannot be combined with an adequate dose of systemic chemotherapy. Thus the potential effect of radiosensitising of the chemotherapy drug to enhance local tumour response and simultaneously treat occult distant metastasis would decrease.

Several institutions have applied pre-operative radiation in conventional fractionation in the treatment of fixed T4 rectal cancer with the goal of converting them in resectable cancer. Minsky et al. [41, 42] compared pre-operative RT 50.4 Gy with or without chemotherapy with 5-FU and a high dose of folinic acid, showing that 90% of the patients with initially unresectable tumours were converted to resectable lesions compared with only 64% of those who received radiation alone. Moreover, a complete

Table 3. Pre-operative treatment and clinical response

Author

Patients Clinical (%)

response

Pathological response (%)

Chari et al. [44]

43

51

27

Habr-Gama et al. [45]

118

30.5

-

Hiotis et al. [46]

488

19

10

Crane et al. [47]

238

47

Not specified

Moutardier et al. [53]

113

-

8

Zmora et al.[49]

109

43

14

Table 4. Pre-operative treatment and results

Author

Patients

Scheme

Median follow-up

pT0 (%)

Down staging (%)

(%)

OS (%)

Bonnen et al. [50]

405

45 Gy+5-FU

46

-

8

81

Sauer et al. [51]

420

50.4 Gy+5-FU

6 vs. 13 (adjuv)

76 at 5 years

Theodoropoulos et al. [52]

88

45 Gy+5-FU/ leucovorin (LV)

33

18

41

10.2

83.9

Moutardier et al. [53]

113

45 Gy

75

8

49.5

9

79

Garcia Aguilar et al. [48]

168

45-60 Gy+5-FU

37

13

58

5

68

Nakagawa et al. [54]

52

50.4 Gy+5-FU/ folinic acid

32

17.9

60.7

Habr-Gama et al. [45]

118

50.4 Gy+LV/ bolus 5-FU

36

4.3

84.7

Chan et al. [55]

128

50 Gy+5-FU/ LV/mitomycin C

-

25

66

pT0, pathological response; LR, local recurrence; OS, overall survival pT0, pathological response; LR, local recurrence; OS, overall survival pathological response was found in 20% of patients who received multimodal treatment. Several phase II trials of pre-operative radiochemotherapy confirmed these results such as our experience, demonstrating the feasibility of tumour shrinkage in T4 rectal cancer, allowing a higher number of curative resections [41-43] (Tables 3, 4).

Results of the CAO/ARO/AIO-94 study from the German Rectal Cancer Group have recently become available [51]. This trial started in 1995 and ended in 2002; a total of 823 patients with T3-T4 or node-positive disease were enrolled. Group A, with pre-opera-tive radiochemotherapy, consisted in 421 patients receiving 5040 cGy in 28 fractions and 5-FU in continuous infusion and then surgery after 6 weeks; another cycle of 5-FU was given one month after surgery. In the post-operative radiochemotherapy Group B, 402 patients were recruited and experienced the same regimen post-operatively plus an additional boost of 540 cGy.

Overall five-year survival was similar in both groups (A: 76%, B: 74%), whereas local control was improved in Group A (6% of recurrence), as compared with Group B (13%). In Group A there were fewer acute 3 or 4 grade (especially diarrhoea, haematologic effects, dermatologic effects) and long-term toxic effects (strictures of the anastomoses, bladder problems, chronic diarrhoea, SBO): respectively 27% and 14%, as compared with Group B (40% and 24%). Post-operative complication rates were similar in both arms, with about 11% of anastomotic leakage of any grade in the pre-operative group as compared with 12% in the post-operative group. The rates of ileus, post-operative bleeding and delayed sacral wound healing were similar also.

The Authors concluded that pre-operative che-moradiation for advanced rectal cancer should be the preferred option because of better local control, reduced toxicity and increased rate of sphincter preservation. Based on results from phase I and II trials, the standard regimen for patients who receive combined modality therapy is continuous 5-FU infusion, and pelvic radiation. Regimens using CPT11 or oxaliplatin-based combined modality therapy plus either continuous infusion of 5-FU or capecitabine are under active development [56].

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