Radiotherapy and Oncology, 13 (1988) 75-81 Elsevier 75

RTO 00491

Combined modality preoperative therapy in poor prognostic rectal adenocarcinoma

Mahroo Haghbin, Ben Sischy and Josephine Hinson Daisy Marquis Jones Radiation Oncology Center, Highland Hospital, Rochester. New York, U.S.A.

(Received 25 May 1987, revision received 21 March 1988, accepted 24 March 1988)

Key wor&: Rectal carcinoma; Adjuvant therapy: Combined radiotherapy-chemotherapy

Summary

Between 1976 and 1986,64 patients with rectal adenocarcinoma who were considered unresectable or had prognostic signs suggestive of high risk for local failure received preoperative adjuvant therapy. They were treated with pelvic irradiation (40 Gy) combined with Muorouracil (S-FU) and mitomycin-C, followed by surgery. All had definitive resections resulting in 12.5% of operative specimens free of tumor and only 26.5% containing nodal metastases. The projected 5-year disease-free survival rate is 64% with an actuarial survival of 68%. No mortality or severe morbidity has been observed. Combined modality therapy is a safe and effective regimen for those rectal tumors in the high risk category.

Introduction

To improve the results of surgical resection in rectal carcinoma, preoperative irradiation as adjuvant therapy has been advocated as early as 1939 [15]. Since then, several large studies have been con- ducted to test the benefit of this method [6].

In 1976, a trial of preoperative irradiation in con- junction with chemotherapy was initiated at the Highland Hospital in Rochester [19]. The protocol was designed for patients whose tumors had char-

Aabbsfir correspondiwce: B. Sischy, Daisy Marquis Jones Ra- diation Oncology Center, Highland Hospital, 1000 South Ave- nue, Rochester, New York, NY 14620. U.S.A.

acteristics indicative of a high risk for local recur- rence. An earlier study had demonstrated the poten- tial beneficial local effect of pelvic irradiation in conjunction with Muorouracii (5-FU) and mito- mycin-C in rectal adenocarcinoma [2]. Laboratory studies have shown enhanced regression in trans- planted rodent tumors by combined administration of X-rays and 5-FU [13,25]. In patients with locally advanced gastrointestinal adenocarcinoma, a con- trolled double-blind trial suggested that 5-FU aug- ments the effect of irradiation [16]. This chemoth- erapeutic agent when used jointly with mitomy tin-C, was found to produce a higher response rate in metastatic alimentary carcinomas as compared with mitomycin-C alone [3].

0167-8140/88/$03.50 @ 1988 Elsevier Science Publishers B.V. (Biomeditil Division)

76

btween August 1976 and August 1986,64 patients with histologically documented adenocarcinoma of t#&&@#~,~ted. A~the:J&ions.jl&rekJeated im t& wr 2#3j of&e me@mb. where the inqidenee of p&vie rqurrenee is hi& specially in the distal t,/3 of t&e organ pq Forty-three tumors were situ- ated within 7 cm of the anal verge, and the remain- iq 21 above this distance (uot beyond 11 cm). The mup eonsistedof47 males and 17 females, ranging in. age from 39 to 82 years with a median of 64 years. The criteria for patient selection is outlined in Tabk 1. Sixteen ksions were defined as unre- sectabk by the referring surgeons, based primarily on fixation. In addition to tumor fixation, large sixe in, as&a&t with deeration [5,lQ,29], nodal in- volvemen~ and poor& dii&entiated histology ES, ! & i.~are.considere& signs predictive of high pel- vie recurrence rate. The frequencies of these tumor charactedstics in our patient population are shown in Table H. No patient with polypoid non-ulcerat- ing tumor was included in the study. Nineteen patients had well differentiated tumors; in 40, the histology was of moderately differentiated type, and in five, poorly differentiated variety existed. The neoplasms were assessed by digital rectal exam- ination,. as. wel.ll. aa, proctosigmoido~opy. Each @tie@: underwent: an initial: ,radiographic; work-up t~:@iud@; the @&&&iii& of distant spread. In the e&r part of study, radionuclide liver scan was o&iw, ww& w&s. sup@&nt&i by mmput& torn_ why 06 abd omen a& pelvis in’ the latter years. A clkst X-ray was also a, part of this investigation. bpatic and’ liver function tests were performed prior to the institution of chemotherapy. Carci- ~~~~~hyonic antigen has been measured since the intro&t&on of this assay.

TABLE1

Ractalcarchtoma: crileria for patient selection.

TABLE11

Rectal carcinoma: frequency of clinical characteristics of tu- mors.

sizer4cm~ 100% Ulceration 100% Deep ulceration 34% Fiction, partial 47% Fixation, complete 25% Association with perirectal lymphadenopathy 3%

The treatment regimen is outlined in Table III. It begins with irradiation to the whole pelvis deliv- ered on an 8 MeV linear accelerator by means of anterior and posterior opposing fields with the patient in prone position. The treated volume en- compasses the primary and pelvic lymph nodes, as illustrated in Fig, 1. The total pelvic dose is 40 Gy to midline given over 4.5 weeks in 1.7-1.8 Gy daily fractions. The S-FU infusion is started on the 2nd day of irradiation. This schedule was designed to take advantage of the temporal relationship be- tween X-rays and S-FU as demonstrated in the lab- oratory [4,26]. Enhanced cell killing is maximized if cells are continuously exposed to ,S-FU following X-ray treatment [4],. The iefusi,on is given in a dose of 1909 mg/mq pet 2a h for 96 h. The infusion tech- nique has also: been observed clinically to be super- ior to the bolus injection, causing less myelo- suppression a!8]. A single dose of mitomycin=C, 10

TABLE III

Rectal carcinoma: preoperative regimen.

Pelvic irradiation Fiilds AP-PA

40 Gy 10 midline in 1.7-1.8 Gy!F in 4.5 weeks on 8 MeV liar accelerator

5-FU. 1000 mg/mz per 24 h x%h On day 2nd and 28th

Mitomycin-C. IO m&n2 one dose On day 2r;d

surgery 4-6 eks later

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Fii 1. Simulati;Sn filin - the superior border of the field is at L5-Sl. The inferior border is at the anal marker or mid-obtur- ator foramina, depending on the location of tumor; with at least

a 2-5 cm margin from the lower edge of tumor.

mg/mz is injected intravenously on the 2nd day. Mitomycin-C and X-rays have been shown to in- teract in an additive manner in vivo [21]. The doses are calculated on the basis of ideal weight in obese individuals. The 96-h infusion of S-FU is repeated on the 28th day of X-ray therapy. In the earlier part of study, eight patients did not receive a second course of S-FU. In four, a hematologic depression was encountered with the first course, and in the remaining, due to difficulty with venous access this part of protocol was omitted. After gaining more experience with this regimen, instead of eliminating the second course of S-FU for those with hemato- logic depression during the first course, the dose was reduced by 20%. Surgical resection is per- formed 4-6 weeks after the conclusion of the com- bined regimen. This interval allows for the irradia- tion and chemotherapy induced inflammatory tis- sue reactions to subside, and for the rectal mass to regress further.

All patients had a curative resection, without re- sidual gross disease. In 62 cases an abdominoperi- neal (AP) resection was performed, and two had primary anastomosis. Five patients with residual

microscopic disease (I33 and CS categories) received additional irradiation. In one case it was delivered intraoperatively with electrons. In the other four, 15-20 Gy was given one month postoperatively through lateral and posterior portals, not exceeding a field size of 8 x 8 cm.

Tumor shrinkage to various degrees was observed clinically in every case. The postsurgical staging of the lesions according to the modified Astler-Coller classification [12] is shown in Table IV. In 12.5% of the patients, no residual neoplasm was seen on microscopic examination. Otl’ry 263% had positive

TABLE IV

Rectal carcinoma: postsurgical staging (modified Astler-Coller classification).

No. %

No micrbxopic residual tumor 8 12.5 Stage A Stage BI Stage BZ Stage Bs

Stage Cl

stage c2

smp c3

A Bl

5 9 19 29.5 12 18.5 3 4.5 6 9.5 8 12.5 3 4.5

Total 64

Lesion limited to mucosa

Nodes negative B2

Bs

Cl

Nodes positive C2

cs

26.5

Extension beyond mucosa, but still within bowel wall

Extension through the entire bowel Wdl

Adherence to or invasion of surrounding organs or strur-tures

Lesion limited to the bowel wall Extension of the lesion through the

entire bowel wall Adherence to or invasion of

surrounding organs or structures

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TABLE V

Rectal carcinoma: results of preoperative regimen.

Disease status No. of Interval (mths) following surgery patients

BaW Median %

Disease-free 37 8+-121+ 84 2 40. Distant mctastases” 15 2-77 12 E

Local recurrence 6 12 - 59 21 20 - Di of other causes 6 2 - 83 28

” I I I, I I I I I I,

n One patient whose initial site of recurrcncc was outside of pel- 0 IO 30 50 70 90 110 130

vis, manifested locoregional disease subscqucntly, bringing the MONTHS number of total local recurrences to 7.

Fig. 2. Life-table analysis of disease-free survival as of April I, 1987.

lymph nodes in their surgical specimen. We did not third year post-treatment, The designation of attempt to compare the pretreatment clinical mea- patients to local or distant failure categories was surements of the tumors with their size in surgical based on the initial site of relapse, which was de- specimens. However, the eight patients with no re- tected by clinical and radiographic evaluation. sidual malignant cells, had masses 5 cm or more in Among the 15 patients whose initial recurrence was diameter at presentation. outside the pelvis, locoregional disease was detected

The analysis of the cases was closed as of April only in one additional patient. For the remaining 1, 1987. Thirty-seven patients are alive with no evi- 14, no manifestation of local recurrence was ever dence of disease. Eighteen have died from rectal observed. We have no postmortem examination in carcinoma. Three individuals with recurrent cancer these cases to verify the absence of pelvic disease. are still living. In the remaining six, a disease-free Figure 2 depicts the life-table analysis of disease- status was terminated with death from intercurrent free survival for the group. Those who died with illnesses. The results in relation to the status o,f the causes other than rectal cancer are censored. The patients, intervals to recurrence, and death (unre- projected disease-free survival rate at S-years is lated to cancer) are summarized in Table V. In 37 64% with an actuarial survival of 68%. patients, the duration of disease-free survival We attempted to establish a correlation between ranges from 8 to 121 months, with a median of 84 postsurgical staging of the tumors and the eventual months. Only seven cases have been observed for less than 2 years. Distant metastases occurred be- tween 2 and 77 months following the inception of therapy; the median time was 12 months. In five patients, distant spread was detected beyond the second year from therapy, and in two cases it was past the fifth year. Six patients presented with pelvic failure. from 12 to 59 months after combined mo- dality regimen; the median time was 21 months. In two instances, local failure was observed in the

outcome. Distant metastases were seen in all the groupings including one case with no residual tu- mor. Table VI shows the postsurgical stagings of both distant and local failures. The numbers are too small to determine a meaningful relationship. How- ever, pelvic recurrence has not been encountered in patients with no residual disease in their surgical specimen or A category. Postsurgical staging and outcome for the 16 patients with complete fixation are presented in Table VII.

TABLE VI

Rectal carcinoma: postsurgical staging of recurrences (modified Astler-caller classification).

No residual tumor A Bl BZ B3 Cl G c3 Total

Distant metastasis I 2 3 2 2 I 3 1” 15

Local recurrence 3 1 I I 6

’ The initial site of recurrence was distant, with locorcgional failure being manifested laler. He had supplemental postoperative irra- diation.

TABLE VII

Rectal carcinoma: postsurgical staging and outcome of 16 patients with complete fixation.

Stage (no.)

BI (3) B2 (4) BS (3) Cl (1) c2 (2)

c3 (3)

Total

Outcome

Disease-free duration (mths)

1 (56) 3 (23, Ill, 112) 1(18)

1 (24) 1 t&J

7

Distant metastases

1

2 I I I”

6

Local recurrence

1

I

2

-.--

Died other C

1

I

a Distant metsatasis followed by locoregional recurrence.

Complications

Acute side-effects were mainly diarrhea and peri- neal epidermitis, which were observed in all the cas- es. The intensity of diarrhea varied from mild to moderate. Symptomatic therapy or occasionally a short rest period brought relief to the patient. Per- ineal skin reaction was not severe except in 10 in- stances which required temporary treatment sus- pension. Adherence to a low residue diet, and at- tention to perineal hygiene can minimize the ad- verse effects. Oral mucositis secondary to 5-FU in- fusion was observed in 15 of 64 cases; the condition was mild and self-limited. Signs of bladder irrita- tion were noted in 9/64 patients, and abated with

symptomatic treatment. No severe hematologic depression was encountered. White blood cell count dropped below 2.0 x 10q/l in 6/64 patients without any associated infectious complications. Decline of the platelet count to less than 100 x 10q/l was seen in 25/64 patients; none manifested any hemorrhagic disorders. Leukopenia and thrombocytopenia were self-limited, and were usually encountered after the second week of combined modality regimen. A brief interruption of treatment was needed in 22 cases which reverted the hematologic values back to normal. We did not observe any undue difficulty with perineal wound healing after the AP resection. Anastomatic leakage was not a problem in those who had an anterior resection.

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No chronic complication has been experienced. Two patients developed signs of small bowel ob- struction. In one case it occurred shortly after the operation as a result of bowel herniation induced by faulty suqicai technique. The other case, man- ifested bowel obstruction caused by adhesions in the second year post-therapy. Both recovered un- eventfully after laparotomy.

Dhmion

There is an increasing awareness that treatment of rectal carcinoma needs to be individualized, based upon the location of the tumor, its extent, and prog- nostic factors predictive of pelvic failure.

The randomized clinical trials of preoperative ir- radiation have used diverse eligibility measures for patient enrollment, and the administered doses have been modest, below 40 Gy. The outcome of these studies have not supported the benefit of such a regimen conclusively. Delivery of higher doses of irradiation in non-randomized protocols has re- sulted in downstaging of the tumors, with decrease in the frequency of lymph node involvement and pelvic recurrences [22,24]. When 46 Gy was given prior to surgery in 17 cases, 2 had no residual tu- mor, and only 4 specimens contained metastatic lymph, nodes [24]. In another program, 50 patients received 50-60 Gy preoperatively, 5 had no malig- nant cells in the resected bowel, and positive nodes were limited to 8 cases [22]. A reduction of Stage C disease has been also observed with lower doses of irradiation (20 Gy) before surgery in randomized protocols of VASAG I [14] and MRC I [8].

Since histopathologic extent of the disease is not known before resection, it has been argued that pre- operative radiotherapy has the disadvantage of needlessly treating the early stage categories that have a good prognosis. If other features can be used for the definition of risk for recurrence, stratifica- tion of the patients can be carried out at presenta- tion for appropriate therapeutic strategies.

We attempted to characterize the poor prognos- tic group on the basis of clinical findings of fixation, large tumor size with ulceration, and/or poorly dif- ferentiated histology. These features which are as- sociated with a high frequency of Stage C disease [5,10,11,17,20], were used as selection criteria. The dose of 40 Gy, in conjunction with chemotherapy for local effect, did not cause any serious morbidity. There was no surgical complication or mortality attributed to the preoperative regimen. Long-term follow-up of the patients has not disclosed any late adverse reaction. In fact, radiotherapy preceding surgery is less likely to cause small bowel damage than following the procedure, when intestinal loops become adherent within the pelvis. Major bowel complications, which were observed in one study, with the administration of postoperative irradiation and S-FU [7], can be the consequence of treating a *large volume to a high dose (60 Gy) in the presence of bowel adhesions. Experience with the use of pre- operative irradiation (34.5 Gy) to pelvis and para- aortic chain lymph nodes, along with 5-FU, was accompanied with acute toxicity as well as post- operative mortality in a randomized trial conducted by EORTC [9]. The treated volume, fraction size, mode of 5-FU administration, and interval to sur- gery could have contributed to the observed effects. In our protocol, the irradiated fields were confined to the primary tumor and pelvic nodes. The daily fraction dose did not exceed 1.8 Gy and 5-FU was administered as an infusion.

The combined modality regimen has yielded an encouraging 5-year disease-free survival rate of 64% in locally advanced rectal carcinoma. The safety and efficacy of this method deserve further study. With the assistance of imaging techniques such as endoluminal ultrasound and computed tomography, preoperative staging of rectal tumors can be refined [l]. Cytofluorometric DNA mea- surements might be of further aid in this respect [23]. A better prediction of risk factors and extent of tumor should enable us to use preoperative ad- juvant therapy more judiciously.

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