nonsurgical management of recurrent colorectal cancer

4278

Nonsurgical Management of Recurrent Colorectal Cancer David J. Vaughn, M.D. , and Daniel G. Huller, M.D.

Most patients with colorectal carcinoma undergo at- tempts at curative surgery. However, some present with metastatic disease and many others ultimately relapse. Most recurrences of colorectal cancer are not resectable and require nonsurigical approaches such as chemotherapy and radiation therapy directed against local recurrences, hepatic metastases, and widely disseminated disease. Nonsurgical therapy for locoregional recurrence of rectal cancer can offer significant palliation. Intraarte- rial chemotherapy for liver metastases increases the like- lihood of response compared to systemic treatments, but has little effect on survival. Extrahepatic progression and hepatic toxicity are important limitations to this regional therapy. 5-fluorouracil (5-FU) is the mainstay of systemic chemotherapy, and efforts to modulate biochemically the cytotoxic effects of 5-FU with folinic acid, phosphonacetyl-L-aspartate, interferon, and other agents have resulted in promising response rates. The different approaches to biochemical modulation are being studied in ongoing cooperative group trials. Novel approaches, including monoclonal antibody therapy, biologic modi- fier therapy, and gene therapy, are under investigation. Cancer 1993; 71:4278-92.

Key words: colorectal cancer, metastatic disease, chemotherapy, radiation therapy.

Each year, more than 150,000 Americans receive a diagnosis of colorectal cancer.' Although 80% of patients initially have complete resection of the primary tumor, nearly half have invasion of the cancer through the serosa or regional lymph node involvement, predis-

Presented at the American Cancer Society Workshop on the Pretreatment Diagnostic Management of Colorectal Cancer and Fol- low-up Management of Recurrent Disease, San Francisco, California, October 30-31, 1992.

From the Hematology/Oncology Division, Department of Medi- cine of the University of Pennsylvania School of Medicine and the University of Pennsylvania Cancer Center, Philadelphia, Pennsyl- vania.

Address for reprints: Daniel G. Haller, M.D., University of Pennsylvania Cancer Center, 6 Penn Tower, 3400 Spruce Street, Phil- adelphia, PA, 19104.

Accepted for publication February 24, 1993.

posing them to a high risk of recurrence.' Recurrent cancer of the large intestine continues to make this disease an important cause of cancer-related death, second only to lung cancer.' Patients with recurrent colorectal cancer can be divided into three groups: those with local or regional recurrences; those with hepatic metastases; and those with widely disseminated disease. His- torically, locoregional failure has been an especially important problem in rectal cancer because of its frequency and because of its association with significant morbidity. Extrapelvic colon cancer also may be associated with locoregional recurrence, but is more likely to present with distant failure, with the liver being the most common initial single site of metastasis. Although isolated resectable recurrences do occur, nonsurgical therapies often are the only options in the management of each category of recurrence of colorectal cancer.

Recurrence of colorectal cancer after complete surgical resection is thought to be caused by progression of residual occult microscopic disease present at the time of initial surgery. The recently published results of trials of effective postoperative adjuvant therapy have shown decreased recurrence and improved survival for colon and rectal cancer. The recently updated Inter- group tial of adjuvant 5-fluorouracil(5-FU) plus levamisole in colon cancer demonstrated a 39% decrease in the risk of recurrence, 32% decrease in the risk of cancer-related deaths, and a 31% decrease in the risk of overall deaths in patients with regional lymph node involvement (Stage C) at a median follow-up of 5 years.3r4

In two trials of adjuvant therapy of high-risk (Stage B,-C) rectal cancer, the combination of postoperative radiation therapy with 5-FU-based systemic chemotherapy has been demonstrated to significantly decrease recurrence rate and the time to recurrence and to improve overall survival compared with a treatment of surgery alone or postoperative radiation therapy

An interesting emerging issue is how adjuvant therapy, the standard of care for Stage C colon and high-risk rectal cancer, will affect the natural history of these diseases with respect to changing patterns of re-

Nonsurgical ManagementlVaughn and Haller 4279

currence. For example, 5-FU/levamisole adjuvant treatment in Dukes C colon cancer resulted in a decreased recurrence rate at all disease sites but with relatively greater improvement in extraabdominal region^.^ An additional issue is whether aggressive postoperative monitoring, including surveillance by carcinoem- bryonic antigen (CEA) levels and imaging techniques such as computed tomography (CT), magnetic reso- nance imaging, and radioimmunoscintography will re- define the natural history of recurrent colorectal cancer and allow earlier detection and treatment of recurrent disease.

Locoregional Recurrence of Rectal Cancer

Locoregional recurrence of rectal cancer is an important cause of morbidity and mortality. The risk of pelvic recurrence is directly related to the stage of the tumor. The incidence of local recurrence of rectal cancer with extension through the wall (Modified Astler-Coller (MAC), B2 and B3; TNM, T,N, and T,N,) or with regional lymph node involvement (MAC, C1; TNM, T,N, or T,N,) has been reported to be 20-40%.8,9 Lesions with both of these poor prognosis characteristics (MAC, C2 or C3; TNM, T,-,, N1.J are associated with an overall recurrence rate of 40-65%.8*9 In addition, there is a relationship between the risk of local failure and the location of the tumor within the rectum; that is, lower segment cancers are much more likely to recur than middle or upper segment lesions." Local failure in patients with rectal cancer may be related to the inability to obtain wide radial surgical margins around the primary tumor when there is infiltration of the tumor through the intestinal wall into perirectal fat. In addition, it may not be possible to adequately excise all of the lymph node regions at risk for recurrence, especially with lower segment tumors. Factors that have not been shown to clearly affect the rate of recurrence include the type of surgery (that is, abdominoperitoneal versus sphincter-sparing resection) and the extent of clear lon- gitudinal surgical margins."

When a pelvic recurrence of rectal cancer occurs, an

Table 1. Management of Locoregional Recurrence of Rectal Cancer

aggressive multimodality approach is warranted because of potentially devastating symptoms, such as pain and organ obstruction." If a pelvic recurrence is amenable to surgical resection, this may represent the best option. An aggressive combined modality approach of surgically resectable, locally recurrent rectal cancer has been reported from the Mayo Clinic; the approach incorporates surgical resection andintraopera- tive radiation therapy, followed by postoperative external beam treatment. In this highly selected group of 24 patients, a local control rate of 85% and prolonged survival of 67% were seen at a mean follow-up of 20 months.', However, most series have shown that most locoregional pelvic recurrences are unresectable, partic- ularly when sympt~matic. '~ Thus, management of unresectable locoregional recurrence with nonsurgical techniques represents the most practical and widely used palliative treatment option (Table 1).

Radiation therapy historically has been the most important modality in the management of symptomatic pelvic recurrences. In retrospective series, this therapy has been associated with subjective improvement, measured by initial pain control and improved quality of life, in 80-90% of patients.15,16 However, long-term prolongation of disease-free and overall survival after palliative radiation alone is u n ~ o m m o n . ~ ~ * ~ ~ Prospective series have examined the role of treatment with external beam radiation therapy alone and in combination with 5-FU-based chemotherapy in patients with locally recurrent, primary locally advanced, and residual rectal

For example, a Radiation Therapy Oncol- ogy Group (RTOG) trial randomized patients to receive external beam radiation alone (4500-5100 rads/5-6 weeks with or without boost) or radiation therapy with concurrent 5-FU, followed by maintenance 5-FU and semustine (methyl-CCNU)." Sixty-four percent of the entire group ultimately experienced local failure, with no significant difference in disease control seen between the two arms. Median survival between the two treatment arms was not significantly different (in the radiation therapy alone group: 17 months; in the combined therapy group: 18 months). A nonsta-

No. of Reference Type patients Treatment Response rates Survival (mo)

DobrowskyI5 R 58 EBR 90% improved pain Median 19.8 2 yr: 29% Pacini16 R 143 EBR 80.4% improved pain 2 yr: 17.5% R~rninger'~ P 129 EBR versus EBR/CT NR Median 17 versus 18

Danjoux'* P 30 EBR/CT 10% objective regression Median 17 Dobrowsky" P 15 EBR/CT 47% objective regression Median 14 R: retrospective; P: prospective; EBR external beam radiation; C T chemotherapy; NR not reported.

2 yr: 36% versus 44%

4280 CANCER Supplement Iune 15, 1993, Volume 71, No. 12

tistically significant trend toward improved survival at 2 years was seen in the combined group (44% versus 36%).

A second prospective trial, by the Eastern Coopera- tive Oncology Group (ECOG), also examined the role of chemoradiation therapy for residual, recurrent, or inoperable rectal cancer.” Patients received either continuous radiation plus 5-FU or split-course radiation plus 5-FU, and some also received postradiation maintenance 5-FU plus methyl-CCNU. An overall objective response rate was observed in only 10% of patients with measurable disease; median survival in each group was 17 months. In both of these prospective trials, toxicity was substantial, especially in patients treated with combined modality therapy. Intestinal complications, including severe diarrhea, small intestinal obstruction, and perforation, were the most important causes of treatment-related morbidity. In fact, the ECOG trial was terminated because of excessive late treatment toxicity, primarily intestinal complications.’* In a recently reported series of 15 patients with inoperable presacral recurrences of rectal cancer, split-course radiation therapy was administered with 5-FU/mitomycin C. This nonrandomized prospective trial showed an objective response rate of 47%, with a median survival of 14 months. Only 6 of 15 patients completed therapy as planned because of excessive gastrointestinal and hematologic toxicity.”

Because of the heterogeneous patient populations treated in these prospective studies, definitive recom- mendations with respect to the optimum management of pelvic recurrences can not be concluded. Given the proven efhcacy of combined chemoradiation therapy in the adjuvant setting of rectal ~ a n c e r , ~ - ~ this has become the standard treatment of local recurrence in patients who have not previously been radiated. However, as demonstrated in the prospective trials of combined modality therapy, toxicity may be substantial. As increasing numbers of patients receive aggressive adjuvant chemoradiation therapy after the primary surgical treatment of rectal cancer, fewer patients will have local failure. When patients who received radiation therapy experience disease recurrence, additional radiation therapy may be precluded and thus treatment may be limited to chemotherapy alone with other palliative measures.

Pelvic arterial chemotherapy given with 5-FU plus mitomycin C administered via the bilateral iliac arteries has been studied in patients with painful pelvic recurrences of rectal cancer who have not responded to prior radiation therapy or systemic chemotherapy. In one series, 50% of these patients experienced short-term (3-4 months) pain relief, and therapy was associated with a median survival of 12 months.” Thus, this form of ther-

apy may not be cost-effective given its technical limitations and short duration of benefit and is not routinely recommended.22 Intraluminal cryotherapy is an innovative therapeutic modality that may be useful for palliative treatment of recurrent rectal cancer. In a pilot series, 20 patients with unresectable local recurrence received cryoprobe treatment of the intraluminal tumor. Nine patients experienced complete symptom relief, with a median symptom-free interval of 11 months; 5 of these 9 patients died without evidence of local disease.23

In addition to specific antitumor therapy, symptomatic pelvic recurrences often may require additional palliative therapy for control of pain. Lumbar-sacral nerve block and the use of opioid analgesics, especially of the long-acting type, may be important treatment modalities used in conjunction with antitumor therapies when the patient has experienced disease progression after radiation and chemotherapy.22 In addition, noncurative surgical procedures such as the placement of ureteral stents and colostomies in patients with organ obstruction caused by pelvic recurrence may offer significant palliation in selected patients.

Liver Metastases

The liver is the most common site of initial distant relapse in colorectal cancer. Although approximately 20% of liver metastases are identified synchronously with presentation of the primary tumor, most become clinically apparent after surgical r e ~ e c t i o n . ~ ~ , ~ ~ Survival of patients with liver metastases caused by colorectal cancer is extraordinarily variable. The commonly accepted median survival of 6 months may be shorter or much longer, depending on major prognostic variables for predicting survival, such as the extent of hepatic involvement, presence or absence of extrahepatic disease, level of abnormalities of liver function tests, and performance status of the patient.26 Although retrospective and prospective series have shown surgical resection to be the only potentially curative approach for the treatment of liver metastases, most patients do not have disease that is resectable. Only approximately 20% of patients who undergo resection are alive and free of disease at 5 year^.^^,^' Thus, nonsurgical modalities remain important in the management of patients with colorectal liver metastases. Standard systemic chemotherapy with 5-FU or 5-FU/leucovorin may be ex- pected to result in objective response rates of 25-4070 in these patients.29 To potentially increase this observed response rate, organ-targeted arterial chemotherapy has been developed to improve the efficacy of treatment for patients with tumor localized to the liver.

The rationale for intraarterial chemotherapy is

Nonsurgical ManagementlVuughn and Huller 4281

based on the hypothesis that increased local drug con- centration may improve the tumor response rate.30 Whereas normal liver parenchyma and early micrometastases are fed by the portal vein, established hepatic metastases are believed to receive most of their blood supply from the hepatic artery.31 Thus, intraarterial hepatic chemotherapy results in higher tumor drug con- centration than that achieved with intravenous adminis- t ra t i~n.~ ' In addition, metabolism of agents, including the fluoropyrimidines, delivered via the hepatic intraarterial route results in the clearance of at least 80% of the administered dose. This allows less exposure of normal extrahepatic tissues to the drug, resulting in less systemic Thus, there is compelling physiologic and pharmacologic rationale for the administration of drugs via the hepatic artery."

In the 1970s, investigators began trials using external pumps to deliver 5-FU and floxuridine via the cath- eterized hepatic artery to patients with liver metastases from a variety of gastrointestinal adenocarcinomas, including colorectal ~ a n c e r . ~ ~ - ~ ~ These early studies demonstrated objective response rates ranging from 25% to 71%, with an average response rate of 55%, suggesting an improvement over standard 5-FU chemotherapy. However, this treatment often required hospital admit- tance and immobilization of the patient. Arterial throm- bosis (go/, on average) and catheter dislodgement (in 10-15% of patients) also were important complica- t i o n ~ . ~ ~ For these reasons, hepatic arterial therapy was not widely accepted by the oncologic community, despite the increased response rates.

The field of arterial-directed chemotherapy for liver metastases was advanced by the development of surgically implanted infusion pumps.41 These pumps have been shown to have advantages to earlier techniques because of the decreased risk of arterial thrombo- sis, catheter dislodgement, and catheter-related sep- s~s .~ ' Cost-benefit analysis comparing these pumps to the external delivery system also has shown the implantable pump to be more economical when more than 4 months of treatment is planned.42

Randomized trials (Table 2) of intraarterial fluorodeoxyuridine via the implantable pump compared with systemic chemotherapy in patients with unresectable hepatic metastases from colorectal cancer have been performed by Kemeny et al.,43 Chang et al.,44 Hohn et al.,45 Martin et al.,46 and Rougier et al.47 Three of the studies used floxuridine as the systemic the rap^:^-^^ whereas two used 5-FU.46,47 All of these studies have shown a statistically significant improved objective response rate in the intrahepatic group (42-62%) compared with the systemic group (10-219'0). However, no definite significant survival advantage for intrahepatic therapy has been demonstrated in any of these studies. In the studies performed by Kemeny et al.43 and Hohn et al.,45 the therapy for patients receiving systemic therapy who experienced hepatic progression could be crossed-over to the intrahepatic therapy. Thus, survival advantages of patients for either therapy alone could not reliably be determined.

In the study by Chang et al., a statistically insignifi- cant survival difference of 17 months for the intrahepatic group was demonstrated compared with 12 months for the systemic group when analyzed by intent-to- treat. However, if only treated patients were analyzed, the median survival of the intrahepatic group was 19 months compared with 13 months for the systemic

The study by Rougier et al. showed a median survival of 14 months for the patients treated with intrahepatic therapy, compared with 10 months for those treated with "palliative" therapy (P < 0.02). However, only half of the latter group received systemic 5-FU, whereas the other half received no chemotherapy. The true survival and response rates for the subgroup treated with systemic 5-FU are not de~cribed.~' Thus, while these studies have nearly always demonstrated a clear advantage of intrahepatic therapy for objective response rates, the effect of this treatment on survival is not clear, perhaps because of methods of study design and data analysis. No randomized trial has compared intrahepatic floxuridine with systemic 5-FU/leucovorin regimens that have been associated with increased re-

Table 2. Randomized Trials of Intrahepatic Floxuridine versus Systemic Floxuridine or 5-Fluorouracil

No. of Response Median survival patients rate (mo)

Reference IH s IH S P value IH S P value

kern en^'^ 48 50 50% 20% 0.001 17 12 0.4 Chang" 21 29 62% 17% < 0.003 17 12 0.27 Hohn" 50 65 42% 10% = 0.0001 16.7 16.1 NS Martin'6 33 36 54% 21% = 0.02 12.6 10.5 0.53 Rougier4' 81 82* 48% 14% NS 14 10 < 0.02 IH: intrahepatic; S: systemic; NS: not stated. * Onlv half of these patients received 5-fluorouracil

4282 CANCER Supplement June 25, 2993, Volume 71, No. 12

sponse rates and survival advantage compared with the use of 5-FU alone.29

There are two major drawbacks to intrahepatic therapy for the treatment of liver metastases from colorectal cancer: extrahepatic progression and toxicity. Despite clearly improved intrahepatic tumor response rates and a trend toward improved survival in some trials with intrahepatic chemotherapy, a review of these data re- veals that consistent improvements in overall and disease-free survival are limited by the development of distant metastasis in extrahepatic sites. Extrahepatic relapse has been reported to occur in 36-50% of patients treated with intrahepatic therapy, most commonly in the lungs.22 Because symptoms and survival are most likely to be determined by the status of hepatic disease, continued intrahepatic therapy occasionally has been recommended, even when extrahepatic progression is present.22 Others have attempted to delay or prevent extrahepatic failure by initiating trials of combined intrahepatic and systemic chemotherapy.

Initial studies from Memorial Sloan-Kettering Cancer Center using combinations of intrahepatic floxuridine and systemic 5-FU/leucovorin have suggested increased gastrointestinal and hepatic toxicity when the systemic chemotherapy regimen was given for 5 succes- sive days and when the systemic chemotherapy regimen closely followed the intrahepatic treatment4* A partial response rate of 56% with a median survival of 16 months was noted in 21 patients treated in this trial. A trial by Safi49 has been reported in which patients with liver metastases were randomized to receive either floxuridine 0.2 mg/kg/day by the intrahepatic route or floxuridine 0.3 mg/kg/day administered simulta- neously by the intrahepatic and systemic routes for 14 days each month. A response rate of 59% was reported in the intrahepatic group and 57% in the combined group. Seventy-nine percent of the intrahepatic and 51 9'0 of the combined group experienced extrahepatic relapse in a median follow-up of 24 months ( P < 0.01). No significant survival differences were observed, and toxicity in both treatment arms was similar.49

At the University of Pennsylvania, a Phase 1/11 trial of combined intrahepatic floxuridine with weekly systemic 5-FU plus high-dose leucovorin is being piloted for patients with liver metastases caused by colorectal cancer. In this trial, the weekly systemic and intrahepatic regimens are separated by rest periods in an attempt to prevent the gastrointestinal, mucosal, and hepatic toxicity reported in the Memorial Sloan-Kettering Cancer Center pilot study. Whether combined intrahepatic and systemic treatment will prove to offer advantages to the use of either treatment modality alone re- mains to be determined.

The second major limitation to intraarterial floxuri-

dine is hepatobiliary toxicity. In a recent review, approximately 25% of patients who received intrahepatic floxuridine had bilirubin elevation, with biliary sclerosis occurring in 159'0.~' Biliary sclerosis is observed most often when high doses of floxuridine (0.3 mg/kg or greater) are infused for 2 or more weeks or when early signs of biliary toxicity, such as an increasing alkaline phospha- tase level, are ignored. Chemical hepatitis also may occur and should be suspected when transaminases are increased. Both of these hepatobiliary toxicities often resolve with temporary cessation of treatment. Perma- nent damage to the biliary tree has been reported."

Innovative approaches to limit hepatobiliary toxicity have been studied. One such approach has been to alternate intrahepatic floxuridine with 5-FU, an agent with less first-pass hepatic extraction and thus less biliary toxicity than floxuridine, but also less effi~acy.~' Al- ternating intrahepatic floxuridine 0. l mg/kg/day for 7 days with intrahepatic bolus 5-FU 15 mg/kg on days 14, 21, and 28 resulted in response rates of 51%, with only approximately 10% of patients requiring dose modification because of hepatobiliary toxicity; this rate is less than that previously demonstrated in control subjects. An alternate approach was proposed by Seifer et al., who conducted a prospective trial in which intrahepatic floxuridine 0.3 mg/kg/day for 2 weeks per month was administered with or without intrahepatic dexamethasone at a total dose of 20 mg during a 2- week period. A trend toward less biliary toxicity, as manifested by decreased bilirubin levels, was noted in the group receiving the dexamethasone, but the difference was not significant (99'0 versus 32%; P = 0.07).52

Circadian modification (CM) of intrahepatic floxuridine infusion has been compared with flat drug administration in a retrospective study of 50 patients at the University of Minnesota.53 By administering the drug via CM with 68% of the drug administered in the early evening (between 3 p.m. and 9 p.m.) and only 3% in the morning (between 3 a.m. and 9 a.m.), the group receiving the CM floxuridine tolerated more of the drug with less hepatic toxicity than did control subjects receiving standard floxuridine. Although innovative approaches to administering floxuridine by the intrahepatic route may reduce hepatic toxicity, none have been demonstrated to be uniformly reliable in a prospective randomized trial, and use of these regimens outside the context of a clinical trial cannot be recommended.

An additional toxicity related to intrahepatic therapy is gastric ulceration, which is reported in 40% of patient^.^' This presumably is attributable to perfusion of the stomach and the duodenum with floxuridine via the small vessels branching from the hepatic artery. The incidence of this toxicity may be markedly decreased by careful surgical techniques, including ligation of the

Nonsurgical Management/Vaughn and Haller 4283

vessels that supply the stomach and duodenum.54 Gas- tric ulceration often resolves upon discontinuation of therapy and may respond to H,-antagonist therapy, such as cimetidine or ranitidine.

In an attempt to increase the response rate with intrahepatic therapy, additional nonrandomized studies have used floxuridine in combination with other agents administered intraarterially, including mitomycin C or platin~m,’~-’~ 5-FU,” or l e u c ~ v o r i n . ~ ~ ~ ’ ~ These studies generally have not shown a dramatic difference in the rate of response compared with that seen with floxuridine alone. In addition, hepatobiliary toxicity was markedly increased in the floxuridine/leucovorin trial^.'^,^^ Additional studies combining floxuridine with other modulators (alpha-interferon) or using intraarterial floxuridine in the adjuvant mode after curative resection of liver metastases are planned.” Finally, innovative Phase I trials have used the intraarterial route for delivering biologic agents to the liver, including interleukin-2 (IL-2)60 and tumor necrosis factor (TNF).61 Although IL-2 produced an overall response rate of less than lo%, TNF showed some promise in patients who had failed to respond to standard chemotherapy, producing an objective response rate of approximately 20%.

Hepatic arterial chemoembolization has been used in the management of liver tumors. This therapy in- volves instillation into the hepatic artery of an embolic mixture that incorporates chemotherapeutic agents.’* By blocking perfusion of the tumor, and by delivering high concentrations of cytotoxic agents directly to the tumor, chemoembolization has resulted in significant response rates in metastatic carcinoid tumors6’ and primary hepatocellular carcinoma^.^^ Recently, chemoembolization trials have been expanded to include hepatic metastases caused by colorectal ~ a n c e r . ~ ~ - ~ ~ The largest series of patients treated with this technique included 52 patients with hepatic metastases from colorectal carcinoma who had failed to respond to systemic chemotherapy.66 In this trial, patients were treated with an embolic mixture of collagen, cisplatin, doxorubicin, and mitomycin C. Thirty-four percent of patients had a more than 50% reduction of measurable tumors on CT, and 78% had a more than 50% reduction in CEA levels. Projected median survival after embolization was 335 days.

Another experimental approach to the directed treatment of liver metastases is percutaneous ethanol injection into the tumor.67 In one series, 14 patients, half with metastatic colorectal cancer, were treated in 175 sessions for a total of 204 ethanol injections without serious complications. In the patients with colorectal metastases, a decline in CEA was noted in six of seven patients. However, significant responses based

on CT criteria were not seen. The best responses in this series were seen in patients with metastases from neuro- endocrine tumors. ”

Investigators at the University of Pittsburgh have reported therapy of unresectable liver metastases from a variety of cancers with the intraoperative placement under ultrasonographic guidance of cryoprobes that subject the tumor to temperatures as low as -180°C. Preliminary results demonstrate that 36 of 53 (68%) patients treated with ”cryosurgery” are alive 1-39 months after treatment (average, 12 months), with nor- malization of CT and CEA levels occurring in 29 patients. 68

Although these innovative liver-directed therapies offer promise of improved local control, the reported nonrandomized series may reflect positive outcomes in highly selected patient cohorts and may not be general- izable. In addition, the progression of untreated hepatic micrometastases and extrahepatic metastatic progression during treatment with these local therapies may limit their efficacy in terms of overall survival.

In summary, randomized studies have shown that the intraarterial route for administering chemotherapeutic agents to liver metastases results in a greater response rate than that seen with systemic chemotherapy. However, intraarterial therapy has not been directly compared with systemic 5-FU/leucovorin in a randomized trial. In addition, survival has not defini- tively been shown to be significantly improved by this therapy. Dose-limiting toxicity, principally hepatobiliary, also affects the widespread use of this treatment. Trials that combine intrahepatic therapy with systemic chemotherapy define ways in which extrahepatic failure may be reduced. Finally, chemoembolization, percutaneous ethanol injection, and cryosurgery are innovative options that need additional testing in clinical trials as palliative therapy for patients with nonresectable symptomatic liver metastases who have failed primary systemic chemotherapy. As local measures, these techniques do not fully address the natural history of recurrent colorectal cancer, which usually is multicentric. Combinations of regional and systemic treatments may allow more comprehensive therapy for these patients.

Disseminated Disease

Since the mid-l950s, the mainstay of systemic chemotherapy for metastatic colorectal cancer has been 5-FU. In collected series of patients, objective response rates obtained with standard bolus 5-FU have been in the range of 10-20%, with no consistent improvement in survival.69 Mitomycin C and the chloroethylnitroso- ureas have shown only marginal activity in patients


with advanced colorectal cancer, whereas other chemotherapeutic agents, alone or in combination with 5-FU, generally have been ineff e ~ t i v e . ~ ~ The most important recent advance in the management of metastatic colorectal cancer has been the evolution of programs that use biochemical modulation of 5-FU.29 Biochemical modulation refers to the alteration of 5-FU cytotoxicity by the addition of other agents, such as leucovorin (folinic acid), recombinant interferon alpha-2a (rIFN a-2a), phosphonacetyl-L-aspartate (PALA), methotrexate, and cisplatin.The tumor cytotoxicity of 5-FU depends on alteration in a number of biochemical pathways involved in nucleotide synthesis. In one important pathway, the metabolite of 5-FU, fluorodeoxyuridine monophosphate (FdUMP), competitively binds to thymidylate synthase, resulting in diminished DNA synthesis by the depletion of thymidine. 5-FU also is metabolized via the ribonucleotide pathway to yield 5- fluorouridine triphosphate (FUTP), a competitive substrate for RNA polymerase that upon incorporation into RNA may be cytot~xic.~' The various modulators of 5- FU act at different points of the metabolic cycle of 5-FU to enhance its cytotoxicity (see Fig. 1).

The best-studied modulator of 5-FU is leucovorin, a reduced folate that enhances the cytotoxicity of 5-FU by increasing the inhibition of thymidylate synthase by FdUMPe7' Multiple clinical trials recently have been reported that establish the efficacy of various combinations of 5-FU/leucovorin in metastatic colorectal cancer compared with standard bolus 5-FU therapy (Table 3).29 Petrelli et aL7' from Roswell Park Cancer Institute (RPCI) reported a treatment program in which 5-FU 600 mg/m2 plus leucovorin 500 mg/m2 (high dose) were administered weekly for 6 weeks, followed by a

2-week rest period. In a Phase I11 trial comparing this regimen to single-agent 5-FU, a statistically significant improvement in objective response rates was seen (48% versus 11%; P = 0.0009).

The efficacy of this regimen was additionally confirmed in a Phase I11 trial by the Gastrointestinal Tumor Study Group (GITSG), in which the same weekly 5-FU plus high-dose leucovorin regimen was compared with weekly 5-FU plus low-dose (25 mg/m2) leucovorin and with 5-FU alone.72 A statistically significant improved response rate of 30% was seen with the high-dose leucovorin treatment arm (P < 0.01) but not with the low- dose leucovorin regimen. Survival was modestly, but not statistically significantly, prolonged. Toxicity with the high-dose leucovorin regimen was substantial. Se- vere diarrhea occurred in 25% of those treated, and 5% of patients died of diarrhea-related events. The investigators advised careful monitoring of patients treated with this regimen, early treatment of diarrhea-related dehydration with intravenous fluids, and cessation of chemotherapy until resolution of all symptoms. Al- though this weekly 5-FU/high-dose leucovorin regimen also occasionally produced mucositis and conjunc- tivitis, significant hematologic toxicity was uncommon. Because of the severe diarrhea associated with this regimen, standard practice reduces the dose of 5-FU to 500 mg/m2 given with leucovorin 500 mg/m2.

A second commonly used regimen of 5-FU/leucovorin was studied prospectively by the North Central Cancer Treatment Group (NCCTG).73 This program initially incorporated 5-FU 370 mg/m2 with leucovorin 200 mg/m2 (high dose) or 20 mg/m2 (low dose) administered for 5 consecutive days monthly. Because of lack of significant toxicity in

IFN LV > FH2 FH4

Thyrnidylate Synthase

5-FdUMP -5-FdUDP -5-FdUTP *5-FDNA

IFN P MTX P 5-FUdR

5-FU -< MTxx 5-FUMP -> J-FUDP,-D 5-FUTP -> 5-FRNA

PALA

the- first group of 100 patients,

Figure 1. Pathways of 5-FU metabolism and the effects of biochemical modulators. After initial phosphorylation of 5-FU to 5-FUMP, additional metabolism along the ribonucleotide pathway yields 5- FUTP, a substrate for RNA polymerase (RNAse); incorporation of 5-FU into RNA may be cytotoxic. Phosphonacetyl-L-aspartate (PALA) inhibits de novo pyrimidine synthesis, depleting UTP, and increasing 5-FU incorporation into RNA. 5-FU also may be metabolized along the deoxynucleotide pathway. 5-FdUMP inhibits thymidylate

~~

synthase (TS) and arrests DNA synthesis. Leucovorin (LV) increases intracellular levels of reduced folates and increases inhibition of thymidylate synthase (TS). Interferon-a (IFN) inhibits thymidylate synthase (TS) and augments conversion of 5-FU to 5-FdUMP. Methotrexate (MTX) decreases purine nucleotide synthesis, resulting in an increase of intracellular phosphoribosylpyrophosphate, favoring the synthesis of 5-FdUMP and FUTP.

Nonsurgical Management/Vaughn and Huller 4285

Table 3. Selected Phase 111 Trials of 5-Fluorouracil(5-FU)/Leucovorin

No. of Reference uatients Dosehchedule Response rate

Median survival

Petrelli7' 44 5-FU 600 mg/m2 + L 500 mg/m2 X 6 wk versus 5-FU 450 mg/m2 X 5 every 4 wk

GITSG72 318 5-FU 600 mg/m2 + L 500 or 25 mg/m2 X 6 wk versus 500 mg/m2 X 5 every 4 wk

mg/m2 X 5 d every 4 wk versus 5FU 500 mg/mz X 5 d every 4 wk

5-FU 370 mg/m2 X 5d + L 500 mg/m2 X 6 d every 4 wk versus 5-FU 370 mg/m2 X 5 d every 4 wk

5-FU 370 mg/m2 + L 200 mg/m2 X 5 d every 4 wk versus 5-FU 370 mg/m2 X 5 d every 4 wk

5-FU 400 mg/m2 + L 200 mg/m2 X 5 d every 4 wk versus 5-FU 480 mg/m2 X 5 d then 600 mcr/m2/wk

NCCTG73 208 5-FU 370-425 mg/m2 + L 20 or 200

D o r o ~ h o w ~ ~ 74

E h r l i ~ h m a n ~ ~ 124

valone7' 153

48% versus 1 1 % (P = 0.0009)

30.3% versus 18.8% versus 12.1% (P < 0.01 for high- dose versus 5-FU alone)

43% versus 26% versus 10% (P = 0.001 for low-dose versus 5-FU alone)

44% versus 13% (P = 0.0019)

33% versus 7% ( P < 0.0005)

18.8% versus 16.9% (P < 0.4)

Estimated 12 mo versus 11 mo (P = 0.6)

55, 45,46 wk (P = 0.08)

53,52, 34 wk (P = 0.05)

62 versus 55 wk (P = 0.25)

54 versus 41 wk (P = 0.05)

24 versus 20 wk (P > 0.4)

L leucovorin; NS: not significant

the investigators increased the 5-FU dose to 425 mg/mz in the low-dose leucovorin treatment arm. These two regimens were compared prospectively to 5-FU alone and to 5-FU in combination with methotrexate and with cisplatin. The low-dose leucovorin schedule produced the highest response rate (43%) compared with the high-dose regimen (26%) or with 5-FU alone (1Oo/o),

In addltion, treatment with either of the leucovorin regimens resulted in a modest, but statistically significant, prolongation of survival compared with 5-FU alone (12.2 months for the high-dose regimen, 12.0 months for the low-dose regimen, and 7.7 months for the 5-FU alone regimen). Quality of life indices, including performance status, weight gain, and symptoms, were significantly improved in the low-dose leucovorin treatment arm. Toxicity of the 5-FU/leucovorin regimens was principally stomatitis, occurring severely in 30% of those in the high-dose treatment arm and in 26% of those in the low-dose treatment arm. Severe diarrhea did not occur more often in the leucovorin treatment arms than in the 5-FU alone treatment arms. No deaths were attributed to nonhematologic toxicity. Severe leukopenia (leukocyte count of less than 2000) occurred in approximately 20% of patients treated with 5-FU and leucovorin. Thus, because of the increased response rate, acceptable toxicity, and lower cost of the 5-FU/ low-dose leucovorin regimen, the authors and othersz9 have recommended this regimen as the standard treatment of metastatic colorectal cancer.

The results of this trial recently were updated, con- firming the efficacy of the 5-day 5-FU with low-dose (20 mg/m2) leucovorin compared with 5-FU and high-

dose leucovorin (200 mg/m2) or a 5-FU/methotrexate ~ombina t ion .~~ As shown in Table 3, other randomized trials of 5-day regimens of 5-FU/leucovorin have been performed, generally using higher doses of leucovorin, ranging from 200 to 500 mg/mz.75-77 In most, statistically significant improved response rates were seen with the combined therapy compared with 5-FU alone. In one trial, a statistically significant increase in survival was reported.76

A direct comparison of the two most commonly used regimens of 5-FU/leucovorin recently was reported, in which 370 patients with advanced colorectal cancer were randomized to receive the GITSG regimen (5-FU 600 mg/mz and leucovorin 500 mg/m2 weekly for 6 weeks, followed by a 2-week rest) or the NCCTG regimen (5-FU 425 mg/m2 and leucovorin 20 mg/m2 daily for 5 days every 4-5 weeks).78 No statistically significant difference was demonstrated between the two regimens with respect to response rate (28% for GITSG, 33% for NCCTG; P = 0.47) or median survival (10 months for both; P = 0.69). Toxicity analysis confirmed diarrhea to be the dose-limiting toxicity of the GITSG regimen, and stomatitis for the NCCTG regimen. Life- threatening and lethal toxicity of the regimens was similar at 2%, but total time in the hospital to manage toxicity was greater for the GITSG regimen (436 versus 317 patient-days; P = 0.07). The authors concluded that the NCCTG regimen is superior based on decreased patient hospital stay for toxicity and treatment cost. However, in this trial the dose of 5-FU used in the high-dose leucovorin regimen was 600 mg/m2, rather than the better tolerated, and more widely used, 500 mg/m2.


A meta-analysis of updated data from ten randomized clinical trials of 5-FU/leucovorin compared with 5-FU alone has been reported.79 A total of 803 patients were treated with 5-FU/leucovorin regimens and 5 78 with 5-FU alone. Treatment with 5-FU/leucovorin either on a weekly or 5-day per month regimen produced a highly significant benefit compared with single-agent 5-FU in terms of overall objective response rates (23% versus 11%; P < However, this increased response rate did not result in improvement in overall survival. The authors attributed the discrepancy between response and survival to the large number of patients in both groups that had no response to therapy and the low complete remission rates of 3% or less in both groups. In addition, data from the NCCTG trial, which demonstrated a survival advantage for patients receiving 5-FU/leucovorin, were not included in the meta-analysis. Many patients with tumor progression after 5-FU therapy alone subsequently received treatment with 5-FU/leucovorin, so a true survival comparison was not possible.

Although progress in treating metastatic colorectal cancer has been made by modulating 5-FU with leucovorin, this therapy is not curative and most patients do not achieve an objective response. Thus, efforts have been made in investigating other modulating agents: specifically, rIFN a-2a, PALA, methotrexate, and cisplatin. rIFN a-2a was shown in preclinical investigation to interact with 5-FU by a variety of mechanisms: by decreasing 5-FU clearance, by decreasing thymidine ki- nase activity, by inhibiting thymidine incorporation into DNA, by decreasing the rate of thymidine phosphorylation,” by enhancing thymidylate synthetase inhibition,” and by increasing intracellular accumulation of FdUMP.” On the basis of this preclinical data, Wadler et aLa3 treated 30 patients with advanced colorectal cancer with 5-FU 750 mg/m2 by continuous infusion for 5 consecutive days, followed by weekly bolus administration and rIFN a-2a 9 X lo6 U thrice weekly. Although no major responses were seen in any of the patients who had previously received 5-FU, a response rate of 76% was demonstrated in previously untreated patients.83 Initial enthusiasm for this regimen was tem- pered by a second Phase I1 study that used the same regimen in untreated patients and showed an overall response rate of 35%, with a median duration of response of 7.5 months. Significant granulocytopenia (43%), mucositis (50%), and a flu-like syndrome of fever, chills, and myalgias seen in nearly all patients were the major to~ici t ies .~~ This combination of 5-FU and rIFN a-2a versus the same 5-FU regimen alone is being examined in Phase I11 trials of previously untreated patients with advanced colorectal cancer to de-

termine the extent to which rIFN a-2a improves the results with this particular 5-FU regimen.

In a dose-escalated pilot study in patients with metastatic gastrointestinal cancers,85 rIFN a-2a in doses ranging from 3 to 9 X lo6 U/m2/day for 7 days was combined with 5-FU 370-425 mg/m2 and high-dose leucovorin 500 mg/m2 administered by bolus for 5 consecutive days per month. Among patients with advanced colorectal carcinoma, an overall objective response rate of 44% was demonstrated. The toxicity of the addition of rIFN a-2a to 5-FU and high-dose leucovorin was examined in matched cycles (that is, the IFN a-2a was administered in the second cycle but not in the first) and was found to increase the incidence of mucositis from 0% to 31%, diarrhea from 0% to 23%, and decrease the median platelet nadir from 216-164 X 103/pL. The median leukocyte and granulocyte na- dirs were not affected. The toxicity induced by the addition of rIFN a-2a occurred in a dose-dependent man- ner and prohibited the escalation of 5-FU dose. The authors recommended the 5-day regimen of 5-FU 370 mg/m2 and leucovorin 500 mg/m2 with rIFN a-2a 5 X lo6 U/mz/day as a regimen with acceptable toxicity that deserves additional study in a Phase I1 trial.

Because the cytotoxicity of 5-FU is partly related to its incorporation into RNA, natural nucleosides such as uridine compete with 5-FU for this incorporation. PALA decreases uridine and cytidine pools by inhibiting pyrimidine synthesis and thus enhances the activity of 5-FU.s6*87 Phase I trials of PALA established that at high doses, the dose-limiting toxicity was neurotoxicity, specifically cerebellar ataxia. However, it also has been shown that maximal inhibition of pyrimidine synthesis occurs at a much lower dose l e ~ e l . ~ ~ , ~ ~ In a Phase I1 study of weekly treatment with PALA at 250 mg/m2 and 5-FU 2600-3250 mg/m2 by 24-hour continuous infusion in advanced colorectal cancer, response rates as great as 43% were dem~nstrated.~’ The regimen in- corporating 5-FU 2600 mg/m2 was well-tolerated, with severe diarrhea and neurotoxicity noted in only a few patients. A second study used PALA 250 mg/m2 and dose-escalated bolus 5-FU at 600, 700, or 800 mg/m2 administered weekly, followed by a 2-week rest.” An overall response rate of 35% was seen. Significant diarrhea was noted in 24% of patients at the 700 mg/m2 dose and 43% at the 800-mg/m2 dose. Significant hematologic toxicity (Grade 4 leukopenia) occurred only at the 800-mg/mz dose. Phase 111 trials comparing weekly continuous infusion 5-FU and bolus PALA with other regimens of biochemically modulated 5-FU are being conducted by the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG) and are depicted in Table 4. These studies also


directly compare the 5-FU/PALA regimen to the weekly infusional high-dose 5-FU regimen alone and should help define the importance of PALA in this regimen.

Methotrexate and cisplatin are other agents that have been used in combination with 5-FU. Methotrex- ate appears to enhance 5-FU cytotoxicity by inhibition of purine metabolism, resulting in an accumulation of phosphoribosylpyrophosphate and, subsequently, an increased formation of 5-FU/ribonucleotide com- p o u n d ~ . ~ ~ The sequential timing of administration of the two agents has been shown to be important. In a prospective randomized trial by Marsh et al.,92 5-FU was given 1 or 24 hours after the administration of methotrexate. A statistically improved response rate and survival benefit was demonstrated with the longer interval regimen. Multiple randomized studies have compared sequential methotrexate/5-FU combinations with 5-FU alone.73,77*93,94 Only one of these showed a statistically significant increase response rate for the methotrexate/5-FU regimen,93 whereas the other studies showed roughly equivalent response rates. Two of the studies showed significant improvement in quality of life variables, such as weight gain, performance status, and relief of symptoms, compared with those associated with single-agent 5-FU the rap^.^^,^^ However, in one of these studies, the regimen was inferior to 5-FU/ low-dose leucovorin in terms of response rate and quality of life variables.73 Thus, although methotrexate mod- ulates 5-FU and this combination may be modestly better than 5-FU alone, most investigators agree that it is not superior to 5-FU/leucovorin in overall cytotoxicity.

Cisplatin was demonstrated to be synergistic with 5-FU in the murine L1210 leukemia line.95 However, initial Phase I1 trials of bolus 5-FU given with cisplatin resulted in excessive myelosuppression, principally significant leukopenia and granul~cytopenia .~~,~~ Random- ized trials of bolus 5-FU/cisplatin have failed to show any benefit compared with 5-FU a l ~ n e . ~ ~ , ~ ' Thus, the addition of cisplatin to 5-FU appears to add significant toxicity without an appropriate increase in benefit and is not recommended as first-line therapy in metastatic colorectal cancer. There are reports that the addition of meth~trexate~~ or cisplatin"' to 5-FU may result in responses in patients who have failed to respond to 5-FU alone, suggesting that these combinations may be useful as salvage regimens in selected patients.

An alternate strategy to biochemical modulation of bolus 5-FU is to enhance its cytotoxicity by alterations of dose and schedule, including continuous infusion. 5-FU has a short half-life (approximately 10-20 min- utes)"' and preclinical studies have addressed this as a basis for ineffective cytotoxicity.lo2 Dose escalation stud-

ies in humans have established 300 mg/m2/day as the maximum tolerated dose for protracted continuous infusion (10-week infusion). At this dose, an objective response rate of 38% was seen in patients with metastatic colorectal ~ a n c e r . ~ ' ~ , ~ ' ~ A Phase I11 trial comparing this dose and schedule of 5-FU with standard 5-day bolus 5-FU alone was performed by the Mid-Atlantic Oncology Program (MAOP).'05 A statistically significant improved response rate was seen in the continuous infusion treatment arm (30%) compared with the bolus treatment arm (7%; P < 0.001). Despite this improvement in response rate, overall median survival was identical in the two treatment arms.

Different patterns of toxicity were observed for each of these regimens. In the standard bolus treatment arm, bone marrow suppression, especially leukopenia, was seen in 14% of patients and stomatitis was noted in 13%. In the continuous infusion group, leukopenia was seen in only 1% of patients and stomatitis in 4%. How- ever, palmar-plantar erythrodysesthesia or "the hand- foot syndrome," a relatively uncommon side effect with bolus 5-FU therapy, occurred in 24% of patients who received protracted infusional therapy. lo6 This syndrome was never life-threatening and was fully reversible with interruption of therapy. Biochemical modulation of continuous infusion 5-FU with other agents is being studied. Bolus cisplatin has been combined with continuous infusion 5-FU and has been compared with continuous infusion 5-FU al~ne.~ '~,~ ' ' The objective of the combined continuous infusion 5-FU/cisplatin regimen was to avoid the severe dose-limiting myelotoxic- ity seen in bolus 5-FU/cisplatin trials, while potentiat- ing 5-FU cytotoxicity. In a randomized study that compared bolus cisplatin with a 5-day continuous-infusion 5-FU regimen, an increased response rate was observed than that seen with 5-FU alone (25% versus 3%; P = 0.001), but survival was not affected, and toxicity was in~reased.''~ In the second trial, protracted infusion 5-FU 300 mg/m2/day was combined with bolus cisplatin and compared with the infusional5-FU alone treatment.'" No benefit was demonstrated from the addition of cisplatin to the regimen in terms of response rates (32% for 5-FU/cisplatin versus 27% for 5-FU). The addition of cisplatin to infusional5-FU can not be recommended.

Thus, significant progress has been made with respect to the administration of 5-FU and its modulators. However, questions remain about the optimum way to treat advanced colorectal cancer with 5-FU-based regimens, both in terms of the benefit of infusional versus bolus therapy and in the role of the various 5-FU modulators. Two ongoing national Phase I11 trials (Table 4) are studying these issues. ECOG 2290 compares weekly


Table 4. Ongoing Phase I11 Trials in Advanced Colorectal Cancer

ECOG 2290

Randomize 9 5-FU 2600 mg IV by continuous infusion over 24 h every wk

5-FU 2600 mg IV by continuous infusion over 24 hr and PALA 250 mg/m’ IV every wk

5-FU 600 mg/m’ IV and leucovorin 125 mg/m2 by mouth every wk x 6,2-week rest, repeat

5-FU 600 mg/m’ IV and leucovorin 500 mg/m’ IV every wk x 6,2-week rest, then repeat

5-FU 750 mg/m’ IV x 5 d then weekly and rIFNa-Za 9 million units 3 x/wk

SWOG 8905

Randomize 9 5-FU 500 mg/m2 IV q every d x 5 d every 5 wk 5-FU 425 mg/m2 IV + low-dose leucovorin 20

mg/m’ IV every d x 5 d every 4 wk x 2 then every 5 wk

5-FU 600 mg/m’ IV + high-dose leucovorin 500 mg/m’ IV on d 1,8,15, and 22 every 4 wk

5-FU 300 mg/m’ by continuous infusion IV d 1-28 every 5 wk

5-FU 200 mg/m’ by continuous infusion IV d 1-28 + low-dose leucovorin 20 mg/m’ on d 1,8,15, and 22 every 5 wk

5-FU 2600 mg/m2 by 24-hr continuous infusion IV d 1,8,15, and 22 every 4 wk

5-FU 2600 mg/m2 by 24-hr continuous infusion preceded by PALA 250 mg/m’ IV d 1,8,15, and 22 every 4 wk

5-FU: 5-fluorouracil; I V intravenous; PALA: phosphonacetyl-L-aspartate; rIFNa-Za: recombinant interferon alpha-2a.

high-dose 24-hour infusional 5-FU alone to this same regimen of 5-FU given with weekly PALA, to weekly bolus 5-FU with high-dose leucovorin (as per the GITSG study) and to weekly bolus 5-FU with weekly oral leucovorin or rIFN a-2a. SWOG 8905 compares a 5-day regimen of bolus 5-FU, to the NCCTG and GITSG regimens for bolus 5-FU/leucovorin, to protracted continuous infusion 5-FU with or without low- dose weekly bolus leucovorin, to weekly high-dose in- fusional5-FU with or without weekly PALA. The goal of these intergroup trials with multiple treatment arms is to address the relative risks/benefits of these 5-FU- based regimens to define the optimal systemic chemotherapy for patients with metastatic colorectal cancer.

A final issue of the treatment of advanced colorectal cancer with 5-FU-based chemotherapy that should be addressed is when to commence treatment. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group recently reported their prospective trial in which a regimen of 5-FU, leucovorin, and methotrexate was administered to patients with metastatic colon cancer on diagnosis of advanced disease or development of

symptoms. Ninety-two patients received treatment on presentation, and 51 of 90 patients in the “expectancy” group received treatment. Overall survival was improved in the initially treated group compared with the expectancy group, with a difference in median survival of 5 months. The symptom-free period and the time to disease progression were longer in the initially treated group (median differences of 8 and 4 months, respectively). Thus, the authors concluded that early treatment of patients with asymptomatic advanced colorectal cancer prolongs survival, the asymptomatic period, and the time to disease progres~ion.’~~

Because most patients with advanced colorectal cancer eventually die of their disease despite chemotherapy, novel therapeutic strategies are being developed, including the use of monoclonal antibodies (MoAb), biologic response modifiers, and gene therapy. MoAb therapy for colorectal cancer has been re- viewed.”’ Among the most widely used murine MoAb are those directed against the tumor-associated anti- gens CEA, C017-1A, or TAG-72. The unconjugated murine 17-1A has been the most widely studied MoAb in advanced colorectal cancer. Several studies have demonstrated that this MoAb could be safely administered, but with objective partial response rates of less than 5% and with minor responses or stable disease in 25% of patient^."^-"^ A dose-response relationship with this agent has not been demonstrated. MoAb with specificity for tumor cells also offer the potential to deliver conjugated cytotoxic moieties to the tumor with decreased exposure to normal tissues. Radionuclides are advantageous for use as the cytotoxic moiety because internalization and activation are not needed for these agents to be effective, and sterilization of nonan- tigen-expressing neighboring cells may be a~hieved.”~

At the University of Pennsylvania, the murine MoAb B72.3 conjugated to 90Y has been administered to patients with refractory TAG-72 expressing tumors, including colorectal cancer. In a Phase I trial of this MoAb in 25 patients, reversible myelosuppression, principally thrombocytopenia, was the dose-limiting toxicity. Doses as large as 15 mCi of 90Y were administered with no objective responses dem~nstrated.”~ In an effort to increase the amount of radioisotope administered, a second Phase I pilot study was performed using the MoAb in combination with ethylenediamine tetraacetic acid (EDTA), a metal chelator that increases urinary clearance of 90Y.116 In this study, increased doses of the radioisotope have been administered, with dose-limiting reversible thrombocytopenia occurring at 15 mCi/m2. No objective responses have been seen in this heterogeneous group of mostly pretreated patients. Future studies may attempt to increase the efficacy of radiolabeled MoAb B72.3 therapy by multiple dosing

Nonsurgical Management/Vaughn and Haller 4289

and by dose escalation of the agent in combination with the radioprotectant interleukin-1 (IL-1), a strategy that has proven successful in murine models.”’,”* Based on the synergistic effects of 5-FU and radiation demonstrated preclinically by By field et al.,lI9 the radiolabeled MoAb B72.3 may additionally be tested in combination with protracted infusional 5-FU in an attempt to attain chemosensitization of the tumor cells to the radionu- clide.

Among the immunobiologic agents that have been used in metastatic colorectal cancer, rIFN a-2a has been studied most extensively. However, this agent’s primary role is as a 5-FU modulator, not as an immuno- modulatory agent.’20 In advanced colorectal cancer, recombinant IL-2, a T-cell growth factor that stimulates proliferation of lymphokine-activated killer cells, has been used. Trials of IL-2 alone, IL-2 plus lymphokine- activated killer cells, and IL-2 with rIFN a-2a in patients with advanced colorectal cancer have demonstrated response rates of O%, 13%, and 7%, respectively.”’ Toxic- ity associated with the administration of IL-2 has been significant. Finally, an emerging field in the treatment of solid tumors that has been pioneered by Rosenberg et

at the National Cancer Institute is that of gene a1.121,122

therapy. Using the administration of genetically modified tumor-infiltrating lymphocytes and IL-2, this therapy has been piloted in patients with advanced melanoma. Preliminary trials are underway at the National Cancer Institute using this treatment in patients with advanced colorectal cancer (personal communication, Rosenberg SA).

Summary

Ongoing research into the development of innovative therapies such as those discussed here and additional investigation of the optimum use of 5-FU will continue to examine the role of treatment in providing improved quality of life and prolonged survival of patients with recurrence of colorectal carcinoma. Optimum management will continue to be dependent on a multidisciplin- ary approach that uses the various modalities provided by surgery, radiation oncology, and medical oncology. These advances, as measured by their success in the management of recurrent colorectal cancer, may prove most useful in the adjuvant treatment of early stage tumors.

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