Each year approximately 130,000 patients are diagnosed with colorectal cancer in the United States, and 56,000 people die of the disease. 1 It is the third most common cause of cancer death in both men and women. Although 5-fluorouracil (5-FU) remains the mainstay of treatment in the advanced and adjuvant setting, there is still much room for improvement. The recent testing and introduction of irinotecan and oxaliplatin, alone or in combination, have provided additional agents for the treatment of colorectal cancer. 2–5 Nevertheless, these therapies still lead to few complete responses in patients with advanced disease. Further approaches that are convenient to deliver and have less toxicity are clearly required. One potential advantage of Doxil is that it may be selectively taken up in the tumors located within the liver. 6,7 Since colorectal cancer frequently metastasizes to the liver, the use of this agent was of particular interest. To determine whether liposomal doxorubicin (Doxil: Sequus Pharmaceuticals, Menlo Park, CA, U.S.A.) was active in this disease, we conducted a phase II trial in patients refractory to 5-FU.
PATIENTS AND METHODS
Patients were required to have a histologically confirmed diagnosis of advanced colorectal adenocarcinoma. Patients may have received prior therapy (adjuvant or for metastatic disease) with 5-FU-containing regimens and one other chemotherapy. Patients may have had disease metastatic to the liver, but may also have had disease elsewhere. All eligible patients met the following entry criteria: presence of radiographically measurable disease, Eastern Cooperative Oncology Group performance status of 2 (Karnofsky 50–60%) or better, adequate bone marrow function (defined as absolute granulocyte count ≥1,500/μl or greater, and platelet count ≥100,000/μl or greater), adequate liver function (defined as a total bilirubin of ≤2.5 mg/dl, regardless of whether patients had liver involvement caused by tumor), adequate renal function as documented by creatinine 2.5 mg/dl or less, and life expectancy of at least 8 weeks. Patients with brain metastases were ineligible. All patients were informed of the investigational nature of the study and provided written informed consent. Pretreatment evaluation included a complete history and physical examination, complete blood count, chemistry profile, and appropriate imaging studies to document measurable disease (the latter to be done within 4 weeks of starting treatment).
The starting dose for all patients on this schedule was Doxil (doxorubicin HCl liposome injection) at 45 mg/m2 given over 60 min. Antiemetics were given as elected by the investigators.
Assessment of Toxicity and Dose Modifications
National Cancer Institute criteria for clinical toxicities were used to evaluate the therapy. Patients were followed with complete blood cell count obtained midcycle and before each dose of Doxil. Electrolytes and liver function studies were also repeated before each treatment. For patients exhibiting grade II palmar–plantar erythrodysesthesia, the dose was to be reduced by 10% if symptoms had resolved after a 1-week delay. If longer delays were required for resolution or grade III or greater toxicity developed, then a 25% reduction was indicated.
For hematologic toxicity, patients were to be treated when the neutropenia or thrombocytopenia had resolved to less than grade I (absolute neutrophil count ≥1,500, platelets ≥75,000). If grade IV neutropenia (absolute neutrophil count <500) or thrombocytopenia (platelet count <25,000) occurred during any cycle, treatment was held until both resolved to grade I and treatment resumed at a 25% dose reduction. An increase in bilirubin up to 3.5 mg/dl in the prior cycle required a 25% reduction of the Doxil dose; if an increase in bilirubin exceeding 3.5 mg/dl occurred and was considered to be unrelated to Doxil, the dose was to be reduced by 50%.
If the patient exhibited stomatitis of grade II or greater after treatment had been discontinued for 1 week, the treatment was to be held for an additional week. If the patient continued to exhibit grade II toxicity after the dose has been delayed for 2 weeks (5 weeks since the last dose), then treatment was to be resumed at 3-week intervals with Doxil at a 25% reduced dose. For all other study drug–related grade III and IV events (gastrointestinal, skin, neurologic, etc.) a 25% reduction of the Doxil dose was recommended.
Assessment of Response
Appropriate radiologic studies and carcinoembryonic antigen (CEA) were repeated after two courses to evaluate initial tumor response. If a response occurred, a repeat study was to be done 1 month later to validate the response. Responses were classified according to World Health Organization criteria. A complete response was defined as the disappearance of all measurable lesions and the appearance of no new lesions for at least 4 weeks. A partial response was defined as a reduction of at least 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions and the absence of new lesions for at least 4 weeks. Stable disease was defined as a reduction of less than 50% or an increase of less than 25% in the sum of the products of the perpendicular diameters of all lesions without any evidence of new lesions for at least 4 weeks. Progressive disease was defined as an increase of greater than 25% in tumor size or the appearance of new lesions. Patients were removed from study for progressive disease, toxicity, or patient’s request. Survival was calculated from the start of therapy to death.
A two-stage design was used to minimize the number of patients to be treated with Doxil in the event that it proved to be a very disappointing or very successful trial. 8 Response (complete and partial) rate was the endpoint for the study, permitting early termination of patient entry after the first 15 response-evaluable patients if extremely unfavorable results were observed. If indeterminate result were observed, a maximum of 30 patients with colorectal cancer were to be studied unless undue toxicity or other medical reasons warrant early termination of patient entry. We planned to accrue 15 response-evaluable patients and if one or fewer response was observed the study would be stopped.
Seventeen patients were treated on the study, including 10 men and 7 women—12 whites, 4 blacks, and 1 Asian (Table 1). The median age of the patients entered in the trial was 57 years, and the median performance status was 1. All but one patient was found to have disease in the liver on review, and that patient had tumor in the pelvis. In addition, tumor was found in the lung, retroperitoneum, or diffusely within the abdomen. All the patients had received at least one prior regimen containing 5-FU; in addition, seven patients had been treated with two regimens. Six patients had received therapy as part of adjuvant treatment. The average time from diagnosis to treatment with Doxil was 14 months.
Response to Treatment
Fourteen of 17 patients received at least two cycles of therapy. One patient had the infusion stopped after 25 minutes because of an allergic reaction and declined to have treatment resumed. Two patients were removed from the protocol after the first cycle because of declining performance status and evidence of disease progression. Nine patients had 2 cycles of therapy, 1 had 3, 2 had 4, 1 had 8, and 1 patient had 17 cycles of therapy. The best response seen was stable disease. The median survival from the start of therapy with Doxil was 4.9 months, with 29% alive at 1 year.
A total of 57 cycles of Doxil were delivered to 17 patients, with a median of 2 cycles administered (range: 1–17 cycles). There was little in the way of hematologic toxicity, with only anemia noted to have toxicity greater than grade I (Table 2). Hand–foot syndrome was the most common toxicity, but only one patient had grade III toxicity requiring two dose adjustments, and one patient had grade II toxicity requiring one dose adjustment. No other patients required dose adjustments for any other toxicities. Nausea or vomiting were reported by three patients. Four patients had allergic reactions during the first cycle, which were successfully treated with diphenhydramine and dexamethasone. One patient decided not to complete the infusion, whereas the other three were able to complete the therapy with these medications and with slowing of the infusion. In subsequent cycles, each of these patients was treated without reactions, using these premedications, and infusing the Doxil over 2 to 6 hours. Two of the patients were also premedicated with ranitidine. The total number of cycles for these patients was 2, 4, and 17. It is notable that the patient who received 17 cycles never required a dose adjustment. She never had evidence of cardiotoxicity, with a radionuclide ejection fraction of 68% at the end of therapy.
Doxorubicin has been found to be an active agent in many tumor types including extensive use in the treatment of gastrointestinal tumors such as gastric cancer. Trials of doxorubicin in colorectal cancer have not been found to have much activity, but previous trials of doxorubicin have used schedules in which the drug was given during short infusions. 9 Differing infusion schedules have yielded improved results and altered toxicity patterns with doxorubicin, 5-FU, paclitaxel, and other drugs. Prolonged infusions of doxorubicin have decreased the risk of cardiotoxicity. 10,11 Pharmacologic studies using Doxil have demonstrated that it results in the prolonged presence of doxorubicin in the blood, mimicking a prolonged infusion, and it appears to have less cardiotoxicity. In this trial, we sought to determine whether Doxil would have improved efficacy when given in patients with colorectal cancer, and also to determine the toxicity of this approach.
We saw no evidence of efficacy as measured by objective shrinkage of the tumors by computed tomography imaging. Stable disease allowing for more than 12 weeks of treatment was only seen in two patients—one who received the drug for 8 cycles and the other for 17 cycles. The latter patient remains alive more than 1 year after treatment with Doxil, having had progression of disease after two other regimens. This suggests that her disease was by nature slowly progressive. In summary, we saw no evidence that Doxil was efficacious in this population of patients.
Doxil was very well tolerated in our study. The regimen of Doxil 45 mg/m2 every 3 weeks was expected to cause a significant amount of hand–foot syndrome, but only two patients required dose adjustments for this problem. The other notable problem was allergic reactions, seen in four patients. With appropriate premedication and slowing of the infusion, continued treatment was possible without complications. This schedule of Doxil appears to be very tolerable and should be considered for the treatment of tumors responsive to doxorubicin. It may be combined with other agents with different patterns of toxicity.
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