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Advantages of Concurrent Biochemotherapy Modified by Decrescendo Interleukin-2, Granulocyte Colony-Stimulating Factor, and Tamoxifen for Patients With Metastatic Melanoma

From the Division of Medical and Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA.

Address reprint requests to Steven J. O'Day, MD, Division of Medical Oncology, John Wayne Cancer Institute at Saint John's Health Center, 2001 Santa Monica Blvd, Suite 1050W, Santa Monica, CA, 90404; emailo\'days@jwci.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen.

PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days.

RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths.

CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

	INTRODUCTION

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THE MEDIAN DURATION of survival for patients with metastatic melanoma is 6 to 9 months and has not changed in the last three decades.^1-3 Single-agent chemotherapy, of which dacarbazine (DTIC) is the prototype, results in response rates of 15% to 20%.^4,5 Higher response rates (25% to 40%)^6-9 have been reported with combination chemotherapy, but median survival has not improved and the 5-year survival rate remains less than 2%.^10-12 Biologic response modifiers are an alternative treatment strategy for metastatic melanoma. Interferon alfa (IFN) and interleukin-2 (IL-2) yield response rates of 15% to 20%^13-15 with durable remissions in a small cohort of patients. High-dose bolus administration of IL-2 has recently been approved by the United States Food and Drug Administration for the treatment of metastatic melanoma on the basis of 7-year follow-up data that demonstrate durable remissions in 5% of patients.^16,17

In efforts to build on the potential additive or synergistic activity of chemotherapy and biologic response modifiers, investigators have developed combination biochemotherapy regimens for metastatic melanoma. The first generation of these regimens involved inpatient sequential biochemotherapy. Several single-institution phase II trials achieved promising results, with response rates of 50% to 60% and complete remission rates of 10% to 20%.^18-25 Durable remissions occurred in approximately 10% of these patients.^26,27 However, sequential biochemotherapy regimens are limited by the toxicity of extended treatment and the costs of prolonged hospitalization (8 to 9 days). Recently, Legha et al²⁸ reported that a 5-day concurrent biochemotherapy regimen demonstrated comparable efficacy (response rate of 64%, complete remission rate of 21%) with reduced toxicity and length of hospital stay compared with that of previous sequential biochemotherapy regimens. These encouraging results led to a multicenter phase III trial (Eastern Cooperative Oncology Group [ECOG]) comparing this concurrent biochemotherapy regimen to combination chemotherapy alone in metastatic melanoma.

In the pilot study reported here, the concurrent biochemotherapy regime of Legha et al was modified in an effort to reduce toxicity further while maintaining or improving efficacy. These modifications consisted of decrescendo IL-2 dosing, routine use of growth factor support with granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. The total IL-2 dose was unchanged, but this agent was administered in a decrescendo schedule, with a higher initial dose in the first 24 hours that decreased progressively on subsequent days. This change in IL-2 dosing is based on preclinical and clinical studies suggesting that decrescendo dosing improves efficacy and reduces cumulative IL-2 toxicity.^29,30 Routine posttreatment G-CSF was implemented because of the high incidence of grade 4 myelosuppression, fever/neutropenia, and infection in Legha's concurrent biochemotherapy trial.²⁸ Tamoxifen was added to the regimen because at the time the study was designed, data suggested potential synergistic effects with chemotherapy.^6-8

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Between July 1995 and September 1997, patients with distant metastatic melanoma (American Joint Committee on Cancer stage IV) were enrolled onto our program of modified concurrent biochemotherapy. Eligibility for this program was based on the following criteria: age at least 18 years but no more than 70 years, histologically confirmed diagnosis of malignant melanoma with measurable American Joint Committee on Cancer stage IV disease, ECOG performance status (PS) of 0 to 2, acceptable end-organ function (total bilirubin < 2.0 mg/dL, serum creatinine < 1.6 mg/dL, WBC count > 3,000/µL, and platelet count > 100,000/µL), and adequate cardiac function and pulmonary reserve. Patients with ischemic heart disease, uncontrolled hypertension, congestive heart failure, arrhythmia requiring therapy, or a left ventricular ejection fraction of < 40% were ineligible, as were those with a recent (no more than 3 months) history of deep vein thrombosis or pulmonary embolus. Patients with a smoking history or symptomatic pulmonary disease were eligible only if pulmonary function tests (forced expiratory volume in 1 second, ratio of 1-second forced expiratory volume to vital capacity) were greater than 75% of predicted. Patients who received prior biochemotherapy or prior chemotherapy plus independent biologic therapy (IFN or IL-2) for metastatic disease were excluded; all other therapy for melanoma was allowed. All prior therapies were to be completed at least 3 weeks before starting biochemotherapy. Patients with brain metastases were eligible if they had fewer than five lesions, all of which were untreated, asymptomatic, and less than 1 cm in diameter. Patients with larger brain lesions required definitive therapy with surgery or stereotactic radiation followed by a 4-week period without the development of new CNS lesions. Patients could not receive concomitant corticosteroids for any reason. All patients gave written informed consent.

Pretreatment Evaluation
The pretreatment evaluation, which was completed no more than 2 weeks before the start of biochemotherapy, included a complete history and physical examination and routine laboratory tests, including complete blood cell (CBC) count with differential and a 12-channel biochemistry panel. A serum pregnancy test was required for women of childbearing potential. Baseline staging of metastatic disease was assessed by computed tomography (CT) scans of the chest, abdomen, and pelvis, and magnetic resonance imaging (MRI) of the brain. ECG and either two-dimensional echocardiography or nuclear cardiac scanning were performed to assess cardiac function. Patients with a smoking history or symptomatic pulmonary disease underwent pulmonary function tests (as described previously, under Patients). A subclavian dual-lumen indwelling catheter was placed in all patients before initiation of biochemotherapy.

Treatment Regimen
Concurrent biochemotherapy was administered in 5-day periods at 21-day intervals. All patients were treated at a community-based hospital (Saint John's Health Center) affiliated with the John Wayne Cancer Institute in Santa Monica, CA. Patients were admitted to the inpatient oncology unit for a 5-day regimen of DTIC, vinblastine, cisplatin, IL-2, IFN2b, and tamoxifen administered as indicated in Table 1. The daily dose of cisplatin was preceded by intravenous (IV) hydration with 1 L of normal saline administered over 2 hours. IL-2 was administered in a decrescendo fashion in a total dose of 36 million IU/m². Tamoxifen was administered daily throughout the 21-day cycle. Beginning on day 6, G-CSF at a dose of 5 µg/kg was administered subcutaneously each day for 7 to 10 days. G-CSF was stopped when the absolute neutrophil count (ANC) exceeded 5,000/µL.

Inpatient Monitoring and Routine Care
The inpatient oncology unit maintained a high nurse-to-patient ratio for all biochemotherapy patients to ensure timely administration of all medications. Vital signs were monitored every 4 hours, weight was measured daily, and intake/output was strictly measured. A CBC count with differential and a 12-channel chemistry panel was performed on days 1, 3, and 5 of each treatment cycle. All patients received continuous hydration with dextrose 5% in water and one-half normal saline with 20 mEq of KCl and 8 mEq of MgSO₄ at an initial rate of 100 mL/h. When systolic blood pressures decreased to less than 90 mmHg, normal saline was given in 500-mL boluses, and the maintenance IV rate was increased to 125 mL/h. Renal-dose dopamine (3 to 5 µg/kg/min IV) was used routinely only in the first 25 patients. Higher doses of dopamine (5 to 10 µg/kg/min IV) were used rarely and only if systolic blood pressure was less than 80 mmHg or patients became symptomatic despite bedrest. Diuretics were seldom used, except for oliguria (urine output < 1,000 mL in 24 hours). Patients were discharged on day 5 after the morning IFN2b dose if they were ambulatory and tolerating oral fluids with antiemetics.

Symptom Management
Biochemotherapy results in a wide spectrum of toxicity that is managed with close patient monitoring, IV fluids, and prophylactic and symptom-directed medications. To control nausea and vomiting, either ondansetron or granisetron was administered daily, and metoclopramide and diphenhydramine were given before the administration of chemotherapy. Symptomatic treatment with lorazepam and prochlorperazine was given as needed. Corticosteroid antiemetics were prohibited. Diarrhea was treated with diphenoxylate and atropine and, occasionally, tincture of opium if diarrhea was severe. If diarrhea was copious and associated with abdominal cramping, stool was evaluated for the Clostridium difficile toxin.

All patients received routine acetaminophen 650 mg orally every 4 hours to reduce constitutional or "flu-like" symptoms associated with biotherapy. Nonsteroidal anti-inflammatory drugs were avoided because of their effect on renal perfusion in combination with cisplatin and IL-2. Prolonged chills and rigors were treated with meperidine 50 mg IV every 4 to 6 hours as needed.

Patients were instructed to apply emollient creams to their skin at least twice daily to ameliorate IL-2 related symptoms. Antihistamines were given for pruritus. Topical corticosteroid creams were avoided. Patients were encouraged to ambulate daily but were monitored closely for orthostatic symptoms.

Follow-Up Monitoring
After discharge from the hospital, patients were monitored twice a week by laboratory studies, including CBC count with differential and a 12-channel chemistry panel with magnesium, and once a week by a physician's evaluation. Patients were instructed to push oral hydration with electrolyte-replenishing fluids during the first week that they were out of the hospital. If patients did not tolerate oral hydration, then IV hydration was given either at the clinic or under the supervision of a home-care nurse.

Patients underwent restaging studies with CT scans of the chest, abdomen, and pelvis after every two cycles of therapy (6 weeks). MRI of the brain was performed after every four cycles and at the completion of therapy, unless patients had preexisting CNS disease (in which case MRI was performed after every two cycles). Patients with progressive disease after the first two cycles of therapy were discontinued from study and observed for survival. Patients with stable or responding disease after two cycles were eligible for two to six additional treatment cycles until maximal response was achieved. Patients who achieved a complete response (CR) at any point during treatment received two additional cycles of therapy. Surgical resection of metastases was performed in selected patients who had a low volume of residual disease after maximal biochemotherapy response.

Treatment cycles were delayed by 1 week if the day 1 platelet count was less than 75,000/µL or the serum creatinine level exceeded 2.0 mg/dL. Chemotherapy doses were modified on subsequent cycles if the platelet count decreased to less than 75,000/µL (25% reduction of DTIC dose) or 50,000/µL (25% reduction of DTIC and cisplatin doses). Chemotherapy doses were also modified if ANC decreased to less than 500/µL (25% reduction of vinblastine dose).

Response Criteria and Data Analysis
Response was evaluated only in patients who had completed at least two cycles of treatment. The response to treatment was assessed by the standard criteria of response and reviewed by the principal investigator and a coinvestigator. CR was defined as the disappearance of all clinical evidence of tumor by physical examination and radiographic studies for at least 4 weeks, during which no new lesions appeared. Partial response (PR) was defined as a greater than 50% reduction in the sum of products of perpendicular diameters of measurable lesions without the appearance of any new lesions for a minimum of 4 weeks. Stable disease (SD) included minor responses and was defined as the following: (1) a less than 25% increase in the sum of the products of the perpendicular diameters of all measurable lesions, or (2) a decrease of 0% to 49% in the sum of the products of the perpendicular diameters of all measurable lesions without appearance of new lesions for at least 8 weeks. Progressive disease (PD) was defined as a 25% or greater increase in the sum of the products of the perpendicular diameters of any measurable lesions or the appearance of any new lesion. The development of CNS metastases was counted as PD regardless of continued response at other disease sites.

Response duration was measured from the first day of treatment (study entry) to first evidence of PD, last follow-up date, or death from any cause. Survival was measured from the first day of treatment (study entry) to death or last follow-up date. Patients who underwent surgical resection of their metastatic tumor(s) after completion of biochemotherapy were censored at the date of surgery to avoid the confounding effect of surgery on the duration of response; thus their response category was determined strictly by their response to biochemotherapy. The Kaplan-Meier method was used to generate time-to-event (survival and time to progression) curves. A logistic regression model was used to investigate correlates of complete response. Univariate logistic analysis was used to test several pretreatment factors, and significant factors of outcome were included in a multivariate logistic model. A Cox proportional hazards model was used to test these factors for correlation with survival in a univariate analysis. Those factors found to be significant in the univariate analysis were tested together in a multivariate model.

	RESULTS

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Patient Characteristics
The 45 patients enrolled onto the study had a median age of 47 years (range, 23 to 68 years); 35 (78%) were male. The vast majority of patients (84%) had poor prognostic attributes, with at least two organ metastatic sites (Table 2). Of the six patients (13%) with brain metastases at study entry, two had been treated surgically or with stereotactic radiation and four had untreated, asymptomatic brain metastases. Before entering the study, 15 patients (33%) had received prior treatment with chemotherapy, 22 patients (49%) had been treated with an allogeneic cellular melanoma vaccine,³¹ and four patients had been treated with IFN. No patient had received prior treatment with high-dose IFN or IL-2. The median time from diagnosis of stage IV melanoma to the initiation of biochemotherapy was only 3 months (range, 0 to 35 months), which reflects the rapid development of extensive metastatic disease. Forty-four patients completed at least two cycles of therapy; one patient chose to discontinue therapy after one cycle but did not experience dose-limiting toxicity. The 45 patients completed a total of 217 treatment cycles (mean, 4.7 cycles; range, one to eight cycles).

Response
Of 45 patients, 44 completed two cycles of therapy and were considered assessable for response. One patient discontinued therapy after one cycle and was included for toxicity and survival analyses only. Of the 44 patients for whom response was evaluated, 10 (23%) had a CR and 15 (34%) had a PR (Table 3). Thus the overall response rate was 57% (95% confidence interval, 42% to 72%). Eleven patients (25%) had SD and eight (18%) had PD. For the entire group, the median time to PD was 6.3 months and the median survival time was 11.4 months (Fig 1). For CR and PR patients, the median time to PD was 7.5 months (range, 3 to 34 months). The only long-term (> 18 months) disease-free survivors in the PR and SD groups were three patients who underwent complete surgical resection of tumor remaining after biochemotherapy. At a maximum follow-up of 36 months for the entire study group (range, 10 to 36 months), 14 patients (32%) are alive: eight (18%) have disease and six (14%) are clinically disease-free.

View larger version (15K): [in this window] [in a new window]   Fig 1. Time to progression and overall survival for all patients (reflects censoring of patients undergoing surgical resection of residual disease at the time of surgery).

Of the 10 patients with a CR to biochemotherapy, all but one had multiple disease sites and eight had symptomatic disease, two with an ECOG PS of 1 and six with an ECOG PS of 2 (Table 4). Relapses among these patients occurred within the first 10 months. One patient who had a CR to biochemotherapy relapsed 4 months after completing treatment but achieved a second CR with reinduction biochemotherapy and remains in remission (patient no. 1, Table 4).

Five patients underwent complete surgical resection of residual disease after maximal response to biochemotherapy. One patient had a large pulmonary mass before treatment and subsequently underwent pneumonectomy after a stable response to biochemotherapy. The four other patients all had multiple sites of disease before biochemotherapy and underwent resection of one or two sites of disease after maximal treatment response. One of the five patients experienced recurrence of disease and died 15 months later of progressive melanoma; another remained in complete remission but died of a cerebrovascular accident 6 months postoperatively. Of the remaining surgical CR patients, two have no evidence of disease at 33+ and 34+ months of follow-up, and one had disease progression at 23 months but remains alive with disease at 31+ months.

Overall, 15 patients (34%) were rendered clinically free of disease. Ten patients achieved a CR to biochemotherapy alone, and an additional five underwent complete surgical resection of tumor that remained after biochemotherapy. Eleven (73%) of the 15 patients are alive at follow-up times ranging from 9+ to 34+ months, and six (40%) remain free of disease. Of the nine patients who developed recurrent disease, four relapsed in the CNS alone or as the first isolated site of recurrence, and five had systemic disease progression without CNS recurrence.

Predictors of Response and Survival
A number of pretreatment factors were evaluated as predictors of response and survival (Table 5). Each factor was tested initially for correlation to overall response (CR + PR) and CR in a univariate logistic regression analysis. Those factors that were found to be significant in the univariate analyses were included in a multivariate logistic regression model. The overall response rate to biochemotherapy could not be correlated with age, ECOG PS, sex, lactate dehydrogenase, albumin, CNS disease, number of organ sites, prior chemotherapy, or anatomic sites of disease. However, CR was correlated with prior chemotherapy and anatomic sites of disease, and no patient who received prior chemotherapy for metastatic disease achieved a CR to biochemotherapy or was a candidate for subsequent surgical resection. Patients with disease confined to soft tissue, lymph nodes, or lung were more likely to achieve a CR to biochemotherapy than were those with metastases to other visceral sites. Similarly, each factor was tested for correlation to survival in a univariate analysis using the Cox proportional hazards model. Those factors found to be significant in the univariate analysis were tested together in a multivariate model. Overall survival was significantly better when pretreatment lactate dehydrogenase was less than 190 IU/L and metastases were confined to soft tissue, lymph nodes, and lung.

Toxicity of Biochemotherapy
Constitutional. All patients experienced flu-like symptoms to varying degrees (fever, chills, rigors, myalgias, fatigue, malaise, and headache). For the majority of patients (> 80%), fever peaked in the first 24 to 48 hours (102° to 105°F) and decreased thereafter, with low-grade fever (99° to 100°F) frequently present at the time of discharge. A prolonged rigor lasting 10 to 30 minutes occurred uniformly on day 1 several hours after the first IFN2b injection and was managed symptomatically with meperidine. A less intense rigor often occurred on day 2. Thereafter, rigors were infrequent. Chills or rigors on days 4 or 5 usually were related to infectious complications. Excluding temporary fluctuation caused by therapy-induced fluid gain, there was typically weight loss of 10 to 20 lb, which accompanied the first two cycles of treatment and then stabilized with subsequent treatment cycles (0 to 5 lb). The median cumulative weight loss during treatment was 18 lb (range, 0 to 58 lb). Patients generally took minimal solid food on days 2 to 5 because of anorexia and nausea; moderate to severe anorexia persisted until day 10 to14 of the cycle. Patients who had major responses to treatment gained weight rapidly after completing treatment.

Hematologic toxicity.
Neutropenia was uncommon and of short duration. The median nadir neutrophil count for cycles 1 and 2 was 962/µL and 1,214/µL, respectively. During these first two cycles, grade 3 neutropenia was observed in 20% of cycles, and grade 4 neutropenia was observed in 24% of cycles. Grade 4 neutropenia lasting for more than 7 days was not observed. Fever complicating neutropenia was observed in only five patients and five cycles (2%). Routine antibiotic therapy was not given. Anemia and thrombocytopenia were common and cumulative with repeated cycles of therapy, requiring blood product support: 27 patients (60%) received RBC transfusions (median, four transfusions; range, two to 12 transfusions), and 18 (40%) received platelet transfusions (median, one transfusion; range, one to six transfusions). The median nadir platelet counts for cycles 1 and 2 were 89,000/µL and 86,000/µL, respectively. During these cycles, grade 3 thrombocytopenia was observed in 11% of cycles, and grade 4 thrombocytopenia was observed in 10% of cycles. Grade 4 thrombocytopenia lasting for 1 week or more was observed in 2% of cycles (cycles 1 and 2).

Nonhematologic toxicity.
Nonhematologic toxicity (Table 6) was graded according to the National Cancer Institute common toxicity criteria. Clinically significant capillary leak syndrome was rare. Systolic hypotension of less than 90 mmHg complicated 43 cycles (20%) but was rarely symptomatic. Lower-dose dopamine (3 to 5 µg/kg/min IV) was infused routinely in the first 25 patients but not thereafter. Higher dopamine doses (5 to 10 µg/kg/min IV) were used rarely. No patient required intensive care unit monitoring. Fluid gain of 5 to 15 lb was common and peaked on day 3 of treatment. Actual maximal weight gain was 0 to 10 lb in 27 patients (60%), 11 to 20 lb in 17 patients (38%), and more than 20 lb in only one patient (2%). Clinically significant pulmonary capillary leak was not seen.

Most infections (18 of 28; 64%) were catheter-related (Staphylococcus epidermidis in 72%; Staphylococcus aureus in 28%) (Table 6). Central lines were removed in all S aureus infections. S epidermidis infections were successfully treated with antibiotic therapy alone. C difficile colitis was the most common non–catheter-related infection and was successfully treated in all patients. There were no deaths related to infection.

Although gastrointestinal side effects were common (nausea, vomiting, diarrhea), grade 3 or 4 gastrointestinal toxicity occurred in only 15 patients (33%) and 25 cycles (12%). These toxicities were managed symptomatically and were reversible in all cases. Grade 3 and 4 renal toxicity occurred in only two patients (4%) and three cycles (1.5%). No patient developed irreversible renal failure or required dialysis (Table 6). Liver function abnormalities in the form of increased enzyme levels and alkaline phosphatase were common during days 1 to 5 but were reversible and clinically inconsequential. Grade 3 AST elevation (> 5.1 times the upper limit of normal) occurred in nine cycles (4%), and grade 3 alkaline phosphatase elevation (> 5.1 times the upper limit of normal) elevation was not observed. Jaundice was not observed and bilirubin elevation to more than 2.0 mg/dL was observed in only two treatment cycles (1%).

All patients developed varying degrees of skin toxicity with erythema and maculopapular rashes. This progressed to dry skin and exfoliation requiring frequent moisturizers. Skin toxicity from IL-2 treatment was frequently associated with pruritus and was managed symptomatically. Electrolyte disturbances (hypokalemia, hypomagnesemia) were common and were treated with aggressive electrolyte replacement during hospitalization. One patient developed a deep vein thrombosis related to a central line without pulmonary embolus. There was one death as a result of CNS hemorrhage on day 12 of the sixth treatment cycle (patient no. 2, Table 5). This patient had undergone stereotactic radiosurgery for several CNS metastases immediately before starting biochemotherapy. These lesions had been stable in the setting of systemic response to biochemotherapy. The patient had a normal platelet count at the time of cerebral hemorrhage.

Length of Stay, Rehospitalization, and Treatment Delay
Inpatient stay was four or five nights in 86% of the 217 total cycles (Table 7). Rehospitalizations for complications between treatments occurred in only 12 cycles (6%), corresponding to 11 patients. Treatment delay of more than 7 days occurred in 44 cycles (20%) and 22 patients. These delays were more common in later cycles (mean cycle for treatment delay, 4.6). Twenty-four of these delays (55%) were due to resolving thrombocytopenia.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The clinical efficacy (overall response rate, 57%; CR rate, 23%; median survival, 11.8 months; durable remission rate, 14%) of the modified concurrent biochemotherapy program described in this report is encouraging and is nearly identical to that of the concurrent biochemotherapy regimen published by Legha et al.²⁸ The efficacy of our modified regimen is noteworthy because it was achieved in patients with a shorter expected survival than those enrolled in Legha's trial²⁸ or those included in high-dose bolus IL-2 protocols.^16,17 These adverse prognostic factors include a greater percentage of patients with (1) previous chemotherapy for metastatic disease, (2) poor risk visceral metastatic sites (liver, bone, brain), (3) disease affecting three or more organ sites, and (4) ECOG PS of 2. The poor prognosis cohort of patients treated with biochemotherapy in this study can be explained by the referral pattern within our institution, in which prominent surgical and vaccine programs appropriately target patients with more indolent metastatic disease. Further assessment of the efficacy of this modified concurrent biochemotherapy regimen needs to be performed in a chemotherapy-naïve patient group, as none of the chemotherapy-pretreated patients in our series achieved a CR, none were candidates for surgical resection after biochemotherapy, and none achieved long-term survival.

The toxicity profile of the modified concurrent biochemotherapy program is very favorable, as evidenced by our ability to safely administer multiple treatment cycles at a community-based hospital without the need for intensive care monitoring. A dedicated, well-trained, and supervised inpatient nursing team, however, is critical. The favorable toxicity profile we observed in this trial is similar to that published by Kielholz et al²⁹ with decrescendo dosing of IL-2 compared with continuous infusion IL-2 at a constant dose. Our IL-2 dosing schedule resulted in peak treatment-related toxicities during the first 24 to 48 hours followed by clinical improvement in the vast majority of patients over the remainder of the hospitalization period. The short inpatient length of stay, low readmission rate, and favorable toxicity profile of modified concurrent biochemotherapy allows it to be reasonably compared to the promising outpatient sequential biochemotherapy regimen (9 days) recently reported by Thompson et al.^32,33

The most clinically important IL-2 toxicity, capillary leak syndrome, was significantly less than that of the concurrent biochemotherapy regimen reported by Legha et al²⁸ and can be attributed to the modified decrescendo IL-2 dosing of our regimen. For example, in this study, the percentage of patients with less than 10 lb, 10 to 20 lb, and more than 20 lb of weight gain as a result of fluid retention was 60%, 38%, and 2%, respectively, compared with 21%, 68%, and 11%, respectively, reported by Legha et al. Patients with fluid retention did not exhibit respiratory compromise due to pulmonary capillary leak. Serious end-organ renal or hepatic hypoperfusion as a complication of capillary leak syndrome was rarely observed in our modified biochemotherapy regimen. Although patients treated on the Legha regimen had a similarly low incidence of serious renal toxicity, approximately 25% (13 patients) developed elevated bilirubin levels that were cumulative, peaking on day 5. This toxicity was presumably related to the dosing of IL-2, as only one patient (2%) in our study developed a bilirubin level of greater than 2 mg/dL in two cycles (1%).

Growth factor support with G-CSF significantly limited the incidence and duration of neutropenia and almost completely prevented complications of fever/neutropenia. Fewer than one half of study patients experienced grade 4 neutropenia, compared with almost all patients in the Legha series.²⁸ Likewise, fever/neutropenia was encountered much less (2%) than in the Legha series (64%). Thrombocytopenia was nearly equivalent in the two studies. Infection is potentially a major problem in biochemotherapy regimens because of neutropenia and IL-2–mediated impairment of neutrophil function. Additionally, IL-2 skin toxicity and frequent central line accessing increases susceptibility to gram-positive infections. As expected, in this trial, infections were predominately gram-positive and related to central-line catheters. The majority were treated with antibiotics alone. Non–catheter-related infections were infrequent, and there were no deaths resulting from sepsis. In subsequent trials, we have implemented further measures to reduce catheter-related infections, including (1) limiting the frequency of central line access, (2) ensuring meticulous sterile technique when catheters are manipulated, and (3) using prophylactic antibiotics.

Low-dose tamoxifen (20 mg daily) was included in the regimen on the basis of published reports of its synergy with chemotherapy in the treatment of metastatic melanoma.^6-8 More recent studies have not substantiated the initial reports with low or higher tamoxifen doses.^34,35 Although a small additional benefit cannot be excluded, the results of this study do not suggest that the addition of low-dose tamoxifen significantly improved the efficacy of concurrent biochemotherapy. We have recently completed a phase I/II trial with escalating doses of tamoxifen to 320 mg in efforts to reach serum tamoxifen levels that correlate with in vitro synergy with cisplatin and reversal of multidrug resistance. Our preliminary results suggest that, despite achieving sufficient serum levels, clinical efficacy is not significantly enhanced.³⁶

Surgical resection of low-volume residual disease after biochemotherapy remains controversial. Five patients achieved a "surgical" CR, and their disease-free and overall survival seemed comparable to that of the biochemotherapy-alone CR group. Patients who did not achieve a CR and were not surgical candidates after PR or SD progressed rapidly (median, 5 to 6 months from study entry), often at sites of residual disease. Although the group of patients with low-volume disease who underwent resection cannot be directly compared with patients in the higher volume, nonresected group, it is likely that they would have experienced disease progression, because no pathologic complete remissions were noted at the time of surgery. This group of patients, however, is too small for meaningful statistical comparison. Additional studies are required to better evaluate the possible benefit from surgery as an adjunct to biochemotherapy in metastatic melanoma.

Our results also confirm the continuing formidable challenge of CNS metastases from melanoma and their impact on quality and duration of life. None of our patients with preexisting CNS metastases demonstrated CNS response to biochemotherapy, despite achieving systemic responses. Equally important, approximately one third of our patients who had a CR to biochemotherapy alone or biochemotherapy followed by surgery relapsed in the CNS as the first and often only site of relapse, which led to rapid demise.

Ongoing phase III studies comparing concurrent biochemotherapy to chemotherapy alone (ECOG) or IL-2 alone (European Organization for Research and Treatment of Cancer) will help define the contribution of the first generation of biochemotherapy regimens in metastatic melanoma. Further efforts to improve efficacy and reduce toxicity of biochemotherapy regimens are critically important and remain the focus of our group and others. The addition of drugs that penetrate the blood-brain barrier to reduce the incidence of CNS metastases as well as the development of a cytokine maintenance program for responders to biochemotherapy are two strategies that we are pursuing in ongoing collaborative clinical trials.

The melanoma population that was examined in this study predominantly included patients with rapidly progressing symptomatic disease at multiple sites who had a short expected survival. This group, which is representative of a large number of patients with metastatic melanoma, is typically offered supportive care alone or single-agent or combination chemotherapy that is without significant palliative or survival advantage. This trial suggests that biochemotherapy treatment strategies with improved toxicity profiles should be considered for these patients, as they present a potential opportunity for durable remissions.

	ACKNOWLEDGMENTS

 
Supported in part by grants CA12582 and CA29605 from the National Cancer Institute, by the Martin H. Weil Fund, by funding from the Wrather Family Foundation (Los Angeles, CA), and by research grants from the Schering-Plough Corporation, Kenilworth, NJ, and Chiron Therapeutics, Emeryville, CA.

We thank the entire nursing and support staff of 3 South at Saint John's Health Center for their dedicated care of our patients, with particular recognition to Annette Sy, Phillip Williams, Tess Duenas, and Donni Esposti for their leadership. We also thank Ruth Weil for her ongoing support of research in the Division of Medical Oncology at the John Wayne Cancer Institute, Santa Monica, CA.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 7, 1998; accepted May 13, 1999.

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