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Oncology Center, Hospital Sirio-Libanes, Sao Paulo, SP 01308-050, Brazil [A. C. B.], and Cutaneous Oncology and Biologic Therapy Programs, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215-5400 [M. A.]
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ABSTRACT |
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 Top ABSTRACT IntroductionBiochemotherapyManagement of Toxicity of...REFERENCES |
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, referred to as biochemotherapy or chemoimmunotherapy, has shown promising antitumor activity in patients with metastatic melanoma. Phase II studies have reported overall response rates ranging from 40 to 60%, with durable complete remissions in 
10% of the patients. Toxicity, however, is often severe and can be life-threatening if the healthcare team is not familiar with toxicity management. In this report, we briefly describe the clinical results of the most effective biochemotherapy regimens and provide a detailed description and management of the most common toxic effects, with emphasis on the concurrent biochemotherapy program initially developed at M. D. Anderson Cancer Center and currently being tested in a slightly modified version in two large-scale Intergroup Phase III trials. |
Introduction |
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TopABSTRACTIntroductionBiochemotherapyManagement of Toxicity of...REFERENCES |
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20% will eventually die secondary to metastatic disease. The treatment of metastatic melanoma remains unsatisfactory, with patient survival dictated primarily by the pace of the disease (2)
. Chemotherapy when used alone produces responses in approximately 10–30% of the patients, but durable remissions are rare, occurring in <2% of patients (2)
. Immunotherapy with high dose IL2
-2 has shown promise with overall responses in 16–20% of patients, with durable remissions in 4–6% of patients (3
, 4)
. This treatment has been associated with significant toxicity, however, limiting its use to young patients with excellent organ function treated at a few select treatment centers. Lower dose IL-2 regimens, IFN-, combinations of IL-2 and IFN-, or other immunotherapy approaches have generally produced lower response rates and few durable remissions (5)
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Biochemotherapy |
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TopABSTRACTIntroductionBiochemotherapyManagement of Toxicity of...REFERENCES |
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and IL-2, referred to as "biochemotherapy" or "chemoimmunotherapy," appear to have attained the highest response rates (2)
. Phase II studies have shown overall response rates ranging from 40 to 60% with CR rates on the order of 10–20% (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
. Durable remissions exceeding 5 years were seen in 10% of the patients, and relapses beyond the 2-year time point were distinctly uncommon, thus suggesting that these patients exhibiting durable responses were likely to be "cured" (6
, 8, 9, 10)
. The results of these Phase II studies are shown in Table 1
. Meta-analyses suggested improved response rates and possibly survival for combinations involving cisplatin, IL-2, and IFN- relative to either chemotherapy or immunotherapy alone. In one analysis involving 631 patients, biochemotherapy regimens produced a response rate of 45% compared to 21 and 15% with IL-2 and IFN- or IL-2 alone, respectively. Median survival, however, was not significantly different between the groups (10.5 months) with 20 and 10% survival rates at 2 and 5 years, respectively (17)
. Another meta-analysis analyzed 154 studies involving over 7000 patients. The highest response rate of 47% and median survival of 10 months were observed in patients who received cisplatin, DTIC, IL-2, and IFN- (18)
.
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with IL-2 administered either i.v. or s.c. (16)
. There were 16 responses including 5 CRs in the 44 patients who received the i.v. IL-2 regimen (response rate, 36%), whereas there were only 6 responses (including 1 CR) in the 36 patients assigned to receive the s.c. IL-2 regimen (response rate, 17%; Ref. 16
). In addition, a study in which patients were randomly assigned to receive either the Dartmouth regimen or the Dartmouth regimen preceded by IL-2 administered by the s.c. route (days -2 to 0) and followed by IFN- (days 1–3) showed no difference in response rate (22% for the biochemotherapy versus 27% for the Dartmouth regimen), median duration of response (2.8 versus 2.5 months), or survival (5 versus 5.5 months; Ref. 19
). The lower overall response rates for the biochemotherapy regimens involving s.c. IL-2 in these two studies relative to the i.v. IL-2 biochemotherapy regimens mentioned previously suggest a potential schedule, dose, and route of administration effect for the IL-2 in biochemotherapy combinations.
By contrast, concurrent biochemotherapy regimens appeared to have to be less complex and toxic while maintaining antitumor activity comparable to other regimens. One such regimen, developed at M. D. Anderson Cancer Center, involved CVD chemotherapy administered concurrently with IL-2 and IFN- for a maximum of six cycles. Tumor responses were observed in 34 of 53 patients (64%), with 20% complete responses and 9% durable CRs (9)
. In another study, this regimen was modified in an effort to reduce toxicity. Modifications included antibiotic and G-CSF prophylaxis, prohibition of long-term central venous access, and restriction to a maximum of four cycles of therapy. Tumor responses were seen in 19 of 40 evaluable patients (response rate, 48%) including 8 CRs (12)
. In addition, this latter regimen was deemed sufficiently tolerable to be incorporated into a large-scale Intergroup Phase III trial.
Phase III Studies.
To date, the preliminary results of four randomized Phase III studies comparing biochemotherapy with chemotherapy or immunotherapy alone have been reported (Table 2)
. The results have been mixed. The European Organization for Research and Treatment of Cancer study compared the decrescendo IL-2 and IFN- regimen of Keilholz et al. (20)
with or without cisplatin. In this study, 138 patients (126 assessable) were randomized to IL-2 plus IFN- alone, versus cisplatin followed by IL-2 plus IFN-. The biochemotherapy regimen produced a statistically superior response rate (P = 0.04), but there was no difference in time to progression or overall survival.
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versus cisplatin followed by IL-2 without IFN-, thus testing the value of IFN- in this biochemotherapy combination. Although the response with the biochemotherapy regimen was higher than with cisplatin plus IL-2 alone (25% versus 16%), this difference was not significant. Furthermore, there was no difference in time to progression or survival.
Rosenberg et al. (22)
reported the results of a Phase III study conducted at the National Cancer Institute. Patients were randomized to receive cisplatin, DTIC, and tamoxifen or cisplatin, DTIC, and tamoxifen followed by IL-2 plus IFN-. In 52 patients treated with chemotherapy alone, there were 14 objective responses (27%) including 4 CRs. In 50 patients treated with biochemotherapy, there were 22 objective responses (44%; P = 0.071), including 3 CRs. There was a trend toward a survival advantage for patients receiving the chemotherapy alone (P = 0.052; median survival of 15.8 months compared with 10.7 months). This unusual survival finding is most likely attributable to either the administration of high dose IL-2 as salvage therapy to patients failing to respond to chemotherapy or imbalances between the treatment arms that can be seen with such small numbers of patients.
More recently, Eton et al. (23) reported the preliminary results of the M. D. Anderson Cancer Center randomized study comparing sequential biochemotherapy with chemotherapy alone. A total of 190 patients were enrolled into the study, and of these, 91 were evaluable in the biochemotherapy arm and 92 in the CVD arm. The overall response rate was 48% for the biochemotherapy arm versus 25% for the CVD arm (P = 0.001) with 6 CRs in the biochemotherapy arm and 1 in the chemotherapy arm. The median time to progression was 4.6 months, and the median survival was 11.8 months for the biochemotherapy arm versus 2.4 months and 9.5 months for the chemotherapy arm (P = 0.0007 for time to progression and P = 0.055 for overall survival). The definite determination of the value of biochemotherapy relative to chemotherapy alone must await the completion of the United States Intergroup trial comparing a modified version of the concurrent biochemotherapy regimen (12) to CVD chemotherapy alone.
The encouraging Phase II biochemotherapy data as well as the results from the M. D. Anderson Phase III trial have made biochemotherapy a popular treatment option for practicing oncologists. Despite the gathering experience with these regimens, management issues still frequently arise. Common problems include the use of steroids to counteract nausea and vomiting, lack of recognition of sepsis, improper i.v. fluid management, and early treatment interruption because of "poor tolerance." This report provides a practical review on the management of biochemotherapy-related toxicity. Because the concurrent biochemotherapy regimen is now the one most commonly used (either on or off protocol), management issues related to this regimen will be emphasized.
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Management of Toxicity of Biochemotherapy |
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. Each toxicity will be described in detail, and practical guidelines concerning its management will be provided.
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injection. On the first day, the fever may reach as high as 39–40°C. In the subsequent days, the fever will usually be less, and the chills become less marked, but the variability in the fever pattern is large. Fig. 1
shows an example of a fever curve. The malaise increases because of the IL-2 and IFN- cumulative effect, reaching its peak on day 5 or 6 and lasting well into the second week, especially in regimens that include week 2 outpatient IFN- administration. Patients start to feel better on the third week, i.e., 1 week prior to initiation of the subsequent cycle.
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Hematological Effects
Description.
All patients will experience varying degrees of anemia, neutropenia, and thrombocytopenia (9)
. The hematological toxicity is cumulative. It is common to observe thrombocytopenia and leukopenia on day 5 that are largely attributable to the biotherapy component of the regimen and tend to resolve rapidly. Significant myelosuppression related to the chemotherapy component is observed during the second and third weeks of therapy. In the original M. D. Anderson studies, growth factors such as G-CSF or erythropoietin were not used routinely, and severe neutropenia and anemia were common events (9)
. For instance, with the concurrent biochemotherapy the hemoglobin level dropped 1–2 g/cycle, and transfusion was necessary in 50% of the patients, including almost all patients receiving more than two cycles of therapy. Neutropenia grade 4 was observed in all patients, and platelet transfusion was required in 40% of the patients (9)
. Various groups have now routinely used prophylactic G-CSF and have observed a significantly lower incidence of neutropenic fever (10, 11, 12)
. The prophylactic use of erythropoietin also significantly reduces the need for blood transfusion during biochemotherapy (24)
.
Management.
To reduce the incidence of neutropenia and neutropenic infection, we suggest that all patients receive G-CSF starting on day 6, 24 h after completion of the therapy and continuing through the week 2 nadir and until the absolute neutrophil count reaches >5,000/µl. In addition, erythropoietin 40,000 units s.c. weekly may also be started on day 6 of cycle 1. Patients experiencing grade 4 neutropenia (WBC <500/µl) or thrombocytopenia (platelets <25,000/µl) should have their doses of DTIC and vinblastine reduced by 25% in subsequent treatment cycles.
Gastrointestinal Effects
Description.
Anorexia, nausea, and vomiting occurs almost universally in patients receiving biochemotherapy. Many patients also experience diarrhea. Nausea and vomiting occur in many patients despite the use of high-doses of 5HT3 receptor antagonists (ondansetron and granisetron). Vomiting is typically most severe on day 1, when DTIC is administered. Delayed nausea and vomiting, lasting from 3 to 7 days after administration of cisplatin, are also common. Higher doses of anti-5HT3 anti-emetics (e.g., 32 mg i.v. qd of ondansetron or 3 mg i.v. qd of granisetron) greatly reduce the incidence of grade 3 nausea and vomiting but clearly are not effective in all patients. The biotherapy and the resultant inability to co-administer steroids are likely responsible for the suboptimal control of the nausea and vomiting, because anti-5HT3 agents usually prevent nausea and vomiting induced by the chemotherapy alone.
Diarrhea usually does not start until day 4 and may continue until days 8–9 of the biochemotherapy regimen. It is common to observe mild constipation in the first 3 days of the biochemotherapy, probably induced by a combination of the anti-5HT3 antagonists and the vinblastine. It is inadvisable, however, to use laxatives to treat the constipation, because it is usually transient and frequently followed by diarrhea induced by the biotherapy. Anorexia is most severe during administration of the therapy and lasts up to 1 week after its completion. Patients may lose 2–3 kg/cycle of therapy. Liver function test abnormalities are, although common, less frequent and milder than those typically seen with high-dose IL-2 or high-dose IFN- regimens (9
, 25)
. Treatment modifications are usually unnecessary.
Management.
In addition to using high-doses of 5HT3 antagonists, we have routinely used a phenothiazine or a butyrophenone, such as perchloperazine 10 mg i.v. every 6–8 h or droperidol 2.5 mg i.v. every 6–8 h around the clock, particularly on days 1 and 2 when nausea and vomiting are usually more intense. We continue the use of the phenothiazine or butyrophenone in patients in which nausea persists after day 2 and change to as needed in those that tolerate therapy better. To reduce the appearance of extrapyramidal side effects and possibly enhance the anti-emetic protection, we routinely add diphenhydramine i.v. and/or lorazepam 0.5–1.0 mg p.o. or i.v. prior to each dose of the phenothiazine or butyrophenone. Although this regimen produces somnolence, it is highly effective in controlling nausea and vomiting in most patients. On a PRN basis, we prescribe additional doses of the phenothiazine or the butyrophenone with diphenhydramine. We do not recommend the use of high-doses of metoclopramide (
1 mg/kg/dose), because this often produces diarrhea, which is already common with biochemotherapy. Lower doses (e.g., 10–20 mg i.v. every 6 h), however, my be useful in some patients. In patients with refractory nausea and vomiting despite the above measures, we have used tetrahydrocannabinol in doses of 5 mg every 6 h ATC. Steroids are prohibited, because they will interfere with the immune activation produced by the biotherapy.
Delayed nausea is best managed with aggressive i.v. hydration, i.v. 5HT3 antagonists, and combinations of the additional drugs mentioned above. Once again, steroids are prohibited. Patients exhibiting vomiting after day 3 of each cycle are at risk for delayed nausea and vomiting. They should only be discharged if nausea is controlled and the patient is taking p.o. fluids without vomiting. Despite the above measures, patients with persistent vomiting during week 2 of a cycle should have their week 2 IFN- doses held (if prescribed as in the Intergroup study), and consideration should be given to a 25% reduction in cisplatin dose during their subsequent cycles of therapy.
Diarrhea can usually be managed with loperamide 4 mg every 4–6 h PRN. Patients with persistent diarrhea, despite the above measures, should be evaluated for a secondary cause, such as Clostridium difficile infection.
During the first 2 weeks of a 3-week biochemotherapy cycle, patients frequently have difficulties with oral intake. In patients that develop severe anorexia, we suggest either tetrahydrocannabinol 2.5 mg p.o. every morning or megestrol acetate 800 mg p.o. every day after the hospital discharge.
Cardiovascular Effects
Description.
The most common cardiovascular toxicities are hypotension and capillary leak syndrome. These occur because of the release of nitric oxide from the endothelial cells, producing vasodilation and increased permeability of the blood vessels (26)
. Unlike the high-dose IL-2 regimens where hypotension can be severe, often requiring management in the intensive care unit, with the concurrent biochemotherapy program hypotension is usually mild to moderate and easily manageable in a general hospital ward (9)
. In our experience, mild hypotension managed with i.v. fluids occurs only in about one-half of the patients, whereas moderate hypotension requiring pressors occurs in 10–40% of the patients (9
, 12)
. Capillary leak is universal, and some fluid retention is even desirable to maintain renal perfusion. Peripheral edema and weight gain, in general between 5 and 10 kg, is common.
Some patients may experience mild dyspnea and exhibit rales on both lung bases, but severe dyspnea, congestive heart failure, or even noncardiogenic pulmonary edema is rare with the concurrent biochemotherapy regimens. Once IL-2 is finished, the patients start to have a brisk diuresis, and their weight returns to baseline within 5 days after completion of the IL-2 infusion (9) . Diuretics are unnecessary unless the patient is experiencing dyspnea. Occasional patients may develop cardiac arrhythmias, most commonly atrial fibrillation (9) . This is more common in patients with a history of atrial arrhythmias and those requiring dopamine. The cardiac toxicities such as myocarditis or myocardial ischemia are uncommon (9) .
Management.
Patients should discontinue any antihypertensive therapy at least 24 h prior to initiating each cycle of biochemotherapy. Blood pressure should be checked every 4 h during IL-2 therapy. Patients experiencing hypotension should have their blood pressure checked at a minimum of every 2 h. Target minimum systolic blood pressure should be 85 mm Hg for patients <40 years of age with no cardiac problems and 90 mm Hg for the remainder of the patients. Patients experiencing a fall in systolic blood pressure below their established target should be managed with a fluid bolus of NS 500 ml i.v. over 30 min and an increase in the rate of the maintenance i.v. fluids, usually from 100 ml/h to 150 ml/h. There is no major advantage for using a colloid such as albumin in this setting (27)
. If the patient does not respond to these measures, then the IL-2 infusion should be interrupted and dopamine at 3 µg/kg/min should be started and the dose titrated to keep systolic blood pressure above the patient’s target. If >6 µg/kg/min of dopamine is required to maintain systolic blood pressure, then phenylephrine should be added, beginning at 0.2 µg/kg/min and titrated up as necessary to maintain blood pressure. It is, however, extremely rare to need to use phenylephrine with the concurrent biochemotherapy regimen, and sepsis should be strongly considered in this setting.
Although during the M. D. Anderson studies IL-2 was not discontinued in the event of hypotension requiring pressors, the approach we currently recommend follows the Intergroup guidelines, which are more conservative. IFN-, cisplatin, and vinblastine should also be held while patients are receiving blood pressure support. When the systolic blood pressure no longer requires dopamine support, IL-2 and IFN- can be resumed at 50% dose reduction. Missed time of the IL-2 infusion should not be made up. Missed IFN-, cisplatin, or vinblastine can be given if hypotension resolves within 6 h of scheduled dosing; otherwise, they should be omitted for that treatment day. Hypotension becomes more severe with successive cycles of therapy. Patients experiencing a second episode of hypotension requiring pressor support, despite a 50% reduction in IL-2 and IFN-, should have the biotherapy held for remaining cycles.
As stressed previously, a critical element in the differential diagnosis of hypotension during IL-2 therapy is sepsis. It is important to emphasize that in the initial biochemotherapy studies, there were 1% deaths because of unrecognized sepsis. Because it is difficult to clinically distinguish between sepsis and IL-2 toxicity, in the event of severe hypotension, we favor that the patient’s blood be pancultured and the patient empirically started on broad-spectrum antibiotics (see "Infection" section for details).
Patients experiencing dyspnea associated with blood oxygen desaturation (<92% O2 saturation) should have all therapy held. The major differential diagnose for dyspnea is IL-2-induced pulmonary edema, infection, and congestive heart failure. In this setting, a chest-X-ray should be ordered, and diuretics or antibiotics should be used on an as-needed basis. In patients that are more susceptible to capillary leak and dyspnea (for instance because of a diastolic myocardial dysfunction), we have successfully used mannitol 40 g i.v. over 1 h every 8 or 12 h ATC to avoid excessive positive fluid balance.
Renal and Electrolyte Disorders
Description.
Significant elevations in serum creatinine occur in about 5–10% of the patients receiving biochemotherapy. Although creatinine elevation during high-dose IL-2 alone therapy is not of great concern because it is primarily pre-renal and rapidly reversible (28)
, elevations of serum creatinine >1.6 mg/dl during concurrent biochemotherapy requires immediate attention. In particular, cisplatin should be held because of it potential to produce acute tubular necrosis in this setting. Although in most instances creatinine elevations quickly resolve after discontinuation of the IL-2, the administration of cisplatin in the setting of an IL-2 induced pre-renal state and can lead to prolonged nephrotoxicity. In the M. D. Anderson Phase II experience with concurrent biochemotherapy, 6% of the 53 patients developed grade III and IV renal toxicity, and 1 patient had permanent renal failure (9)
while in the modified concurrent biochemotherapy regimen; significant nephrotoxicity was rare, with only 6 patients requiring a modification in cisplatin dosing (12)
.
Mild hyponatremia is seen in almost all patients and is typically dilutional in nature. Moderate to severe hypomagnesemia, attributable to cisplatin-induced salt-wasting, is seen in about one-half of the patients and can be severe, leading to muscle weakness and even potentially life-threatening cardiac arrhythmias (8 , 9) . Hypomagnesemia becomes progressively worse with each successive cycle of therapy and therefore requires close monitoring (8 , 9) .
Management.
It is imperative to maintain adequate urine output to reduce the possibility of acute renal failure. We recommend that patients have a urinary output 100 ml/h; otherwise, some form of therapeutic intervention should be instituted. We strongly suggest that a standing order be written to contact the attending physician if the urine output is <800 ml/8-h shift. If this happens, we initially recommend NS bolus 500 ml i.v. over 30 min as well as an increase in the maintenance i.v. fluids rate from 125 to 150 ml/h. If these measures are not effective within 3 h, then one should consider starting low-dose dopamine at renal doses, i.e., 1–2 µg/kg/min. Patients should have voided at least 500 ml in the 4 h before cisplatin administration. If adequate urine output cannot be maintained, then cisplatin should be held. Our experience suggests that dopamine is the most effective therapeutic strategy to enhance diuresis. This recommendation is also supported by a randomized trial that showed that dopamine in renal doses reduced the incidence of renal failure in patients receiving IL-2 alone (29)
. If hydration alone is inadequate to induce urine flow at the time cisplatin is scheduled, then one could consider furosemide 20 mg i.v. push or mannitol 40 g i.v. over 30 min to stimulate diuresis. Proceed with cisplatin only when adequate urine output has been documented. Patients with serum creatinine >1.6 mg/dl despite fluid bolus should have their cisplatin dose for that day held. Patients with serum creatinine >2.0 µg/dl are at serious risk for acute renal failure and, thus, should have their cisplatin held for the remainder of that particular cycle.
Hyponatremia is usually mild and does not require therapy; however, hypomagnesemia requires aggressive replacement therapy. If a patient develops hypomagnesemia in the hospital despite MgSO4 i.v. replacement, this patient should always be discharged with an oral supplementation of magnesium, i.e., magnesium oxide 400 mg p.o. three times per day and have the magnesium levels checked initially twice per week. If the magnesium drops to <1 mEq/l, it should be replaced i.v., i.e., 32 mEq in 500 ml NS i.v. over 2 h. The oral magnesium supplementation should be maintained throughout the biochemotherapy program and for least 3 weeks after completion of the last cycle, because the magnesuria continues for many weeks after the biochemotherapy is discontinued. Because oral magnesium formulation may produce diarrhea, it should be avoided during periods of diarrhea, and i.v. replacement should be used during this period.
Infection
Description.
The incidence of infection with the biochemotherapy protocols is clearly higher than for chemotherapy-alone programs. The major factors that lead to the increased infection rate are the more prolonged neutropenia, IL-2-mediated impairment of neutrophil function (30)
, IL-2 skin toxicity, and frequent accessing of the central line. In fact, in the initial Phase II concurrent biochemotherapy regimen at M. D. Anderson, 64% of the patients developed febrile neutropenia and 45% frank bacteremia (9)
. In these initial trials, all patients had an indwelling catheter that remained throughout the whole biochemotherapy treatment and was the most common site of infection. The most common bacterial organisms included coagulase-negative staphylococci (77%), Staphylococcus aureus (7%), and Gram-negative bacteria (15%).
In the modified concurrent biochemotherapy regimen, routine antibiotic and G-CSF prophylaxis was instituted in an effort to reduce the incidence of bacteremia (12) . In addition, it was required that central venous catheters be removed at the end of each 5-day inpatient treatment cycle. These modifications reduced the incidence of significant infections to <5%. Only two episodes of catheter-related infection were observed in 44 patients treated with this approach (12) .
At the Hospital Sírio-Libanês, the use of an antibiotic-coated catheter called Spectrum (Cook, Inc., Bloomington, IN) only during the hospital stay has been associated with a dramatic reduction in the incidence of infection; there was only 1 catheter-related infection among 30 patients treated. In contrast, O’Day et al. (10) from the John Wayne Cancer Center reported a 42% incidence of infection, of which the vast majority was catheter related in patients that were discharged with an indwelling central venous catheter despite the use of G-CSF. Thus, the removal of the central venous catheter after each 5-day treatment course appears to be the most critical component of the strategy to reduce infection in patients receiving biochemotherapy.
Management.
We favor the insertion of a central venous catheter prior to each treatment and removal when the patient is discharged. Despite the inconvenience and discomfort for the patient, the virtual elimination of catheter-related infections and hospital admissions because of infections justifies this approach. We also recommend prophylactic administration of an oral antibiotic (usually cephalexin 500 mg p.o. twice per day) at the beginning of each cycle of biochemotherapy, continuing until about day 15 and the administration of G-CSF from days 5 or 6 until at least absolute neutrophil count 5,000/µl (usually by day 15 of each treatment cycle). In addition, patients experiencing fevers after day 3 should be assumed to potentially have an infection. We recommend routinely obtaining blood cultures in this setting, and in patients with other findings suggestive of infection (i.e., hypotension, purulent drainage at the catheter site, severe skin rash manifested by moist desquamation, or neutropenia), broad spectrum i.v. antibiotics should be initiated, i.e., Vancomycin plus a third or fourth generation cephalosporin or a carbapenem (i.e., Cefepime or Meropenem). Vancomycin is critical because coagulase-negative staphylococci is very prevalent in IL-2-treated patients (9, 10, 11)
. Quantitative blood cultures, one from the central line and one from the peripheral line, should be obtained to help determine whether the infection is catheter related. Patients with documented neutropenic infection should have a 25% reduction in DTIC and vinblastine doses for subsequent cycles of therapy.
Cutaneous and Mucosal
Description.
All patients experience some degree of acute skin toxicity manifested usually as diffuse erythema or maculopapular rashes. The skin rash is very mild on the first day of therapy and gets gradually worse by the end of the IL-2 therapy (day 5). It usually resolves within 5 days after completion of the IL-2 infusion (Fig. 2)
. In some patients, the rash is associated with severe itching. Dry skin and mild to moderate exfoliation of the skin are common in the latter 2 weeks of the 3-week biochemotherapy cycle (Fig. 2)
. In 20% of the patients, we observed a painful oropharyngeal erythema, apparently not caused by infectious agents but related to the IL-2 therapy. It subsides 2–4 days after discontinuation of the IL-2 therapy but may recur in subsequent cycles. Alopecia is mild after two cycles of therapy but can be more noticeable in patients that receive more than two cycles of therapy. Vitiligo is observed in about 10–20% of patients (31
, 32)
. This toxicity is observed only in melanoma patients treated with IL-2, suggesting that tumor antigen expression is required to break down tolerance to host tumor and cross-reacting melanocyte antigens (31)
. In several instances, this toxicity has been reported to be associated with tumor response, supporting an autoimmune mechanism of action for the biochemotherapy (31
, 32) .
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Endocrine
Description.
Hypothyroidism is clearly associated with high-dose IL-2 therapy, with an incidence ranging from 21 to 47% (33, 34, 35)
. However, the precise incidence of this toxicity with concurrent biochemotherapy has not been established, because it has not been evaluated systematically. It is important to emphasize that hypothyroidism may be difficult to diagnose in patients with metastatic cancer because the symptoms of hypothyroidism, such as fatigue and elevation of the lactic dehydrogenase, may mimic clinical recurrence, easily misleading the clinician. In IL-2-treated patients complaining of fatigue, hypothyroidism should always be considered in the differential diagnosis.
Management.
Monitoring of thyroid function tests every 3 months is advisable. Only replacement therapy with levothyroxine is necessary to keep thyroid-stimulating hormone levels within the normal limits.
Neurological
Description.
Peripheral neuropathy is attributable primarily to cisplatin and to a lesser extent to vinblastine and is manifested as numbness in the toes and sole of the foot and less commonly in the tip of the fingers. This symptomatology may evolve to pain. It is common in patients who receive more than four or more cycles of therapy. In 20% of the patients, it can be severe (grade 3 or 4), with patients complaining of pain particularly when they stand for prolonged periods of time (9)
. The peak symptoms do not occur until 1–3 months after completion of the biochemotherapy program; therefore, any symptoms during therapy must be taken seriously and treatment modified accordingly.
During the hospital stay, insomnia is common in great part because of the frequent monitoring of the vital signs and urine output. Neuropsychological effects, such as failure in the cognitive performances, increased latency, and depression, also occur but are often underdiagnosed. Although confusion is a common dose-limiting toxicity of high-dose IL-2-alone regimens, it is rarely seen with biochemotherapy. In fact, only 2 of 44 patients receiving the modified concurrent biochemotherapy regimen developed CNS toxicity (12) . Both of these patients had undergone prior cranial radiation for CNS metastases, indicating that such prior therapy is likely a risk factor for CNS toxicity. Rarely, myositis with rhabdomyolysis has been reported (36 , 37) .
Management.
There is no optimal therapy for cisplatin-related peripheral neuropathy. In our experience, gabapentin 300 mg p.o. on the first day, 300 mg p.o. twice per day on the second day, and 300 mg p.o. three times per day from the third day after is highly effective in controlling painful neuropathic symptoms. Gabapentin does not affect the numbness, however. Insomnia responds readily to lorazepam 1–2 mg at bedtime. At the earliest symptoms of depression, we start Sertraline 50 mg p.o. every day and maintain this antidepressant throughout the remainder of the biochemotherapy program.
Miscellaneous
It is important to know that patients treated with high-dose IL-2 are more likely to experience hypersensitivity reactions to cisplatin or DTIC (38)
. Likewise, patients treated with IL-2-based regimens are more prone to adverse reactions to i.v. contrast, particularly within 2 weeks of the IL-2 therapy (39)
.
Concurrent Biochemotherapy and Ancillary Orders
To help the practicing oncologist, we have provided a sample of a biochemotherapy order sheet (Table 4)
. We have also provided a sample of an admitting order sheet, which is routinely used for the concurrent biochemotherapy regimen (Table 5)
. Use of such sample sheet should help avoid inadvertent omission of important parameters and standing orders. We also favor providing a calendar upon discharge that describes treatment and scheduled tests and an information sheet describing worrisome side effects that should prompt a call to the covering physician.
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FOOTNOTES |
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2 The abbreviations used are: IL, interleukin; CR, complete response; DTIC, dacarbazine; CVD, cisplatin, vinblastine, and dacarbazine; G-CSF, granulocyte-colony stimulating factor; 5HT3, 5-hydroxytryptamine; qd, every day; PRN, as needed (pro re nata); NS, —; CNS, central nervous system; ATC, —.
Received 3/27/01; accepted 6/ 7/01.
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TopABSTRACTIntroductionBiochemotherapyManagement of Toxicity of...REFERENCES |
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