Evaluation of anemia, neutropenia and skin toxicities in standard or dose-dense doxorubicin/cyclophosphamide (AC)–paclitaxel or docetaxel adjuvant chemotherapy in breast cancer

J. Schwartz*, S. M. Domchek, W.-T. Hwang and K. Fox

Hospital of the University of Pennsylvania, Philadelphia, PA, USA

* Correspondence to: Dr J. Schwartz, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA. Tel: +1-401-274-1122; Email: jschwartz{at}wihri.org


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Results of CALGB 9741 demonstrated that administering standard doxorubicin/cyclophosphamide (AC)–paclitaxel therapy for adjuvant therapy of breast cancer in a dose-dense fashion with colony-stimulating factors increases efficacy, decreases severe neutropenia, but may increase the need for blood transfusions. A chart review was performed to evaluate the rates of anemia, neutropenia and skin toxicities with dose-dense and traditional AC–taxane chemotherapy.

Patients and methods: A total of 112 patients received one of four treatments: non-dose-dense AC–paclitaxel (NDD Pac), dose-dense AC–paclitaxel (DD Pac), non dose-dense AC–docetaxel (NDD Doc), or dose-dense AC–docetaxel (DD Doc).

Results: Transfusion rates were not increased in the dose-dense population; however, rates of grade 2–4 anemia (23% versus 0%, P=0.029), as well as erythropoietin use (58% versus 0%, P <0.0001), were significantly increased in the DD Pac group compared with the NDD Pac group. Grade 3 skin toxicities were significantly increased in the DD Doc group compared with the NDD Doc group (70% versus 11%, P <0.0001).

Conclusions: These results demonstrate that dose-dense AC–taxane therapy may increase rates of anemia and the need for erythropoietin, and decrease rates of neutropenia. The utility of DD Doc appears limited by skin toxicities and its use outside of a clinical study should not be recommended.

Key words: anemia, breast cancer, docetaxel, dose-dense, doxorubicin, erythropoietin, hand–foot syndrome, neuropathy, paclitaxel


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Dose intensity, defined as the amount of drug delivered per unit time (mg/m2/week), has been shown to correlate with outcome in adjuvant chemotherapy treatment of breast cancer [1Go]. However, attempts to capitalize on the dose-responsiveness by escalating doses in standard schedules have so far not been successful [2Go]. Dose-density refers to administration of drugs with a shortened treatment interval [1Go]. This concept is supported by the observation that breast cancer cells grow by non-exponential Gompertzian kinetics, whereby tumor regrowth is more rapid in a volume-reduced state, such as between chemotherapy cycles [3Go, 5Go].

The CALGB 9741 trial was designed to test this concept of dose-density and initial results were recently reported. Patients were randomized to either concurrent doxorubicin/cyclophosphamide (AC)–paclitaxel (T) every 3-weeks, sequential A->T->C every 3-weeks, dose-dense concurrent AC–paclitaxel, or dose-dense sequential A->T->C. The dose-dense arms were given with filgrastim. Results at 36 months follow-up showed a significant increase in overall and disease-free survival for the dose-dense arms [4Go]. Standard non-hematologic toxicity was reported for over 1900 patients. However, data regarding dose modifications, delays, blood transfusions and hospitalizations were reported for only 20% of patients in the trial. The transfusion rate in the combination dose-dense arm was high (13%) and no information was available concerning the use of recombinant erythropoietin (rhEpo) products for anemia.

Docetaxel is frequently substituted for paclitaxel in adjuvant 3-weekly, non-dose-dense AC–paclitaxel (NDD Pac) in clinical practice and there has been interest in the possibility of substituting dose-dense AC–docetaxel (DD Doc) for dose-dense AC–paclitaxel (DD Pac). Although no large studies of dose-dense AC–docetaxel exist, small trials of sequential dose-dense doxorubicin/docetaxel indicate increased rates of skin toxicity and anemia [6Go, 7Go].

The current evaluation was conducted to evaluate retrospectively the incidence and severity of certain toxicities of dose-dense chemotherapy in clinical practice. In particular, anemia, neutropenia and skin toxicities were evaluated in patients receiving NDD Pac, DD Pac, standard AC–docetaxel (NDD Doc), and DD Doc at a single institution multidisciplinary breast center. Furthermore, consequences of toxicities were evaluated, such as transfusions, use of rhEpo agents, hospitalizations for febrile neutropenia, and dose delays or reductions from the toxicities.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Potential patients were identified using computerized pharmacy usage lists of the relevant chemotherapy agents from January 2002 to December 2003 in our outpatient breast center. Medical records were identified for patients who received NDD Pac, DD Pac, NDD Doc or DD Doc as adjuvant therapy for primary operable breast cancer. The initial doses utilized were doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, paclitaxel 175 mg/m2 and docetaxel 100 mg/m2.

A retrospective chart review was performed to evaluate the main outcomes of anemia, neutropenia and skin toxicities. Laboratory data (hemoglobin and absolute neutrophil count) and skin reaction information, such as location, symptoms, severity and treatment, were collected and toxicity graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0. Ramifications of the toxicities were also collected, such as dose delays, reductions and discontinuations, hospitalizations for febrile neutropenia, and treatments such as transfusions, colony stimulating factors and rhEpo. Dose delay, for any reason, was also collected. Baseline demographic information, such as age, weight, allergies, medications, menopausal and nodal status, was collected to evaluate for possible risk factors for toxicity. Also, if a patient was identified as having a NCI CTC grade 2–4 skin, or grade 2–3 nail toxicity, the patient was contacted for a brief questionnaire to obtain additional information about the toxicity, such as activities of daily living affected by the reaction, exacerbating factors, treatments that provided relief and date of final resolution.

As this was a descriptive analysis utilizing all available patients, no power analysis was performed. Statistical analysis using Fisher's exact test was used when indicated. The University of Pennsylvania IRB approved this study. All patients signed a chemotherapy consent prior to receiving any chemotherapy, and if patients were identified as having a skin toxicity from the chart review, they signed an additional Institutional Review Board approved informed consent before completing the skin questionnaire.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In total, 112 patients were identified by medical records as having received one of the aforementioned regimens for adjuvant therapy of breast cancer from January 2002 to December 2003 as follows: NDD Pac, n=20; DD Pac, n=26; NDD Doc, n=56; DD Doc, n=10. The DD Doc group was very small because use was halted in early 2003 due to an increased rate of unacceptable rate of skin toxicity, as described below.

Population
In our population, all regimens were used in both node-negative and node-positive, ER(+)/ER(–), and pre- and postmenopausal women. Both dose-dense regimens were used in primarily premenopausal women. Most women were node positive (84%). All node-negative patients were considered high risk by one or more of the following: tumor size greater than 2 cm, high grade, ER negativity, or age <35 years. All node-negative patients who received dose-dense therapy were ER-negative plus one or more of the other aforementioned high-risk variables. Sixty-seven per cent (four of six) of the node-negative dose-dense patients were premenopausal (see Table 1).


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Table 1. Patient population

 
Anemia
Only two patients in our population received transfusions, one in DD Pac and one in DD Doc. RhEpo products were started in the DD groups soon after the Hg fell below 11 mg/dl. The DD Pac group in our study had a higher rate of grade 2–4 anemia (23% versus 0%, P=0.029) and a significantly greater rate of rhEpo use (58% versus 0%, P < 0.0001) compared with NDD Pac. In contrast, 21% of the NDD Doc and 20% of the DD Doc groups received rhEpo (see Table 2).


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Table 2. Anemia (Hb)a and associated complications

 
Neutropenia
As expected, the standard use of filgrastim or pegfilgrastim with the DD Pac and DD Doc regimens decreased the rates of grade 3–4 neutropenia and hospitalizations for febrile neutropenia compared with the non dose-dense groups (see Table 3).


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Table 3. Neutropenia (ANC)a and associated complications

 
Dose delays—neutropenia
The number of patients requiring dose delays secondary to neutropenia was significantly decreased in the DD Pac group compared with the NDD Pac group (0% versus 25%, P=0.011). Thirty-two per cent of patients in the NDD Doc group experienced a dose delay due to neutropenia, and overall 45% experienced any dose delay in the NDD Doc group. The median number of days of the dose delays was 7 days in all treatment groups (range 3–10) (see Table 4).


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Table 4. Dose delays

 
Dose delays—neuropathy
There was a trend towards increased delays due to neuropathy in the DD Pac group compared with the NDD Pac group (23% versus 15%, P=0.49). The median number of days of the dose delays was 7 days in all treatment groups (range 3–10) (see Table 4).

Skin toxicities
The DD Doc group was found to have an unacceptably high rate of skin toxicities, and its use was stopped after a total of 10 patients were treated. The total rate of any grade 3 skin toxicity, including nail toxicity (onycholysis), skin rash, or hand–foot syndrome, was 80% compared with 11% in the NDD Doc group (P <0.0001). One other DD Doc patient had grade 2 skin/nail toxicity for a 90% (nine of 10) rate of skin toxicity in our DD Doc population. All 10 DD Doc patients were premedicated with dexamethasone 8 mg twice daily for 3 days. In addition, two patients in the DD Pac group experienced hand–foot syndrome during the end of the AC portion of therapy.

A case report of one of the nine DD Doc patients who experienced severe skin toxicity is presented below, as an example of the nature and progression of the skin toxicities.

A 44-year-old premenopausal woman with a T3, node-negative, ER(–) breast cancer was given adjuvant AC–docetaxel on a dose-dense schedule. After the first cycle of docetaxel, the patient noted transient pruritis of the cheeks and hands. One day after the second cycle of docetaxel, a tingling, painful, pruritic erythema of the hands, feet and face was noted. Both sides of the hands and feet were red with large darker red plaques. The pain worsened after the third dose of docetaxel and desquamation started soon after. The patient also reported very painful nail beds and hands, which made daily activities challenging, onycholysis, itchy/watery eyes, which sometimes inhibited her vision, and tenderness of the soles, which made walking uncomfortable for 2–3 weeks. Methylprednisolone dose packs were given after the third and fourth cycles of docetaxel dose with little relief, but the patient did report that soaking her hands in Epsom salts, using moisturizers, and artificial tears did improve her symptoms. No cycles of docetaxel were held or delayed. The patient reported that the pain and tingling decreased 2 weeks after the final docetaxel dose, the desquamation resolved over 1 month after docetaxel, and after 6 months a remaining ‘reddish’ appearance and mild tingling of the face, hands and feet resolved.

In summary, DD Doc caused a severe hand–foot syndrome sometimes accompanied by a rash in the face or extremities, onycholysis and increased lacrimation, which sometimes impaired vision in the majority of patients. The median time to skin toxicity was 1 day after the second dose of docetaxel or 15 days after the first dose of docetaxel, and the median time to onycholysis was 6 weeks after the first docetaxel dose. The reaction of the hands and feet was associated with a painful burning or stinging sensation, which inhibited the activities of daily living of the affected patients for, on average, 2 weeks, before a gradual resolution in the form of desquamation over a period of 2–3 months. The reactions started immediately after the first docetaxel dose, worsened with each docetaxel cycle, and started to resolve only after the docetaxel was discontinued. Sixty per cent of patients had therapy discontinued prematurely due to these reactions. Oral and topical steroids and antihistamines had little success in providing relief for patients. Most patients did, however, report relief with use of moisturizers. There was no correlation between patient demographics such as age, weight, allergies, medications, menopausal or nodal status and the rate of skin reactions in our population (see Table 5).


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Table 5. Skin toxicitiesa and associated complications

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The purpose of this evaluation was to quantify and describe the skin and hematologic toxicities seen in non-dose-dense and dose-dense adjuvant therapies for breast cancer that were already in use at our institution. We report a high rate of severe skin and nail toxicities with dose-dense AC–docetaxel. Overall, 90% of patients reported either nail toxicity, rash or hand–foot syndrome, with 80% of patients experiencing a grade 3 toxicity. Previous small pilot trials have shown that dose-dense doxorubicin and docetaxel can be given concurrently successfully, but certain toxicities increase when these agents are given sequentially in a dose-dense fashion as adjuvant therapy. In two studies which examined sequential versus concurrent dose-dense doxorubicin and docetaxel, grade 3–4 hand–foot or skin toxicity was seen in 30%–40% of sequential versus 0% of concurrent patients [6Go, 7Go]. Our evaluation provided detailed descriptions of the skin toxicities from sequential dose-dense treatment, which are consistent with the other reports in the literature [6Go, 7Go, 10Go]. Several other trials have successfully given concurrent dose-dense doxorubicin plus docetaxel without an increase in skin toxicities, suggesting that sequential therapy with dose-dense doxorubicin and then docetaxel causes an increase in certain toxicities [8Go, 9Go].

The exact mechanisms by which a sequential rather than concurrent schedule of dose-dense doxorubicin/docetaxel causes an increase in severe skin reactions are unknown. Although docetaxel has been reported to cause isolated cases of mild hand–foot syndrome in other settings, the increased rate of severe reactions with biweekly dosing was not expected. Paclitaxel causes hand–foot syndrome with less frequency than docetaxel in the literature; however, there were two cases of hand–foot syndrome in the DD Pac group.

Whether this phenomenon with dose-dense doxorubicin and docetaxel is due to a unique dose or sequence-dependant interaction is unclear. Pharmacokinetic analyses available in the literature do not indicate a significant interaction when doxorubicin and docetaxel are given sequentially. However, these analyses were based on single-dose studies and not extended dosing durations [11Go]. Moreover, there is no current evidence to suggest that colony-stimulating factors contribute to these particular toxicities. One theory is that an interaction between doxorubicin and docetaxel that is specific to dose-dense sequential therapy does exist. Alternatively, the more frequent dosing and size of the doses may saturate the metabolic capacity of the liver, and the resultant increase in drug serum levels may cause more pronounced toxicities of docetaxel, which is reported to cause hand–foot syndrome, or even doxorubicin, which can also cause hand–foot syndrome when body exposure time (AUC) is increased, such as with liposomal doxorubicin. This increased AUC of doxorubicin, as well as skin toxicity related to paclitaxel, may be two of the reasons why hand–foot syndrome was seen with DD Pac and not just during DD Doc.

Risk factors predicting populations at higher risks of these toxicities, as well as successful prevention strategies for docetaxel-induced skin toxicities, have not been found so far. While premedication with steroids successfully prevents hypersensitivity and edema in several trials, we did not find that steroids reliably protect against or treat docetaxel-induced skin reactions, which has been corroborated by other studies [15Go]. Dose reduction has been reported to occasionally prevent skin toxicities in further cycles. However, in our study the reactions continued to worsen with each successive cycle in all affected patients [7Go]. Pyridoxine has been tried with some success in a small study, and recently reported data suggest that acral cooling may be an effective prevention strategy for docetaxel-related skin toxicity [12Go–14Go]. Our current evaluation similarly did not find any patient risk factors for toxicity such as weight, age or menopausal status, and the only treatment found to give relief for skin toxicities in our experience, albeit small, were moisturizing products.

RhEpo products were used more frequently in the dose-dense setting than in the standard dose setting at our institution. This may reflect increased hematopoeitic toxicity, a lower threshold of clinicians to institute prophylactic use given the transfusion rates in CALGB 9741 or, most likely, a combination of these two factors. Although this evaluation had a small sample size, the fact that there was only one red blood cell transfusion in the DD Pac group is probably due to the frequent rhEpo use, and provides some evidence that transfusions may be prevented by rhEpo use in the dose-dense setting.

Our study did support the conclusions of CALGB 9741 in regards to dose-dense regimens reducing the rates of grade 4 neutropenia and febrile neutropenia, probably due to the consistent use of colony-stimulating factors with dose-dense therapy. Neutropenia was measured in this evaluation similar to CALBG 9741, with blood counts obtained on the day of each chemotherapy cycle, and to assess possible febrile neutropenia. Although the dose-dense therapies do seem to decrease the rate of dose delays from neutropenia, which may improve dose intensity, there was an increased rate of dose delays from neuropathy, although treatment still occurred within a median of 7 days.

This evaluation also provided some information about the differences in toxicities between the standard NDD Pac and NDD Doc, although this was not the main outcome of the evaluation, and was not compared statistically. NDD Doc did tend towards increased anemia, rhEpo use and febrile neutropenia compared with NDD Pac. Although the rates of neuropathy are generally lower with docetaxel than paclitaxel, our NDD Doc population still experienced some dose delays from neuropathy and had more total dose delays than NDD Pac. The frequency of dose delays in both the NDD Pac and Doc groups was surprising. However, the differences in toxicities and delays between the AC-taxanes will become more evident when ongoing large studies of these regimens are published in the future.

This evaluation is limited by its retrospective, non-randomized, and single-center nature; our results, however, provide some interesting directions for further research. AC–docetaxel should not be used in a dose-dense fashion unless studies can identify safe and effective dosages of the agents as well as toxicity prevention strategies. Since this study was not designed to grade neuropathy, the incidence and dose delays from neuropathy should be prospectively studied in patients receiving dose-dense therapies. Differences in neuropathy may become significant if studied in a larger setting.

The interim results of CALGB 9741 did show dose-dense AC–paclitaxel to be an effective and improved therapy for breast cancer patients, and the use of this regimen will certainly increase. A cost-effectiveness analysis would be useful to balance the increased use of colony-stimulating factors and rhEpo associated with dose-dense therapy, with the possible decrease in hospitalizations for febrile neutropenia and inconvenient cycle delays. This information, in addition to quality-of-life data, would assist clinicians in individualizing therapy for breast cancer patients by utilizing additional risk/benefit information for the dose-dense therapy.

Our evaluation also adds to the existing data, which indicate that dose-dense sequential AC–docetaxel causes severe and unacceptable skin toxicities, and its use should not be recommended outside a clinical trial until a mechanism to reduce the toxicity is elucidated.


    Acknowledgements
 
We would like to thank Kamakshi Rao for her guidance with this manuscript.

Received for publication June 30, 2004. Revision received October 6, 2004. Accepted for publication October 11, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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9. Jackisch C, von Minckwitz G, Eidtmann H et al. Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin cyclophosphamide/docetaxel in operable breast cancer: second interim analysis. Clin Breast Cancer 2002; 3: 276–280.[Medline]

10. Zimmerman GC, Keeling JH, Burris HA et al. Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. Arch Dermatol 1995; 131: 202–206.[Abstract]

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12. Eich D, Scharffetter-Kochanek K, Eich HT et al. Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in breast cancer. Am J Clin Oncol 2002; 25: 599–602.[CrossRef][ISI][Medline]

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