Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 1, 2011, pp. 68-73

Indian Journal of Cancer, Vol. 48, No. 1, January-March, 2011, pp. 68-73

Original Article

Comparative study of the toxicity of 5-fluorouracil-adriamycin-cyclophosphamide versus adriamycin-cyclophosphamide followed by paclitaxel in carcinoma breast

Dhanya S Palappallil¹, Bindu Latha R Nair², KL Jayakumar³, Ramani T Puvathalil²

¹ Department of Pharmacology, Government Medical College, Kottayam, Kerala, India
² Department of Pharmacology, Government Medical College, Kottayam; and Thiruvananthapuram, Kerala, India
³ Department of Radiotherapy, Government Medical College, Thiruvananthapuram, Kerala, India

Correspondence Address:
Dhanya S Palappallil
Department of Pharmacology, Government Medical College, Kottayam, Kerala
India
dspblac@yahoo.co.in

Code Number: cn11011

Abstract

Keywords: Fluorouracil-Adriamycin-Cyclophosphamide, Adriamycin-Cyclophosphamide, toxicity, breast carcinoma

Introduction

Carcinoma of the breast accounts for 14.5 - 23.5% of all the cancers in India and is second in position to carcinoma of the cervix. ^[1] With improved social education and advocation of early detection of breast cancer the number of people found to have breast cancer has increased. The initial attempts to control cancer concentrated on aggressive local surgery with extirpation of the regional lymph nodes. The therapeutic armamentarium now includes radiotherapy, chemotherapy, and immunotherapy.

Chemotherapy kills the cells at a rate faster than the re-growth of the cells. All anticancer drugs known to date are toxic for the tumor as well as the host. This is logical because all malignant tumors originate from normal tissue and there are only small biochemical differences between the two types of cells. The limitations of chemotherapy are drug toxicity due to lack of specificity, insensitivity of the tumor cells, intrinsic / acquired resistance to cytostatic drug, accelerated growth of tumor cells, heterogeneity of the tumors, and the Gompertzian kinetics of tumor growth with slow / no growth, interrupted by random growth spurts that make the tumor grow during chemotherapy-free intervals.

The primary goal of cancer treatment is the eradication of cancer. When cure is possible, treatment may be undertaken despite the certainty of severe and life-threatening toxicities. Every cancer treatment has the potential to cause harm and treatment that produces benefit with less toxicity may be given. The therapeutic indices of many regimens are quite narrow and most treatment is given to the point of toxicity. When the clinical goal is palliation, careful attention to minimizing the toxicity of treatments becomes a significant goal. One of the challenges of cancer treatment is to use the various treatment modalities alone and together in a manner that maximizes the chances for patient benefit. Communication between patients and their physicians is the primary vehicle through which complex treatment decisions are made. ^[2] Quality of life and late effect evaluation should be judiciously integrated into selected clinical trials, to better discern the acute and long-term influence of treatment on patients. Interventions that will reduce the side effects and increase the quality of life should be sought.

There are many regimens available for the treatment of carcinoma of the breast. The most time-tested and popular regimen in our institute is the FAC regimen. The AC-P regimen has been introduced only a few years ago and data regarding the toxicity profile of this regimen is yet to be complete, nevertheless, the AC-P regimen has gained popularity and is being tried in many centers world over. Toxicities, tolerability, and survival rates need to be evaluated in our community also. Data regarding use of the AC-P regimen is very sparse, especially in the Indian population. This study is aimed at learning about the toxicities of this regimen and comparing it with the existing treatment regimen, which will enable the proper selection of patients for each regimen, as also help in the implementation of counter measures to avoid the development of toxicities, with a constant vigil on the patients during the chemotherapeutic cycles. The objectives are:

1. To study the different types of toxicities seen in patients on the FAC and AC-P regimens for carcinoma breast.
2. To assess the severity of the toxicities by grading them according to the WHO guidelines and Karnofsky performance status. ^[3],[4]
3. To compare the toxicity profile of the two regimens.

Materials and Methods

This was a prospective observational study conducted in the Department of Radiotherapy, Government Medical College, between February 2007 to and July 2008. A total of 50 patients were included in each group after satisfying the inclusion criteria, which consisted of a postoperative pathology report of carcinoma breast, age between 20 and 70 years, and Karnofsky performance status ≥ 60. Those who were not willing to participate in the study, those receiving another chemotherapy regimen after Modified Radical Mastectomy for breast carcinoma, those diagnosed with distant metastasis, inadequate hematopoietic, hepatic, and / or renal function, and pregnant ladies were excluded from the study. Structured proforma validated by the statistician was used for collecting data.

The Research and Ethics committees′ approval was obtained. Patients satisfying the entry criteria were enrolled in the study. A written informed consent was obtained from the patient. A detailed elucidation of the history and clinical examination was performed prior to initiation of the treatment. General examination was done and performance status was assessed. Systemic examination included examination of all the organ systems.

Allocation of the patients to the chemotherapy regimens was based on the severity of the disease. High-risk patients were allocated to the AC-P regimen. Risk of the patients was determined by age (younger patients at higher risk), large tumor size, lymph node status, extra capsular extension, and high tumor grade. Others received the FAC regimen. They were personally interviewed, to detect the development of any such toxicity symptoms during the course of chemotherapy and the review visits.

FAC regimen

F-5 Fluorouracil 500 mg/m ² as intravenous infusion repeated after 21 days

A-Doxorubicin 50 mg/m ² as intravenous infusion repeated every 21days

C-Cyclophosphamide 500 mg/m ² as intravenous infusion repeated every 21 days

Six such cycles were given followed by radiation

AC followed by P regimen

A-Doxorubicin 60 mg/m ² as intravenous infusion repeated every 21days

C-Cyclophosphamide 600 mg/m ² intravenous infusion repeated every 21 days

Four such cycles were given; this was followed by radiation, followed by P-Paclitaxel 175 mg/m ² intravenous infusion repeated every 21 days x 4 cycles.

Premedication for AC-P regimen, with Dexamethasone 8 mg, Ranitidine 50 mg, and Pheniramine maleate 25 mg intravenously, was given on the day before and on the day of paclitaxel infusion.

Antiemetics, such as Granisetron, were given in both the regimens before starting the chemotherapy.

All the patients were assessed during the course of each cycle of chemotherapy and were observed for the immediate occurrence of any of the toxicities. All of them were followed up during their repeat visits. The toxicities like anemia, leukopenia, and thrombocytopenia were assessed based on the investigations done on the tenth day of the cycle. The patients were personally interviewed for subjective toxicities such as nausea, vomiting, and the like, and their toxicity grades were assessed based on the personal diary maintained during their revisits. The patient was clinically examined for other toxicities like alopecia, peripheral neuropathy, and other dermatological toxicities. All the data collected was entered in the proforma sheet. The toxicities developed were graded according to the WHO guidelines.

Data analysis was done with the help of the Excel 2007 and SPSS 16 statistical software. The toxicity grades were entered in the Excel 2007 worksheet for each variable. The highest toxicity during any cycle was considered as the toxicity grade for that patient. The chi-square test was done to assess the difference between the two groups, as grades were categorical variables. The performance status was assessed using the Karnofsky performance scale. Descriptive statistics was used to describe the various types of toxicities and their WHO grading.

The WHO grades toxicities into five grades, which are, Grades 0, 1, 2, 3, and 4, which are ascending grades of the toxicity. Grade 0 represents normal values or absence of toxicity, whereas, grade 4 represents maximum toxicity that can occur for a variable, except for alopecia where grade 2 is the highest toxicity (complete hair loss).

Results

A total of 100 patients who underwent modified radical mastectomy for carcinoma of the breast, which was histopathologically proven, were allocated for the study. All the patients recruited for the study were females.

The age range of patients included in the study as shown in [Table - 1] was between 20 and 65 with a mean age of 44 years. The median age was 48 in the FAC and 40 in the AC-P group. The maximum number of patients fell in the age group of 36 - 50 years in both regimens, that is, FAC (54%) and AC-P (44%).

Overall comparison shown in [Table - 2] indicated that a significant increase in toxicities such as anemia, hyper pigmentation, stomatitis, and diarrhea were seen with the FAC regimen, while leukopenia, myalgia, arthralgia, and peripheral neuropathy were more common with the AC-P regimen.

Anemia and thrombocytopenia developed only in the FAC regimen. Grade 1 anemia was the most common (34%) and grade 3 the least common (6%). Leukopenia, a life-threatening toxicity developed in 83 out of 100 patients taken in for the study. Comparison of the two regimens showed that all patients on the AC-P regimen developed leukopenia, whereas, only 33 patients in the FAC regimen developed leukopenia. A majority of the patients on an FAC regimen developed only grade 1 leukopenia, while patients on the AC-P regimen progressed to grades 2 and 3.

Nausea and vomiting were the most intolerable toxicities seen in patients receiving both these regimens. Although grade 3 nausea was seen more common in patients on the AC-P regimen, more patients in the FAC regimen developed higher grades of vomiting.

Stomatitis a major toxicity in patients receiving the FAC regimen developed in 80%, while in patients on the AC-P regimen stomatitis was infrequent, occurring only in 4%. Diarrhea developed in four patients on the FAC regimen, while none in the AC-P regimen developed this toxicity.

Hyperpigmentation was a major toxicity in the FAC regimen, as 49 patients developed the toxicity, whereas in the AC-P regimen only one patient developed the toxicity. Alopecia was a distressing toxicity that affected patients of both the regimens and all of them developed complete hair loss (grade 2) during the course of the treatment.

The incidence of myalgia in the FAC regimen was much less (4%) as compared to the AC-P regimen (92%). In the AC-P regimen 78% patients developed grade 1 arthralgia, whereas, only three patients in the FAC regimen developed the same.

Peripheral Neuropathy a late toxicity was more in patients on the AC-P regimen (82%) and only two patients in the FAC regimen developed peripheral neuropathy.

[Table - 3] shows the other toxicities seen in the treatment regimens, which could not be graded according to the WHO toxicity grading. One patient developed severe dyspnea, chest tightness, and itching after being given Doxorubicin infusion. Two patients developed severe upper respiratory tract infection, which was treated with antibiotics.

There were no dropouts or mortality in either regimen during the study period.

Performance statuses of the patients were estimated using the Karnofsky performance scale. The scale ranged from zero to one hundred. The zero in the scale denoted a dead patient whereas a scale of 100 denoted a normal patient. The patients were interviewed regarding their ability to do daily activities and take care of themselves, and a score was fixed. The scoring was done before each chemotherapeutic cycle and repeated during all the visits. Thus 300 assessments were done (50 patients x 6 cycles) for the FAC regimen and 400 (50 patients x 8 cycles) for the AC-P regimen.

[Table - 4] shows that 92% of assessments in patients on the AC-P regimen showed a performance scale of 70 as compared to 80% for those on FAC. Comparison of the regimens showed that the quality of life was more affected in patients receiving the FAC regimen.

Discussion

The adverse effects to anticancer therapy are well known and limit the effectiveness of the therapy, prompting investigators to continue seeking new therapies or combinations that can produce a high response while reducing the incidence and severity of the side effects.

This study was conducted to compare the toxicity profiles of two popular regimens used for adjuvant chemotherapy in carcinoma breast, namely the FAC and AC-P regimens, and it extended for a period of 18 months. The median age of patients who received the FAC regimen was 48 years while that for the AC-P regimen was 40 years, which indicated that younger patients were included in the AC-P regimen. Many recent trials of adjuvant chemotherapy examined how best it was to incorporate taxanes in the regimens. Henderson et al. states that the addition of four cycles of paclitaxel after administration of AC was associated with a better outcome. ^[5] In the study conducted by Martin et al., it was found that the disease-free survival of five years was significantly more when taxanes were incorporated in the regimen. ^[6] Hence, younger and high-risk patients were allocated to the AC-P regimen.

The differences in anemia and leukopenia between the two groups were statistically significant. Significant anemia requiring transfusion in patients receiving the FAC regimen (43.1%) was reported in a South Indian study by Sambasiviah et al. ^[7] However, the study done by Martin et al. in a western population showed a higher incidence of anemia (91.5%) and Grade 3 - 4 neutropenia (65.5%), with a taxane containing regimen. ^[6] As stated by Abu Khalaf et al. grade 3 - 4 neutropenia developed in 91% of the patients receiving the AC-P regimen and many of them progressed to neutropenic sepsis. ^[8] Thrombocytopenia was infrequent in both the regimens in this study. In the study done by Buzdar et al., thrombocytopenia was absent with FAC regimen, but a few patients (18%) developed thrombocytopoenia with the same regimen in a similar study done by Wood et al. ^[9],[10] Thrombocytopenia developed in both the regimens in the study by Martin et al. ^[6]

Different gastrointestinal adverse effects like nausea, vomiting, stomatitis, and diarrhea were compared, which showed that patients allocated to both the regimens developed comparable nausea and vomiting. The review of literature indicates that nausea, vomiting, stomatitis, and diarrhea were seen in patients receiving FAC and AC-P. ^[5],[10] However, the incidence was much less as compared to our study where nausea and vomiting occurred in > 90% of the patients receiving both the regimens. In the study done by Abu Khalaf et al., nausea or vomiting occurred in 24% of the patients receiving the AC-P regimen, which was much less when compared to our study subjects receiving the AC-P regimen (98%). ^[8] However, mucositis was less (4%) in our study subjects as compared to 18% in the study by Abu Khalaf et al. ^[8] In the study conducted by Martin et al. nausea and vomiting were significantly more in patients receiving FAC while in our study it was almost equal. ^[6] In the same study stomatitis and diarrhea were more when taxane containing regimen was used. The study conducted by Sambasiviah et al. indicated that mucositis (13.6%) was more common in patients receiving FAC, which was consistent with our study. ^[7]

Dermatological adverse effects such as hyperpigmentation and alopecia were compared apart from nail changes, thinning of hair, and photosensitivity. In the study conducted by Martin et al., skin changes were more in the taxane containing regimen, while the incidence of alopecia was similar in both the groups. ^[6] In the south Indian study by Sambasiviah et al. alopecia was seen in all patients receiving the FAC regimen. ^[7] In other studies done by Buzdar et al. and Wood et al., high incidence of alopecia with FAC was noted, while in the study done by Henderson et al. all patients receiving AC-P developed alopecia. ^[5],[9],[10]

A comparison of musculoskeletal adverse effects such as myalgia and arthralgia showed that both the adverse effects were more with the AC-P regimen. In the study comparing FAC and TAC by Martin et al., a significant increase in these adverse effects was seen in patients receiving taxanes. ^[6] In the study done by Burtness et al. myalgia and arthralgia were seen only in 10%, while in the studies conducted by Abu Khalaf et al. this was 6%. ^[8],[11]

Peripheral neuropathy was a significant adverse effect of the AC-P regimen, which developed in 82% of the patients, while only 4% on the FAC regimen developed this adverse effect, which showed that it was statistically significant. These findings were consistent with the studies by Martin et al., which showed that the neurosensory adverse effects were more (25.2%) in the taxane containing regimen. ^[6] In the study done by Burtness et al. and Abu Khalaf et al. this adverse effect was seen in patients receiving regimens that contained paclitaxel, but the overall incidence was less. ^[8],[11] As the patients in the AC-P regimen received pre-medication prior to paclitaxel infusion, none of them developed hypersensitivity reactions, which had been reported with the use of paclitaxel.

Limitations

1. By increasing the sample size and the duration of the study the comparison of the toxicity profiles, tolerability, and survival rate could be assessed with a better possible outcome.
2. The survival of patients with these regimens could be discovered by conducting a prolonged study, extending for at least five years, whereas, this study was conducted for a period of one-and-a-half years.
3. Pharmacoeconomic evaluation needs to be performed to assess the affordability of the drugs in a country like India.
4. Since young age was a high-risk criterion, those in the younger age group were allocated to the AC-P regimen and hence age matching could not be for the FAC regimen. This is because ethical concerns prevented the use of a more expensive regimen, when cheaper alternatives such as the FAC regimen were available for use in the older age group, for the assessment of toxicity, especially in an illness such as cancer.

Conclusion

This study compares the toxicity profiles of two popular regimens used in carcinoma of the breast and it was conducted on the South Indian population. The study showed that both the regimens had different profiles of toxicities, with statistically significant differences. The most common toxicities observed in the FAC regimen were anemia, stomatitis, diarrhea, and hyperpigmentation while leukopenia, arthralgia, myalgia, and peripheral neuropathy were more visible with the use of the AC-P regimen. According to the performance scale, the AC-P regimen was better tolerated than the FAC regimen. Most of the data obtained in the study were consistent with the data available in literature. The small differences between this data and the Western data could be due to the ethnic differences and this need to be evaluated with tools available in the emerging horizon of pharmacogenomics.

References

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2.	Adjuvant Therapy for Breast Cancer. NIH Consensus Statement Online 2000;17:1-23.  Back to cited text no. 2
3.	National Cancer Institution_NCI Toxicity Criteria formatted. Available from: http://www.download.bham.ac.uk/bctu/AML16/Trial/DocsForExistingCentres/National%20Cancer%20Institution_NCI%20Toxicity%20Criteria%20formatted.pdf .  Back to cited text no. 3
4.	Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncol 1984;2:187-93.  Back to cited text no. 4
5.	Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976-83.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.	Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, et al. Adjuvant docetaxel for node- positive breast cancer. N Engl J Med 2005;352:2302-13.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.	Kuraparthy S, Reddy KM, Yadagiri LA, Yutla M, Venkata PB, Kadainti SV, et al. Epidemiology and patterns of care for invasive breast carcinoma at a community hospital in Southern India. World J Surg Oncol 2007;5:56.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.	Abu-Khalaf MM, Windsor S, Ebisu K, Salikooti S, Ananthanarayanan G, Chung GG, et al. Five-year update of an expanded phase II study of dose-dense and intense doxorubicin, paclitaxel and cyclophosphamide (ATC) in high-risk breast cancer. Oncology 2005;69:372-83.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.	Buzdar AU, Blumenschein GR, Gutterman JU, Tashima CK, Hortobagyi GN, Smith TL, et al. Postoperative adjuvant chemotherapy with fluorouracil, doxorubicin, cyclophosphamide and BCG vaccine: A follow up report. JAMA 1979;242:1509-13.  Back to cited text no. 9  [PUBMED]
10.	Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node- positive carcinoma breast. N Engl J Med 1994;330:1253-9.   Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.	Burtness B, Windsor S, Holston B, DiStasio S, Staugaard-Hahn C, Abrantes J, et al. Adjuvant sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide (ATC) for high-risk breast cancer is feasible in the community setting. Cancer J Sci Am 1999;5:224-9.  Back to cited text no. 11  [PUBMED]

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