Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 2, 2011, pp. 158-164

Indian Journal of Cancer, Vol. 48, No. 2, April-June, 2011, pp. 158-164

Original Article

Management of primary and metastatic triple negative breast cancer: Perceptions of oncologists from India

PM Parikh¹, S Gupta², B Parikh³, BK Smruti⁴, J Issrani⁵, S Topiwala⁵, C Goswami⁶, GS Bhattacharya⁷, T Sen⁸, JS Sekhon⁹, H Malhotra¹⁰, S Nag¹¹, RT Chacko¹², K Babu Govind¹³, T Raja¹⁴, AK Vaid¹⁵, DC Doval¹⁶, S Gupta¹⁶, PK Das¹⁷

¹ Indian Co-operative Oncology Network, Mumbai, India
² Tata Memorial Hospital, Mumbai, India
³ Bombay Hospital, Mumbai, India
⁴ Leelavati Hospital, Mumbai, India
⁵ Sanofi Aventis, Mumbai, India
⁶ BP Poddar Hospital, Kolkata, India
⁷ Advanced Medical and Research Center, Kolkata, India
⁸ Apollo Glenagles Hospital, Kolkata, India
⁹ Dayanand Medical College, Ludhiana, India
¹⁰ Birla Cancer Center, Jaipur, India
¹¹ Jehangir Hospital, Pune, India
¹² CMC, Vellore, India
¹³ Kidwai Memorial Institute of Oncology, Bangalore, India
¹⁴ Apollo Speciality Hospital, Chennai, India
¹⁵ Meedanta Hospital, Gurgaon, NCR, India
¹⁶ Rajiv Gandhi Cancer Institute, India
¹⁷ Apollo Hospital, India

Correspondence Address: P M Parikh Indian Co-operative Oncology Network, Mumbai India purvish1@gmail.com

DOI: 10.4103/0019-509X.82874

Abstract

Keywords: Current practices, chemotherapy, survey

Introduction

Breast cancer is one of the commonest cancers among women in India, particularly in the urban areas. Its incidence has overtaken that of cervical cancer in many population based cancer registries. ^[1] Among the advances in the management of breast cancer over the last decade, one of the most notable ones is the recognition and acceptance of taxanes as standard treatment for early as well as advanced breast cancer. ^[2] At the same time, incremental knowledge and insight into several subtypes of breast cancer is becoming crucial to optimal management of patients, especially the so called triple negative subgroup. To assess the knowledge and understanding of current evidence as well as its practical application, a series of meetings were conducted in several Indian cities over the last two years under the banner of "Pink Poll". These were supported by an unrestricted educational grant from M/S Sanofi Aventis India Limited. This report highlights the most salient findings of the Pink Poll - II that was conducted in 2009 in seven Indian cities (Mumbai, Delhi, Chandigarh, Hyderabad, Kolkata, Bangalore, and Jaipur).

Materials and Methods

A core group of senior oncologists with academic interest in breast cancer met and decided to structure the meeting as a case based discussion. The format included hypothetical cases with sequential management questions, each having relevant multiple choice options as answers [Table - 1] and [Table - 2]. The framework of the questions and the offered choices were decided by consensus in the core group and represented either the most suitable treatments based on available evidence or therapeutic options that although not based on high level evidence, are commonly practiced in India. For each case, a senior oncologist was selected as a moderator.

The audience was initially requested to vote electronically to choose the option that best described their current treatment practice for each case scenario. Thereafter, each option was discussed by a junior oncologist using published or presented evidence. This was followed by a senior oncologist providing personal insight into the application of that therapeutic option in everyday practice scenario in India. The audience was requested to vote again after discussion of the evidence for each option with the intention of evaluating the change in opinion. In addition to live voting by the attending delegates, the cases were also offered as an internet based poll to registering oncologists. The current report collates the responses from both the internet based and audience polls with respect to the important questions that were a part of Pink Poll II.

The cases were germane to commonly faced questions on systemic therapy in clinical practice with the details as follows:

The first case considered the management of metastatic breast cancer [Table - 1]. This described a 42-year-old premenopausal lady who presented with lump in her right breast confirmed on fine needle aspiration cytology to be invasive ductal carcinoma (IDC). She had undergone modified radical mastectomy. Her surgical pathology was recorded as having shown a 4.2 cm primary tumor with 3/20 axillary lymph nodes positive for metastases, presence of lymphovascular emboli and was triple negative (i.e. negative for estrogen [ER], progesterone [PgR], and HER-2 receptors). She received six cycles of TAC chemotherapy (docetaxel, doxorubicin, and cyclophosphamide) ^[3] as adjuvant treatment without undue complications. After a disease free interval of 18 months, the patient presented with dry cough and was detected to have lung metastases on computerized tomography (CT) scanning. There was no evidence of brain, liver or bone metastases and she was in good general condition. At this stage, the participants were requested to vote on the further treatment options.

The second case represented the management of a patient in the adjuvant setting [Table - 2]. This was a 50-year-old female with a history of hypertension for 10 years, diabetes mellitus for 5 years, and coronary artery disease requiring revasularization who presented with a lump in the left breast. At the time of current presentation, she was asymptomatic from the point of view of cardiac disease with good effort tolerance and well controlled hypertension and diabetes on medications. The echocardiogram revealed normal ejection fraction and left ventricular systolic function with left ventricular hypertrophy. After fine needle aspiration cytology (FNAC) confirmation of invasive cancer, the patient underwent modified radical mastectomy. The histopathology revealed a high grade invasive duct carcinoma that was 2.2 cm in maximum dimension with presence of lymphovascular emboli. One out of 17 lymph nodes had metastatic carcinoma. The tumor was negative for ER, PgR, and HER-2 receptors. At this point of the presentation, the participants were requested to select an appropriate adjuvant chemotherapy regimen for her.

The voting of the participating oncologists was recorded, collated, and analyzed.

Results

A total of 152 oncologists from all over India participated in this project. All participants did not poll for all questions. The results represent only those who chose to vote for each question. The results are divided into two broad sections, the metastatic and the adjuvant.

For the metastatic setting [Case 1], [Table - 1] the results are as follows:

Question 1: What systemic therapy will you choose for her?

Of the 104 respondents to this question, 10 (9.6%) opted for taxanes as single agent, 46 (44.2%) opted for the combination of taxane and platinum, 28 (26.9%) chose a capecitabine combination, and 20 (19.2%) chose other regimens as their preferred treatment for this patient of metastatic triple negative breast cancer with lung metastases who relapsed 18 months after completion of an adjuvant TAC regimen.

Question 2: What would be expected survival of this patient?

Of the 115 respondents to this question, 30 (26.1%) expected the survival to be between 6-12 months, 55 (47.8%) expected the survival to be between 12-18 months, 23 (20.0%) expected the survival to be between 18-24 months, and only 7 (6.1%) expected the survival to be between 24-30 months for this patient.

Question 3: If she had lung metastasis at initial presentation, what first line chemotherapy would you have chosen?

Of the 112 respondents to this question, 75 (66.9%) opted for the combination of docetaxel and anthracycline as an initial treatment, 22 (19.6%) opted for the combination of paclitaxel and anthracycline, only 4 (3.6%) chose a non-taxane anthracycline regimen, and 11 (9.8%) chose other regimens as their preferred initial treatment for this patient.

Question 4: The patient received six cycles of single agent capecitabine. After an initial response, her disease again started showing progression in the lung. What are the options at this stage?

Of the 98 respondents to this question, 13 (13.3%) opted for single agent poly ADP ribose polymerase (PARP) inhibitor, 15 (15.3%) opted for the combination of taxane and PARP inhibitor, 31 (31.6%) chose a combination of platinum and PARP inhibitor, 34 (34.7%) chose a combination of gemcitabine and PARP inhibitor, and 5 (5.1%) chose a combination of anthracycline and PARP inhibitor as third line therapy after failure with anthracycline-taxane and capecitabine.

For the adjuvant setting [Case 2], [Table - 2] the results are as follows:

Question 1: In response to a question on the use of adjuvant chemotherapy in this 50-year-old woman with a previous history of coronary revascularization, diabetes, and hypertension with currently preserved left ventricular systolic function who has single node positive, triple negative breast cancer the response was the following: 123 responded; 48 (39%) chose four cycles of AC followed by 12 cycles of weekly paclitaxel, 41 (33.3%) chose the non-anthracycline containing TC regimen for four cycles, and 34 (27.7%) chose the third generation TAC regimen for six cycles.

Question 2: In response to the same question as the previous one, but without a history of coronary revascularization, diabetes or hypertension, 69 (61%) now chose six cycles of TAC, 31 (27.7%) chose four cycles of AC followed by 12 weekly cycles of paclitaxel, and 12 (10.7%) chose four cycles of TC.

Question 3: In response to the baseline probability of 10 year survival without adjuvant chemotherapy for the above patient with some cardiac risk, there were 95 respondents; 50 (52.6%) felt that the probability of survival was 25%, 27 (28.4%) felt that the probability was 50%, 17 (17.9%) felt that the probability was 75%, and 1 (1.1%) felt the probability of survival was 100%.

Question 4: In response to the absolute benefit of adjuvant chemotherapy on overall survival, there were 79 respondents; 30 (38.0%) felt that this was 10-20%, 31 (39.2%) estimated this to be 20-30%, 14 (17.7%) estimated this to be 30-40%, and 4 (5.1%) estimated this to be 40-50%.

Question 5: In response to the choice of adjuvant treatment, if her tumor had been estrogen receptor positive, there were 78 respondents; 64 (82.0%) chose sequential chemotherapy and hormonal therapy, 8 (10.3%) chose tamoxifen for 5 years, and 6 (7.7%) chose single agent aromatase inhibitors for 5 years.

Discussion

Breast cancer, especially triple negative breast cancer, has seen significant evolution in understanding of its biology and therapy. There is rapid dissemination of knowledge to practicing oncologists due to advances in information technology. This study reports the collated perception of a group of oncologists from different regions of India in a variety of commonly encountered clinical scenarios in the management of metastatic and primary triple negative breast cancer. It must be stated that the choices presented here may not be reflective of the entire range of opinion, since the voting oncologists were constrained to choose from the options presented to them. However, the options were selected by a core group of academic oncologists to focus on controversial or commonly faced situations with the aim of capturing current practices in India. We, therefore, believe that this survey reveals important insight into prevalent practice in India with respect to the management of triple negative breast cancer.

For triple negative breast cancer who develop metastasis after having received adjuvant anthracycline-taxane (case scenario 1), the largest fraction (44.2%) chose a combination of taxane and platinum as their choice of treatment. This reflects the widespread perception and experience that platinum agents are efficacious in triple negative breast cancer, despite the lack of evidence from large trials. ^[4],[5],[6] It may also reflect the widespread comfort of Indian oncologists in using taxane-platinum combinations in a variety of malignancies including ovarian, lung, head and neck etc. The manageable adverse event profile and "reasonable" cost also possibly contribute to this preference. Since there is a lack of randomized data to indicate that this option should be the preferred standard of care in this scenario, such a trial would be well received. The second choice of the participating oncologists (26.9%) was the capecitabine regimen. This probably reflects the perceived ease of using oral agents, especially, after the dose reduction to 2000 mg/m2/day that is widely practiced in India and other Asian countries. This dosing reflects the preference for reducing toxicity at the cost of maintaining dose intensity, a perception not based on high level evidence. Interestingly, only 9.6% preferred a single agent taxane for this patient. This is appropriate, considering that she had been treated with a taxane earlier and had developed visceral metastases. The answers to this question reflect the preference for combination chemotherapy over single agents in metastatic breast cancer among Indian oncologists although this question was not specifically designed to answer this question.

In response to the question on the likely duration of survival of this patient, the largest fraction (47.8%) expected the survival to be 12-18 months, whereas 26.1% estimated it to be 6-12 months. A recent study ^[7] showed that the post distant-relapse median survival of patients with triple negative breast cancer was 9 months which was significantly shorter than 22 months for those with non triple negative disease. Thus, just over a quarter of the polled oncologists were accurate, the majority being somewhat over optimistic.

In response to a scenario in the first case of an initial chemo naive presentation with triple negative metastatic breast cancer, the overwhelming majority (86.5%) chose the upfront use of anthracycline in combination with a taxane, with the majority preferring a combination with docetaxel rather than paclitaxel. The preference for docetaxel in this combination is appropriate, given the concerns about sequence dependent synergistic cardiac toxicity between anthracyclines and paclitaxel. ^[8],[9] Although there is some evidence for improvement of survival in metastatic breast cancer with the use of anthracycline and taxane combination, ^[10],[11] it is probable that the preplanned sequential use of these agents will result in a similar outcome. ^[10] Only 3.6% of respondents chose to use an anthracycline regimen in this chemo naive scenario. This likely reflects the practice of oncologists from large tertiary academic hospitals and those in private practice. We believe that a large fraction of patients with metastatic and primary breast cancers in India, especially those in public hospitals, continue to be treated with anthracycline combinations.

In response to the question on the use of PARP inhibitors as third line treatment after failure of anthracycline-taxane and capecitabine, the respondents chose it either as single agent or in a variety of combinations. Interpretation is difficult since participants may have given different answers had they been given non-PARP choices, especially options like ixabepilone and vinorelbine.

The second case presented a scenario of balancing the need for aggressive adjuvant chemotherapy in the setting of increased cardiac risk. It is important to note that baseline cardiac risk (without any systemic cancer directed therapy) in a 50-year-old woman with a previous history of coronary revascularization, diabetes and hypertension with left ventricular hypertrophy, and normal systolic function was not addressed in any question.

The additional cardiac risk of anthracycline chemotherapy has been evaluated in surveillance epidemiology and end results (SEER) database of 43,338 patients. ^[12] The hazard ratio for congestive heart failure (CHF) was 1.26 for anthracycline use, 1.79 for increasing age, 1.45 for hypertension, 1.74 for diabetes, and 1.58 for coronary artery disease all of which were statistically significant. Since the patient in question had multiple co-morbidities, her risk for CHF is likely higher than any of the above ratios and it would be prudent to consider a non cardiac toxic regimen in such individuals. Oncologists are used to balancing the potential risks and benefits of any treatment, even when the decision does not lend itself to straightforward algorithmic process. Despite the higher than usual cardiac risk in this patient, 66.7% of oncologists chose an anthracycline regimen, testifying both to the perceived efficacy of this class of drugs and the suboptimal non-anthracycline options currently available. Four cycles of the TC regimen ^[13] has proven its superiority in one modest sized trial over four cycles of AC, but there remains continuing unease with reducing the duration of chemotherapy from six to four cycles. ^[14] The ongoing intergroup study comparing six cycles of TAC to six cycles of TC regimen will hopefully answer the question of anthracycline utility in the setting of an optimal control arm.

When the question was modified to eliminate the cardiac risk factors, the number opting for anthracycline chemotherapy increased to 89.3%, again emphasizing that anthracyclines continue to be perceived as important elements of breast cancer management. The number opting for the intensive TAC regimen more than doubled to 61.6% in the latter scenario indicating its high perceived efficacy. Whether such a high fraction of Indian oncologists actually use this regimen remains an open question, in view of its significant risk of febrile neutropenia. ^[3],[15]

The question regarding prognosis and overall survival of such patients showed no consensus regarding perceived benefit of adjuvant chemotherapy. This highlights the gap between easily available facts and their manifest perception. According to the "Adjuvant!" program that has been validated in a large database ^{[16],[17],[18],[19]} and easily accessible to community oncologists for prognosticating individual patients, the chance of 10 year survival in this scenario is 46% without any additional treatment. It is interesting that more than half of respondents under-estimated this patient′s probability of survival without adjuvant chemotherapy (selecting 25%), whereas almost one fifth estimated it to be more than 75%, an overestimate. Does this suggest that even experienced clinicians are often erroneous in their estimation of patients′ prognoses? Or does it reflect complexity beyond the mathematical algorithm used in "Adjuvant!"? For instance, oncologists practicing in private hospitals see patients with early disease, well controlled co-morbidities who are more compliant with medical advice, whereas those from the public hospitals see a different set of patients. Whether such experiences influence selection in a gaming scenario such as this is unknown, but plausible.

The estimate of benefit from adjuvant chemotherapy revealed that 77.2% of respondents felt this amounted to an absolute increase of 10-30% in survival. For the same patient characteristics, "Adjuvant!" showed a benefit of 8% for first generation (CMF like) to 20% for third generation (TAC like) regimens. Not surprisingly, the overwhelming majority of respondents (82%) continued to favor the use of chemotherapy even if this patient′s tumor had been hormone responsive - consistent with robust data from the Early Breast Cancer Trialists′ Group analyses. ^[20]

In summary, we report here the results of a first-of-its-kind, unique interactive survey of practicing Indian oncologists with respect to their perceptions and choices in systemic management of metastatic and primary triple negative breast cancer. We believe that this data offers an important insight into the patterns of practice and preferences of a diverse cross-section of practicing oncologists in this country. We are also cognizant of the possibility of bias in the results, since this activity was supported by an unrestricted educational grant from a single pharmaceutical company with a specific interest in one of the taxane drugs. Nevertheless, these results can pave the way for a seamless integration of personal preferences and expertise within the framework of evidence based practice in India. It will also be useful for identifying unmet needs and unique challenges for our country, hopefully a nidus for meaningful investigator initiated cooperative research programs.

References

Copyright 2011 - Indian Journal of Cancer

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