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    -  Iyer P
    -  Radhakrishnan V
    -  Balasubramanian A
    -  Sridevi V
    -  Krishnamurthy A
    -  Dhanushkodi M
    -  Sundersingh S
    -  Ganesarajah S

 
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ORIGINAL ARTICLE
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Study of pathological complete response rate with neoadjuvant concurrent chemoradiation with paclitaxel in locally advanced breast cancer


1 Department of Radiotherapy, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India
2 Department of Medical Oncology, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India
3 Department of Surgical Oncology, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India
4 Department of Pathology, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India

Date of Submission10-Jun-2019
Date of Decision17-Nov-2019
Date of Acceptance18-Nov-2019
Date of Web Publication08-Jul-2020

Correspondence Address:
Priya Iyer,
Department of Radiotherapy, Cancer Institute (W.I.A), Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_524_19

PMID: 32675440

  Abstract 


Background: Neoadjuvant concurrent chemoradiation (CTRT) is not widely practiced in breast cancers. The current study presents our experience with the use of neoadjuvant CTRT in patients with locally advanced breast cancers (LABC) treated at our center.
Methods: The study included all consecutive female patients with inoperable stage III LABC treated at Cancer Institute (W.I.A), Chennai, India, from December 2015 to September 2016. Data were collected retrospectively from the patients' case records. The impact of neoadjuvant CTRT on the pathological complete response (pCR) and survival was analyzed. Neoadjuvant chemotherapy consisted of 4 cycles of adriamycin and cyclophosphamide given either before or after 4 cycles of paclitaxel. All chemotherapy cycles were given once in 3 weeks. Concurrent radiotherapy was incorporated with 2 cycles of paclitaxel.
Results: The study included 100 patients with a median age of 49 years, among whom 9 (9%) had IIIA disease, 73 (73%) IIIB, and 18 (18%) had IIIC disease. The hormone receptor-positive disease was observed in 36 (36%) patients, triple-negative in 24 (24%), and Her2/neu positive disease in 40 (40%) patients. All patients were operable after completing the planned neoadjuvant treatments. Ninety-one out of 100 (91%) patients underwent modified radical mastectomy whereas 9 (9%) did not consent for surgery. Among the patients who underwent MRM, 34/91 (37.7%) patients had a pCR. Moreover, pCR was observed in 12/22 (54.5%) patients with triple-negative disease, 10/34 (29.4%) patients with hormone receptor-positive disease, and 12/35 (34.2%) patients with Her2/neu positive disease (P = 0.19). Most common morbidity observed was grade 3 skin reactions. The 2-year event-free survival and overall survival for the entire cohort was 73.1% and 88%, respectively.
Conclusion: Neoadjuvant CTRT is associated with a higher pCR rate than what has been reported with neoadjuvant chemotherapy alone. Further prospective studies are required to confirm our findings.


Keywords: Breast cancer, chemotherapy, radiotherapy



How to cite this URL:
Iyer P, Radhakrishnan V, Balasubramanian A, Sridevi V, Krishnamurthy A, Dhanushkodi M, Sundersingh S, Ganesarajah S. Study of pathological complete response rate with neoadjuvant concurrent chemoradiation with paclitaxel in locally advanced breast cancer. Indian J Cancer [Epub ahead of print] [cited 2020 Aug 7]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=289209





  Introduction Top


Concurrent chemoradiation (CTRT) is the standard of care for treating carcinomas of the head and neck, esophagus, rectum, cervix, anal canal, lung, stomach, bladder, and pancreas.[1] However, its role is not well established in the treatment of breast cancer. Carcinoma breast is the most common malignancy seen in women across the world.[2] Its incidence in low middle- income countries (LMIC) like India has rapidly increased over the last two decades.[2] In contrast to high-income countries (HIC), a significant proportion of patients in LMIC tend to present in advanced stages.[3] Approximately 40% of all patients presenting to our centre have locally advanced breast cancer (LABC) and the majority of them are inoperable at presentation. It is common to see patients at our centre presenting with breast tumors measuring more than 10 cm in size, fixed axillary nodal masses, and fungating tumors. In our experience, neoadjuvant chemotherapy (NACT) by itself is inadequate for achieving tumor shrinkage and operability with negative margins. Therefore, we routinely use neoadjuvant CTRT in patients with inoperable LABC to make them amenable for surgery and improve the pathological complete response (pCR) rates. The rationale of using CTRT rather than NACT include better local tumor control because of the radio-sensitizing effect of chemotherapy and addressing systemic disease simultaneously. In addition, pCR with NACT in breast cancer has been observed to be associated with improved survival. [1,4-6] The aim of our study was to assess the safety, efficacy, and the pCR rates in patients with inoperable LABC treated at our center with neoadjuvant CTRT using paclitaxel.


  Patients and Methods Top


All consecutive women with inoperable LABC treated at Cancer Institute (W.I.A), Chennai, India, with neoadjuvant CTRT from December 2015 to September 2016 were included in the study. The procedures followed in the study were in accordance with the ethical standards of the hospital ethics committee and with the Helsinki Declaration of 1975, as revised in 2000. Data were extracted retrospectively from the patients' case records. All treatment decisions were taken by the hospital multidisciplinary tumor board. Informed consent was obtained from the patients prior to starting treatment. Diagnosis of breast cancer was established by a core needle biopsy followed by histopathological examination. Estrogen receptor (ER), progesterone receptor (PR) and Her2/neu receptor status, and Ki-67 index were assessed on the biopsy specimen using immunohistochemistry (IHC). IHC results were interpreted as per the standard criteria. Patients were Her2/neu positive if the IHC score was 3+ or if fluorescent in situ hybridization (FISH) was positive with an IHC score of 2+. Staging workup for the patients included contralateral breast mammogram, ultrasound of the abdomen and pelvis, technetium-99 bone scan, and contrast-enhanced computed tomography (CT) of the chest which also included a screening of the liver. Any abnormal lesion detected in the liver during the screening CT was confirmed through a proper CT scan of the abdomen. Patients were staged according to the American Joint Committee for Cancer (AJCC) staging system, 7th edition. Patients with LABC who had pectoralis muscle infiltration, ipsilateral supraclavicular, or internal mammary lymph nodal involvement and in patients in whom surgery would entail positive or close margins as per the surgeons perspective, patients with fixed axillary nodal involvement, and extensive peau d'orange were considered inoperable at presentation at our center and were offered treatment with neoadjuvant CTRT.

The patients in the study received 4 cycles of paclitaxel either before or after 4 cycles of adriamycin and cyclophosphamide (AC) as the NACT regimen. Paclitaxel was given at a dose 175 mg/m2 as a 3-hour infusion, adriamycin 60 mg/m2 slow intravenous bolus, and cyclophosphamide 600 mg/m2 as 1-hour infusion. All chemotherapy regimens were given once in 3 weeks. Radiotherapy was incorporated between the 1st to 3rd cycle of paclitaxel. CTRT with paclitaxel was started first followed by neoadjuvant AC chemotherapy except in patients with a large volume disease which could not be encompassed in the radiation field where neoadjuvant AC chemotherapy was initiated first followed by CTRT with paclitaxel. The decision to sequence NACT and neoadjuvant CTRT was based on the treating radiation oncologist's decision. Patients at our center with operable LABC were treated with the same NACT protocol followed by surgery and sequential radiotherapy. Radiotherapy consisted of 3D conformal therapy delivered at a dose of 46 Gy in 23 fractions to the breast and regional nodes (axilla, supraclavicular, and internal mammary). Treatment planning was performed on Eclipse version 15.5. Treatment was delivered using megavoltage linear accelerators with 6 MV energy or higher.

Modified radical mastectomy (MRM) was performed after 4–5 weeks of completion of neoadjuvant treatment. Women with Her2/neu positive disease were treated with adjuvant trastuzumab, wherever feasible.[7] Cardiac function was assessed with an echocardiogram performed before and after the completion of trastuzumab. Women with hormone-receptor-positive status received postoperative endocrine therapy according to their menopausal status.

Adverse events and toxicity were assessed by the treating oncologist as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 and the Radiation Therapy Oncology Group (RTOG) toxicity grading criteria.[8],[9] Patients were assessed once a week by the treating physician for clinical response assessment, treatment tolerability, and toxicity. Toxicities were captured as recorded in the patients' case records. Any delay of more than 1 week from the planned duration of RT was recorded as delay in radiation therapy.

pCR was defined as the absence of invasive carcinoma in breast or lymph nodes (ypT0N0) or residual in situ carcinoma (ypTisN0).[10]

Patients with ER/PR positive and Her2/neu negative tumor were defined as hormone receptor-positive disease. Patients with Her2/neu positive tumors were defined as Her2/neu positive disease irrespective of the ER/PR status. Patients whose tumors were ER, PR, and Her2/neu negative were defined as triple-negative disease. Event-free survival (EFS) was calculated from the date of diagnosis to the date of relapse or progression. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. All patients were censored for survival analysis at the last follow-up or death whichever was earlier. EFS and OS were estimated using the Kaplan-Meier method and variables were compared using the log-rank test. Univariate and multivariate analyses were performed to identify prognostic factors for survival. Categorical variables were compared using the Chi-square test. A P value of less than 0.05 was considered statistically significant. Statistical analysis was done using SPSS software (IBM SPSS Statistics Version 16.0).


  Results Top


One hundred patients were treated with neoadjuvant CTRT during the study period at Cancer Institute (W.I.A), Chennai, India. The median age was 49 years (range 30–70 years). Thirty-nine patients were premenopausal (39%), 57 were postmenopausal (57%), and 4 patients were perimenopausal (4%) at presentation.

Nine out of 100 patients (9%) were diagnosed with stage III A disease, 73 (73%) in stage III B, and 18 (18%) in stage IIIC (18%). Invasive ductal carcinoma was the pathology seen in all the patients. Forty-three patients out of 100 (43%) received neoadjuvant CTRT followed by NACT, whereas 57 patients (57%) received NACT followed by neoadjuvant CTRT.

All the patients in the study were operable after the neoadjuvant treatment. Ninety-one patients out of 100 (91%) underwent MRM. Eighteen out of 40 patients with Her2/neu positive disease received adjuvant trastuzumab, 3 patients received trastuzumab for 1 year, and the remaining 15 patients received trastuzumab weekly for 9 cycles. The remaining nine patients did not consent for surgery.

Among the patients who underwent MRM, 34/91 (37.7%) patients had a pCR. pCR was observed in 12/22 (54.5%) patients with triple-negative disease, 10/34 (29.4%) patients with hormone receptor-positive disease, and 12/35 (34.2%) patients with Her2/neu positive disease (P = 0.19). Patients who received neoadjuvant CTRT followed by NACT demonstrated a pCR rate of 43.9% (18/41) whereas patients who received NACT followed by neoadjuvant CTRT had a pCR of 32% (16/50) (P = 0.24). [Table 1] provides the demographic and clinical details of the patients in the present study.
Table 1: Patient and tumor characteristics

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Grade 3 skin toxicity (moist desquamation) was observed in 24/100 (24%) patients, all of whom had a delay in their planned duration of radiation by more than a week. The median delay in radiation due to grade 3 skin morbidity was 10 days (range 7–14 days). None of the patients had grade 4 skin toxicity. Grade 3 febrile neutropenia was observed in 4 patients (4%) with paclitaxel, none of which were during CTRT. During RT, 26/100 (26%) patients required filgrastim for the management of neutropenia. None of the patients developed symptomatic pneumonitis or any cardiac morbidity. Delayed wound healing (>4 weeks) was observed in 24/91 (26.3%) patients after MRM. Postoperative wound infection was observed in 13/91 (14%) patients and all the infections were superficial and were managed conservatively. Secondary suturing was required in 3/91 (3.2%) patients.

The median follow-up was 24.5 months (range 6.5–32.5 months). The 2-year EFS and OS for all the patients were 73.1% and 88%, respectively [Figure 1] and [Figure 2]. The 2-year OS and EFS for stages IIIA, IIIB, and IIIC were 100%, 89.3%, 77.8% (P = 0.13) and 100%, 73.4% and 59.3%, respectively (P = 0.1). The OS and EFS for patients who received neoadjuvant CTRT followed by NACT compared to NACT followed by CTRT were 95.1% vs 83.1% (P = 0.08) and 85.7% vs 64.3% (P = 0.03), respectively. The OS and EFS for patients with pCR and no pCR were 94.1% vs 88.1% (P = 0.49) and 79.7% vs 71.5% (P = 0.15), respectively.
Figure 1: Kaplan-Meier curve demonstrating the event-free survival of the patients in the study

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Figure 2: Kaplan-Meier curve demonstrating the overall survival of the patients in the study

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Out of 9 patients who did not undergo surgery, 5/9 (55.5%) patients had a complete clinical response and are disease-free on follow-up. Among these 5 patients, 2/5 (40%) patients were hormone receptor-positive and Her2/neu negative and 3/5 (60%) patients were triple-negative. The remaining 4/9 (44.4%) patients were hormone-receptor negative and Her2/neu positive and had disease progression on follow-up. Three out of the 4 patients have died, and 1 patient is alive and on follow-up. All the 4 patients received 9 weeks of trastuzumab after completing neoadjuvant CTRT and NACT.


  Discussion Top


Inoperable LABC poses a challenge for the oncologists since response rates may vary depending on the inherent tumor biology.[1] Not all patients receiving NACT become operable at the end of chemotherapy. Nevertheless, surgery plays the main role in the treatment of nonmetastatic breast cancers and is directly related to superior OS and disease-free survival (DFS) as compared to patients who do not undergo surgery.[11] Therefore, operability is one of the goals of treatment in an inoperable LABC.

There has not yet been a uniform definition of pCR, which has made reporting and interpretation of data from neoadjuvant trials challenging. The Food and Drug Administration (FDA) of USA defines pCR as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0) and this recommendation was based on the Chemotherapy Neoadjuvant in Breast Cancer (CTNeoBC) pooled analysis study.[10] We used the FDA definition to define pCR in our study. The CTNeoBC study did not show a difference in survival between patients having ypT0/ypN0 vs ypTis/ypN0, however, a study by von Minckwitz Gunter et al. showed that patients with ypT0/ypN0 had better survival when compared to patients with ypTis/ypN0.[10],[12]

Several trials conducted on the effect of NACT on operable breast cancer patients have shown an inverse relationship between the amount of residual disease in the breast and axilla, post-NACT and survival. [1,4-6] Patients with pCR have better prognosis and significantly improved DFS.[1]

Our study suggests that neoadjuvant CTRT improved the operability and pCR rates in patients with inoperable LABC. All patients were found to be operable after completing the planned NACT and neoadjuvant CTRT.

Shanta et al. in a study with 1117 patients with stage II and III breast cancer treated with neoadjuvant CTRT using CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) or FEC (5-fluorouracil, epirubicin, and cyclophosphamide) or FAC (5-fluorouracil, adriamycin, and cyclophosphamide) reported a pCR rate of 45.1%, whereas our study reported a pCR rate of 37.7%.[13] However, the present study included only inoperable LABC and used paclitaxel with CTRT whereas the study by Shanta et al. included early and LABC treated with multi-agent CTRT.

The pCR rates observed with paclitaxel concurrent with RT in literature have varied from 16%–46% [Table 2].[14-17] The wide variation in pCR rates could be because of the differences in the receptor status, radiation, and chemotherapy dose and use of other chemotherapy drugs in the neoadjuvant setting. The present study used neoadjuvant adriamycin and cyclophosphamide in addition to CTRT, unlike other studies which did not include anthracyclines and alkylating agents as NACT. The higher pCR rates in our study could also be due to the incorporation of adriamycin and cyclophosphamide as NACT.
Table 2: Studies with Neoadjuvant CTRT with Paclitaxel in breast cancer

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It was observed in our study that patients who received neoadjuvant CTRT followed by NACT had a higher pCR rate as compared to patients who received initial NACT followed by neoadjuvant CTRT (48.7% vs 38%, P = 0.3). Patients with bulky tumors received NACT prior to neoadjuvant CTRT because the tumor could not be encompassed in the radiation field. The increased tumor burden in the upfront NACT group could be a reason for the lower pCR observed in this group compared to the upfront CTRT group. However, this finding needs to be confirmed in a prospective randomized trial as there was a bias in selecting patients who received initial NACT followed by neoadjuvant CTRT rather than vice-versa.

Patients with the triple-negative disease had the highest pCR (54.5%) followed by Her2/neu positive (34.2%) and hormone receptor-positive disease (29.4%). These results are consistent with the observation of higher pCR rates in patients with triple-negative breast cancer receiving NACT.[6]

Formenti et al. used paclitaxel at a dose of 60 mg/m2 given weekly with radiotherapy to a total dose of 50 Gy.[17] However, they had to reduce the dose of paclitaxel to 30 mg/m2 and RT dose to 45 Gy as they observed increased skin morbidity with a higher dose of paclitaxel and radiotherapy.[17] We used a radiotherapy dose of 46 Gy/23 fractions and observed a grade 3 skin toxicity of 25% and no grade 4 skin toxicity. Our findings indicate that the chemotherapy dose intensity need not be reduced when given concurrently with conventional doses of radiotherapy. A previous study from our center used a radiation dose of 40 Gy and reported pCR rates like the current study.[13] However, increasing the radiotherapy dose beyond 46 Gy may increase skin toxicity. Studies that have used radiotherapy doses more than 46 Gy or have used a boost to the tumor have reported a higher incidence of pulmonary toxicity.[17] Clinically, we did not observe any symptomatic pulmonary toxicity in our study.

The deterioration of quality of life after CTRT in breast cancer has been reported to be comparable to that observed with sequential chemotherapy and radiotherapy.[18] However, CTRT offers the advantage of reducing the total duration of treatment in breast cancer compared to conventional chemotherapy followed by radiotherapy.

The present study used once in 3 weeks paclitaxel schedule instead of the weekly or twice a week schedule reported by other authors. Once in 3 weeks paclitaxel schedule is easier to administer and does not seem to increase toxicity in comparison to the weekly schedule.

The main concern with neoadjuvant CTRT in breast cancers is the intense radiosensitizing effect of chemotherapy which reflects as morbidity on the treated radiation areas and the associated surrounding normal structures.[19] In general, skin morbidity is observed, and very rarely pulmonary and cardiac morbidity may be seen.[19] In our study, all patients developed grade 2 skin morbidity, 24% of the patients developed grade 3 skin morbidity, but none of the patients had pulmonary or cardiac toxicity. This is comparable to the skin morbidity observed in other studies on neoadjuvant CTRT published in the literature.[14-17] There is a concern that neoadjuvant CTRT may increase skin toxicity compared to postmastectomy radiation (PMRT). However, reports in the literature show that the grade 3 skin reaction rates are similar after neoadjuvant CTRT and PMRT.[20],[21] A prospective study of 247 patients who received PMRT after adjuvant chemotherapy reported a grade 3 skin reaction in 28.4% of patients.[20] A study by Parekh et al. reported a grade 3 skin reaction in 12/50 (24%) patients who received PMRT.[21]

Postmastectomy surgical site wound infection was observed in 14% of our study patients, this is higher than the 3–4% infection rate reported in patients from developed countries who received NACT prior to mastectomy.[22] Whether neoadjuvant CTRT contributed to an increased superficial skin infection in our cohort of patients is not known as comparable data from India on surgical site infections in patients who received neoadjuvant chemotherapy followed by mastectomy has not been reported.

Patients with pCR after NACT have better survival outcomes compared to patients who did not achieve a pCR.[5] However, we could not show a survival benefit in our study because of the small sample size and short duration of follow-up. The 2-year EFS and OS reported in our study are better than those reported by Kao et al. and comparable to Formenti et al.[16],[17]

Nine patients in our study refused to consent to undergo MRM after completion of neoadjuvant treatment despite extensive counselling. This highlights the fear of surgery in certain patients and the belief that disease has been cured in patients who achieve CR with neoadjuvant CTRT and NACT and therefore do not want to undergo surgery.

Her2/neu positive (3+ on IHC or FISH positive) patients in our study received adjuvant short-course trastuzumab every week for 9 weeks. The original trials of short-course trastuzumab included chemotherapy with trastuzumab but since our patients had completed all cycles of chemotherapy in the neoadjuvant period, no adjuvant chemotherapy was added to the short-course trastuzumab. Patients were treated with short-course adjuvant trastuzumab rather than 1 year of adjuvant trastuzumab due to financial implications of the longer duration of treatment.

Cross study comparison shows that neoadjuvant CTRT is associated with improved pCR compared to NACT in breast cancer. However, only a phase 3 randomized trial can conclusively answer whether neoadjuvant CTRT, when compared to NACT, is associated with a significant increase in pCR and survival, and our center is currently recruiting patients for a trial investigating the same.

The present study has limitations which include the retrospective nature and short follow-up. Randomized trials comparing neoadjuvant CTRT to NACT are required to confirm its effectiveness. Till then neoadjuvant CTRT in breast cancer will remain experimental.


  Conclusion Top


Neoadjuvant CTRT in LABC is associated with higher pCR rates than what is reported with NACT alone. More trials exploring the benefit of neoadjuvant concurrent chemoradiation with many patients and longer follow-up are required to accept it as a routine practice in the treatment of LABC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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