Neoadjuvant Concurrent Chemo-radiation with Paclitaxel and Trastuzumab versus Neoadjuvant chemotherapy with trastuzumab followed by sequential radiation in locally advanced Her2 neu positive breast cancers: a phase 2 randomized controlled trial

Introduction

Locally advanced breast cancers (LABC) account for 30-50% of all breast cancer diagnosed in India. Her2-positive tumors comprise 20% of all locally advanced breast cancers (LABC) . LABC has been defined as tumors larger than 5 cm, those associated with bulky/fixed axillary lymph nodes or tumors with skin involvement. (TNM stage III, T3-4 or N2-3) .  With the advent of anti-Her2 directed therapies, the rate of pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS) in Her2-positive LABC have increased.

The current standard of care for treating Her2-positive LABC is neoadjuvant chemotherapy (NACT) with anti-Her2 targeted therapy followed by surgery and sequential radiotherapy . Approximately 40 % of all patients presenting to our center have LABC and most of them are inoperable at presentation. It is common to see patients at our center presenting with breast tumors measuring more than 10 cm in size, fixed axillary nodal masses and fungating tumors. In our experience, neoadjuvant 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 pCR rates. The rationale of using CTRT rather than NACT alone includes better local tumor control because of the radio-sensitizing effect of chemotherapy and addressing systemic disease simultaneously.

pCR to neoadjuvant treatment is an important surrogate marker for OS in breast cancer especially in the triple-negative and Her2 positive subset . Studies have shown that neoadjuvant CTRT in LABC improves pCR . However, most of these studies are retrospective and have a small number of patients. Literature has also shown that CTRT in LABC is safe and well-tolerated .

Anti-Her2 receptor-targeted antibody, trastuzumab, has been given safely concurrent with adjuvant radiotherapy in breast cancer and is the standard of care . The rationale of using chemotherapy and anti-Her2 therapy combined with radiation is that there will be a synergistic effect of both the agents with radiation thereby improving the pCR.

The present study aims to compare the effect of  CTRT and anti Her2 therapy versus  NACT and anti Her 2 therapy on the pCR and its safety, efficacy and effect on quality of life in Her 2 neu positive LABC.

Hypothesis

Null hypothesis: The pCR rates with CTRT with trastuzumab is similar to the pCR obtained with NACT with trastuzumab.

Alternate hypothesis: The pCR with CTRT with trastuzumab is 12 % more than the pCR obtained with NACT with trastuzumab.

Aim of Study

·  To evaluate the safety, tolerability, efficacy and pathological complete response rates (pCR) of concurrent chemo-radiotherapy (CTRT) and trastuzumab and compare it with neoadjuvant chemotherapy and trastuzumab followed by sequential radiotherapy (RT)  in Her2 positive locally advanced breast cancer (LABC)

Primary Objective

·       To compare the pathological response rate of CTRT and trastuzumab with the standard regimen in Her2 positive LABC

Secondary Objective

·       To assess the toxicity of CTRT with trastuzumab in LABC and compare it with the standard treatment

·       To compare the quality of life of patients between the two regimens

Materials and Methods

Study type/design:  Phase 2 randomized controlled trial, Two arm.

Study site:  Cancer Institute (WIA), Chennai.

Study enrolment period:3 years.

Follow-up duration: All patients will be followed up as per institute policy. It will be 3 monthly for a period of 3 years, 6 monthly for another 2 years and yearly once thereafter. Followup data will be collected for all patients enrolled in the trial.

Sample Size:  126 patients, 63 patients in each arm (Simon selection design).