INTRODUCTION
Head-and-neck squamous cell cancer (HNSCC) is one of the most common cancers in India.[ 1 ] Most HNSCCs present in the locally advanced stage.[ 2 , 3 ] Palliative treatment is warranted for a substantial proportion of patients with HNSCC during the natural course of the disease. Platinum forms an important component of the treatment, either neoadjuvant or concurrent with radiotherapy in the curative setting and as palliative first-line therapy, in combination with cetuximab or pembrolizumab.[ 4 , 5 ] Patients with platinum-refractory HNSCC and those who have progressed on first-line therapy have dismal outcomes.[ 6 ] Nivolumab and pembrolizumab are the two agents approved for treatment in platinum-refractory HNSCC based on the results of CheckMate 141 and KEYNOTE-040 trials.[ 7 , 8 ] However, in resource-limited settings, only 1% of the patients can access these treatments.[ 9 ] Hence, there is a need for innovation in this setting.
PUTTING IN PERSPECTIVE
Central question
Does the combination of paclitaxel and Mycidac-C prolong survival in patients with head-and-neck cancer after >1 previous line of therapy?
Key findings
Median age 51 years, male predominance (92.9%), majority with oral cavity cancers (78.6%), 60.7% patients had received 2 previous lines of therapy
Median PFS was 2.9 months (95% CI, 2.36-3.48)
Median OS was 4.9 months (95% CI, 3.78-5.99)
Anemia (93.9%) and increased ALT (17.9%) and AST (14.3%) were the most common toxicities (all grades)
Impact
Paclitaxel + Mycidac-C combination chemotherapy can be an option in LMICs such as India, where the majority of patients cannot afford immunotherapy or targeted therapy
Mycidac-C is a potent toll-like receptor-2 agonist which induces cell-mediated immune response targeting desmocollin-3 (DSC3)-expressing cancer cells. The immune response generated is pure T helper 1 (Th1) type.[ 10–12 ] In a study in 221 patients with advanced non-small-cell lung cancer, Mycidac-C when added to cisplatin and paclitaxel did not improve outcomes in the overall patient cohort. However, in the subgroup analysis, there was a significant improvement in survival in the patients with squamous cell carcinoma; overall survival (OS) improved by 127 days (299 vs. 172 days) in the intent-to-treat population (hazard ratio, 0.55; 95% confidence interval [CI], 0.32-0.95; P = 0.046).[ 13 ]
It is not known whether the addition of Mycidac-C to paclitaxel would lead to an improvement in outcomes in platinum-refractory HNSCC. Therefore, we assessed the outcomes in our patients with relapsed refractory HNSCC, who were treated with paclitaxel and Mycidac-C combination therapy. In this manuscript, we provide the initial data regarding the efficacy and safety of this combination in the post-first-line relapsed refractory HNSCC setting.
MATERIALS AND METHODS
General study details
This was a retrospective, single-center, observational study conducted between August 2019 and May 2020 in the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary care oncology center in Mumbai, India. The study was approved by the Institutional Ethics Committee (project ID: 900835) on Sep 6, 2021. The study protocol is provided as Supplementary Appendix 1 . The Institutional Ethics Committee waived the requirement of obtaining a written informed consent, given the retrospective nature of the study. The study was conducted according to the ethical principles established by the Declaration of Helsinki and Good Clinical Practice Guidelines and by the Indian Council of Medical Research. Being a retrospective study, it was not registered in a public clinical trials registry. No funding was received for the study.
Supplementary Appendix 1
Aims/objectives
Our primary objective was to determine the survival outcomes in terms of progression-free survival (PFS) and OS in patients with relapsed, refractory, or metastatic HNSCC, post-first-line therapy, who were treated with concurrent paclitaxel and Mycidac-C combination therapy. Our secondary objective was to determine the safety of the combination.
Participants
We included patients with advanced recurrent/metastatic HNSCC, aged 18 years and above, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3, who had received at least one line of previous therapy, and were treated with the combination of paclitaxel and Mycidac-C. Patients could have received previous therapies with a platinum agent, taxane (docetaxel), 5-fluorouracil (5FU), triple oral metronomic chemotherapy (methotrexate, celecoxib, erlotinib), gemcitabine, or pemetrexed. Platinum refractory state was defined as progression of disease while on platinum-based therapy or within 6 months of completion of therapy.
Study methodology
We prospectively maintain a database in Microsoft Excel of patients with head-and-neck cancer on palliative chemotherapy in our medical oncology head-and-neck outpatient department. This palliative chemotherapy database was accessed for this study. The following queries were raised in the database: “patients who received paclitaxel and Mycidac-C combination” and “patients who received at least one line of therapy.” A list of 40 patients was obtained. Of these 40 patients, 28 were included [Figure 1 ]. The baseline demographic and clinicopathological parameters including age, sex, ECOG PS, site of malignancy, and the previous lines of therapy were extracted from the case records and the electronic medical records. In addition, the starting date of paclitaxel and Mycidac-C, the date of the last dose of paclitaxel and Mycidac-C, and the number of cycles administered were also documented. The date of progression and the date of death were recorded. The response to therapy, as assessed every 2 months according to the Response Evaluation Criteria in Solid Tumors, version 1.1, was noted. Adverse effects were graded as per the Common Terminology Criteria for Adverse Events, version 5 and were recorded.
Figure 1: The process of enrollment, therapy, follow-up, and evaluation of patients in the study. HNSCC = head and neck squamous cell cancer
Definitions
PFS was defined as the time from the start of the paclitaxel + Mycidac-C chemotherapy to the progression of disease or death due to any cause, whichever occurred first. OS was defined as the time from the start of the paclitaxel + Mycidac-C chemotherapy to death due to any cause.
Statistics
No formal sample size calculation was performed as this was a retrospective analysis. We used the Statistical Package for the Social Sciences (SPSS Inc. Released 2007, SPSS for Windows, Version 16.0; Chicago, SPSS Inc) for data analysis. The baseline characteristics have been presented with descriptive statistics. Non-continuous variables were expressed in absolute numbers and percentages, and continuous variables were expressed as medians with ranges. The Kaplan-Meier method was used to estimate the PFS and OS.[ 14 ] The reverse Kaplan-Meier method was used for the estimation of follow-up.
RESULTS
Baseline patient characteristics
Of the 28 patients included in the study, 25 (89.3%) had platinum-refractory disease and three (10.7%) had platinum-sensitive disease. The median age was 51 years; the cohort was predominantly male (26, 92.9%), with oral cavity cancer (22, 78.6%), and had received platinum therapy previously (27, 96.4%). There were 21 patients (75%) who were initially treated with curative intent, while seven (25%) received upfront palliative intent therapy (either due to extensive disease precluding surgery or radiation therapy or due to metastatic disease at presentation). There were two patients (7.1%) who had received nivolumab in previous lines. The baseline patient characteristics and the previous treatment details are provided in Table 1 .
Table 1: Baseline characteristics and previous treatment details
Administration of therapy
Patients were given an intravenous injection of paclitaxel 80 mg/m2 on days 1, 8, and 15, every 28 days. Mycidac-C was injected as 0.2 ml intradermally (0.1 ml in each deltoid), started 1 week before chemotherapy and subsequently injected as 0.1 ml intradermally on day 8 and day 15 of each cycle. The median numbers of cycles of paclitaxel and Mycidac-C administered were 3 (range, 1-6) and 2.5 (range, 1-6), respectively. Although Mycidac-C was administered along with paclitaxel, there was a discrepancy between the median number of cycles administered for the two drugs. Paclitaxel was given intravenously, while Mycidac-C was injected intradermally. If the patient had experienced any skin reactions, inflammation, and so on at the Mycidac-C injection site, Mycidac-C was withheld, whereas paclitaxel was continued intravenously.
Outcomes
At a median follow-up of 3.4 months (range, 0.2-18.1), 26 patients had events for PFS (20 had disease progression and six had died) and 26 patients had events for OS. One patient was lost to follow-up and one patient refused further chemotherapy. None of the patients achieved a complete response or a partial response. Six patients (21.4%) had stable disease and 20 patients (71.4%) progressed on treatment. The median PFS and OS were 2.9 months (95% CI, 2.36-3.48) and 4.9 months (95% CI, 3.78-5.99), respectively.
Toxicity
The paclitaxel + Mycidac-C combination was well tolerated. There were no grade 4 or 5 adverse events. The most common adverse effects were anemia (all grades: 26, 93.9%; grade 3: 4, 14.3%), and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, seen in five (17.9%) and four (14.3%) patients, respectively. Four patients (14.3%) developed neutropenia, two (7.1%) developed diarrhea, and two (7.1%) developed peripheral neuropathy. One patient developed an abscess at the site of Mycidac-C injection [Table 2 ].
Table 2: Adverse events from paclitaxel-Mycidac-C combination therapy
DISCUSSION
To the best of our knowledge, this is the first report on the use of paclitaxel and Mycidac-C in patients with advanced relapsed/refractory HNSCC. We found that the combination resulted in a median PFS of 2.9 months (95% CI, 2.36–3.48) and a median OS of 4.9 months (95% CI, 3.78–5.99), (Supplementary appendix 2 ), which were roughly similar to the results reported with nivolumab and pembrolizumab. In CheckMate 141, the study that evaluated the efficacy of nivolumab in platinum refractory HNSCC, the median PFS was 2.0 months (95% CI, 1.9–2.1) with nivolumab versus 2.3 months (95% CI, 1.9–3.1) with standard therapy (hazard ratio for disease progression or death, 0.89, 95% CI, 0.70–1.13; P = 0.32).[ 7 ] The median OS was 7.5 months (95% CI, 5.5-9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0-6.0) in the group that received standard therapy. The OS was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70, 97.73% CI, 0.51-0.96; P = 0.01), and the estimated 1-year survival was 36% with nivolumab compared to 16.6% with standard therapy. In the KEYNOTE-040 study, the median PFS was 2.1 months (95% CI, 2.1-2.3) with pembrolizumab and 2.3 months (95% CI, 2.1-2.8) with standard of care.[ 8 ] The median OS was 8.4 months (95% CI, 6.4-9.4) with pembrolizumab and 6.9 months (95% CI,5.9-8.0) with standard-of-care; the estimated 1-year survival was 37.0% (95% CI, 31-43.1) in the pembrolizumab group and 26.5% (95% CI, 21.2-32.2) in the standard-of-care group.
Supplementary Appendix 2
Mycidac-C works as an immunomodulator to generate an immune response.[ 10–12 ] Thus, like the novel immunotherapy agents, the activity of Mycidac-C relies on the response of the immune cells to the cancer cells. Mycidac-C has proven efficacy in squamous cell carcinoma of the lung and has minimal adverse events attributed to it. In patients with advanced non-small-cell lung cancer, the addition of Mycidac-C to the combination chemotherapy regimen of paclitaxel and cisplatin led to a prolongation of survival by 127 days in the squamous cell carcinoma subgroup (hazard ratio, 0.55; 95% CI, 0.32-0.95; P = 0.046) and a prolongation of OS from 233 to 299 days in the patients who had received four cycles of chemotherapy (hazard ratio, 0.64; 95% CI,0.41-0.98; P = 0.04), although there was no survival benefit in the overall population.[ 13 ] In another Phase II study on 48 patients with advanced non-small-cell lung carcinoma, Mycidac-C in combination with cisplatin and etoposide chemotherapy for six cycles resulted in improved response rates and survival. The response rates were better in patients who received chemotherapy and Mycidac-C compared to patients who received chemotherapy alone (38% vs. 27%, respectively). The median survival in the combination therapy arm was 11 months compared to 7 months in the chemotherapy arm.[ 15 ] In our study, all the patients had relapsed/refractory HNSCC, which has an overall worse prognosis as compared to squamous cell carcinoma of the lung. Platinum-based regimens are the first line of therapy in non-small-cell lung cancer and are quite effective. The patients included in the study by Belani et al .[ 13 ] were treatment-naive and had received platinum-based chemotherapy regimens, whereas in our study, majority of the patients were platinum refractory . Similarly, in the study by Pant et al. ,[ 15 ] the chemotherapy backbone was platinum based (cisplatin + etoposide). A comparison of the results of studies conducted in quite different cohorts of patients, that is, treatment-naïve patients with advanced squamous cell lung carcinoma versus patients with platinum-refractory HNSCC, is not ideal. This makes comparison of the results of our study with the other studies using Mycidac-C difficult.
In our patient cohort, paclitaxel 80 mg/m2 was administered weekly on days 1, 8, and 15 of a 28-day cycle. Mycidac-C was administered as an initial loading dose of 0.2 ml intradermally (0.1 ml in each deltoid) 1 week before chemotherapy and subsequently as 0.1 ml intradermally on days 8 and 15 of each cycle. In the study by Belani et al. ,[ 13 ] in patients with non-small-cell lung cancer who were randomized to the chemotherapy + Mycidac-C arm, 0.2 ml of Mycidac-C was injected intradermally over each deltoid a week before initiating chemotherapy, and subsequently, 0.1 ml of Mycidac-C was administered on days 8 and 15 of each cycle of chemotherapy. In that study, patients received a 3-h infusion of 175 mg/m2 of paclitaxel, immediately followed by 1-h infusion of 100 mg/m2 of cisplatin on the first day of a 21-day cycle for a total of four cycles (chemotherapy backbone).
Single agent paclitaxel has been earlier studied in relapsed refractory HNSCC. In a study by Grau et al. ,[ 16 ] in 60 patients with platinum-resistant recurrent or metastatic HNSCC, the median OS was 8.5 months (95% CI, 5.7-11.2). Partial responses and stable disease were observed in 26 (43.3%) and nine (15%) patients, respectively. In our study, there were no complete or partial responses; six patients (21.4%) had stable disease and 20 (71.4%) progressed on treatment. The results of our study compare poorly to those of Grau et al .[ 16 ] for several reasons. First, in the study by Grau et al. ,[ 16 ] 53.3% of the patients had received only one line of treatment before paclitaxel, whereas in our study, 17.9% of patients had received only one line of previous systemic therapy. Thus, our study enrolled a much more heavily pretreated cohort of patients. Second, in the study by Grau et al. ,[ 16 ] the locations of the primary tumor were larynx (33.3%), oropharynx (50%), and hypopharynx (16.7%) and there were no patients with an oral cavity primary; in our study, 78.6% of the patients had an oral cavity primary. Of all the head-and-neck cancers, oral cavity cancers have the worst prognosis. In another retrospective analysis by Chevalier et al .[ 17 ] of patients with HNSCC who had progressed after first-line platinum-based chemotherapy and cetuximab and were treated with either paclitaxel + cetuximab or paclitaxel alone, the median PFS was 2.9 months for the paclitaxel + cetuximab arm versus 2.5 months for the paclitaxel alone arm. The median OS was 5.5 months for paclitaxel + cetuximab versus 4.2 months for paclitaxel alone. In the study by Chevalier et al. ,[ 17 ] all the patients had received only one line of therapy, that is, cisplatin + cetuximab + 5FU, whereas in our study, majority of the patients had received two previous lines of therapy. Moreover, with respect to the site of primary, majority of the patients in the study by Chevalier et al .[ 17 ] had an oropharyngeal primary (31% in the paclitaxel + cetuximab arm, 51% in the paclitaxel alone arm), whereas in our study, 78.6% of the patients had an oral cavity primary.
In our study, the majority of the patients were male and had oral cavity cancers. Our patient population was comparatively young (median age, 51 years). Majority of the patients had received at least two previous lines of therapy, including two patients who had received immunotherapy with nivolumab. One patient had progressed after two cycles of nivolumab, whereas the other patient received only one cycle due to financial constraints. In the CheckMate 141 study, the cohort was older (median age, 60 years) and oral cavity and oropharyngeal cancers had an almost equal distribution (48.5% vs. 35.5%, respectively). Patients were less heavily pretreated; the majority had received only a single line as previous therapy.[ 7 ] In the KEYNOTE-040 study, the median age was 60 years; 57% patients had received first-line therapy in the recurrent metastatic setting. Compared to these studies, our cohort was heavily pretreated, and cancer of the oral cavity predominated, which has a worse prognosis compared to cancers of other head-and-neck regions.
In our study, 13 patients (46.4%) had received previous taxane-based therapy. In all those cases, docetaxel was the taxane received as neoadjuvant chemotherapy (as part of the TPF regimen [docetaxel, platinum, 5FU]). As there is no preferred or approved chemotherapy regimen in the second line and beyond in relapsed refractory or metastatic HNSCC, the choice of therapy in this setting depends on the physician preference, adequacy of organ functions, side effect profile, and the resources to manage the expected side effects, among other considerations. Paclitaxel, being a widely used chemotherapeutic drug with easily manageable side effects, was selected as the chemotherapy regimen, even though some patients had received previous docetaxel therapy.
The paclitaxel + Mycidac-C combination was well tolerated. The most common adverse effects were anemia, seen in 26 (93.9%) patients, and increased ALT and AST levels, seen in five (17.9%) and four (14.3%) patients, respectively. The adverse events were as anticipated for any chemotherapy drug combination, including both hematologic and non-hematologic toxicities, predominantly myelosuppression and liver injury. Grade 3 adverse events were anemia in three patients (14.3%) and transaminitis and skin ulcer in one patient each (3.6%). In the study by Belani et al. ,[ 13 ] common adverse events were nausea and vomiting, diarrhea, weakness, weight loss, anorexia, alopecia, and neuropathy, which were similar in both the arms. In the study by Pant et al. ,[ 15 ] the most prevalent hematological toxicities were neutropenia, leukopenia, and anemia in the group receiving Mycidac-C and chemotherapy (13%, 5%, and 4%, respectively) compared to the group receiving chemotherapy alone (18%, 10%, and 5%, respectively). Common non-hematological toxicities in both the groups were asthenia, anorexia, vomiting, and dyspnea, the incidence of which were significantly lesser in the group receiving Mycidac-C and chemotherapy (21%, 13%, 8%, and 7%, respectively) than in the group receiving chemotherapy alone (28%, 20%, 16%, and 13%, respectively). Thus, the Mycidac-C combination was better tolerated compared to chemotherapy alone, which resulted in a higher compliance rate.
One of the issues faced was the administration of the drug via the intradermal route, which could lead to local site infection and scarring. Sometimes, the local skin reaction may progress to form an abscess which may require surgical debridement. This was noted in our study as well. One patient had developed an abscess at the injection site. In the study by Belani et al. ,[ 13 ] injection site adverse events were significantly higher in the patients receiving Mycidac-C.
Immune checkpoint inhibitors, such as nivolumab and pembrolizumab which are used in the platinum-refractory setting, have a different toxicity profile compared to conventional chemotherapy. In the CheckMate 141 study, in the nivolumab alone arm, the common adverse events (any grade) were fatigue (14%), nausea (8.5%), rash (7.6%), decreased appetite (7.2%), pruritus (7.2%), diarrhea (6.8%), and anemia (5.1%). Grade 3 or 4 adverse events were fatigue (2.1%) and anemia (1.3%).[ 7 ] In the KEYNOTE-040 trial, the common adverse events were hypothyroidism (13%), fatigue (13%), diarrhea (8%), rash (8%), asthenia (7%), and anemia (7%).[ 8 ] Adverse events of grade 3 and above occurred in 13% of the patients.[ 8 ] In comparison, the most common adverse effects in our study were anemia (93.9%) and increased ALT (17.9%) and AST (14.3%) levels.
Patients with relapsed and metastatic HNSCC have a very poor prognosis. The treatment paradigm in this patient population was changed after publication of the EXTREME study.[ 4 , 18 , 19 ] Addition of cetuximab to chemotherapy led to a significant increase in OS, and it ushered in a new era in HNSCC. Around 11 years later, KEYNOTE-048 was published, which led to a addition of pembrolizumab as the first-line therapy in recurrent or metastatic HNSCC.[ 5 , 18 ] However, patients with platinum-refractory disease have universally poor outcomes and immunotherapy has been tried in this setting also. Nivolumab and pembrolizumab are the current recommended therapies for platinum-refractory HNSCC.[ 7 , 8 , 20 ] The trials of nivolumab and pembrolizumab in platinum-refractory HNSCC reported that the median OS in this patient population is less than a year. Thus, novel agents are needed for treatment of HNSCC in platinum-refractory disease and for treatment in later lines. However, the accessibility of these agents in low- and middle-income countries (LMICs) is below 5%.[ 9 , 21–23 ] Oral metronomic chemotherapy with methotrexate, celecoxib, and erlotinib has been tried in this setting.[ 24 ] There is an urgent need for developing regimens with a combination of drugs active in this cohort of patients, which can improve outcomes and be accessible to the majority of the population. Mycidac-C is accessible and if it proves its efficacy in a randomized study, then it would be a good alternative to the immunotherapy options in patients with relapsed/metastatic HNSCC who have progressed on the standard first-line therapy.
The study was not without limitations. This was a single-center, retrospective study. The drug was given on compassionate grounds to those patients who wanted further treatment. We were unable to compare our results to treatment of a similarly heavily pretreated cohort of patients who received paclitaxel alone or Mycidac-C alone. However, the data are from a relatively homogeneous population with predominantly oral cavity cancer, with most patients being platinum-refractory. Thus, this combination therapy needs to be further tested in the setting of a randomized study.
CONCLUSION
Head-and-neck cancers are common with poor outcomes in relapsed/metastatic disease. There is an unmet need for developing efficacious low-cost therapies in our country. The combination of paclitaxel and Mycidac-C has promise in relapsed/metastatic HNSCC. However, it will need validation in a randomized controlled study.
Author contributions
Conception or design of the work: RS, AS, VP, VN, NM, KP; data collection: RS, AS; data analysis and interpretation: VP, RS, AS; drafting the article: VP, RS, AS; critical revision of the article: VP, VN, NM, KP; final approval of the version to be published: all authors; accountable for all aspects of the work: all authors
Data sharing statement
Individual de-identified participant data will be made available on reasonable request from Dr. Vijay Patil <[email protected] >, starting from the date of publication until 10 years after publication. Requests beyond this timeframe will be considered on a case-by-case basis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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