Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

👉 TAX 324 Posner, M.D et al Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer.

👉Background

• A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck:
  • Compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy

👉 Methods

• In the TAX 324 they randomly assigned 501 patients:
  • All of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation:
    • To receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy:
      • With weekly carboplatin therapy and radiotherapy for 5 days per week
• The primary end point was overall survival

👉 Results

• With a minimum of two-years of follow-up (≥ 3 years for 69% of patients):
  • Significantly more patients survived in the TPF group than in the PF group:
    • Hazard ratio for death, 0.70; P=0.006
• Estimates of overall survival at three-years were:
  • 62% in the TPF group
  • 48% in the PF group
• The median overall survival was:
  • 71 months in the TPF
  • 30 months in the PF:
    • P = 0.006
• There was better locoregional control in the TPF group than in the PF group (P=0.04)
• The incidence of distant metastases in the two groups did not differ significantly (P=0.14)
• Rates of neutropenia and febrile neutropenia were higher in the TPF group
• Chemotherapy was more frequently delayed because of hematologic adverse events in the PF group

👉 Conclusions

• Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy:
  • Had a significantly longer survival than did patients who cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy:
    • ClinicalTrials.gov number, NCT00273546

• Prospective randomized trials addressing the safety of breast reconstruction in the older patient population don’t exist, and are unlikely to take place in the future
• The available literature largely consists of single institution experiences with various types of breast reconstruction in older patients
• This data shows that, in the older breast cancer patients determined to be good candidates for breast reconstruction:
  • The latter is generally safe in this patient population
• A study by Sada et al from the Mayo Clinic reported that, among women 65 years and older who underwent immediate breast reconstruction:
  • 12.6% experienced postoperative complications
  • Whereas women younger than 65 had a lower complication rate of 6.8% (p=0.04)
  • Similarly, older patients undergoing immediate breast reconstruction:
    • Were more likely to require a reoperation for postoperative hematoma:
      • 5.3% vs. 0.9%, p=0.006
  • It is reassuring that complication rates are quite low overall, and there were no differences between older and younger patients undergoing breast reconstruction with respect to skin flap necrosis or unplanned readmission
• Autologous breast reconstruction performed in carefully selected patients 65 years and older has also been reported to be safe and successful, as has been shown in a single institution report by Brendler-Spaeth et al, and in another retrospective series by Wähmann et al
• Additionally, Brendler-Spaeth et al reported that immediate and delayed autologous breast reconstruction in older breast cancer patients was associated with similarly low complication rates
• Furthermore, autologous breast reconstruction was shown to be associated with better long-term aesthetic outcomes in older breast cancer patients based on the meta-analysis by Hamnett and Subramanian
• Rates of breast reconstruction in elderly patients are lower than among younger patients:
  • Approximately 1% versus 45%, respectively
• A single institution study by Siotos et al demonstrated that older age was an independent risk factor for not receiving breast reconstruction (OR=0.18, 95%CI:0.08-0.40)
• The existing literature is limited in that it is not possible to discern whether older patients are not being offered breast reconstruction as often as their younger counterparts or if they are less likely to opt for it
• The available data demonstrate rather low complication rates reported in older breast cancer patients undergoing breast reconstruction, and they underscore an opportunity to extend the option of breast reconstruction to older patients interested in pursuing it and deemed to be good surgical candidates
• References
  • Dolen UC, Law J, Tenenbaum MM, Myckatyn TM. Breast reconstruction is a viable option for older patients. Breast Cancer Res Treat. 2022;191(1):77-86. doi: 10.1007/s10549-021-06389-z
  • Chang-Azancot L, Abizanda P, Gijón M, et al. Age and breast reconstruction. Aesth Plast Surg. 2023;47(1):63-72. doi: 10.1007/s00266-022-03024-0
  • Sada A, Day CN, Hoskin TL, Degnim AC, Habermann EB, Hieken TJ. Mastectomy and immediate breast reconstruction in the elderly: trends and outcomes. Surgery. 2019;166(4):709-714. doi: 10.1016/j.surg.2019.05.055
  • Brendler-Spaeth CI, Jacklin C, See JL, Roseman G, Kalu PU. Autologous breast reconstruction in older women: a retrospective single-centre analysis of complications and uptake of secondary reconstructive procedures. J Plast Reconstr Aesthet Surg. 2020;73(5):856-864. doi: 10.1016/j.bjps.2019.11.039
  • Wähmann M, Wähmann M, Henn D, et al. Geriatric patients with free flap reconstruction: a comparative clinical analysis of 256 cases. J Reconstr Microsurg. 2020;36(2):127-135. doi: 10.1055/s-0039-1697646
  • Hamnett KE, Subramanian A. Breast reconstruction in older patients: a literature review of the decision-making process. J Plast Reconstr Aesthet Surg. 2016;69(10):1325-1334. doi: 10.1016/j.bjps.2016.06.003
  • Lee RXN, Cardoso MJ, Cheung KL, Parks RM. Immediate breast reconstruction uptake in older women with primary breast cancer: a systematic review. Br J Surg. 2022; 109(11):1063-1072. doi: 10.1093/bjs/znac251
  • Siotos C, Lagiou P, Cheah MA, et al. Determinants of receiving immediate breast reconstruction: an analysis of patient characteristics at a tertiary care center in the US. Surg Oncol. 2020;34:1-6. doi: 10.1016/j.suronc.2020.02.017

• The management of breast cancer has become increasingly complex and multidisciplinary, with increasing imaging studies, appointments, and often, second or third opinions patients seek for care
• Together, many of these factors have led to lengthening time intervals between diagnosis and surgery
• At the same time, time from diagnosis to surgical treatment of 60 days:
  • Is now a Commission on Cancer quality metric
• Minimizing delays in treatment is a sensical goal believed to lead to improved outcomes
• The precise time frame that is considered reasonable and safe versus detrimental to breast cancer survival is not known, although a number of recent large retrospective studies have evaluated this.  
•  Bleicher et al:
  • In a 2016 study of nearly 100,000 women > 65 years of age in the SEER-Medicare database
  • Showed that overall survival decreased by 9% after a 60-day delay from diagnosis to surgery
  • In addition, the association between overall survival and time to surgery:
    • Was significant for stage I (HR 1.13, p<0.001) and stage II (HR 1.06, p<0.01):
      • But not for stage III breast cancer patients
  • The association between breast cancer-specific survival and time to surgery (HR 1.84, p=0.02) persisted solely for stage I patients:
    • Likely attributable to the baseline mortality in this group being smaller than the relative impact imposed by a delay in treatment
•  A 2020 study of ~ 350,000 patients (of all ages) in the NCDB with stage I to III breast cancer treated with up front surgical therapy examined the relationship between overall survival, time to surgery, and biologic subtype of breast cancer (i.e. triple negative, ER+PR+, HER2+):
  • Prevailing opinion prior to this study was that delays would be more detrimental to those with more biologically aggressive tumors such as TN or HER2+ due to downstream delays in adjuvant systemic therapy resulting from delayed surgical treatment
  • This study found that overall survival was observed to decline with every month delay in surgical treatment (HR 1.1, p<0.001):
    • This did not vary by biologic subtype (p>0.33).
•  A more recent 2023 study of NCDB stage I to III breast cancer patients treated with up front surgery analyzed survival for every one-week interval after 30 days post-diagnosis
  • Median time to surgery was 30 days:
    • 90% of patients underwent surgery within 60 days
  • Delays of 9 weeks or greater were found to be more common in younger women and the uninsured
  • They found that there was no significant association between time to surgery and survival for any of the groups:
    • Until after 9 weeks post-diagnosis
  • A surgical delay of 9 weeks or longer after diagnosis was associated with worse overall survival (HR 1.15, p < 0.001):
    • Compared with surgery within 4 weeks of diagnosis
  • Again, no significant interaction was found between tumor biologic subtype and time to surgery’s association with survival
  • Therefore, the conclusion was made that 8 weeks or shorter serve as a standard quality metric for timeliness of surgery. 
• References
  • Bleicher RJ et al. Preoperative delays in the US Medicare population with breast cancer. J Clin Oncol 2012; 30:4485-92
  • Bleicher RJ et al. Time to Surgery and Breast Cancer Survival in the United States. JAMA Surg 2016; 2:330-9
  • Mateo AM et al. Time to Surgery and the Impact of Delay in the Non-Neoadjuvant Setting on Triple-Negative Breast Cancers and Other Phenotypes. Ann Surg Oncol 2020; 27:1679-92
  • Wiener AA et al. Reexamining Time From Breast Cancer Diagnosis to Primary Breast Surgery. JAMA Surg 2023; 158:485-92

• Per the American Society of Clinical Oncology /College of American Pathologists (ASCO / CAP) guidelines:
  • Tumors with an immunohistochemical result of 2+ (equivocal):
    • HER2 / CEP17 ratio of > 2.0 and copy number of > 4.0 are considered positive
• References
  • Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline focused update. J Clin Oncol. 2018;142(11):1364-1382.
  • Lin L, Sirohi D, Coleman JF, Gulbahce HE. American Society of Clinical Oncology/College of American Pathologists 2018 focused update of breast cancer HER2 FISH testing guidelines. results from a National Reference Laboratory. Am J Clin Pathol. 2019;152(4):479-485.

• Trastuzumab and pertuzumab:
  • Can cause decrease in ejection fraction in up to 20% of patients:
    • Although this is often reversible
• Trastuzumab:
  • Can less commonly cause pneumonitis
• Pertuzumab:
  • Can cause rash and diarrhea
• References
  • Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
  • Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol.2013;24(9):2278-2284.

• Dose-dense doxorubicin and cyclophosphamide:
  • This regimen is associated with a high risk for febrile neutropenia (>20%)
• References
  • Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol. 2015;33(28):199-212.
  • Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431-1439.

• The APT trial:
  • Showed a 3-year rate of survival free from invasive disease of:
    • 98.7% for node negative tumors up to 3 cm in size:
      • With use of weekly paclitaxel / trastuzumab for 12 weeks followed by trastuzumab for 12 months
• References
  • Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. New Engl J Med. 2015;372(2):134-141.
  • Tolaney SM, Guo H, Pernas S, Barry WT, Dillon DA, Ritterhouse L. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.J Clin Oncol. 2019;37(22):1868-1875.

• Neutropenia:
  • Is found in up to 79.5% of patients on Palbociclib:
    • Neutropenia and the risk for infections:
      • Must be discussed with patients prior to initiation of treatment
• Other common adverse effects of this drug include:
  • Fatigue (37.4%)
  • Nausea (35.1%)
  • Alopecia (32.9%)
• References
  • Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in advanced breast cancer. New Engl J Med. 2016;375(20):1925-1936.
  • Finn RS, Crown JP2, Lang I3, Boer K4, Bondarenko IM5, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.

• In the Suppression of Ovarian Function Trial (SOFT):
  • Ovarian function suppression given for 5 years:
    • Reduced disease-free survival (DFS) events when added to 5 years of adjuvant tamoxifen:
      • 78.9% to 83.2% DFS at 8 years, hazard ratio (HR) of 0.76, P = .009
  • One-third of women entered in the SOFT trial were randomized to receive the aromatase inhibitor exemestane plus ovarian function suppression and they had an even better disease-free survival.
• References
  • Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Lang I, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Eng J Med.2018;379(2):122-137.
  • Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.

• There is a sequence of disease progression from:
  • Atypia / dysplasia, to in situ carcinoma, to invasive cancer
• Leukoplakia and erythroplakia:
  • Are terms given to clinically identifiable lesions:
    • That may harbor invasive cancer or undergo malignant transformation
• Precursor lesions may present as:
  • Small patches or as a large verrucous plaques
  • The surface can be:
    • Brown to red (erythroplakia) or may have circumscribed whitish plaques (leukoplakia)
    • White spots may ulcerate
• Leukoplakia:
  • Develops as a result of chronic irritation of the mucous membranes by carcinogens
    • This irritation stimulates proliferation of epithelial and connective tissue
  • Histopathologic examination reveals:
    • Underlying hyperkeratosis associated with epithelial hyperplasia
  • In the absence of underlying dysplasia:
    • Leukoplakia rarely (less than 5 %) is associated with progression to malignancy (Ridge, 2013; Massano et al., 2006; Thompson, 2003)
• Erythroplakia:
  • Red spots, friable adjacent normal mucosa:
    • Characterize erythroplakia
  • It is associated with underlying epithelial dysplasia and has a much greater potential for malignancy than leukoplakia:
    • Carcinoma is found in nearly 40 % of the cases of erythroplakia (Ridge, 2013)
• The classification of the world health organization (WHO) of precursor lesions is as follows (Barnes, 2005):
  • Squamous cell hyperplasia:
    • Hyperplasia describes an increase in the number of cells:
      • This can be in the spinous layer (acanthosis), and / or in the layers of basal / parabasal cells (progenitor compartment) called basal cell hyperplasia
  • Dysplasia:
    • Is characterized by cellular atypia, loss of normal cellular maturation, and loss of epithelial stratification:
      • Mild dysplasia:
        • Squamous intraepithelial neoplasia 1
      • Moderate dysplasia:
        • Squamous intraepithelial neoplasia 2
      • Severe dysplasia or carcinoma in situ:
        • Squamous intraepithelial neoplasia 3
    • The probability of developing a carcinoma depends on the degree of dysplasia:
      • In the case of severe dysplasia:
        • Up to 24% of patients may have an occult invasive squamous cell cancer (Ridge, 2013)