Abstract
Background/Aim: Advanced unresectable and metastatic non-melanoma skin cancers (NMSC) are rare, but often arise in elderly patients. When surgery or irradiation are no longer feasible, chemotherapy is often precluded by the patient's age and comorbidities. Whether low-dose multi-agent chemotherapy could be an alternative for this vulnerable population in an outpatient setting was the issue examined in this retrospective analysis. Patients and Methods: Twenty-six patients with advanced unresectable or metastatic NMSC received weekly multi-agent chemotherapy with carboplatin at an area under the curve of 2 or 40 mg total dose of cisplatin, with 15 IU total dose of bleomycin, 40 mg total dose of methotrexate, and 500 mg total dose of 5-fluorouracil (CMF-b) until best response, toxicity, or progression of their disease. Results: Twenty-four patients were treated as outpatients; two were hospitalized. Twenty-three patients were previously treated with surgery or radiotherapy. The median age was 68 years (range=44-100 years). The median number of cycles was 6 (range=1 to 17). The overall response rate was 61.5% (seven complete remissions, nine partial remissions) for the entire cohort and 63.6% (two complete remissions and five partial remissions) for patients >80 years. The median duration of response was 6.1 months (range=1.6–63 months). Responses longer than 6 months were obtained in 11/26 (42.3%) of the entire cohort and in 4/11 (36.3%) patients >80 years. Symptom improvement was observed in 17 patients (65.3%). Toxicity was acceptable, with grade 3 renal failure (n=1) and grade 3 or 4 myelotoxicity (n=2). Conclusion: CMF-b is a safe, weekly low-dose multi-agent regimen that offers palliation for vulnerable patients with NMSC.
Non-melanoma skin cancers (NMSC) mainly comprise of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). Both BCC and SCC are extremely common neoplasms, but their true incidence is poorly defined, given the lack of reliable registration in most countries. It is estimated that BCC and SCC represent approximately 80% and 20% of NMSCs, respectively. NMSCs typically develop in elderly patients, with an average age at diagnosis of 75 years.
Most NMSCs are detected early and can be cured by surgery alone. However, in rare instances (<5%), NMSCs recur despite appropriate initial treatment, are neglected, or cannot be completely resected because they arise in locations where surgery could be debilitating. In such situations, irradiation with curative or palliative intent has led to a good response rate and tolerance (1-6).
For patients with unresectable and previously irradiated NMSC, treatment strategy is challenging. Platinum-based and methotrexate chemotherapy are possible therapeutic options, with objective responses of 68-85.7% in the literature. Such treatments are, however, associated with significant toxicity and their administration at full dose is often precluded by comorbidities or old age (7-10).
We, therefore, designed a new regimen using several drugs with theoretical efficacy in epithelial tumoral diseases (platinum derivatives, methotrexate, fluorouracil, and bleomycin), combining them at low dose in a weekly schedule, with the goal of optimizing efficacy and tolerance in frail patients.
Patients and Methods
Patients. We retrospectively studied all patients with unresectable NMSC, treated at the Department of Oncology of the Geneva University Hospitals between January 1994 and December 2008, to whom weekly polychemotherapy with carboplatin or cisplatin, methotrexate, fluorouracil, and bleomycin (CMF-b) was administered. Cases were deemed unresectable if surgery could produce severe esthetic or functional defects, or in the case of metastatic disease or comorbidities.
This study was performed according to the ethical rules of the Ethical Committee of our Institution and followed the standards of the Helsinki Declaration.
Chemotherapy and follow-up. The multi-agent regimen (CMF-b) was designed to include carboplatin at an area under the curve (AUC) of 2 or cisplatin at a total dose 40 mg, with bleomycin at a total dose of 15 IU, methotrexate at a total dose of 40 mg, and 5-fluorouracil at a total dose of 500 mg. All drugs were administered weekly, as an outpatient chemotherapy (or inpatient in the case of comorbidities). Folinic acid rescue (i.e. 30 mg every 6 h nine times) was started 12 h after the administration of methotrexate. Supportive measures included anti-emetic prophylaxis with 5-hydroxytryptamine antagonists antagonists and dexamethasone. One cycle was defined as 1 week of treatment. The choice of cisplatin or carboplatin was left to the treating physician based on their assessment of the risk of potential toxicities (e.g. renal failure, myelotoxicity). Chemotherapy was administered until stable best response, progressive disease, or unacceptable toxicity. The response to therapy was assessed by clinical examination every 3 weeks during treatment, then every 3 or 4 weeks until progression.
Results
Patient characteristics, treatment regimen, clinical responses, and toxicities are described in Tables I and II. Twenty-six patients with histologically confirmed unresectable BCC (n=2) or SCC (n=24) of the skin were treated between 1994 and 2008 with the CMF-b regimen. There was a male predominance (n=21, 80.7%) and the median age was 68 years (range=44-100 years). Twenty (76.9%) and 11 (42.3%) patients were over 65 and 80 years, respectively. There was no patient selection, with an ECOG performance ≥1 in 42.2% of the entire cohort and in 72.7% of patients older than 80 years. Comorbidities were frequent with diabetes with/without cardiopathy (n=7), immunocompromised status (five with chronic lymphatic leukemia or lymphoma, one with HIV, and one with renal transplant), or other cancer (one of the prostate and one of the head and neck).
Twenty-four patients received the treatment at full dose, whilst methotrexate was avoided or administered at 80% of the planned dose in two patients. Eight patients were treated with cisplatin-based and 18 with carboplatin-based chemotherapy. Twenty-four patients (92.3%) received treatment as outpatients. A median of 6 cycles (range=1-17) was delivered. The 11 patients older than 80 years received a median of five cycles (range=3-16 cycles). Overall, the regimen was safe and well-tolerated, with 12 events (any grade) of treatment-related renal or bone marrow toxicities. One patient required hydratation for grade 3 renal failure, and three patients had a transient increase in creatinine levels (grade 2). Myelotoxicity was also moderate with two cases of grade 1 (one thrombopenia and one leucopenia), three cases of grade 2 (anemia and leucopenia), one grade 3 (anemia and leucopenia), and one grade 4 leucopenia.
The overall response rate was 61.5%, with seven complete responses (CRs) and nine partial responses (PRs). Stable disease (SD) was obtained in four additional cases, whilst disease in six patients only progressed under treatment. For patients over 80 years (n=11), an overall response rate of 63.6% (two CRs and five PRs) was observed, with two additional SDs. Major clinical benefit was obtained for 17/26 patients (65.3%), with pain reduction (n=2), pain resolution (n=4), cosmetic improvement (n=4), partial or complete neurological recovery (n=2), and both pain and neurological improvement (n=4). Some patients experienced major recovery of severe neurological defects, such as diplopy (n=1), facial palsy (n=2), palpebral ptosis (n=1), trigeminal anesthesia (n=1), and deafness (n=1).
Another criterion for assessing the impact of a palliative treatment is the duration of the benefit. The median duration of the response was 6.1 months (range=1.6-63.8 months), with some long-term responders. Responses longer than 6 months and 12 months were obtained by 11/26 patients (42.3%) and 7/26 patients (26.9%), respectively. Patients over 80 years (n=11) had an average response duration of 4.3 months (range=1.8-47.3 months), with four of them presenting a response longer than 6 months. Six patients in the cohort showed a response duration of longer than 2 years (range=2.5-5.3 years).
To what extent previous treatments may limit the therapeutic potential of this regimen was an additional issue to be addressed in this analysis. Three patients received this low-dose weekly regimen as first-line treatment, with one CR, one PR, and one SD; six patients received the regimen after incomplete surgery, with one CR, one PR, one SD, and three with progressive disease (PD); and six patients received the regimen after radiotherapy, with four PRs and two SDs. The other 11 patients were treated after failure of both surgery and radiotherapy and five CRs, three PRs, one SD, and two PDs were observed. Although a definitive answer cannot be given with the limited number of events in this study, previous surgery and irradiation did not seem to alter the efficacy of this low-dose weekly regimen.
Discussion
Locally advanced or metastatic NMSC remains a complex medical challenge, considering the morbidity may generate the old age at which it usually occurs, the intrinsic limits of localized therapies, and the rarity of this situation, precluding performance of large trials. However, studies performed two decades ago have clearly established that cisplatin, alone or in combination with other drugs, is a valuable option that may lead to a response rate of around 60-80% (7-11). Unfortunately, the toxicity of cisplatin at the usual dose is high for this patient population. For example, in one of the largest trials in this setting, Guthrie et al. reported major side-effects, with 14% febrile neutropenia and 32% renal failure (9). Moderate to severe neutropenia and neutropenic fever were reported in 38% and 6%, respectively, of 39 patients treated with interferon alpha, 13-cis-retinoic acid, and cisplatin (11). Such toxicities are poorly in line with a palliative intent and, consequently, cisplatin at the standard dose is often inappropriate in clinical practice.
Thus, we made the hypothesis that fractionating chemotherapy could improve its feasibility and tolerability while maintaining efficacy. This was motivated by the first patient of this report who presented with a very aggressive relapse in the previously operated and irradiated left retroauricular region. Pain was 10/10 and painkillers were poorly effective. Cisplatin at the standard dose was not possible due to severe cardiac comorbidities. The weekly regimen (CMF-b) was built, based on age, comorbidities, and reduced organ function and performance status. Very good partial remission was obtained with progressive pain disappearance (Table II). Twenty-six patients have now been treated according to this innovative weekly regimen. Despite certain methodological biases inherent to a retrospective analysis, our data are interesting for several reasons.
Firstly, efficacy is quite satisfactory, with an objective response rate of more than 60%, and a clinically relevant duration of response of around 6 months. Although a direct comparison is not possible, this suggests that the efficacy of this weekly polychemotherapy is similar to high-dose chemotherapy regardless of age and comorbidities. Moreover, the quality of observed responses also suggests that our regimen could be useful before surgery or irradiation for large-sized tumors (Figures 1 and 2), as described with high-dose cisplatin (7).
Secondly, a remarkable palliative effect was obtained in a large proportion of patients. Advanced NMSC is frequently the cause of major pain, disfigurement or other severe cosmetic damage, and neurological defects due to perineural invasion. A strong reduction or even disappearance of symptoms relating to the tumoral disease was observed in 17 patients, including impressive recovery of cranial nerve palsies and deafness (n=6).
Thirdly, toxicity was acceptable, including in elderly and frail patients, and compared very favorably with previous series using cisplatin at the standard dose alone or in combination (6-10). Weekly assessment of blood cell counts, electrolytes, and renal function are, however, warranted, and weekly administration should sometimes be postponed or interrupted to avoid cumulative myelotoxicity or kidney damage.
Finally, it should be emphasized that despite age and comorbidities, more than 90% of patients were not hospitalized for the administration of chemotherapy. This is a major benefit, mainly because this may avoid depriving elderly patients of their social and psychologically protective environment.
Exploiting the high levels of epidermal growth factor receptor (EGFR) expressed by most NMSCs, Maubec et al. recently reported an overall response rate of 38% in a phase II trial testing the efficacy of EGFR antibody cetuximab alone in 36 patients with unresectable NMSC (12). Although the highest response rates published later in studies recapitulating the published cases may be overestimated, cetuximab is obviously an interesting additional or alternative option (13-17). It would be very interesting to explore the therapeutic potential of cetuximab combined with weekly CMF-b in young or fit patients with symptomatic NMSC for whom rapid and hopefully long-term efficacy is the main objective. On the other hand, which therapeutic sequence is the best (CMF-b followed by cetuximab or the opposite) for elderly or frail patients remains to be determined.
In summary, our data show that CMF-b is a well-tolerated and efficient outpatient weekly multi-agent chemotherapy which improves local control and symptoms regardless of age and comorbidities. Advanced or metastatic NMSCs are often the source of major symptoms that reduce quality of life. In this setting, we propose that there is no reason to exclude chemotherapy with strong palliative potential in elderly patients regardless of comorbidities.
Acknowledgements
The Authors would like to thank Pierre Alberto for discussions leading to the initial design of this chemotherapy regimen more than 20 years ago.
Footnotes
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received February 7, 2016.
- Revision received March 28, 2016.
- Accepted April 1, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved