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What’s left of chemotherapy?

Orazio Caffo

• From the accidental discovery of therapeuticeffect of sulfur mustards, CT was for decades theonly anticancer strategy

• The HT was discovered to be as an efficaciousalternative but only for few hormone-sensitivecancers

• Today, it appears that the maximum level of CTefficacy was reached and novel anticancerstrategies are being explored

The case of adjuvant RXs

Cancer Proposable adjuvant RXs

Breast CT / HT* / TT**

Colon/rectum CT

Lung CT

Ovary CT

Brain CT

Kidney NA

Testis CT

Prostate HT

* only ER+ pts** only HER+ pts in combination with CT

The case of “chemo-resistant”tumors:renal cancer

• In renal cancer evidences never supported the use of CT in these tumors

The case of “chemo-resistant”tumors:melanoma

• CT use in pts with melanoma produceddisappointing OS outcomes

The case of hormone-dependent tumors:breast cancer

• CT was historically considered as analternative mainly in tumors with aggressivefeatures or which were (or became) resistentto the anti-hormonal agents

The case of hormone-dependent tumors:prostate cancer

• HT was historically considered the referencetreatment for this tumor with poor OSoutcomes when the disease became“hormone-resistant”

• CT led to an OS gain in HRPC cancer

ADT

mCRPC

Enzalutamide

Cabazitaxel

Abiraterone

Abiraterone

Docetaxel

Ra 223*

nmCSPC

mCRPC

nmCRPC

mCSPC

* from 3rd line

Enzalutamide

ADT

mCRPC

Enzalutamide

Cabazitaxel

Abiraterone

Abiraterone

Docetaxel

Ra 223*

nmCSPC

mCRPC

nmCRPC

mCSPC

* from 3rd line

Enzalutamide

Docetaxel

ADT

mCRPC

Enzalutamide

Cabazitaxel

Abiraterone

Abiraterone

Docetaxel

Ra 223*

nmCSPC

mCRPC

nmCRPC

mCSPC

* from 3rd line

Enzalutamide

Enzalutamide

Apalutamide

Darolutamide

Abiraterone

Docetaxel

Enzalutamide

Apalutamide

The case of CT mildly-sensitive tumors:NSCLC

• Chemotherapy was historically the referencetreatment for this cancer

• The OS outcomes were disappointing

months

4,96

7,227,77

8,669,17

8,6

0

1

2

3

4

5

6

7

8

9

10

BSC 1995-2001 P alone PE Old Cis + no PE New Cis + Carbo +

+45,5%

+11%

+17,9%

+10,2% -11,4%

CT-related OS gains

Mhanna L et al. Curr. Treat. Options in Oncol. (2019) 20: 60

Duchemann B et al Eur Resp J 2015

Wu, SG. & Shih, JY. Mol Cancer (2018) 17: 38

The case of CT mildly-sensitive tumors:ovarian cancer

• Chemotherapy was historically the referencetreatment for this cancer

• The OS outcomes were disappointing (mainlyin platinum-refractory pts)

The case of CT mildly-sensitive tumors:colorectal cancer

• Chemotherapy was historically the referencetreatment for this cancer

• Our ability to chronicize the metastaticdisease was partially achieved

Conclusions

• Scientific achievements and regulatory enhancementshave resulted in a dramatic increase in targeted andimmunologic cancer drug approvals.

• The resulting change in clinical guidelines has causedsome to posit a chemotherapy-free future for cancertreatment.

• The realities of disease natural history, current practice,and ongoing clinical trials suggest that such a future ismuch further off.

• As long as chemotherapy remains critical to cancertreatment, additional research is needed to increase itspatient-centricity.