Britain's Josh Tarling and former champion Primoz Roglic abandoned the Giro d'Italia after crashes on a dramatic stage 16.
Isaac del Toro clung on to the leader's pink jersey but had his lead drastically cut by Britain's Simon Yates and Richard Carapaz, who moved up to third overall.
Italy's Christian Scaroni won the stage from Piazzola sul Brenta to San Valentino after breaking clear on the final climb with XDS Astana team-mate and compatriot Lorenzo Fortunato, who took second.
Welshman Tarling, 21, slid on a very wet surface early on Tuesday's stage and suffered a heavy crash into a barrier.
Slovenian Roglic, one of the pre-race favourites, crashed shortly after on a slippery descent alongside Ecuador's Carapaz.
Roglic, 35, briefly attempted to carry on before climbing into his Red Bull-Bora-Hansgrohe team car.
The 2023 winner suffered his third crash of the week on Saturday and lost crucial time to his general classification rivals on Sunday's stage 15.
However, 2019 winner Carapaz recovered from his fall to launch a powerful attack late to leave Del Toro and Yates behind.
Yates responded with his own attack to drop Mexican Del Toro, who managed to fight to hold on to the race lead.
UAE Team Emirates-XRG rider Del Toro now leads Visma-Lease a Bike's Yates by 26 seconds, with Carapaz of EF Education-EasyPost just five second further back.
Canada's Derek Gee also made up time on Del Toro is now fourth overall, a minute down on Carapaz.
Spain's Juan Ayuso, Del Toro's team-mate and another of the pre-race favourites, cracked and lost considerable time to fall out of the top 10, having started the day in third.
Yates' twin brother Adam has moved up to 10th overall, with fellow Britons Max Poole (13th), Tom Pidcock (16th) and James Knox (19th) all inside the top 20.
Wednesday's stage 17 is another day in the mountains from San Michele all'Adige to Bormio.
Tarling was part of a seven-rider breakaway that had established a 30-second lead over the peleton as the race resumed in heavy rain after Monday's second rest day.
He slid out on a roundabout, with his bike going from under him and his body hitting the barrier.
Ineos Grenadiers confirmed the 2023 European time trial champion would not continue.
"Josh Tarling has unfortunately had to abandon the Giro d'Italia following a crash on today's stage," the team said on social media.
"Our team doctor is with him and he is undergoing further assessment. We will provide an update on his condition as soon as possible."
The three-week Italian race began well for the Welsh rider when he claimed his first Grand Tour stage win with victory in the stage two time trial.
Tarling was unable to repeat that success in the race's second time trial, but finished second, seven seconds behind Dutchman Daan Hoole, on stage 10.
Although there were no further individual efforts against the clock to come before Sunday's finish in Rome, Tarling would have been hoping to complete a three-week Grand Tour for the first time.
Italian Alessio Martinelli also abandoned after falling into a ravine during a descent.
The 24-year-old was conscious as he was taken to hospital, with his VF Group-Bardiani CSF-Faizane team later saying tests had ruled out any fractures.
Christian Scaroni (Ita/XDS Astana) 5hrs 35mins 05secs
Lorenzo Fortunato (Ita/XDS Astana) Same time
Giulio Pellizzari (Ita/Red Bull-Bora-Hansgrohe) +55secs
Richard Carapaz (Ecu/EF Education-EasyPost) +1min 10secs
Derek Gee (Can/Israel-Premier Tech) +1min 23secs
Jefferson Cepeda (Ecu/Movistar) +1min 43secs
Michael Storer (Aus/Tudor Pro Cycling) +1min 52secs
Simon Yates (GB/Visma-Lease a Bike) Same time
Gijs Leemreize (Ned/Team Picnic PostNL) +2mins 19secs
Yannis Voisard (Tudor Pro Cycling) +2mins 31secs
Isaac del Toro (Mex/UAE Team Emirates-XRG) 61hrs 31mins 56secs
Simon Yates (GB/Visma-Lease a Bike) +26secs
Richard Carapaz (Ecu/EF Education-EasyPost) +31secs
Derek Gee (Can/Israel-Premier Tech) +1min 31secs
Damiano Caruso (Ita/Bahrain Victorious) +2mins 40secs
Egan Bernal (Col/Ineos Grenadiers) +3mins 23secs
Michael Storer (Aus/Tudor Pro Cycling) +3mins 31secs
Antonio Tiberi (Ita/Bahrain Victorious) +4mins 07secs
Giulio Pellizzari (Ita/Red Bull-Bora-Hansgrohe) +4mins 36secs
Adam Yates (GB/UAE Team Emirates-XRG) +5mins 08secs